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Recent Articles in Journal of the American Society of Nephrology: JASN

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Proceedings of the 5th International Conference on Hypertension and the Kidney, February 2006, Madrid, Spain.
J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S157-303. [Abstract]

Volkova N, McClellan W, Klein M, Flanders D, Kleinbaum D, Soucie JM, Presley R
Neighborhood Poverty and Racial Differences in ESRD Incidence.
J Am Soc Nephrol. 2007 Dec 5;
Poverty is associated with increased risk of ESRD, but its contribution to observed racial differences in disease incidence is not well-defined. To explore the contribution of neighborhood poverty to racial disparity in ESRD incidence, we analyzed a combination of US Census and ESRD Network 6 data comprising 34,767 patients that initiated dialysis in Georgia, North Carolina, or South Carolina between January 1998 and December 2002. Census tracts were used as the geographic units of analysis, and the proportion of the census tract population living below the poverty level was our measure of neighborhood poverty. Incident ESRD rates were modeled using two-level Poisson regression, where race, age and gender were individual covariates (level 1), and census tract poverty was a neighborhood covariate (level 2). Neighborhood poverty was strongly associated with higher ESRD incidence for both blacks and whites. Increasing poverty was associated with a greater disparity in ESRD rates between blacks and whites, with the former at greater risk. This raises the possibility that blacks may suffer more from lower socioeconomic conditions than whites. The disparity persisted across all poverty levels. The reasons for increasingly higher ESRD incidence among US blacks as neighborhood poverty increases remain to be explained. [Abstract]

Li C, Wang W, Summer SN, Westfall TD, Brooks DP, Falk S, Schrier RW
Molecular Mechanisms of Antidiuretic Effect of Oxytocin.
J Am Soc Nephrol. 2007 Dec 5;
Oxytocin is known to have an antidiuretic effect, but the mechanisms underlying this effect are not completely understood. We infused oxytocin by osmotic minipump into vasopressin-deficient Brattleboro rats for five days and observed marked antidiuresis, increased urine osmolality, and increased solute-free water reabsorption. Administration of oxytocin also significantly increased the protein levels of aquaporin-2 (AQP2), phosphorylated AQP2 (p-AQP2), and AQP3 in the inner medulla and in the outer medulla plus cortex. Immunohistochemistry demonstrated increased AQP2 and p-AQP2 expression and trafficking to the apical plasma membrane of principal cells in the collecting duct, and increased AQP3 expression in the basolateral membrane. These oxytocin-induced effects were blocked by treatment with the vasopressin V2 receptor antagonist SR121463B, but not by treatment with the oxytocin receptor antagonist GW796679X. We conclude that vasopressin V2 receptors mediate the antidiuretic effects of oxytocin, including increased expression and apical trafficking of AQP2, p-AQP2, and increased AQP3 protein expression. [Abstract]

Liu F, Brezniceanu ML, Wei CC, Chénier I, Sachetelli S, Zhang SL, Filep JG, Ingelfinger JR, Chan JS
Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes.
J Am Soc Nephrol. 2007 Dec 5;
The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension. [Abstract]

Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM
Low Birth Weight Increases Risk for End-Stage Renal Disease.
J Am Soc Nephrol. 2007 Dec 5;
Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD. [Abstract]

Schneider CA, Ferrannini E, Defronzo R, Schernthaner G, Yates J, Erdmann E
Effect of Pioglitazone on Cardiovascular Outcome in Diabetes and Chronic Kidney Disease.
J Am Soc Nephrol. 2007 Dec 5;
Patients with diabetes and chronic kidney disease (CKD) are at particularly high risk for cardiovascular disease (CVD). This post hoc analysis from the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. CKD, defined as an estimated GFR <60 ml/min per 1.73m(2), was present in 597 (11.6%) of 5154 patients. More patients with CKD reached the primary composite end point (all-cause mortality, myocardial infarction (MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle) than patients without CKD (27.5 versus 19.6%; P < 0.0001). Patients with CKD were also more likely to reach a secondary composite end point (all-cause mortality, MI, and stroke). Patients who had CKD and were treated with pioglitazone were less likely to reach the secondary end point (hazard ratio 0.66; 95% confidence interval 0.45 to 0.98), but this association was not observed among those with better renal function. In addition, there was a greater decline in estimated GFR with pioglitazone (between-group difference 0.8 ml/min per 1.73 m(2)/yr) than with placebo. In conclusion, CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and preexisting macrovascular disease. Patients who had CKD and were treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke, independent of the severity of renal impairment. [Abstract]

Pavlakis M
Resolved: in minimizing kidney transplant immunosuppression, steroids should go before calcineurin inhibitors: con.
J Am Soc Nephrol. 2007 Dec;18(12):3028-30. [Abstract]

Tu X, Chen X, Xie Y, Shi S, Wang J, Chen Y, Li J
Anti-inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal Injury.
J Am Soc Nephrol. 2007 Nov 28;
Recent evidence suggests that platelet activation and angiotensin II may each contribute to glomerular inflammation and fibrosis. Clopidogrel inhibits platelet activation and may also reduce inflammation. This study investigated the anti-inflammatory and renoprotective effects of clopidogrel and irbesartan in the five-sixths nephrectomy rat model of chronic kidney disease. After 8 wk of treatment, 24-h proteinuria, serum creatinine, and histologic scores of glomerular sclerosis and tubulointerstitial damage were significantly lower in treated compared with untreated rats. Clopidogrel/irbesartan combination therapy had greater effects than either drug alone. Rats that underwent five-sixths nephrectomy had higher markers of platelet activation (plasma GMP-140 and renal cortical fibrin deposition) than sham-operated rats, and clopidogrel attenuated these effects. Clopidogrel and irbesartan similarly reduced the accumulation of ED-1-expressing macrophages in the cortical glomeruli and the interstitium. Combination therapy almost completely abolished macrophage infiltration and attenuated the expression of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, TGF-beta1, and connective tissue growth factor. In conclusion, combination treatment with clopidogrel and irbesartan, more so than either alone, decreases early renal injury induced by five-sixths nephrectomy by inhibiting renal inflammation. [Abstract]

Awad AS, Rouse M, Liu L, Vergis AL, Rosin DL, Linden J, Sedor JR, Okusa MD
Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes.
J Am Soc Nephrol. 2007 Nov 28;
Adenosine 2A receptor (A2AR) activation was recently shown to be renoprotective in diabetic nephropathy. A2AR are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein alpha-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A2AR agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A2AR antagonist ZM241385 reversed the effects of ATL313. In vitro, A2AR mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A2AR-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleoside-induced injury in vitro. ATL313 was ineffective, however, in the presence of the A2AR antagonist and in A2AR-deficient podocytes. It was concluded that A2AR activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton. [Abstract]

Alpers CE, Kowalewska J
Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy.
J Am Soc Nephrol. 2007 Nov 28;
Fibrillary glomerulonephritis is a now widely recognized diagnostic entity, occurring in approximately 1% of native kidney biopsies in several large biopsy series obtained from Western countries. The distinctive features are infiltration of glomerular structures by randomly arranged fibrils similar in appearance but larger than amyloid fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. It is widely but not universally recognized to be distinct from immunotactoid glomerulopathy, an entity characterized by glomerular deposits of immunoglobulin with substructural organization as microtubules and with clinical associations with lymphoplasmacytic disorders. The pathophysiologic basis for organization of the glomerular deposits as fibrils or microtubules in these entities remains obscure. [Abstract]

Bloom RD, Reese PP
Chronic kidney disease after nonrenal solid-organ transplantation.
J Am Soc Nephrol. 2007 Dec;18(12):3031-41.
Chronic kidney disease (CKD) is a common complication after nonrenal solid-organ transplantation. The risk for CKD is influenced by many factors, some of which have a direct impact on how such patients are treated in the pre-, peri-, and posttransplantation settings. This review describes hazards for acute and chronic kidney injury, with particular emphasis on calcineurin inhibitor-mediated nephrotoxicity. Rather than a detailed description of management issues that are common to the general CKD population, highlighted are aspects that are more specific to nonrenal solid-organ transplant recipients with a focus on liver, heart, and lung recipients. Strategies to minimize nephrotoxic insults and retard progressive renal injury are discussed, as are issues that are pertinent to dialysis and transplantation. Finally, future approaches to prevent and treat CKD without compromising function of the transplanted organ are addressed. [Abstract]

Bustamante M, Hasler U, Leroy V, de Seigneux S, Dimitrov M, Mordasini D, Rousselot M, Martin PY, Féraille E
Calcium-sensing Receptor Attenuates AVP-induced Aquaporin-2 Expression via a Calmodulin-dependent Mechanism.
J Am Soc Nephrol. 2007 Nov 21;
Recent evidence suggests that arginine vasopressin (AVP)-dependent aquaporin-2 expression is modulated by the extracellular calcium-sensing receptor (CaSR) in principal cells of the collecting duct, but the signaling pathways mediating this effect are unknown. Using a mouse cortical collecting duct cell line (mpkCCDcl4), we found that increasing the concentration of apical extracellular calcium or treating with the CaSR agonists neomycin or Gd(3+) attenuated AVP-dependent accumulation of aquaporin-2 mRNA and protein; CaSR gene-silencing prevented this effect. Calcium reduced the AVP-induced accumulation of cAMP, but this did not occur by increased degradation of cAMP by phosphodiesterases or by direct inhibition of adenylate cyclase. Notably, the effect of extracellular calcium on AVP-dependent aquaporin-2 expression was prevented by inhibition of calmodulin. In summary, our results show that high concentrations of extracellular calcium attenuate AVP-induced aquaporin-2 expression by activating the CaSR and reducing coupling efficiency between V2 receptor and adenylate cyclase via a calmodulin-dependent mechanism in cultured cortical collecting duct cells. [Abstract]

Balazs Z, Schweizer RA, Frey FJ, Rohner-Jeanrenaud F, Odermatt A
DHEA Induces 11{beta}-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins.
J Am Soc Nephrol. 2007 Nov 21; [Abstract]

Wattanakit K, Cushman M, Stehman-Breen C, Heckbert SR, Folsom AR
Chronic Kidney Disease Increases Risk for Venous Thromboembolism.
J Am Soc Nephrol. 2007 Nov 21;
Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population. [Abstract]

Bailey MA, Paterson JM, Hadoke PW, Wrobel N, Bellamy CO, Brownstein DG, Seckl JR, Mullins JJ
A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess.
J Am Soc Nephrol. 2007 Nov 21;
The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11betaHSD2 permits glucocorticoids to activate the mineralocorticoid receptor, and the hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. An 11betaHSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11betaHSD2(-/-) mice had BP approximately 20 mmHg higher on average compared with wild-type mice but were volume contracted, not volume expanded as expected. Initially, impaired sodium excretion associated with increased activity of the epithelial sodium channel was observed. By 80 days of age, however, channel activity was abolished and 11betaHSD2(-/-) mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11betaHSD2(-/-) mice were double those in wild-type mice, and alpha1-adrenergic receptor blockade rescued the hypertensive phenotype, suggesting that vasoconstriction contributes to the sustained hypertension in this model. In summary, it is proposed that renal sodium retention remains a key event in apparent mineralocorticoid excess but that the accompanying hypertension changes from a renal to a vascular etiology over time. [Abstract]

He L, Sun Y, Takemoto M, Norlin J, Tryggvason K, Samuelsson T, Betsholtz C
The Glomerular Transcriptome and a Predicted Protein Protein Interaction Network.
J Am Soc Nephrol. 2007 Nov 21;
To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein-protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease. [Abstract]

Wang X, Wu Y, Ward CJ, Harris PC, Torres VE
Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease.
J Am Soc Nephrol. 2007 Nov 21;
The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD. [Abstract]

Grantham JJ
Therapy for Polycystic Kidney Disease? It's Water, Stupid!
J Am Soc Nephrol. 2007 Nov 21; [Abstract]

Baud L, Letavernier E
PPARalpha contributes to tubular protection.
J Am Soc Nephrol. 2007 Dec;18(12):3017-8. [Abstract]

Markowitz GS, Radhakrishnan J, D'Agati VD
Towards the incidence of acute phosphate nephropathy.
J Am Soc Nephrol. 2007 Dec;18(12):3020-2. [Abstract]

Rosenberg ME, Gupta S
Stem cells and the kidney: where do we go from here?
J Am Soc Nephrol. 2007 Dec;18(12):3018-20. [Abstract]

Novak JE, Szczech LA
Feast and Famine: Epidemiology and Clinical Trials in Chronic Kidney Disease.
J Am Soc Nephrol. 2007 Nov 14; [Abstract]

Matas AJ
Resolved: in minimizing kidney transplant immunosuppression, steroids should go before calcineurin inhibitors: pro.
J Am Soc Nephrol. 2007 Dec;18(12):3026-8.
Without direct comparison or randomized controlled trials, two experts square off on the difficult choice of trying to reduce the usage of one of two drugs with well-known side effects after kidney transplantation. [Abstract]

Johnson TS, Fisher M, Haylor JL, Hau Z, Skill NJ, Jones R, Saint R, Coutts I, Vickers ME, El Nahas AM, Griffin M
Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease.
J Am Soc Nephrol. 2007 Dec;18(12):3078-88. [Abstract]

Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI
Hemoglobin variability and mortality in ESRD.
J Am Soc Nephrol. 2007 Dec;18(12):3164-70.
Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subject's absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R2 = 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality. [Abstract]

Komenda P, Beaulieu M, Seccombe D, Levin A
Regional Implementation of Creatinine Measurement Standardization.
J Am Soc Nephrol. 2007 Nov 14;
Because patients may receive care at multiple locations within a geographic area, serum creatinine measurements must be standardized across laboratories to enable comparisons of reported estimated glomerular filtration rate (eGFR). The results of a successful creatinine standardization program designed to minimize the contribution of laboratory error to the reporting of eGFR are reported; 107 laboratories, which tested creatinine on 124 analyzers from six different manufacturers, voluntarily participated. Each laboratory received a correction factor to apply to its creatinine measurements to standardize them to the isotope dilution mass spectrometry reference method. The adjusted values were then used to calculate eGFR using the Modification of Diet in Renal Disease (MDRD) equation. The standardization program reduced the average total error in the measurement of creatinine from 23.9 to 8.7% and the average analytical bias from 16.5 to 2.7%. Implementing this program on a larger scale could reduce the rate of incorrect classification of stage 3 chronic kidney disease by 84%. [Abstract]

Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP
LPA1 receptor activation promotes renal interstitial fibrosis.
J Am Soc Nephrol. 2007 Dec;18(12):3110-8.
Tubulointerstitial fibrosis in chronic renal disease is strongly associated with progressive loss of renal function. We studied the potential involvement of lysophosphatidic acid (LPA), a growth factor-like phospholipid, and its receptors LPA(1-4) in the development of tubulointerstitial fibrosis (TIF). Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) for up to 8 d, and kidney explants were prepared from the distal poles to measure LPA release into conditioned media. After obstruction, the extracellular release of LPA increased approximately 3-fold. Real-time reverse transcription PCR (RT-PCR) analysis demonstrated significant upregulation in the expression of the LPA(1) receptor subtype, downregulation of LPA3, and no change of LPA2 or LPA4. TIF was significantly attenuated in LPA1 (-/-) mice compared to wild-type littermates, as measured by expression of collagen III, alpha-smooth muscle actin (alpha-SMA), and F4/80. Furthermore, treatment of wild-type mice with the LPA1 antagonist Ki16425 similarly reduced fibrosis and significantly attenuated renal expression of the profibrotic cytokines connective tissue growth factor (CTGF) and transforming growth factor beta (TGFbeta). In vitro, LPA induced a rapid, dose-dependent increase in CTGF expression that was inhibited by Ki16425. In conclusion, LPA, likely acting through LPA1, is involved in obstruction-induced TIF. Therefore, the LPA1 receptor might be a pharmaceutical target to treat renal fibrosis. [Abstract]

Wijnhoven TJ, Lensen JF, Wismans RG, Lefeber DJ, Rops AL, van der Vlag J, Berden JH, van den Heuvel LP, van Kuppevelt TH
Removal of heparan sulfate from the glomerular basement membrane blocks protein passage.
J Am Soc Nephrol. 2007 Dec;18(12):3119-27.
Heparan sulfate (HS) within the glomerular basement membrane (GBM) is thought to play a major role in the charge-selective properties of the glomerular capillary wall. Recent data, however, raise questions regarding the direct role of HS in glomerular filtration. For example, in situ studies suggest that HS may prevent plasma macromolecules from clogging the GBM, keeping it in an "open" state. We evaluated this potential role of HS in vivo by studying the passage of protein through the glomerular capillary wall in the presence and absence of HS. Intravenous administration of neuraminidase removed neuraminic acid--but not HS--from the GBM, and this led to albuminuria. Concomitant removal of HS with heparinase III, confirmed by ultrastructural imaging, prevented the development of albuminuria in response to neuraminidase treatment. Taken together, these results suggest that HS keeps the GBM in an open state, facilitating passage of proteins through the glomerular capillary wall. [Abstract]

Li L, Truong P, Igarashi P, Lin F
Renal and bone marrow cells fuse after renal ischemic injury.
J Am Soc Nephrol. 2007 Dec;18(12):3067-77. [Abstract]

Shah P, Tramontano A, Makker SP
Intramolecular epitope spreading in Heymann nephritis.
J Am Soc Nephrol. 2007 Dec;18(12):3060-6.
Immunization with megalin induces active Heymann nephritis, which reproduces features of human idiopathic membranous glomerulonephritis. Megalin is a complex immunological target with four discrete ligand-binding domains (LBDs) that may contain epitopes to which pathogenic autoantibodies are directed. Recently, a 236-residue N-terminal fragment, termed "L6," that spans the first LBD was shown to induce autoantibodies and severe disease. We used this model to examine epitope-specific contributions to pathogenesis. Sera obtained from rats 4 weeks after immunization with L6 demonstrated reactivity only with the L6 fragment on Western blot, whereas sera obtained after 8 weeks demonstrated reactivity with all four recombinant fragments of interest (L6 and LBDs II, III, and IV). We demonstrated that the L6 immunogen does not contain the epitopes responsible for the reactivity to the LBD fragments. Therefore, the appearance of antibodies directed at LBD fragments several weeks after the primary immune response suggests intramolecular epitope spreading. In vivo, we observed a temporal association between increased proteinuria and the appearance of antibodies to LBD fragments. These data implicate B cell epitope spreading in antibody-mediated pathogenesis of active Heymann nephritis, a model that should prove valuable for further study of autoimmune dysregulation. [Abstract]

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Recent Articles in American Journal of Physiology. Renal physiology

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Lee HT, Kim M, Song JH, Chen SW, Gubitosa G, Emala Sr CW
Sevoflurane mediated TGF-{beta}1 signaling in renal proximal tubule cells.
Am J Physiol Renal Physiol. 2007 Dec 5; .
Several volatile anesthetics including sevoflurane protect against renal ischemia reperfusion (IR) injury in vivo by reducing necrosis and inflammation. Furthermore, in cultured renal tubule cells, sevoflurane directly induced the phosphorylation of the cytoprotective kinases, extracellular signal-regulated protein kinase (ERK) and Akt, upregulated heat shock protein 70 (HSP70) and attenuated nuclear translocation of the pro-inflammatory transcription factor NFkappaB. Subsequently, we showed that sevoflurane increased the release of TGF-beta1 in human proximal tubule (HK-2) cells via externalization of plasma membrane phosphatidylserine (PS) and this increase in TGF-beta1 protected HK-2 cells against hydrogen peroxide-mediated necrosis. In this study, we wanted to determine whether the sevoflurane-mediated phosphorylation of ERK and Akt, induction of HSP70 and reduction in NFkappaB activation are due to TGF-beta1 receptor mediated signaling after PS externalization in HK-2 cells. Exogenous TGF-beta1 as well as a liposome mixture containing PS mimicked sevoflurane-mediated ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Sevoflurane as well as TGF-beta1 caused the nuclear translocation of the SMAD3 transcription factor in HK-2 cells. Furthermore, a neutralizing TGF-beta1 antibody or exogenous annexin to bind PS prevented sevoflurane induced ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Finally, a TGF-beta1 antibody as well as annexin attenuated the reduction in nuclear translocation of NFkappaB by sevoflurane. Therefore we demonstrate in this study that sevoflurane-mediated cytoprotective and anti-inflammatory effects in HK-2 cells are at least partially due to the externalization of PS and activation of TGF-beta1 signaling pathways. Key words: acute renal failure, Akt, volatile anesthetic, ERK. [Abstract]

Bing Y, Xu J, Harris RC, Zhang MZ
Renal Localization and Regulation of 15-Hydroxyprostaglandin Dehydrogenase.
Am J Physiol Renal Physiol. 2007 Dec 5;
Tissue prostaglandin levels are determined by both biosynthesis and catabolism. The current studies report the expression and localization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin catabolism in the kidneys. We also investigated potential interactions between 15-PGDH and cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis. Both 15-PGDH mRNA and protein levels were significantly higher in kidney cortex than papilla, which is opposite to the expression pattern of COX-2. In situ hybridization indicated that 15-PGDH mRNA was mainly localized to the tubular epithelial cells in kidney cortex and outer medulla, but not in the glomerulus or papilla. Dual immunofluorescent staining indicated that 15-PGDH was expressed in the proximal tubule, medullary and cortical thick ascending limbs and cortical and outer medullary collecting duct but not in the macula densa or papilla. 15-PGDH levels were significantly lower in a macula densa cell line (MMDD1) than a proximal tubule cell line. Although a high salt-diet decreased COX-2 expression in macula densa, it increased macula densa 15-PGDH expression in both mouse and rat kidneys. In MMDD1 cells, a COX-2 inhibitor increased 15-PGDH while a COX-1 inhibitor had no effect. Furthermore, intense 15-PGDH immunofluorescent staining was found in both macula densa and glomerulus in COX-2 knockout mice. The intrarenal distribution of 15-PGDH and its interactions with COX-2 suggest that differential regulation of COX-2 and 15-PGDH may play an important role in determining levels of prostaglandins involved in regulation of salt, volume, and blood pressure homeostasis. Key words: prostaglandin, cyclooxygenase, macula densa. [Abstract]

Lynch IJ, Rudin A, Xia SL, Stow LR, Shull GE, Weiner ID, Cain BD, Wingo CS
Impaired Acid Secretion in Cortical Collecting Duct Intercalated Cells from H,K-ATPase-deficient Mice: Role of HK Isoforms.
Am J Physiol Renal Physiol. 2007 Dec 5;
Two classes of H pumps, H,K-ATPase and H-ATPase, contribute to luminal acidification and HCO3 secretion in the collecting duct (CD). At least two H,K-ATPase &#945;-subunits are expressed in the CD: HK&#945;1 and HK&#945;2. Both exhibit K-dependence but have different inhibitor sensitivities. The HK&#945;1 H,K-ATPase is Sch-28080-sensitive whereas the pharmacological profile of the HK&#945;2 H,K-ATPase is not completely understood. The present study used a non-pharmacological, genetic approach to determine the contribution of HK&#945;1 and HK&#945;2 to cortical CD (CCD) intercalated cell (IC) proton transport in mice fed a normal diet. Intracellular pH (pHi) recovery was determined in ICs using in vitro microperfusion of CCD after an acute intracellular acid load in wild-type (WT) mice and mice of the same strain lacking expression of HK&#945;1, HK&#945;22, or both H,K-ATPases (HK&#945;1,2). A-type and B-type ICs were differentiated by luminal loading with BCECF-AM and peritubular chloride removal from CO2/HCO3 buffered solutions to identify the membrane locations of Cl/HCO3 exchange activity. H-ATPase- and Na/H exchange-mediated H transport were inhibited with bafilomycin A1 (100 nM) and ethyl-isopropyl-amiloride (EIPA 10 &#956;M), respectively. Here we report: (1) initial pHi and buffering capacity were not significantly altered in the ICs of HK&#945; deficient mice; (2) either HK&#945;1 or HK&#945;2 deficiency resulted in slower acid extrusion in ICs; and (3) A-type ICs from HK&#945;1,2 deficient mice had significantly slower acid extrusion when compared to the A-type ICs from HK&#945;1 deficient mice alone. Key words: potassium, microperfusion, pH, acid-base balance, P-type ATPase. [Abstract]

Giehl K, Graness A, Goppelt-Struebe M
The small GTPase Rac1 is a regulator of mesangial cell morphology and thrombospondin-1 expression.
Am J Physiol Renal Physiol. 2007 Nov 28;
Thrombospondin-1 (TSP-1), which is synthesized by mesangial cells, is known for its anti-angiogenic activity and its ability to activate latent TGFbeta. TSP-1 is upregulated in renal diseases associated with tissue remodeling. Therefore, we hypothesized that the expression of TSP-1 might be modulated by changes in cell morphology involving proteins of the Rho family. Spreading of mesangial cells after detachment and reseeding was characterized by the formation of lamellipodia and focal adhesions, pointing towards a Rac-1-mediated rearrangement of actin structures. Clustering of focal adhesion proteins was also observed in a model system of nocodazole-induced disruption of microtubules. These morphological alterations were impeded by pharmacological inhibition of Src-family kinases, of the small GTPase Rac-1, or by downregulation of Rac-1 by siRNA. Upon cell spreading, TSP-1 was upregulated in the absence and much more prominently in the presence of serum, but also after nocodazole treatment. TSP-1 upregulation was controlled by activation of Src-family kinases, ERK 1/2 and Rac-1, whereas activation of RhoA-ROCK signaling was not linked to TSP-1 induction. We thus provide evidence that TSP-1 expression is induced by common signaling pathways, which are activated by morphological alterations of renal mesangial cells or by soluble factors as contained in serum, and these pathways include Src-family kinases, ERK 1/2 and Rac-1. Our data suggest that tissue remodeling activates gene expression of pathophysiologically relevant proteins such as TSP-1. Key words: Cytoskeleton, Rho proteins, Src kinases. [Abstract]

Li XC, Zhuo JL
In vivo regulation of AT1a receptor-mediated uptake of [125I]-Val5-angiotensin II in the kidney and adrenals of AT1a receptor-deficient mice.
Am J Physiol Renal Physiol. 2007 Nov 28;
Using AT1a receptor-deficient mice (Agtr1a-/-) and in vivo autoradiography, we tested the hypothesis that intracellular uptake of angiotensin II (Ang II) in the kidney and adrenals is primarily mediated by AT1a receptors and the response is regulated by prevailing endogenous Ang II. Wild-type (Agtr1a+/+) and Agtr1a-/- mice were pretreated with captopril (25 mg/kg/day) or losartan (10 mg/kg/day) for 2 weeks before [(125)I]-Val(5)-Ang II was infused for 60 min. Intracellular uptake of [(125)I]-Val(5)-Ang II was determined by quantitative in vivo autoradiography after circulating [(125)I]-Val(5)-Ang II was washed out. Compared with wild-types, basal intracellular Ang II levels were 65% lower in the kidney (p<0.001), but plasma Ang II levels were 3-folds higher in Agtr1a-/- mice (p<0.01). While plasma [(125)I]-Val(5)-Ang II levels were similar, urinary excretion of [(125)I]-Val(5)-Ang II was 4-folds higher in Agtr1a-/- mice (p<0.001). By contrast, intracellular [(125)I]-Val(5)-Ang II levels were 80% lower in the kidney and adrenals of Agtr1a-/- mice (p<0.01). Captopril decreased endogenous plasma and renal Ang II levels (p<0.01), but it increased intracellular uptake of [(125)I]-Val(5)-Ang II in the kidney and adrenals of both wild-type and Agtr1a-/- mice (p<0.01). Losartan largely blocked renal and adrenal uptake of [(125)I]-Val(5)-Ang II in both wild-type and Agtr1a-/- mice. Thus 80% of intracellular Ang II uptake in the kidney and adrenals is mediated by AT1a receptors, whereas AT1b receptor- and other non receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT1a receptor-mediated uptake of extracellular Ang II may play a physiological role in the kidney and adrenals. Key words: Adrenal glands, Angiotensin II, Autoradiography, kidney, Receptor-mediated endocytosis. [Abstract]

Feng NH, Lee HH, Shiang JC, Ma MC
Transient Receptor Potential Vanilloid Type 1 Channels Act as Mechanoreceptors and Cause Substance P Release and Sensory Activation in Rat Kidneys.
Am J Physiol Renal Physiol. 2007 Nov 21;
Stimulation of capsaicin receptors results in an increase in afferent renal nerve activity (ARNA), but it is unclear how capsaicin contributes to sensory activation intrarenally. Here, we studied the relationships between capsaicin receptor activation, substance P (SP) release, and the sensory response in the rat renal pelvis. Immunoblots showed that one of the capsaicin receptors, transient receptor potential vanilloid type 1 channel (TRPV1), was found in various renal tissues and was especially abundant in the renal pelvis, where most sensory nerve fibers originate. Interestingly, immunolabeling showed co-localization of TRPV1, SP, and the panneuronal marker PGP9.5 in the renal pelvis. Electrophysiological recordings showed that SP and capsaicin activated the same mechanosensitive ARNA in a single-unit preparation. Intrapelvic administration of capsaicin or a specific TRPV1 agonist, resiniferatoxin, resulted in a dose-dependent increase in multi-unit ARNA and SP release, and these effects were blocked by the TRVP1 blocker capsazepine. Inhibition of the SP receptor by L-703,606 largely prevented capsaicin- or resiniferatoxin-induced ARNA. Capsazepine also prevented intrapelvic pressure (IPP)-dependent ARNA activation and contralateral diuresis/natriuresis in the renorenal reflex at an IPP of 20 mmHg, but had no effect at an IPP of 50 mmHg. These data indicate that TRPV1, a low-pressure baroreceptor, is present in the renal pelvis and exclusively regulates neuropeptide release from primary renal afferent C-fibers in response to mechanostimulation. Key words: Transient receptor potential vanilloid type 1 channels, Mechanoreceptor, Substance P, Neurokinin-1 receptor, Renorenal reflex. [Abstract]

Rahuel C, Filipe A, Ritie L, El Nemer W, Patey-Mariaud N, Eladari D, Cartron JP, Simon-Assmann P, Le Van Kim C, Colin Y
Genetic inactivation of the laminin {alpha}5 chain receptor Lu/BCAM leads to kidney and intestinal abnormalities in the mouse.
Am J Physiol Renal Physiol. 2007 Nov 21;
Lu/BCAM has been recognized as unique receptor for laminin alpha5 chain in human red blood cells and as co-receptor in epithelial, endothelial and smooth muscle cells. Since limited information is available regarding the function of this adhesion glycoprotein in vivo, we generated Lu/BCAM-null mice and looked for abnormalities in erythroid cells as well as in kidney and intestine, two tissues showing alteration in laminin alpha5 chain deficient mice. We first showed that in contrast to human, wild type murine red cells failed to express Lu/BCAM. Lu/BCAM-null mice were healthy and developed normally. However, while no alteration of the renal function was evidenced, up to 90 % of the glomeruli from mutant kidneys exhibited abnormalities characterized by a reduced number of visible capillary lumens and irregular thickening of the glomerular basement membrane. Similarly, intestine analysis of mutant mice revealed smooth muscle coat thickening and disorganization. Since glomerular basement membrane and smooth muscle coat express laminin alpha5 chain and are in contact with cell types expressing Lu/BCAM in wild type mice, these results provide evidence that Lu/BCAM, as a laminin 521 receptor, is involved in vivo in the maintenance of normal basement membrane organization in the kidney and intestine. Key words: basement membrane , glomeruli, KO mice, intestine, Lu/BCAM. [Abstract]

Bae EH, Lee KS, Lee J, Ma SK, Kim NH, Choi KC, Frokiaer J, Nielsen S, Kim SY, Kim SZ, Kim SH, Kim SW
Effects of {alpha}-Lipoic Acid on Ischemia/Reperfusion-Induced Renal Dysfunction in Rats.
Am J Physiol Renal Physiol. 2007 Nov 21;
We investigated whether alpha-lipoic Acid (alpha-LA), an antioxidant, attenuates the ischemia/reperfusion (I/R)-induced dysregulation of these transporters. Male Sprague-Dawley rats were clamped of both renal pedicles for 40 minutes. alpha-LA (80 mg/kg) was administered intraperitoneally before and immediately after inducing the ischemia. After 2 days, the expression of aquaporins (AQPs), sodium transporters and nitric oxide synthases (NOS) was determined in the kidney by immunoblotting and immunohistochemistry. The expression of endothelin-1 (ET-1) mRNA was determined by real-time polymerase chain reaction. Activities of adenylyl cyclase and guanylyl cyclase were measured by stimulated generation of cAMP and cGMP, respectively. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was markedly decreased in response to I/R. The expression of type VI adenylyl cyclase was decreased in I/R-injury rats, which was counteracted by the treatment of alpha-LA. AVP-stimulated cAMP generation was blunted in I/R rats, which was then ameliorated by alpha-LA treatment. alpha-LA treatment attenuated the downregulation of AQPs and sodium transporters. The expression of endothelial NOS was decreased in I/R rats, which was prevented by alpha-LA. The cGMP generation in response to sodium nitroprusside was blunted in I/R rats, which was also significantly prevented by alpha-LA. The mRNA expression of ET-1 was increased, which was recovered to the control level by alpha-LA treatment. In conclusion, alpha-LA treatment prevents I/R-induced dysregulation of AQPs and sodium transporters in the kidney, possibly through preserving normal activities of local AVP/cAMP, NO/cGMP and ET systems. Key words: -lipoic acid, aquaporins, sodium transporters, I/R injury, endothelin. [Abstract]

Carattino MD, Passero CJ, Steren CA, Maarouf AB, Pilewski JM, Myerburg MM, Hughey RP, Kleyman TR
Defining an inhibitory domain in the alpha subunit of the epithelial sodium channel.
Am J Physiol Renal Physiol. 2007 Nov 21;
Epithelial sodium channels (ENaC) are processed by proteases as they transit the biosynthetic pathway. We recently observed that furin-dependent processing of the alpha subunit of ENaC at two sites within its extracellular domain is required for channel activation due to release of a 26-residue inhibitory domain. While channels with alpha subunits lacking the furin sites are not cleaved and have very low activity, channels lacking the furin sites as well as the tract between these sites (alphaD206-R231) are active. We analyzed channels with a series of deletions in the tract alphaD206-R231 and lacking the alpha subunit furin consensus sites in Xenopus laevis oocytes. We found an eight-residue tract that, when deleted, restored channel activity to the level found in oocytes expressing wild type ENaC. A synthetic peptide, LPHPLQRL, representing the tract alphaL211-L218 inhibited wild type ENaC expressed in oocytes with an IC50 of 0.9 microM, and inhibited channels expressed in collecting duct cells and human primary airway epithelial cells with IC50s of between ~50 to 100 microM. Analyses of peptides with deletions within this inhibitory tract indicate that eight residues is the minimal backbone length that is required for ENaC inhibition. Analyses of 8-mer peptides with conserved and non-conserved substitutions suggest that L(1), P(2), H(3), P(4), and L(8) are required for inhibitory activity. Our findings suggest that this eight-residue tract is a key conserved inhibitory domain that provides epithelial cells with a reserve of channels that can be activated as required by proteases. Key words: epithelial sodium channel, peptide inhibitors, proteases, furin. [Abstract]

Carlstrom M, Brown RD, Edlund J, Sallstrom J, Larsson E, Teerlink T, Palm F, Wahlin N, Persson AE
Role of Nitric Oxide Deficiency in the Development of Hypertension in Hydronephrotic Animals.
Am J Physiol Renal Physiol. 2007 Nov 21;
Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF-sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either L-NAME or L-arginine. Blood samples for ADMA, SDMA, L-arginine analysis were taken and the renal tissue was used for histology and determination of NOS proteins. TGF-characteristics were determined by stop-flow pressure technique before and after administration of 7-NI or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF-response were greater in the hydronephrotic group. 7-NI administration increased TGF-reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, nNOS inhibition had no effect. L-arginine attenuated TGF-response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and eNOS proteins were lower in animals with hydronephrosis. In conclusion, reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF-mechanism, plays an important role in the development of hypertension. Key words: hydronephrosis, hypertension, nitric oxide, tubuloglomerular feedback, ADMA. [Abstract]

Celie JW, Reijmers RM, Slot EM, Beelen RH, Spaargaren M, Ter Wee PM, Florquin S, van den Born J
Tubulointerstitial heparan sulfate proteoglycan changes in human renal diseases correlate with leukocyte influx and proteinuria.
Am J Physiol Renal Physiol. 2007 Nov 21;
Heparan sulfate proteoglycans (HSPGs) are well-known for their proposed role in glomerular filtration. In addition, HSPGs can bind the leukocyte adhesion molecule L-selectin and chemokines, suggesting a role in inflammation. We examined a panel of biopsies representing different human primary kidney diseases for L-selectin and monocyte chemoattractant protein-1 (MCP-1) binding. In various renal diseases L-selectin and MCP-1 binding to interstitial perivascular matrix HSPGs is increased, which is significantly associated with leukocyte influx. In proteinuric diseases including membranous glomerulopathy, minimal change disease, but also IgA nephropathy and lupus nephritis, increased binding of L-selectin and MCP-1 to tubular epithelial cell (TEC) HSPGs is observed, which colocalizes with increased basolateral syndecan-1 and anti-HS 10E4 staining. shRNA-mediated silencing demonstrates that syndecan-1 on TECs indeed mediates L-selectin binding. Increased TEC expression of IL-8 in biopsies of proteinuric patients suggests that the increase in luminal protein may activate TECs to increase expression of L-selectin and MCP-1 binding syndecan-1. Strikingly, urinary syndecan-1 from proteinuric patients is less capable of binding L-selectin compared to urinary syndecan-1 from healthy controls, although syndecan-1 concentrations are similar in both groups. Together, our data show pronounced tubulointerstitial HSPG alterations in primary kidney disease, which may affect the inflammatory response. Key words: adhesion molecule, chemokine, tubular epithelial cells, inflammation. [Abstract]

Kennedy DJ, Elkareh J, Shidyak A, Shapiro AP, Smaili S, Mutgi K, Gupta S, Tian J, Morgan E, Khouri S, Cooper CJ, Periyasamy SM, Xie Z, Malhotra D, Fedorova OV, Bagrov AY, Shapiro JI
Partial Nephrectomy as a Model for Uremic Cardiomyopathy in the Mouse.
Am J Physiol Renal Physiol. 2007 Nov 21;
Because of the plethora of genetic manipulations available in the mouse, we performed partial nephrectomy in the mouse and examined whether the phenotypical features of uremic cardiomyopathy described in humans and rats were also present in the murine model. 5/6(th) nephrectomy was performed using a combination of electrocautory to decrease renal mass on the left kidney and right surgical nephrectomy. This procedure produced substantial and persistent hypertension as well as increases in circulating concentrations of marinobufagenin. Invasive physiological measurements of cardiac function demonstrated that 5/6(th) nephrectomy resulted in impairment of both active and passive left ventricular relaxation at 4 weeks whereas tissue Doppler imaging detected changes in diastolic function after 6 weeks. Morphologically, hearts demonstrated enlargement and progressive fibrosis, and biochemical measurements demonstrated downregulation of the sarcoplasmic reticulum calcium ATPase as well as increases in collagen-1, fibronectin and vimentin expression. Our results suggest that partial nephrectomy in the mouse establishes a model of uremic cardiomyopathy which shares phenotypical features with the rat model as well as patients with chronic renal failure. Key words: Cardiomyopathy, renal failure, Reactive oxygen species, Cardiotonic steroids, Fibrosis. [Abstract]

Ohnishi H, Mizuno S, Nakamura T
Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure.
Am J Physiol Renal Physiol. 2007 Nov 21;
During a progression of acute renal failure (ARF), renal tubular S3-segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48-hours post-renal ischemia, tubular destruction became evident, followed by 2-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days post-ischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase of BMDC in renal tubules. Under the HGF-neutralized states, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1-receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus, possible cascades include: 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 up-regulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 up-regulation and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus, we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF. Key words: acute renal failure, tubular repair, HGF, SDF1, hypoxia. [Abstract]

Abdullah HI, Pedraza PL, McGiff JC, Ferreri NR
CaR activation increases TNF production by mTAL cells via a Gi-dependent mechanism.
Am J Physiol Renal Physiol. 2007 Nov 21;
We evaluated the contribution of CaR-mediated Gi-coupled signaling to TNF production in mTAL cells. A selective Gi inhibitor, Pertussis toxin (PTX), but not the inactive B-oligomer binding subunit, abolished CaR-mediated increases in TNF production. The inhibitory effect of PTX was partially reversed by using an adenylate cyclase inhibitor. CaR-mediated TNF production also was partially reversed by a cAMP analog, 8-Br-cAMP. IP1 accumulation was CaR-dependent and blocked by PI-PLC; partial inhibition also was observed with PTX. CaR increased calcineurin (CaN) activity by approximately 3-fold and PTX prevented CaR-mediated increases in CaN activity, an NFAT cis-reporter construct, and a TNF promoter construct. The interaction between Gi and PKC was determined, as we previously showed that CaR-mediated TNF production was CaN- and NFAT-mediated and Gq-dependent. CaR activation increased PKC activity by 2-fold, an effect abolished by transient transfection with a dominant negative CaR construct, R796W, or pretreatment with PTX. Inhibition with the pan specific PKC inhibitor, GF 109203X (20 nM) abolished CaR-mediated increases in activity of CaN, an NFAT reporter, and a TNF promoter construct. Collectively, the data suggest that Gi-coupled signaling contributes to NFAT-mediated TNF production, in a CaN- and PKC-dependent manner, and may be part of a CaR mechanism to regulate mTAL function. Moreover, concurrent Gq and Gi signaling is required for CaR-mediated TNF production in mTAL cells via a CaN/NFAT pathway that is PKC-dependent. Understanding CaR-mediated signaling pathways that regulate TNF production in the mTAL is crucial to defining novel mechanisms that regulate extracellular fluid volume and salt balance. Key words: TNF, Calcium-sensing receptor, G-proteins, loop of Henle, NFAT. [Abstract]

Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, Faubel S, Edelstein CL
Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice.
Am J Physiol Renal Physiol. 2007 Nov 14;
Fractalkine (CX3CL1) is expressed on injured endothelial cells and is a potent chemoattractant and adhesion molecule for macrophages carrying the fractalkine receptor (CX3CR1). The aim of this study was to investigate the role of CX3CL1, and its ligand CX3CR1, in ischemic acute renal failure (ARF) in mice. On immunoblotting, CX3CL1 protein expression in the kidney increased markedly in ischemic ARF. On immunofluorescence staining, the intensity of CX3CL1 staining in blood vessels was significantly more prominent in ischemic ARF compared to controls. A specific anti-CX3CR1 antibody (25 microg IP 1hr before induction of ischemia) was functionally and histologically protective against ischemic ARF. CX3CR1 is predominantly expressed on macrophages. Macrophage infiltration in the kidney in ischemic ARF was significantly decreased after anti-CX3CR1 antibody treatment. To determine the role of macrophages in ischemic ARF, macrophages in the kidney were depleted using liposomal-encapsulated clodronate (LEC). LEC resulted in significant functional and histological protection against ischemic ARF. In summary, in ischemic ARF, 1) there is upregulation of CX3CL1 protein in the kidney, specifically in blood vessels, 2) CX3CR1 inhibition using a specific antibody is partially protective and is associated with reduced macrophage infiltration in the kidney, 3) macrophage depletion in the kidney is protective. Key words: fractalkine, macrophages, acute renal failure. [Abstract]

Shi H, Patschan D, Dietz GP, Bahr M, Plotkin M, Goligorsky MS
Glial cell line-derived neurotrophic growth factor increases motility and survival of cultured mesenchymal stem cells and ameliorates acute kidney injury.
Am J Physiol Renal Physiol. 2007 Nov 14;
Glial cell line-derived neurotrophic growth factor (GDNF), a member of the transforming growth factor family, is necessary for renal organogenesis and exhibits changes of expression in models of renal disease. Having demonstrated the participation of nestin-expressing cells in renoprotection, we hypothesized that growth factors and transcription factors similar to those operating in the nervous system should be also operant in the kidney. Using cultured kidney-derived mesenchymal stem cells (MSC) abundantly expressing nestin, we confirmed expression of GDNF by these cells and demonstrated GDNF-induced expression of GDNF. The cellular expression of nestin paralleled that of GDNF expression. Immunohistochemical and Western blot analyses of kidneys obtained from post-ischemic mice showed that expression of GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of nestin. GDNF-treated mice were protected against acute ischemia. To address potential mechanisms of the observed renoprotection, in vitro studies showed that GDNF accelerated MSC migration in a wound healing assay. Hypoxia did not accelerate the motility of MSC and reduced the expression of GDNF in MSC by approximately 2-fold. GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish a) an autoregulatory circuit of GDNF-induced GDNF expression in renal MSC; b) induction of GDNF expression in post-ischemic kidneys; c) the ability of exogenous GDNF to ameliorate ischemic renal injury; and d) a possible contribution of GDNF-induced motility and improved survival of MSC to renoprotection. Key words: Glial cell-derived neurotrophic growth factor, nestin, acute kidney injury, mesenchymal stem cell, apoptosis. [Abstract]

Pollock JS, Carmines PK
Diabetic Nephropathy: Nitric Oxide and Renal Medullary Hypoxia.
Am J Physiol Renal Physiol. 2007 Nov 14;
There is no abstract associated with an Editorial Focus Key words: diabetic nephropathy, renal medulla, hypoxia, nitric oxide. [Abstract]

Habib SL, Riley DJ, Mahimainathan L, Bhandari B, Choudhury GG, Abboud HE
Tuberin Regulates the DNA Repair Enzyme OGG1.
Am J Physiol Renal Physiol. 2007 Nov 7;
The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. The TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors, both angiomyolipomas and renal cell carcinomas. We investigated a potential role for tuberin in regulating a key DNA repair pathway. Downregulation of tuberin in human renal epithelial cells using siRNA resulted in a marked decrease in the abundance of the 8-oxoG-DNA glycosylase (OGG1). Mouse embryonic fibroblasts deficient in tuberin (Tsc2(-/-) and Tsc2(+/-)) also had markedly decreased OGG1 mRNA and protein expression, as well as undetectable OGG1 activity accompanied by accumulation of 8-oxodG. Gel shift analyses and chromatin immunoprecipatation identified the transcription factor NF-YA as a regulator of OGG1 activity. The binding of NF-YA to the OGG1 promoter was significantly reduced in Tsc2(-/-) compared to Tsc2(+/+) cells. Introduction of Tsc2 cDNA into the tuberin-deficient cells restored NF-YA and OGG1 expression. Transcriptional activity of the OGG1 promoter was also decreased in tuberin-null cells. In addition, mutation of both CAAT boxes, the sites to which NF-YA binds, completely inhibits OGG1 promoter activity. These data provide the first evidence that tuberin regulates a specific DNA repair enzyme, OGG1. This regulation may be important in the pathogenesis of kidney tumors in patients with TSC. Key words: Tuberin, DNA Repair, NF-YA. [Abstract]

Dominguez JH, Mehta JL, Li D, Wu P, Kelly KJ, Packer CS, Temm CJ, Goss E, Cheng L, Zhang S, Patterson CE, Hawes JW, Peterson RG
Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: Ablation of renal vascular and epithelial manifestations.
Am J Physiol Renal Physiol. 2007 Nov 7;
.LOX-1 is a multifunctional membrane receptor that binds and internalizes oxidized LDL (oxLDL). We tested the hypothesis that blockade of LOX-1 with an anti-LOX-1 antibody limits nephropathy in male rats with diabetes and dyslipidemia (ZS rats: F1 hybrid product of Zucker fatty diabetic rats and Spontaneous Hypertensive Heart Failure rats). Lean ZS rats (LM) were controls, while untreated obese ZS (OM), ZS obese rats injected with non-specific rabbit IgG (OM-IgG, 2 microg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab, 2 microg intravenous injection given weekly) were the experimental groups. The rats were treated from 6 to 21 weeks of age. All obese groups had severe dyslipidemia, and hyperglycemia. Kidneys of obese rats expressed LOX-1 in capillaries and tubules, were larger, accumulated lipid, had intense oxidative stress, leukocyte infiltration, depressed mitochondrial enzyme level and function, and peritubular fibrosis (all p<0.05 vs lean ZS rats). Injections with LOX-1 antibody limited these abnormalities (p<0.01 vs. data in OM or OM-lgG rats). In vitro, renal epithelial LOX-1 expression was verified in a cultured proximal tubule cell line. Our study indicates that anti-LOX-1 (vascular and epithelial) therapy may effectively reverse critical pathogenic elements of nephropathy in diabetes and dyslipidemia. Key words: renal failure, diabetic nephropathies, atherosclerosis, oxidized LDL receptors. [Abstract]

Sanchez-Lopez E, Rodriguez-Vita J, Cartier C, Ruperez M, Esteban V, Carvajal G, Rodrigues-Diez R, Plaza JJ, Egido J, Ruiz-Ortega M
Inhibitory effect of interleukin-1-{beta} on Angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells.
Am J Physiol Renal Physiol. 2007 Nov 7;
Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix (ECM) accumulation. Angiotensin II (AngII) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and ECM proteins, such as type IV collagen. During renal injury, AngII and the macrophage-produced cytokine interleukin-1-beta (IL-1-beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between AngII and IL-1-beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we have investigated whether IL-1-beta could regulate AngII-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by AngII. IL-1-beta did not increase the production of CTGF and type IV collagen, but significantly inhibited AngII-induced CTGF and type IV collagen overexpression. Moreover, IL-1-beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1-beta and AngII caused a synergistic increase on MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1-beta effects were dependent on activation of ERK/MAPK, but independent p38-MAPK, JNK, PI3K/Akt and ROCK pathways. In summary, these data indicate that IL-1-beta inhibited AngII-mediated type IV collagen production, via CTGF down-regulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1-beta abrogates AngII-induced CTGF production, describing antagonistic activities of pro-inflammatory cytokines on AngII actions. Key words: connective tissue growth factor, Metalloproteinases, ERK. [Abstract]

Graciano ML, Nishiyama A, Jackson KE, Seth DM, Ortiz RM, Prieto-Carrasquero M, Kobori H, Navar LG
Purinergic Receptors Contribute to Early Mesangial Cell Transformation and Renal Vessel Hypertrophy during Angiotensin II-Induced Hypertension.
Am J Physiol Renal Physiol. 2007 Nov 7;
Chronic Ang II infusions lead to increases in intrarenal Ang II levels, hypertension and tissue injury. Increased blood pressure also elicits increases in renal interstitial fluid (RIF) ATP concentrations which stimulates cell proliferation. We evaluated the contribution of purinergic receptor activation to Ang II induced renal injury in rats by treating with clopidogrel, a P2Y12 receptor blocker, or with PPADS, a non-selective P2 receptor blocker. Alpha-actin expression in mesangial cells, afferent arteriolar wall thickness (AAWT), cortical cell proliferation, and macrophage infiltration were used as early markers of renal injury. Clopidogrel and PPADS did not alter blood pressure, renin or kidney Ang II content. Alpha-actin expression increased from control of 0.6+/-0.4% of mesangial area to 6.3+/-1.9% in Ang II infused rats and this response was prevented by clopidogrel (0.4+/-0.2%) and PPADS. The increase in AAWT from 4.7+/-0.1mm to 6.0+/-0.1mm in Ang II rats was also prevented by clopidogrel (4.8+/-0.1mm) and PPADS. Ang II infusion led to interstitial macrophage infiltration (105+/-16 cell/mm2 vs 62+/-4 cell/mm2) and tubular proliferation (71+/-15 vs 20+/-4 cell/mm2) and these effects were prevented by clopidogrel (52+/-4 cell/mm2 and 36+/-3 cell/mm2) and PPADS. RIF ATP levels were higher in Ang II infused rats than in control rats (11.8+/-1.9 nmol/L vs 5.6+/-0.6 nmol/L, p < 0.05). The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation, renal inflammation and vascular hypertrophy observed in Ang II dependent hypertension. Key words: purinergic receptors, angiotensin II, hypertension, renal damage, clopidogrel. [Abstract]

Patterson ME, Mullins JJ, Mitchell KD
RENOPROTECTIVE EFFECTS OF NEURONAL NOS DERIVED NITRIC OXIDE AND CYLCLOOXYGENASE-2 METABOLITES IN TRANSGENIC RATS WITH INDUCIBLE MALIGNANT HYPERTENSION.
Am J Physiol Renal Physiol. 2007 Oct 31;
The present study was performed to determine the effects of nNOS and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible ANG II-dependent malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n=7) were fed a normal diet containing indole-3-carbinol (I3C; 0.3%) for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were assessed in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC, 1 mg/hr). In hypertensive Cyp1a1-Ren2 rats, L-SMTC increased MAP from 169+/-3 to 188+/-4 mmHg (P<0.01), which was a smaller increase than in non-induced rats (124+/-9 to 149+/-9 mmHg, P<0.01, n=5). Additionally, L-SMTC decreased RPF to a similar extent (-34+/-13% vs. -35+/-12%) in the hypertensive and normotensive rats (4.1+/-0.2 to 2.7+/-0.5 and 3.1+/-0.3 to 2.0+/-0.3 ml/min.g, respectively, P<0.01) but did not alter GFR in either group. In additional experiments, administration of the COX-2 inhibitor, nimesulide (3 mg/kg iv), during simultaneous infusion of L-SMTC decreased MAP in both hypertensive and non-induced rats (182+/-2 to 170+/-3 mmHg and 153+/-3 to 140+/-3 mmHg, respectively, P<0.01). Nimesulide also decreased RPF (1.9+/-0.2 to 0.8+/-0.1 ml/min.g, P<0.01) and GFR (0.9+/-0.1 to 0.4+/-0.1 ml/min g, P<0.01) in hypertensive rats but did not alter RPF or GFR in non-induced rats. The present findings demonstrate that both nNOS-derived NO and COX-2 metabolites exert pronounced renal vasodilator influences in hypertensive Cyp1a1-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyp1a1-Ren2 rats are not dependent on nNOS activity. Key words: nimesulide, L-SMTC, renal hemodynamics, renin-angiotensin system, kidney. [Abstract]

Fellner SK, Arendshorst WJ
Angiotensin II-stimulted calcium entry mechanism in afferent arterioles: role of transient receptor potential canonical channels and reverse Na+/Ca2+ exchange.
Am J Physiol Renal Physiol. 2007 Oct 31;
In afferent arterioles, the signaling events that lead to an increase in cytosolic Ca(2+) concentration ([Ca(2+)]i) and initiation of vascular contraction are increasingly being delineated. We have recently studied angiotensin II (Ang II) mediated effects on sarcoplasmic reticulum mobilization of Ca(2+) and the role of superoxide and cyclic adenosine diphosphoribose (cADPR) in these processes. Now we investigate the participation of transient receptor potential canonical channels (TRPC) and a Na(+)/Ca(2+) exchanger (NCX) in Ca(2+) entry mechanisms. Afferent arterioles, isolated with the magnetized polystyrene bead method, were loaded with fura-2 to measure [Ca(2+)]i ratiometrically. We observed that the ClCa2+ channel blocker niflumic acid (NFA) (10 and 50 micro M) affects neither the peak nor plateau [Ca(2+)]i response to Ang II. Arterioles were pretreated with ryanodine (100 microM) and TMB-8 to block SR mobilization via the ryanodine receptor (RyR) and IP3 receptor (IP3R), respectively. The peak [Ca(2+)]i response to Ang II was reduced by 40%. Addition of 2APB to block TRPC mediated Ca(2+) entry inhibited the peak and plateau [Ca(2+)]i Ang II responses 80% and 74%. Flufenamic acid (FFA) (50 microM), which stimulates TRPC6, caused a sustained increase of [Ca(2+)]i of 146 nM. This response was unaffected by diltiazem or nifedipine. KB-R7943 (at the low concentration of 10 microM) inhibits reverse (but not forward) mode NCX. KB-R7943 decreased the peak [Ca(2+)]i response to Ang II by 48% and to FFA by 38%. We conclude that TRPC6 and reverse mode NCX may be important Ca(2+) entry pathways in afferent arterioles. Key words: renal microcirculation, vascular smooth muscle cell, voltage-gated calcium entry. [Abstract]

Hwang SY, Woo CW, Au-Yeung KK, Siow YL, Zhu TY, O K
Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor kappa B activation.
Am J Physiol Renal Physiol. 2007 Oct 31;
Hyperhomocysteinemia or an elevation of blood homocysteine (Hcy) levels is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of homocysteine (Hcy) on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor kappa-B (NF-kB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underling such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 weeks. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-kB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-kB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-kB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-kB oligodeoxynucleotide to inhibit NF-kB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-kB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia. Key words: homocysteine, kidney , chemokine, nuclear factor kappa B. [Abstract]

Gattineni J, Sas D, Dagan A, Dwarakanath V, Baum MG
Effect of Thyroid Hormone on the Postnatal Renal Expression of NHE8.
Am J Physiol Renal Physiol. 2007 Oct 31;
We have previously demostrated that there are developmental changes in proximal tubule Na(+)/H(+) exchanger (NHE) activity. There is a maturational increase in postnatal brush border membrane (BBM) NHE3 protein abundance and decrease in NHE8 protein abundance. This study determined if thyroid hormone plays a role in the rat renal maturational isoform switch from NHE8 to NHE3 and if thyroid hormone regulates NHE8. Administration of thyroid hormone to neonatal rats, prior to the normal postnatal increase in serum thyroid hormone levels, resulted in a premature increase in NHE3/beta-actin BBM protein abundance and mRNA abundance. Thyroid hormone caused a premature decrease in BBM NHE8/beta-actin protein abundance, while there was no change in mRNA expression. Rats made hypothyroid from birth were studied at 28 days. In these hypothyroid adult rats, the maturational increase in BBM NHE3 protein abundance and NHE3 mRNA expression was prevented. In contrast the developmental decrease in BBM NHE8 protein abundance was prevented in hypothyroid adults, but mRNA expression was unchanged in hypothyroid rats. To determine if the effect of thyroid hormone was due to a direct epithelial effect, we studied NRK (normal rat kidney) cells in culture. Thyroid hormone caused a decrease in surface expression of NHE8, determined by biotinylation. NHE8 activity, measured as the sodium dependent rate of intracellular pH recovery from an acid load, was less with thyroid treatment than control. In conclusion, thyroid hormone plays a potential role in the developmental isoform change from NHE8 to NHE3 and decreases NHE8 activity. Key words: proximal tubule , renal development, Na/H exchanger. [Abstract]

Vallon V
P2 RECEPTORS IN THE REGULATION OF RENAL TRANSPORT MECHANISMS.
Am J Physiol Renal Physiol. 2007 Oct 31;
Extracellular nucleotides (e.g., ATP) regulate physiological and pathophysiological processes through activation of nucleotide P2 receptors in the plasma membrane. Examples include such diverse processes as communication from taste buds to gustatory nerves, platelet aggregation, nociception or neutrophil chemotaxis. Over the last ~15 years evidence accumulated that also cells in renal epithelia release nucleotides in response to physiological stimuli, and that these nucleotides act in a paracrine and autocrine way to activate P2 receptors and play a significant role in the regulation of transport mechanisms and cell volume regulation. This review discusses potential stimuli and mechanisms involved in nucleotide release in renal epithelia, and summarizes the available data on the expression and function of nucleotide P2 receptors along the native mammalian tubular and collecting duct system. Using established agonist profiles for P2 receptor subtypes, significant insights have been gained particularly on a potential role for P2Y2-like receptors in the regulation of transport mechanisms in the collecting duct. Due to the lack of receptor subtype-specific antagonists, however, the in vivo relevance of P2 receptor subtypes is unclear. Studies in gene knockout mice provided first insights including an antihypertensive activity of P2Y2 receptors that is linked to an inhibitory influence on renal Na(+) and water transport. We are only beginning to unravel the important roles of extracellular nucleotides and P2 receptors in the regulation of the diverse transport mechanisms of the kidney. Key words: kidney, nucleotide, ATP, collecting duct, blood pressure. [Abstract]

Gillen DL, Worcester EM, Coe FL
Reply to gambaro and abaterusso.
Am J Physiol Renal Physiol. 2007 Nov;293(5): [Abstract]

Gambaro G, Abaterusso C
Pathophysiology of hypercalciuria.
Am J Physiol Renal Physiol. 2007 Nov;293(5): [Abstract]

Taruno A, Niisato N, Marunaka Y
Intracellular calcium plays a role as the second messenger of hypotonic stress in gene regulation of SGK1 and ENaC in renal epithelial A6 cells.
Am J Physiol Renal Physiol. 2007 Oct 24;
In A6 cells, a renal cell line derived from Xenopus laevis, hypotonic stress stimulates the amiloride-sensitive Na(+) transport. Hypotonic action on the Na(+) transport is composed of two phases, a non-genomic early phase and a genomic delayed phase. Although previous works reported that during the genomic phase hypotonic stress stimulates the transcription of Na(+) transport-related genes, such as SGK1 and subunits of epithelial sodium channel (ENaC), increasing the Na(+) transport, the mechanism is still unknown. We focused the present study on the role of the intracellular Ca(2+) in the hypotonicity-induced SGK1 and ENaC subunits transcription. Since hypotonic stress raises the intracellular Ca(2+) concentration in A6 cells, we hypothesized that Ca(2+)-dependent signals participate in the genomic action. Using real-time QRT-PCR and western blotting techniques and measuring short-circuit currents, we observed that: 1) BAPTA/AM and W7 blunted the hypotonicity-induced expression of SGK1 mRNA and protein, 2) ionomycin dose-dependently stimulated expression of SGK1 mRNA and protein under an isotonic condition and the time course of the stimulatory effect of ionomycin on SGK1 mRNA was remarkably similar to that of hypotonic action on SGK1 mRNA, 3) hypotonic stress stimulated the transcription of three ENaC subunits in an intracellular Ca(2+)-dependent manner, and 4) BAPTA/AM retarded the delayed phase of hypotonic stress-induced Na(+) transport without any effect on the early phase. These observations indicate for the first time that the intracellular Ca(2+) plays a role as the second messenger in the hypotonic stress-induced Na(+) transport by stimulating the transcription of SGK1 and ENaC subunits. Key words: ENaC, A6 cells, Na+ transport. [Abstract]

Akintola AD, Crislip ZL, Catania JM, Chen G, Zimmer WE, Burghardt RC, Parrish AR
PROMOTER METHYLATION IS ASSOCIATED WITH THE AGE-DEPENDENT LOSS OF N-CADHERIN IN THE RAT KIDNEY.
Am J Physiol Renal Physiol. 2007 Oct 24;
The cadherins are cell adhesion molecules required for cellular homeostasis and N-cadherin is the predominant cadherin expressed in proximal tubular epithelial cells in humans and rats. Our laboratory previously reported an age-dependent decrease in renal N-cadherin expression; the levels of N-cadherin mRNA and protein expression decreased in parallel, implicating a transcriptional mechanism in the age-dependent loss of expression (19). In this study, we examined the hypothesis that promoter hypermethylation underlies the loss of N-cadherin expression in aging rat kidney. We cloned the 5' flanking region of the rat N-cadherin gene and observed basic promoter activity in a 3992-bp region localized immediately upstream of the ATG start site. Nucleotide analysis revealed 87% identity with the human N-cadherin minimal promoter region. Consistent with a role for regulation by DNA methylation, we found that a dense CpG island, which spans 1214-bp, flanks the rat N-cadherin gene; a similar CpG profile was found in the human N-cadherin 5' flanking region. Methylation specific PCR analysis demonstrated that the promoter region of N-cadherin is heavily methylated in aged, but not young, rat kidney. In contrast, the promoter region is not methylated in either young or aged rat liver; this corresponds to the finding that aging is not associated with decreased N-cadherin expression in the liver. In addition, N-cadherin expression is markedly induced in NRK-52E cells treated with the DNA methyltransferase inhibitor 5-aza-2'deoxycytidine, further suggesting that methylation at CpG in the promoter region may underlie the age-dependent decrease in renal N-cadherin expression. Key words: N-cadherin, methylation, aging. [Abstract]

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Recent Articles in Kidney International

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Allory Y, Audard V, Fontanges P, Ronco P, Debiec H
The L1 cell adhesion molecule is a potential biomarker of human distal nephron injury in acute tubular necrosis.
Kidney Int. 2007 Dec 5; .
The L1 cell adhesion molecule (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily. We evaluated its expression in human acute kidney injury and assessed its use as a tissue and urinary marker of acute tubular injury. Using immunohistochemical studies with antibodies to the extracellular or cytoplasmic domains, we compared L1 expression in normal kidneys in 24 biopsies taken from patients with acute tubular necrosis. L1 was found at the basolateral and the lateral membrane in all epithelial cells of the collecting duct in the normal kidney except for intercalated cells. In acute tubular necrosis, L1 lost its polarized distribution being found in both the basolateral and apical domains of the collecting duct. Further, it was induced in thick ascending limb and distal tubule cells. Apically expressed L1 found only when the cytoplasmic domain antibody was used in biopsy specimens of patients with acute tubular necrosis. The levels of urinary L1, normalized for creatinine, were significantly higher in all 24 patients with acute tubular necrosis compared to five patients with prerenal azotemia or to six patients with other causes of acute kidney injury. Our study shows that a soluble form of human L1 can be detected in the urine of patients with acute tubular necrosis and that this may be a marker of distal nephron injury.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002640. [Abstract]

Perkovic V, Cass A, Patel AA, Suriyawongpaisal P, Barzi F, Chadban S, Macmahon S, Neal B
High prevalence of chronic kidney disease in Thailand.
Kidney Int. 2007 Dec 5;
We describe the prevalence of stage III and IV chronic kidney disease in Thailand from a representative sample of individuals aged 35 years and above using a stratified, multistage, cluster-sampling method. Population estimates were calculated by applying sampling weights from the 2000 Thai census. Glomerular filtration rates were estimated from serum creatinine using the Cockroft-Gault and the simplified Modification of Diet in Renal Disease (MDRD) formulae. The prevalence of stage III disease among individuals aged 35 years and above was estimated to be about 20% using the Cockroft-Gault formula and about 13% from the MDRD formula. Stage IV disease was present in about 0.9 and 0.6% of this population using the respective formulae. The highest prevalence rates were observed in less well-developed rural areas and the lowest in developed urban areas. The prevalence of chronic kidney disease was significantly higher than that reported in individuals over 40 years old from the United States for both stage III and IV disease and higher than the reported incidence in Taiwan and Australia. This high prevalence of chronic kidney disease in Thailand has obvious implications for the health of its citizens and for the allocation of health-care resources.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002701. [Abstract]

Curhan GC, Taylor EN
24-h uric acid excretion and the risk of kidney stones.
Kidney Int. 2007 Dec 5;
There is uncertainty about the relation between 24-h urinary uric acid excretion and the risk of calcium oxalate nephrolithiasis. In addition, the risk associated with different levels of other urinary factors needs clarification. We performed a cross-sectional study of 24-h urine excretion and the risk of kidney stone formation in 3350 men and women, of whom 2237 had a history of nephrolithiasis. After adjusting for other urinary factors, urinary uric acid had a significant inverse association with stone formation in men, a marginal inverse association with risk in younger women, and no association in older women. The risk of stone formation in men and women significantly rose with increasing urine calcium and oxalate, and significantly decreased with increasing citrate and urine volume, with the change in risk beginning below the traditional normal thresholds. Other urinary factors were also associated with risk, but this varied by age and gender. Our study does not support the prevailing belief that higher urine uric acid excretion increases the risk for calcium oxalate stone formation. In addition, the current definitions of normal levels for urinary factors need to be re-evaluated.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002708. [Abstract]

Gura V, Ronco C, Nalesso F, Brendolan A, Beizai M, Ezon C, Davenport A, Rambod E
A wearable hemofilter for continuous ambulatory ultrafiltration.
Kidney Int. 2007 Dec 5;
Ultrafiltration is effective for treating fluid overload, but there are no suitable machines for ambulatory treatment. This study summarizes the use of a light-weight wearable continuous ambulatory ultrafiltration device consisting of a hollow fiber hemofilter, a battery operated pulsatile pump, and two micropumps to control heparin administration and ultrafiltration. Six volume-overloaded patients underwent ultrafiltration for 6 h with treatment discontinued in one patient due to a clotted catheter. Blood flow averaged 116 ml min(-1), the ultrafiltration rate ranged from 120-288 ml h(-1) with about 150 mmol of sodium removed. Blood pressure, pulse, and biochemical parameters remained stable with no significant hemolysis or complications. Our data show that the wearable hemofilter appears to be safe, effective, and practical for patients. This device could have a major impact on the quality of life of fluid-overloaded patients with heart failure. Additional studies will be needed to confirm these initial promising results.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002711. [Abstract]

Liu FY, Li XZ, Peng YM, Liu H, Liu YH
Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition.
Kidney Int. 2007 Dec 5;
Transforming growth factor-beta (TGF-beta) signaling has been linked with tubular epithelial to mesenchymal cell transition. In this study, we examined the role of Arkadia, an E3 ubiquitin ligase that is critically required for TGF-beta signaling during epithelial to mesenchymal cell transition. We found that when normal human renal tubular epithelial cells in culture were stimulated with TGF-beta1, which increased their levels of Arkadia, Smurf2, TGF-beta type I receptor (TbetaRI), and Smad7 mRNA, but had low levels of Smad7 protein. When these cells were preincubated with Arkadia siRNA (small interfering RNA) and lactacystin (an inhibitor of proteasomal degradation), the TGF-beta(1) induced expression of Smad7, alpha-smooth muscle actin, and E-cadherin was partly reversed, but the expression of TbetaRI protein and Smad7 mRNA was not affected. In contrast, Smurf2 siRNA had no influence on the expression of these targets. Our studies suggest that Arkadia stimulates renal tubular epithelial to mesenchymal cell transition through degradation of Smad7.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002713. [Abstract]

Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan P, Bonventre JV
Urinary biomarkers in the early diagnosis of acute kidney injury.
Kidney Int. 2007 Dec 5;
A change in the serum creatinine is not sensitive for an early diagnosis of acute kidney injury. We evaluated urinary levels of matrix metalloproteinase-9 (MMP-9), N-acetyl-beta-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) as biomarkers for the detection of acute kidney injury. Urine samples were collected from 44 patients with various acute and chronic kidney diseases, and from 30 normal subjects in a cross-sectional study. A case-control study of children undergoing cardio-pulmonary bypass surgery included urine specimens from each of 20 patients without and with acute kidney injury. Injury was defined as a greater than 50% increase in the serum creatinine within the first 48 h after surgery. The biomarkers were normalized to the urinary creatinine concentration at 12, 24, and 36 h after surgery with the areas under the receiver-operating characteristic curve compared for performance. In the cross-sectional study, the area under the curve for MMP-9 was least sensitive followed by KIM-1 and NAG. Combining all three biomarkers achieved a perfect score diagnosing acute kidney injury. In the case-control study, KIM-1 was better than NAG at all time points, but combining both was no better than KIM-1 alone. Urinary MMP-9 was not a sensitive marker in the case-control study. Our results suggest that urinary biomarkers allow diagnosis of acute kidney injury earlier than a rise in serum creatinine.Kidney International advance online publication, 5 December 2007; doi:10.1038/sj.ki.5002715. [Abstract]

Patel TV, Goes N
Page kidney.
Kidney Int. 2007 Dec;72(12): [Abstract]

Liu KL, Lee WJ, Chang CC, Chueh SC, Chen SJ
Cobras in the bladder?
Kidney Int. 2007 Dec;72(12): [Abstract]

Kang KP, Jeong YB, Lee S, Kim W, Kim YK, Park SK
The Case mid R: An elderly diabetic man with urinary tract infection.
Kidney Int. 2007 Dec;72(12): [Abstract]


Journal club.
Kidney Int. 2007 Dec;72(12): [Abstract]

Rovin BH, Hebert LA
Thiazide diuretic monotherapy for hypertension: Diuretic's dark side just got darker.
Kidney Int. 2007 Dec;72(12):
Diuretic monotherapy is the current recommendation of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for initial antihypertensive therapy. There is mounting concern, however, that the benefits of diuretic's superior blood pressure control may be offset by its multiple metabolic disturbances that increase cardiovascular risk. Reungjui et al. document a new concern, nephrotoxicity by thiazide monotherapy. This and other recently published evidence of diuretic's 'dark side' is discussed.Kidney International (2007) 72, 1423-1426. doi:10.1038/sj.ki.5002656. [Abstract]

Harris PC
Genetic complexity in Joubert syndrome and related disorders.
Kidney Int. 2007 Dec;72(12):
The recent identification of RPGRIP1L as a Joubert syndrome gene brings the total of known genes to five. Three of these are also associated with the lethal Meckel syndrome, and two with Senior-Løken syndrome; both of these disorders share Joubert syndrome phenotypes, illustrating the genetic complexity of this.Kidney International (2007) 72, 1421-1423. doi:10.1038/sj.ki.5002577. [Abstract]

Perico N, Remuzzi G
Inhibition of TGF-beta expression: A novel role for thiazolidinediones to implement renoprotection in diabetes.
Kidney Int. 2007 Dec;72(12):
Actual strategies to delay progression of diabetic nephropathy provide imperfect protection when started late in the course of the disease. Ohtomo et al. now demonstrate that thiazolidinedione treatment was associated with a remarkable improvement in proteinuria and renal function, offering a new potential treatment for diabetic nephropathy.Kidney International (2007) 72, 1419-1421. doi:10.1038/sj.ki.5002654. [Abstract]


In this issue.
Kidney Int. 2007 Dec;72(12): [Abstract]

Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H
Expression and role of connexins in the rat renal vasculature.
Kidney Int. 2007 Nov 28;
Gap junctions are present in the juxtaglomerular apparatus enabling intercellular communication. Our study determined the location of different connexin subtypes within the juxtaglomerular apparatus of the rat, and the role of these subtypes in renal hemodynamics through the use of specific mimetic peptides. Immunohistochemical analysis showed connexins 37 and 40 expression in the endothelial and renin-secreting cells of the afferent arteriole, while connexin 40 was also found in extra- and intraglomerular mesangial cells. In contrast, connexin 43 was weakly expressed in endothelial cells of the afferent arteriole and within the glomerulus. Intra-renal infusion of the peptides (GAP) reported to block specific gap junctions ((Cx37,43)GAP27 or (Cx40)GAP27), elevated blood pressure, plasma renin activity, and angiotensin II levels, while decreasing renal plasma flow without a significant change in the glomerular filtration rate. Subsequent restoration of blood pressure reduced both renal plasma flow and glomerular filtration rate. In contrast, (Cx43)GAP26 reduced glomerular filtration rate without alterations in blood pressure, renal plasma flow, plasma renin activity, or angiotensin II levels. Hence, connexins 37 and 40 are expressed in the rat juxtaglomerular apparatus and these proteins control, in part, the renin-angiotensin system and renal autoregulation.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002673. [Abstract]

Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM
Exploring the biology of vascular calcification in chronic kidney disease: What's circulating?
Kidney Int. 2007 Nov 28;
Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium x phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or 'damage' of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002696. [Abstract]

Bushinsky DA, Michalenka AC, Strutz KL, Donahue S, Asplin JR
Effect of bolus and divided feeding on urine ions and supersaturation in genetic hypercalciuric stone-forming rats.
Kidney Int. 2007 Nov 28;
Because urine ion excretion varies throughout the day, clinicians monitor 24 h urine samples to measure ion excretion and supersaturation in kidney stone patients. However, these results are averages and may not reflect maximal supersaturation which drives stone formation. We measured ion excretion and saturation in genetic hypercalciuric stone-forming rats on both a normal or low calcium diet over 0-3, 3-6 and 6-24 h using two feeding protocols, where the daily food allotment was fed either as a bolus or divided into three portions. With a normal calcium diet, urine calcium, oxalate, volume, and calcium oxalate supersaturation were significantly greater on the bolus compared to the divided feeds in the prandial and postprandial periods. Bolus eaters also excreted more calcium and oxalate and had increased volume over 24 h. Maximal calcium oxalate supersaturation was greater during the initial time periods than during the entire 24 h, regardless of the feeding schedule. With the low calcium diet, the effect of bolus feeding was reduced. Thus, urine ion excretion and supersaturation vary with the type of feeding. If these results are confirmed in man, it suggests that eating as a bolus may result in greater prandial and postprandial calcium oxalate supersaturation. This may increase growth on Randall's plaques and promote stone disease.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002699. [Abstract]

Kuwana H, Terada Y, Kobayashi T, Okado T, Penninger JM, Irie-Sasaki J, Sasaki T, Sasaki S
The phosphoinositide-3 kinase gamma-Akt pathway mediates renal tubular injury in cisplatin nephrotoxicity.
Kidney Int. 2007 Nov 28;
Nephrotoxicity is a frequent complication of cisplatin-based chemotherapy often limiting its use. In this study, we attempted to the role of the phosphoinositide-3 kinase (PI3K)-gamma-Akt pathway in this form of acute kidney injury. Using PI3K-gamma knockout mice, we found that a conventional dose of cisplatin was more lethal in the knockout mice where the blood urea nitrogen and serum creatinine were significantly higher in them than in wild-type mice. Phosphorylation of Akt in the renal tubules was abrogated in the knockout mice with the severity of renal dysfunction and numbers of TUNEL (terminal deoxynucleotidyl transferase (TdT) mediated nick-end labeling)-positive renal tubule cells being higher in the knockout than in wild-type mice. Cisplatin treatment significantly increased. Caspase-3 activity, histone-associated DNA fragments, and number of annexin V-positive cells was significantly higher in cisplatin-treated primary cultured renal tubular epithelial cells of knockout mice. Transfection of dominant-active forms of Akt and PI3K-gamma ameliorated apoptosis of the tubule epithelial cells derived from the knockout mice. Our results suggest that the PI3K-gamma-Akt pathway lessens apoptosis and plays a critical role in the maintenance of renal function in cisplatin-induced acute kidney injury.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002702. [Abstract]

Villa-Bellosta R, Barac-Nieto M, Breusegem SY, Barry NP, Levi M, Sorribas V
Interactions of the growth-related, type IIc renal sodium/phosphate cotransporter with PDZ proteins.
Kidney Int. 2007 Nov 28;
Despite similar molecular structures, the growth-related sodium/phosphate cotransporter NaPiIIc is regulated differently than the main NaPiIIa phosphate transporter. Using two-hybrid systems and immunoprecipitation, we identified several proteins that interact with NaPiIIc that might account for this differential regulation. NaPiIIc interacted with the PDZ domain-containing sodium-hydrogen exchange-regulating factor (NHERF) 1 and NHERF3 through novel binding motifs in its C terminus. NaPiIIc from brush-border membranes coprecipitated with both NHERF1 and NHERF3, with more NHERF3 co-precipitated in rats fed a low-phosphorus diet. NaPiIIc colocalizes with both NHERF1 and NHERF3 in brush-border membranes of rats fed either a low- or high-phosphorus diet. When mouse NaPiIIc was transfected into opossum kidney cells, it was localized mainly in apical microvilli and the trans-Golgi. Both confocal and total internal reflection microscopy show that NaPiIIc colocalizes with NHERF1 and NHERF3 in the apical microvilli, and this was not altered by truncation of the last three amino acids of NaPiIIc. Interactions of NaPiIIc with NHERF1 and NHERF3 were modulated by the membrane-associated 17 kDa protein (MAP17) similarly to NaPiIIa, but only the MAP17-NaPiIIc-NHERF3 complexes were internalized to the trans-Golgi. Our study shows that NaPiIIc interacts with a limited number of PDZ domain proteins, and the mechanisms and consequences of such interactions differ from those of NaPiIIa.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002703. [Abstract]

Badve SV, Hawley CM, McDonald SP, Mudge DW, Rosman JB, Brown FG, Johnson DW
Automated and continuous ambulatory peritoneal dialysis have similar outcomes.
Kidney Int. 2007 Nov 28;
We compared survival and death-censored technique survival in patients on automated peritoneal dialysis (automated dialysis) or on continuous ambulatory peritoneal dialysis. All 4128 patients from the Australia and New Zealand Dialysis and Transplant Registry who started peritoneal dialysis over a 5-year period through March 2004 were included. Times to death and death-censored technique failure were analyzed by Cox proportional hazards models while a conditional risk set model computed technique failure. Compared to patients treated entirely with continuous ambulatory peritoneal dialysis, automated peritoneal dialysis patients were more likely to be young, Caucasian, have marginally lower body mass index, and were less likely to have baseline cardiovascular disease or diabetes. Using univariate and multivariate analysis, our study showed there were no significant differences in patient survival and death-censored technique failure between the two types of peritoneal dialysis modalities.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002705. [Abstract]

van den Hoven MJ, Wijnhoven TJ, Li JP, Zcharia E, Dijkman HB, Wismans RG, Rops AL, Lensen JF, van den Heuvel LP, van Kuppevelt TH, Vlodavsky I, Berden JH, van der Vlag J
Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria.
Kidney Int. 2007 Nov 28;
Heparan sulfate in the glomerular basement membrane has been considered crucial for charge-selective filtration. In many proteinuric diseases, increased glomerular expression of heparanase is associated with decreased heparan sulfate. Here, we used mice overexpressing heparanase and evaluated the expression of different heparan sulfate domains in the kidney and other tissues measured with anti-heparan sulfate antibodies. Glycosaminoglycan-associated anionic sites were visualized by the cationic dye cupromeronic blue. Transgenic mice showed a differential loss of heparan sulfate domains in several tissues. An unmodified and a sulfated heparan sulfate domain resisted heparanase action in vivo and in vitro. Glycosaminoglycan-associated anionic sites were reduced about fivefold in the glomerular basement membrane of transgenic mice, whereas glomerular ultrastructure and renal function remained normal. Heparanase-resistant heparan sulfate domains may represent remnant chains or chains not susceptible to cleavage. Importantly, the strong reduction of glycosaminoglycan-associated anionic sites in the glomerular basement membrane without development of a clear renal phenotype questions the primary role of heparan sulfate in charge-selective filtration. We cannot, however, exclude that overexpression of heparanase and heparan sulfate loss in the basement membrane in glomerular diseases contributes to proteinuria.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002706. [Abstract]

Doné SC, Takemoto M, He L, Sun Y, Hultenby K, Betsholtz C, Tryggvason K
Nephrin is involved in podocyte maturation but not survival during glomerular development.
Kidney Int. 2007 Nov 28;
Nephrin, a major component of the glomerular slit diaphragm (SD), is both a structural protein as well as a signaling molecule influencing foot process (FP) formation and maintenance of podocyte integrity. Analyses of near-term embryonic kidneys showed normal cellular viability and no apoptosis in glomeruli from nephrin knockout mice. Moreover, expression and location of other SD or glomerular basement membrane components were similar in wild-type and mutant mice as was the location and levels of most podocyte-specific proteins. Transcriptional profiling showed that the lack of nephrin had minor impact on the expression of genes for FPs and SD proteins. Claudin 3, a tight-junction protein normally absent in glomeruli, was upregulated threefold in the knockout mice, suggesting a role of nephrin in claudin 3 gene expression within the glomeruli. Our results suggest that nephrin is expressed late in the process of podocyte differentiation and is a locus for the formation of SD and FP maintenance and physical integrity in vivo. Nephrin does not seem to have a primary role in cell survival but has a small impact on gene regulation during glomerular development.Kidney International advance online publication, 28 November 2007; doi:10.1038/sj.ki.5002707. [Abstract]

Dong J, Li YJ, Lu XH, Gan HP, Zuo L, Wang HY
Correlations of lean body mass with nutritional indicators and mortality in patients on peritoneal dialysis.
Kidney Int. 2007 Nov 21;
Detection of malnutrition in dialysis patients is important since this is a predictor of morbidity and mortality. Lean body mass (LBM) reflects the somatic protein store and this was measured by creatinine kinetics, anthropometry, and biometric impedance in 210 incident Chinese patients on continuous ambulatory peritoneal dialysis. The study was started in the third month of dialysis and the patients were followed for an average of 29 months. We devised three models of survival by combining the three different LBM measures with several nutritional markers and recognized outcome predictors. Follow-up was censored for transplantation or transfer to hemodialysis with an end point of death while on peritoneal dialysis. Statistical correlations were observed among the LBM values determined by all the three methods and these correlated significantly with both left and right hand grip strength but not with nutritional markers. LBM by creatinine kinetics, mean arterial pressure, and the calcium-phosphorus product were significant, independent predictors of death in one survival model. Anthropometry and bioelectric impedance were not significant predictors of death in the other two models. Our study suggests that LBM measured by creatinine kinetics, anthropometry, and bioelectrical impedance correlates well with the somatic protein store but not with the general nutritional status.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002644. [Abstract]

Zaidi M, Singh N, Kamran M, Ansari N, Nasr SH, Acharya A
Acute onset of hematuria and proteinuria associated with multiorgan involvement of the heart, liver, pancreas, kidneys, and skin in a patient with Henoch-Schönlein purpura.
Kidney Int. 2007 Nov 21; [Abstract]

Vupputuri S, Shoham DA, Hogan SL, Kshirsagar AV
Microalbuminuria, peripheral artery disease, and cognitive function.
Kidney Int. 2007 Nov 21;
Kidney disease may be linked to a decline in cognitive activity. We examined the association of microalbuminuria and cognitive function in a general population of older adults in the United States drawn from the National Health and Nutrition Examination Survey of 1999-2002. Cognitive function was measured by digit symbol substitution in 2386 participants 60 years of age and older of whom 448 had microalbuminuria. Covariates included age, gender, race/ethnicity, education, smoking, diabetes, and hypertension. Among participants with peripheral artery disease, those with microalbuminuria had a significantly lower cognitive function score compared to those with a normal albumin-to-creatinine ratio. The association between microalbuminuria and cognitive function was weak in those without peripheral artery disease. But in those with peripheral artery disease, the odds of microalbuminuria associated with cognitive function in the lowest and middle tertiles was 6.5 and 3.5, respectively.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002672. [Abstract]

Tang SC, Leung JC, Chan LY, Eddy AA, Lai KN
Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy.
Kidney Int. 2007 Nov 21;
Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins have renoprotective effects. We studied the cellular mechanisms for this effect in adriamycin-treated mice receiving captopril, losartan, simvastatin, or their combinations. The mice developed albuminuria, renal insufficiency, and parenchymal inflammation/fibrosis accompanied by overexpression of intrarenal converting enzyme and angiotensin II. Only captopril consistently improved these abnormalities and reduced the cortical expression of several proinflammatory and profibrotic factors including transforming growth factor-beta (TGF-beta). These effects were independent of blood pressure, accompanied by increased urine N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels, and the restoration of renal angiotensin-converting enzyme and angiotensin II to baseline levels. Losartan or simvastatin alone or together had no effect, and their addition to captopril did not enhance protection. In vitro, angiotensin II stimulated TGF-beta in renal tubular cells via mitogen-activated protein kinase (MAPK) signaling. Captopril or Ac-SDKP suppressed angiotensin II-induced MAPK activation and TGF-beta secretion. Angiotensin-converting enzyme inhibition confers renoprotection in adriamycin nephropathy by reducing intrarenal angiotensin II and augmenting Ac-SDKP expression that together attenuate MAPK signaling and its downstream proinflammatory and fibrogenic properties. The addition of receptor blocker and/or statin failed to potentiate such effects.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002674. [Abstract]

Fervenza FC, Torra R, Lager DJ
Fabry disease: An underrecognized cause of proteinuria.
Kidney Int. 2007 Nov 21; [Abstract]

Kirchhoff F, Krebs C, Abdulhag UN, Meyer-Schwesinger C, Maas R, Helmchen U, Hilgers KF, Wolf G, Stahl RA, Wenzel U
Rapid development of severe end-organ damage in C57BL/6 mice by combining DOCA salt and angiotensin II.
Kidney Int. 2007 Nov 21;
The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models; however, this strain appears to be resistant to hypertension-induced renal injury. We developed a new model of hypertensive end-organ damage in C57BL/6 mice by combining deoxycorticosterone acetate (DOCA) and salt with angiotensin II infusion. The systolic blood pressure (SBP) was significantly elevated in DOCA salt-angiotensin II mice compared to control mice or mice treated individually with DOCA salt or angiotensin II. Hypertensive glomerular damage, increased expression of profibrotic and inflammatory genes, albuminuria, tubular casts, increased plasma cholesterol, cardiac hypertrophy, and fibrosis were found in mice treated with DOCA salt-angiotensin II. The SBP in the angiotensin II-infused group was further increased by increasing the infusion rate; only mild injury was observed in these mice, suggesting that blood pressure was not a causal factor. Removal of DOCA and the angiotensin pump lowered blood pressure to normal; however, albuminuria along with the glomerular and cardiac damage did not completely resolve. Our study describes a new model of hypertensive end-organ damage and repair in C57BL/6 mice.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002689. [Abstract]

Zhu J, Sun N, Aoudjit L, Li H, Kawachi H, Lemay S, Takano T
Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes.
Kidney Int. 2007 Nov 21;
Nephrin is a slit diaphragm protein critical for structural and functional integrity of visceral glomerular epithelial cells (podocytes) and is known to be tyrosine phosphorylated by Src family kinases. We studied the role of phosphoinositide 3-kinase (PI3K), activated via the phosphorylation of nephrin, in actin cytoskeletal reorganization of cultured rat podocytes. Phosphorylation of rat nephrin by the Fyn kinase markedly increased its interaction with a regulatory subunit of PI3K. Stable transfection of rat nephrin in the podocytes with podocin led to nephrin tyrosine phosphorylation, PI3K-dependent phosphorylation of Akt, increased Rac1 activity, and an altered actin cytoskeleton with decreased stress fibers and increased lamellipodia. These changes were reversed with an inhibitor of PI3K and not seen when the nephrin-mutant Y1152F replaced wild-type nephrin. Rac1 and Akt1 contributed to lamellipodia formation and decreased stress fibers, respectively. Finally, in the rat model of puromycin aminonucleoside nephrosis, nephrin tyrosine phosphorylation, nephrin-PI3K association, and glomerular Akt phosphorylation were all decreased. Our results suggest that PI3K is involved in nephrin-mediated actin reorganization in podocytes. Disturbed nephrin-PI3K interactions may contribute to abnormal podocyte morphology and proteinuria.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002691. [Abstract]

Hsu YH, Chen CH, Hou CC, Sue YM, Cheng CY, Cheng TH, Lin H, Tsai WL, Chan P, Chen TH
Prostacyclin protects renal tubular cells from gentamicin-induced apoptosis via a PPARalpha-dependent pathway.
Kidney Int. 2007 Nov 21;
To study the protective effect of prostacyclin (PGI2) we increased PGI2 production by infected NRK-52E cells with an adenovirus carrying cyclooxygenase-1 and prostacyclin synthase. PGI2 overexpression protected these cells from gentamicin-induced apoptosis by reducing cleaved caspase-3 and caspase-9, cytochrome c, and decreasing generation of reactive oxygen species. Expression of the nuclear receptor of PGI2, peroxisome proliferator-activated receptor-alpha (PPARalpha), was reduced during gentamicin treatment of the cells, while its overexpression significantly inhibited gentamicin-induced apoptosis and the amount of cleaved caspase-3. Transformation with PPARalpha short interfering RNA abolished the protective effect of PGI2 overproduction in gentamicin-treated cells. The PPARalpha activator docosahexaenoic acid given to gentamicin-treated mice significantly reduced the number of apoptotic cells in renal cortex, but this protective effect was not seen in PPARalpha knockout mice. Our study suggests that increased endogenous PGI2 production protects renal tubular cells from gentamicin-induced apoptosis through a PPARalpha-signaling pathway.Kidney International advance online publication, 21 November 2007; doi:10.1038/sj.ki.5002704. [Abstract]

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Recent Articles in American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation

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Stratta P, Barbieri S, Lazzarich E, Fenoglio R, Quaglia M
Nephrocalcinosis in phosphate nephropathy following oral phosphate purgative: a role for underlying subclinical primary hyperparathyroidism?
Am J Kidney Dis. 2007 Dec;50(6):1053; author reply 1053-4. [Abstract]

Beyea A, Block C, Schned A
Acute phosphate nephropathy following oral sodium phosphate solution to cleanse the bowel for colonoscopy.
Am J Kidney Dis. 2007 Jul;50(1):151-4. [Abstract]

Vachharajani TJ, Moossavi S
Managing dialysis catheter-related Staphylococcus aureus bacteremia.
Am J Kidney Dis. 2007 Dec;50(6):1052; author reply 1052. [Abstract]

Maya ID, Carlton D, Estrada E, Allon M
Treatment of dialysis catheter-related Staphylococcus aureus bacteremia with an antibiotic lock: a quality improvement report.
Am J Kidney Dis. 2007 Aug;50(2):289-95.
BACKGROUND: Dialysis catheter-related bacteremia is often treated successfully by instilling an antibiotic-heparin solution into the catheter lumen (an antibiotic lock) in conjunction with systemic antibiotic therapy without removal of the catheter. The efficacy of this therapy is uncertain in Staphylococcus aureus bacteremia. DESIGN: Quality improvement report. SETTING & PARTICIPANTS: 113 catheter-dependent hemodialysis outpatients with S aureus catheter-related bacteremia treated with a standardized antibiotic lock protocol. Data for all patients with catheter-related bacteremia are recorded in a prospective database. QUALITY IMPROVEMENT PLAN: In conjunction with systemic antibiotic therapy (vancomycin for methicillin-resistant S aureus or cefazolin for methicillin-sensitive S aureus), an antibiotic lock was instilled into each catheter lumen after each dialysis session for 3 weeks. MEASURES: Treatment failure is defined as persistent fever after 48 hours of antibiotic therapy or recurrent S aureus bacteremia within 90 days. Clinical cure is defined as resolution of fever and no recurrence of bacteremia. Major infection-related complications within 6 months were documented. RESULTS: The catheter could not be salvaged in 67 patients (59%) because of persistent fever in 40 patients and recurrent bacteremia in 27 patients. A clinical cure was achieved in 46 patients (41%). A serious complication of catheter-related bacteremia occurred in 9.7% of all patients (11 of 113 patients). Serious complications were observed in 25% of patients (10 of 40 patients) with persistent fever, but only 1.4% of all other patients (1 of 73 patients; P < 0.0001). LIMITATIONS: This was a single-center study. Serum antibiotic levels were not measured. CONCLUSIONS: Routine antibiotic lock therapy is not appropriate for patients with S aureus catheter-related bacteremia. Serious complications occur primarily in patients with persistent fever. [Abstract]

Pham TP, Wilkinson AH, Pham TP
Evaluation of the potential living kidney donor.
Am J Kidney Dis. 2007 Dec;50(6):1043-51. [Abstract]

Chen N, Pan X, Xu Y, Wang Z, Shi H, Yan F, Dong X
Two brothers in one Chinese family with collagen type III glomerulopathy.
Am J Kidney Dis. 2007 Dec;50(6):1037-42. [Abstract]

Cotant CL, Rao PS
Elevated fibroblast growth factor 23 in a patient with metastatic prostate cancer and hypophosphatemia.
Am J Kidney Dis. 2007 Dec;50(6):1033-6. [Abstract]

Ahmed MS, Hou SH, Battaglia MC, Picken MM, Leehey DJ
Treatment of idiopathic membranous nephropathy with the herb Astragalus membranaceus.
Am J Kidney Dis. 2007 Dec;50(6):1028-32.
A 77-year-old woman with nephrotic syndrome secondary to idiopathic membranous nephropathy was treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, cyclosporine A, and mycophenolate mofetil, without response. After more than 2 years of unremitting nephrosis, she began therapy with the herb Astragalus membranaceus, used by traditional Chinese physicians to treat various immune disorders, including glomerulonephritis. After institution of Astragalus at a dose of 15 g/d, there was a marked decrease in proteinuria. Nephrotic syndrome recurred after temporary cessation of Astragalus therapy, with complete remission of nephrosis observed after its reintroduction. The clinical course of this patient suggests that Astragalus may have beneficial effects in patients with idiopathic membranous nephropathy. [Abstract]

Faguer S, Bouissou F, Dumazer P, Guitard J, Bellanné-Chantelot C, Chauveau D
Massively enlarged polycystic kidneys in monozygotic twins with TCF2/HNF-1beta (hepatocyte nuclear factor-1beta) heterozygous whole-gene deletion.
Am J Kidney Dis. 2007 Dec;50(6):1023-7.
TCF2, the gene encoding for hepatocyte nuclear factor 1beta, is involved in early renal development. Mutations in TCF2 lead to heterogeneous renal phenotypes. Antenatal ultrasonography may show unilateral/bilateral hyperechogenic or enlarged cystic kidneys. In children or adults, cystic renal hypoplasia/dysplasia is a common feature, occasionally associated with maturity-onset diabetes of the young type 5 and genital tract abnormalities. We report an unusual presentation characterized by massively enlarged polycystic kidneys mimicking autosomal dominant polycystic kidney disease in monozygotic twins. Bilateral enlarged cystic kidneys were discovered in week 13 of a gemellic pregnancy. Postnatally, kidney size increased in both children, reaching 16 cm at 20 years. Nephromegaly was associated with bilateral cysts and a slowly decreasing glomerular filtration rate (40 mL/min/1.73 m(2) at 20 years). There was neither pancreatic nor genital malformation. Non-type 1 diabetes mellitus was diagnosed incidentally in both twins at 20 years. Knowledge of early-onset diabetes (at age 19 years) in their father prompted us to search for the TCF2 mutation. Genetic analysis showed complete TCF2 heterozygous whole-gene deletion in both twins. Genetic testing could not be performed in the father. Bilateral massively enlarged polycystic kidneys mimicking autosomal dominant polycystic kidney disease in young adults may be related to TCF2 mutation. Although uncommon, this new phenotype enlarges the clinical spectrum of kidney involvement associated with TCF2 mutation. In this case, maturity-onset diabetes of the young-type diabetes paved the way to accurate diagnosis. [Abstract]

Koppelstaetter C, Peschel R, Glodny B, Riegler P, Passler W, Lhotta K
Fenestration of the Gerota's fascia as symptomatic treatment of floating kidneys.
Am J Kidney Dis. 2007 Dec;50(6):1020-2.
A 16-year-old man presented with severe nephrotic syndrome complicated by massive perirenal fluid. Percutaneous drainage of fluid was performed 3 times, followed by improvement in renal function and hypertension, but perirenal fluid recurred within days. Nephrotic syndrome was unresponsive to steroid therapy. A laparoscopic bilateral fenestration of Gerota's fascia and peritoneum allowed permanent drainage of fluid into the peritoneal cavity. During the same procedure, a renal wedge biopsy was performed. Histological examination showed advanced focal glomerular sclerosis of the tip lesion variant. The glomerular disease was refractory to further treatment with cyclophosphamide, mycophenolate, and rituximab. However, perirenal fluid did not recur despite persistent nephrotic syndrome, showing that fenestration of Gerota's fascia is a successful treatment of floating kidneys in such patients. [Abstract]

Satyan S, Light RP, Agarwal R
Relationships of N-terminal pro-B-natriuretic peptide and cardiac troponin T to left ventricular mass and function and mortality in asymptomatic hemodialysis patients.
Am J Kidney Dis. 2007 Dec;50(6):1009-19.
BACKGROUND: Although the cardiac biomarker troponin T (cTnT) is related strongly to mortality in patients with end-stage renal disease, the independent association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and cTnT levels in predicting outcomes is unknown. The objective of this study is to determine factors associated with NT-pro-BNP and cTnT and determine whether these levels are associated with mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Asymptomatic hemodialysis patients (n = 150) in 4 university-affiliated hemodialysis units. EXPOSURE & OUTCOMES: For cross-sectional analysis, echocardiographic variables as exposures and NT-pro-BNP and cTnT levels as outcomes; for longitudinal analysis, association of NT-pro-BNP and cTnT levels as exposures to all-cause and cardiovascular disease mortality as outcomes. RESULTS: In a multivariate regression analysis, low midwall fractional shortening, a measure of poor systolic function, was an independent correlate of log NT-pro-BNP level (P < 0.01), whereas left ventricular mass index was an independent correlate of cTnT level (P < 0.01). During a median follow-up of 24 months, 46 patients died, 26 of cardiovascular causes. NT-pro-BNP levels had a strong graded relationship with all-cause (hazard ratios [HRs], 1.54, 4.78, and 4.03 for increasing quartiles; P < 0.001) and cardiovascular mortality (HRs, 2.99, 10.95, and 8.54; P < 0.01), whereas cTnT level had a weaker relationship with all-cause (HRs, 1.57, 2.32, and 3.39; P < 0.01) and cardiovascular mortality (HRs, 0.81, 2.12, and 2.14; P = 0.1). The combination of the 2 biomarker levels did not improve the association with all-cause or cardiovascular mortality compared with NT-pro-BNP level alone. NT-pro-BNP level was a marker of mortality even after adjusting for left ventricular mass index and midwall fractional shortening. LIMITATIONS: Our cohort was predominantly black and of limited sample size. CONCLUSION: NT-pro-BNP level strongly correlates with left ventricular systolic dysfunction and is associated more strongly with mortality than cTnT level in asymptomatic hemodialysis patients. [Abstract]

Panuccio V, Cutrupi S, Pizzini P, Mallamaci F, Tripepi G, Zoccali C
Neuropeptide Y and markers of osteoblast activity in dialysis patients: a cross-sectional study.
Am J Kidney Dis. 2007 Dec;50(6):1001-8.
BACKGROUND: In mice, neuropeptide Y (NPY) decreases bone turnover by means of a parathyroid hormone-independent effect on osteoblast activity. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: We studied the relationship between levels of NPY and biomarkers of osteoblast activity in 161 nondiabetic patients with end-stage renal disease (131 patients, hemodialysis; 30 patients, continuous ambulatory peritoneal dialysis). PREDICTORS & OUTCOMES: We performed an analysis of demographic and clinical variables associated with NPY as a dependent variable and a second analysis testing the association of NPY (as an independent variable) with markers of osteoblast activity. RESULTS: Peritoneal dialysis as treatment modality (beta = 0.37; P < 0.001) and longer duration of dialysis therapy (beta = 0.24; P < 0.01) were independently related to plasma NPY. NPY level was related inversely (P < 0.001) to serum alkaline phosphatase and bone alkaline phosphatase levels (P = 0.01). The NPY-alkaline phosphatase link was confirmed in a multiple regression analysis adjusting for a series of potential confounders, including parathyroid hormone. In a categorical analysis in which the study population was divided according to NPY quartiles, the proportion of patients with low alkaline phosphatase levels was lowest in the first 2 NPY quartiles (26%) and highest in NPY quartile 4 (80%; P < 0.001), and this association held true in a multiple logistic regression analysis, indicating that the risk of low alkaline phosphatase level increases in parallel with NPY level. LIMITATIONS: The hypothesis generated by this cross-sectional study needs to be confirmed in cohort studies. CONCLUSIONS: The inverse relationships between levels of NPY and biomarkers of bone turnover support the hypothesis that NPY may be implicated in low bone turnover in dialysis patients by a central parathyroid-independent mechanism. [Abstract]

Klinger M, Arias M, Vargemezis V, Besarab A, Sulowicz W, Gerntholtz T, Ciechanowski K, Dougherty FC, Beyer U
Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial.
Am J Kidney Dis. 2007 Dec;50(6):989-1000.
BACKGROUND: C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients. STUDY DESIGN: Open-label, multicenter, randomized, parallel-group, phase 3 study. SETTING & PARTICIPANTS: Dialysis patients (age >or= 18 years). INTERVENTION: Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly. OUTCOMES & MEASUREMENTS: The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population. RESULTS: Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated. LIMITATIONS: Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin. CONCLUSIONS: Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients. [Abstract]

Wiggins KJ, Johnson DW, Craig JC, Strippoli GF
Treatment of peritoneal dialysis-associated peritonitis: a systematic review of randomized controlled trials.
Am J Kidney Dis. 2007 Dec;50(6):967-88.
BACKGROUND: Peritonitis frequently complicates peritoneal dialysis. Appropriate treatment is essential to reduce adverse outcomes. Available trial evidence about peritoneal dialysis peritonitis treatment was evaluated. SELECTION CRITERIA FOR STUDIES: The Cochrane CENTRAL Registry (2005 issue), MEDLINE (1966 to February 2006), EMBASE (1985 to February 2006), and reference lists were searched to identify randomized trials of treatments for patients with peritoneal dialysis peritonitis. INTERVENTIONS: Trials of antibiotics (comparisons of routes, agents, and dosing regimens), fibrinolytic agents, peritoneal lavage, and intraperitoneal immunoglobulin. OUTCOMES: Treatment failure, relapse, catheter removal, microbiological eradication, hospitalization, all-cause mortality, and adverse reactions. RESULTS: 36 eligible trials were identified: 30 trials (1,800 patients) of antibiotics; 4 trials (229 patients) of urokinase; 1 trial of peritoneal lavage (36 patients); and 1 trial of intraperitoneal immunoglobulin (24 patients). No superior antimicrobial class was identified. In particular, glycopeptides and first-generation cephalosporins were equivalent (3 trials, 387 patients; relative risk [RR], 1.84; 95% confidence interval [CI], 0.95 to 3.58). Simultaneous catheter removal/replacement was superior to urokinase at decreasing treatment failures (1 trial, 37 patients; RR, 2.35; 95% CI, 1.13 to 4.91). Continuous and intermittent intraperitoneal antibiotic dosing were equivalent regarding treatment failure (4 trials, 338 patients; RR, 0.69; 95% CI, 0.37 to 1.30) and relapse (4 trials, 324 patients; RR, 0.93; 95% CI, 0.63 to 1.39). One trial showed superiority of intraperitoneal antibiotics over intravenous therapy. LIMITATIONS: The method quality of trials generally was suboptimal and outcome definitions were inconsistent. Small patient numbers led to inadequate power to show an effect. Interventions, such as optimal duration of antibiotic therapy, were not evaluated. CONCLUSIONS: Trials did not identify superior antibiotic regimens. Intermittent and continuous antibiotic dosing are equivalent treatment strategies. [Abstract]

Fadrowski JJ, Frankenfield D, Amaral S, Brady T, Gorman GH, Warady B, Furth SL, Fivush B, Neu AM
Children on long-term dialysis in the United States: findings from the 2005 ESRD clinical performance measures project.
Am J Kidney Dis. 2007 Dec;50(6):958-66.
BACKGROUND: The Centers for Medicare & Medicaid Services End-Stage Renal Disease Clinical Performance Measures (CPM) Project contains one of the largest databases of prevalent pediatric dialysis patients in the United States. Since 2005, the CPM Project has included not only children on long-term hemodialysis (HD) therapy, but also those on long-term peritoneal dialysis (PD) therapy. This study describes demographic and clinical characteristics and compares them between patients on HD and PD therapy. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: Children aged 0 to younger than 18 years included within the 2005 End-Stage Renal Disease CPM Project. PREDICTOR: Demographic and clinical characteristics, with emphasis on dialysis modality. OUTCOMES & MEASUREMENTS: Achievement of values for hemoglobin, dialysis adequacy, and serum albumin as recommended by recent National Kidney Foundation-Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines and Recommendations. RESULTS: Of 1,453 patients examined, 692 received HD and 761 received PD. There was no significant difference by dialysis modality in the likelihood of having a mean hemoglobin level of 11 g/dL or greater; however, HD patients were significantly more likely to have a mean hemoglobin level less than 10 g/dL (19% versus 14% of PD patients; P = 0.02). Although statistically significant, the absolute difference in mean hemoglobin levels between patients receiving HD versus PD was small (11.4 versus 11.6 g/dL). Eighty-nine percent of patients receiving HD and 87% of patients receiving PD achieved the recommended modality-specific Kt/V (P = 0.4). Children receiving HD were more likely than those receiving PD to have a mean serum albumin level of 4.0/3.7 g/dL or greater (bromcresol green/bromcresol purple laboratory method): 46% versus 33% (P < 0.001). LIMITATIONS: Because of study design, only associations can be described. CONCLUSIONS: A significant number of children had hemoglobin, serum albumin, and/or Kt/V values outside the recommended targets. Future research is needed to better define the risk relationships of these predictors with morbidity and mortality in children on dialysis therapy, evaluate the benefit of treating to certain treatment targets, and understand reasons for failing to reach treatment targets in individual patients or patient groups. [Abstract]

Lindner G, Funk GC, Schwarz C, Kneidinger N, Kaider A, Schneeweiss B, Kramer L, Druml W
Hypernatremia in the critically ill is an independent risk factor for mortality.
Am J Kidney Dis. 2007 Dec;50(6):952-7.
BACKGROUND: Hypernatremia is common in the intensive care unit (ICU). We assessed the prevalence of hypernatremia and its impact on mortality and ICU length of stay (LOS). STUDY DESIGN: Retrospective analysis. SETTING & PARTICIPANTS: All patients admitted to a medical ICU of a university hospital during a 35-month observation period. PREDICTOR: Hypernatremia (serum sodium > 149 mmol/L) after admission to the ICU. OUTCOMES & MEASUREMENTS: Main outcomes were 28-day hospital mortality and ICU LOS. Demographic factors, main diagnosis, and severity of illness. Cox proportional hazards regression models were used for data analysis. RESULTS: Of 981 patients, 90 (9%) had hypernatremia, on admission to the ICU in 21 (2%) and developed during the ICU stay in 69 patients (7%). Of these 981 patients, 235 (24%) died; LOS was 8 +/- 9 (SD) days. Mortality rates were 39% and 43% in patients with hypernatremia on admission or that developed after admission compared with 24% in patients without hypernatremia (P < 0.01). LOS was 20 +/- 16 days in patients with hypernatremia compared with 8 +/- 10 days in patients without hypernatremia (P < 0.001). In multivariable analysis, hypernatremia was an independent risk factor for mortality (relative risk, 2.1; 95% confidence interval, 1.4 to 3.3). LIMITATIONS: Retrospective design, absence of data for long-term mortality. CONCLUSIONS: Most cases of hypernatremia in the ICU developed after admission, suggesting an iatrogenic component in its evolution. Hypernatremia is associated with increased mortality. Strategies for preventing hypernatremia in the ICU should be encouraged. [Abstract]

Sinsakul M, Sika M, Rodby R, Middleton J, Shyr Y, Chen H, Han E, Lehrich R, Clyne S, Schulman G, Harris R, Lewis J
A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease.
Am J Kidney Dis. 2007 Dec;50(6):946-51.
BACKGROUND: Preclinical data suggest that cyclooxygenase 2 inhibitors decrease proteinuria and preserve glomerular structure in animal models of diabetic nephropathy. The objective of this study is to compare the efficacy and safety of celecoxib with placebo for decreasing proteinuria in patients with diabetic nephropathy. STUDY DESIGN: Placebo-controlled double-blinded crossover design. SETTING & PARTICIPANTS: 24 patients with type 1 or 2 diabetes mellitus, proteinuria with protein of 500 mg/d or greater, and serum creatinine level of 3.0 mg/dL or less. INTERVENTION: Patients were randomly assigned to: (1) 6 weeks of celecoxib followed by a 3-week washout period, followed by 6 weeks of placebo followed by another 3-week washout; or (2) 6 weeks of placebo followed by a 3-week washout, followed by 6 weeks of celecoxib followed by another 3-week washout period. All patients were administered quinapril, 20 to 40 mg/d, or irbesartan, 150 to 300 mg/d. All patients were administered aspirin, 81 mg/d. OUTCOMES & MEASUREMENTS: Proteinuria was assessed by means of protein-creatinine ratio. Data were analyzed using the mixed-effect statistical model. RESULTS: There was no significant difference in urinary proteinuria after 6 weeks of treatment with placebo or celecoxib (proteinuria ratio, celecoxib versus placebo, 1.041; 95% confidence interval, 0.846 to 1.282). Celecoxib had no significant effect on potassium or estimated glomerular filtration rate. Frequencies of adverse events were similar between the placebo and celecoxib treatments. LIMITATIONS: This pilot study was not designed to evaluate the safety or long-term clinical effects of celecoxib. CONCLUSIONS: Celecoxib, 200 mg/d, for 6 weeks did not alter proteinuria. Few adverse events were noted in this high-risk population. [Abstract]

Trachtenberg F, Barregård L
The effect of age, sex, and race on urinary markers of kidney damage in children.
Am J Kidney Dis. 2007 Dec;50(6):938-45.
BACKGROUND: The aim of this study is to examine the effects of age, sex, and race on the excretion and concentrations of albumin, gamma-glutamyl transpeptidase (gamma-GT), N-acetyl-beta-d-glucosaminidase (NAG), alpha(1)-microglobulin (alpha1M), and creatinine in children. STUDY DESIGN: Secondary analysis of a clinical trial, The New England Children's Amalgam Trial, which examined effects of amalgam dental fillings. SETTING & PARTICIPANTS: 534 children aged 6 to 10 years at baseline were recruited from Boston, MA, and rural Maine. PREDICTORS: Age, sex, and race. OUTCOMES & MEASUREMENTS: Urine samples were collected annually for 5 years and analyzed for creatinine, albumin, gamma-GT, NAG, and alpha1M concentrations. Repeated-measures analysis of covariance was used to model effects of age, sex, and race on these values, as well as calculated excretion rates. RESULTS: All measures of creatinine and gamma-GT increased significantly with age. Albumin and gamma-GT concentration and excretion (milligrams per gram of creatinine or units per gram creatinine) were significantly greater for girls compared with boys. alpha1M concentration and creatinine excretion were greater for boys compared with girls. Creatinine concentration was significantly greater for blacks than for whites and Hispanics. Creatinine excretion and all gamma-GT levels were significantly greater for blacks and Hispanics compared with non-Hispanic whites. LIMITATIONS: The study population, recruited for a clinical trial, was of lower socioeconomic status than the general population. The high limit of detection for alpha1M resulted in a majority of samples less than the detection limit. CONCLUSIONS: We recommend considering age, sex, and race in the interpretation of urinary markers. It also is recommended that epidemiological studies and clinical trials account for age, sex, and race in statistical models comparing urinary markers of kidney damage. [Abstract]

Imai E, Horio M, Nitta K, Yamagata K, Iseki K, Tsukamoto Y, Ito S, Makino H, Hishida A, Matsuo S
Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan.
Am J Kidney Dis. 2007 Dec;50(6):927-37.
BACKGROUND: Glomerular filtration rate (GFR)-estimating equations based on serum creatinine level may not be accurate across racial groups because of differences among races in creatinine generation. The Modification of Diet in Renal Disease (MDRD) Study equation was developed in whites and African Americans, but performance was not evaluated in Japanese. STUDY DESIGN: Diagnostic test accuracy. Cross-sectional retrospective study of 3 patient groups. Equation development in 2 groups (n = 247 in 2002 to 2004; n = 214 in 2003 to 2004 with measured GFR <90 mL/min/1.73 m(2)); external validation in a separate group (n = 153 from 1988 to 1994). SETTING & PARTICIPANTS: Hospitalized Japanese patients with chronic kidney disease in 3 medical centers. REFERENCE TEST: Measured GFR (mGFR) computed from renal clearance of inulin. INDEX TEST: Estimated GFR (eGFR) using the isotope dilution mass spectrometry (IDMS)-traceable 4-variable MDRD Study equation, a modified IDMS MDRD Study equation with a Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) coefficient derived in the development data set, and a new equation derived by refitting coefficients in the MDRD Study equation in the development data set. MEASUREMENTS: Current creatinine assays were calibrated to standardized creatinine. Performance of equations was assessed as bias, accuracy, root-mean-squared error, and correlation coefficient of eGFR versus mGFR. RESULTS: In the development data set, eGFR using the IDMS MDRD Study equation overestimated mGFR throughout the entire range. In the validation data set, the IDMS MDRD Study equation with the JSN-CKDI coefficient 0.741 and the new equation (JSN-CKDI) performed with significantly less bias and greater accuracy than the IDMS MDRD Study equation, but were similar to each other in accuracy and bias in patients with eGFR less than 60 mL/min/1.73 m(2). In the combined development and validation data sets, the JSN-CKDI coefficient was 0.763 (95% confidence interval, 0.743 to 0.783). LIMITATIONS: Possible drift in creatinine assays over time, possible lower creatinine generation in hospitalized patients, exclusion of patients with higher GFR from the development data set. CONCLUSION: GFR estimates using the IDMS MDRD Study equation with the JSN-CKDI coefficient or the new JSN-CKDI equation are more accurate than the IDMS MDRD Study equation in hospitalized Japanese patients with eGFR less than 60 mL/min/1.73 m(2). More studies are necessary to verify the accuracy of the JSN-CKDI coefficient and JSN-CKDI equation in other settings in Japan and elsewhere in Asia. [Abstract]

Selvin E, Manzi J, Stevens LA, Van Lente F, Lacher DA, Levey AS, Coresh J
Calibration of serum creatinine in the National Health and Nutrition Examination Surveys (NHANES) 1988-1994, 1999-2004.
Am J Kidney Dis. 2007 Dec;50(6):918-26.
BACKGROUND: The calibration of serum creatinine values to standardized creatinine and the commutability of serum creatinine across surveys are essential to the correct use of National Health and Nutrition Examination Survey (NHANES) data for kidney function and for generating estimates of the burden of kidney disease in the United States. STUDY DESIGN: Calibration study of serum creatinine in NHANES III (1988-1994) and NHANES 1999-2000, 2001-2002, and 2003-2004 to directly compare creatinine measurements from the original surveys with standard creatinine measured using an assay traceable to known gold-standard methods. We also assessed predictors of differences between methods (potential interferences) in this general population. SETTING & PARTICIPANTS: The NHANES are ongoing cross-sectional surveys of the civilian noninstitutionalized population of the United States. We selected random samples of approximately 200 stored specimens from persons aged 60 years or older from each survey (NHANES III, 1999-2000, 2001-2002, and 2003-2004). MEASUREMENTS: Stored serum specimens from the 4 NHANES surveys were analyzed for serum creatinine by using a Roche enzymatic assay implemented at the Cleveland Clinic Research Laboratory (CCRL). The Roche assay is traceable to gold-standard reference methods. The original NHANES serum creatinine values were obtained using the Jaffé method (kinetic alkaline picrate) implemented in several different laboratories. RESULTS: Overall agreement between the original NHANES values (Jaffé method) and CCRL measurements (Roche enzymatic) was high, but substantial biases were observed in NHANES III and 1999-2000. No bias was observed in NHANES 2001-2002 and 2003-2004. Final calibration equations to correct serum creatinine values in the relevant surveys are provided. Assay differences were independent of sex, race/ethnicity, and bilirubin and triglyceride levels, but weakly related to age and glucose concentration. LIMITATIONS: We were not able to examine drift in measurements over time within each survey or directly evaluate freeze-thaw effects. CONCLUSIONS: The magnitude of differences in serum creatinine measurements in NHANES III and 1999-2000 from standard creatinine would result in large differences in estimates of kidney function (10% to 20%). Thus, correction of original creatinine values in NHANES III and 1999-2000 is essential, but no correction is needed for NHANES 2001-2002 or 2003-2004. [Abstract]

Minutolo R, Gabbai FB, Borrelli S, Scigliano R, Trucillo P, Baldanza D, Laurino S, Mascia S, Conte G, De Nicola L
Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8-week uncontrolled trial.
Am J Kidney Dis. 2007 Dec;50(6):908-17.
BACKGROUND: Nondipping status is associated with greater cardiovascular morbidity and mortality and faster progression of chronic kidney disease (CKD). We examined whether shifting 1 antihypertensive drug from morning to evening restores the circadian rhythm of blood pressure in nondipper patients with CKD. STUDY DESIGN: 8-week clinical trial without a control group. SETTING & PARTICIPANTS: We selected from our outpatient renal clinic 32 patients with CKD with estimated glomerular filtration rate less than 90 mL/min/1.73 m(2) and night-day ratio of mean ambulatory blood pressure (ABP) greater than 0.9, but with normal daytime ABP (<135/85 mm Hg) to avoid the required therapy intensification. INTERVENTION: Shifting 1 antihypertensive drug from morning to evening. OUTCOMES: Percentage of patients changing the night-day ratio of mean ABP from greater than 0.9 to 0.9 or less 8 weeks after the shift. MEASUREMENTS: Office blood pressure/ABP and proteinuria at baseline and after the shift. RESULTS: There were 55% men with a mean age of 67.4 +/- 11.3 years and estimated glomerular filtration rate of 46 +/- 12 mL/min/1.73 m(2). They were treated with 2.4 +/- 1.4 antihypertensive drugs. After the drug shift, the night-day ratio of mean ABP decreased in 93.7% of patients, with normal circadian rhythm restored in 87.5%. The nocturnal systolic and diastolic ABP decrease was not associated with an increase in diurnal ABP and was independent from number and class of shifted drug. Office blood pressure in the morning also decreased (from 136 +/- 16/77 +/- 10 to 131 +/- 13/75 +/- 8 mm Hg; P = 0.02). Urinary protein excretion decreased from 235 +/- 259 to 167 +/- 206 mg/d (P < 0.001). LIMITATIONS: Absence of a control group and patients with severe proteinuria or uncontrolled daytime ABP. CONCLUSIONS: In nondipper patients with CKD, changing the timing of antihypertensive therapy decreases nocturnal blood pressure and proteinuria. [Abstract]

Rahman M, Appel LJ
Should reducing nocturnal blood pressure be a therapeutic target in CKD? The time is ripe for a clinical outcomes trial.
Am J Kidney Dis. 2007 Dec;50(6):901-3. [Abstract]

Greenberg A
Tolvaptan, an oral vasopressin V2 receptor antagonist for heart failure?
Am J Kidney Dis. 2007 Dec;50(6):904-7. [Abstract]

Schultheiss UT, Göbel H, von Gersdorff G, Stubanus M, Walz G, Gerke P
Quiz page December 2007: diarrhea and anuria in a recipient of an en bloc infant kidney transplant.
Am J Kidney Dis. 2007 Dec;50(6):A41-3. [Abstract]

Bunnapradist S, Danovitch GM
Evaluation of adult kidney transplant candidates.
Am J Kidney Dis. 2007 Nov;50(5):890-8. [Abstract]

Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB, Graves E, Byron D, Cook WJ
Acute renal failure due to a primary renal B-cell lymphoma.
Am J Kidney Dis. 2007 Nov;50(5):885-9. [Abstract]

Trebbin W, Monteleone P
Dialysis in Africa: a personal perspective on a demonstration project in Cameroon.
Am J Kidney Dis. 2007 Nov;50(5):880-4.
Despite belief to the contrary, technologically sophisticated medical care can be established in developing countries. The process requires intense effort. Preliminary work must include resolving ethical dilemmas, acquiring adequate funding, establishing supply lines, and cultivating proper political support within the host country. Our organization, WORTH (World Organization of Renal Therapies) has successfully launched and is maintaining a dialysis unit in the sub-Saharan African country of Cameroon. So far our complications rate has been trivial, and our metrics indicate that we are successfully delivering safe, effective treatment that can preserve the lives of people with end-stage renal disease in a part of the world where medical care is laboring under difficult conditions. Work is about to begin in establishing a second dialysis unit in that country. We try here to delineate our experience, and we offer a direct challenge to other nephrologists to be activists in delivering modern, advanced technology medicine to more challenging places than those where it is currently flourishing. [Abstract]

Lubowsky ND, Siegel R, Pittas AG
Management of glycemia in patients with diabetes mellitus and CKD.
Am J Kidney Dis. 2007 Nov;50(5):865-79. [Abstract]

Mistry K, Ireland JH, Ng RC, Henderson JM, Pollak MR
Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis.
Am J Kidney Dis. 2007 Nov;50(5):855-64.
Nephronophthisis is a form of autosomal recessive hereditary cystic kidney disease that typically progresses to end-stage renal disease by early adulthood. Conversely, focal segmental glomerulosclerosis is a histological glomerular phenotype that can be familial, primary (idiopathic), or secondary to a multitude of pathological processes affecting the kidney, including such tubulointerstitial diseases as nephronophthisis. Mutations in 6 distinct nephronophthisis genes have been described to date. We describe a consanguineous Filipino family with 2 novel sequence variants in the NPHP4 gene. Affected individuals presented with end-stage renal disease and histological features of focal segmental glomerulosclerosis on biopsy. They also had atypical radiological findings, making the clinical diagnosis of the genetic syndrome difficult. Furthermore, although ocular abnormalities and hearing loss were described previously, this is the first report of hepatic disease in patients with mutations in NPHP4. The diagnosis of nephronophthisis was made by means of mutational analysis of the NPHP4 gene after isolation of a region of homozygosity in affected individuals by using whole-genome single-nucleotide polymorphism analysis. Because establishment of the correct diagnosis has implications for therapeutic interventions, prognosis, and, in the case of heritable diseases, appropriate genetic counseling for affected individuals and their families, this report emphasizes the importance of obtaining meticulous clinical information, considering alternative diagnoses, and, when possible, performing genetic evaluation to confirm the diagnosis. We outline an approach to patients with hereditary kidney disease, focusing specifically on the molecular genetic techniques available to evaluate such families and determine a chromosomal region of interest and, subsequently, the diagnosis. [Abstract]

Sajjad I, Baines LS, Salifu M, Jindal RM
The dynamics of recipient-donor relationships in living kidney transplantation.
Am J Kidney Dis. 2007 Nov;50(5):834-54.
Psychosocial issues in kidney transplant donors and recipients are a cause for concern. We reviewed studies that investigated psychosocial issues in donors and recipients of living kidney transplants. A variety of instruments were used for this purpose. However, there was a lack of consensus regarding the structure and method of psychosocial assessment in living kidney donors. We found that only a few centers currently carry out a systematic psychosocial follow-up of recipients and their donors. The majority of psychosocial studies were of living kidney donors, indicating a preference of researchers to study psychosocial issues in live kidney donors. We believe living kidney transplant recipients are also an important group, and more studies should be done to better understand the psychosocial issues in this group. The majority of studies were retrospective in nature. We also discuss relationships, interactions, and communication patterns that characterize living kidney donation. We place emphasis on understanding the relational history of donors and recipients to provide supportive intervention and enable the potential donor make an informed decision about surgery. We recommend comprehensive psychosocial screening before and after transplantation and donation. This may decrease psychological problems and increase satisfaction with the transplantation process. Furthermore, the transplant community will need to address the type of instruments, duration of follow-up, and funding sources to carry out our recommendations. [Abstract]

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Recent Articles in The Prostate

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Mehrotra J, Varde S, Wang H, Chiu H, Vargo J, Gray K, Nagle RB, Neri JR, Mazumder A
Quantitative, spatial resolution of the epigenetic field effect in prostate cancer.
Prostate. 2007 Nov 30;
BACKGROUND: Although a field effect in which transformed cells extend beyond morphologically evident tumor has been proposed in cancer, little direct evidence exists as to its magnitude and spatial resolution. We tested this hypothesis using molecular techniques to detect epigenetic changes in the primary tumor and surrounding tissues. METHODS: Ex vivo core biopsies, each spaced approximately 1 mm apart, were generated from 37 unique prostatectomy samples. The first core biopsy was confirmed to be histologically positive for cancer, and the subsequent biopsies were confirmed to be histologically negative. The methylation ratio of GSTP1, APC, RARbeta2, and RASSF1A were measured for all of the 159 cores. RESULTS: No field effect, defined as absence of epigenetically transformed cells, for GSTP1 was observed whereas APC, RARbeta2, and RASSF1A showed a field effect up to 3 mm from the malignant core in three prostatectomy samples. Furthermore, for each case, different patterns of the field effect were observed. The field effect appeared most pronounced with RARbeta2. In 11 prostatectomy samples in which a second focus of cancer was identified, cells harboring RARbeta2 methylation extended a large distance away from the primary tumor in one sample. Bisulfite sequencing of RARbeta2 confirmed the presence of epigenetic aberrations. CONCLUSIONS: This study quantifies previous observations of methylation in histologically negative samples and provides important assessment of field effects based on epigenetic events in cancer. These molecular approaches set the stage for consideration of such data in prospective trials for assessment of surgical margins and prediction of recurrence. Prostate (c) 2007 Wiley-Liss, Inc. [Abstract]

Wolf P, Alt K, Bühler P, Katzenwadel A, Wetterauer U, Tacke M, Elsässer-Beile U
Anti-PSMA immunotoxin as novel treatment for prostate cancer? High and specific antitumor activity on human prostate xenograft tumors in SCID mice.
Prostate. 2007 Nov 28;
BACKGROUND: Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo. METHODS: The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts. RESULTS: In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC(50) value = 220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected. CONCLUSIONS: A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer. Prostate (c) 2007 Wiley-Liss, Inc. [Abstract]

Moore ML, Teitell MA, Kim Y, Watabe T, Reiter RE, Witte ON, Dubey P
Deletion of PSCA increases metastasis of TRAMP-Induced prostate tumors without altering primary tumor formation.
Prostate. 2007 Nov 28;
BACKGROUND: Prostate stem cell antigen (PSCA) is expressed in normal epithelium of various tissues, in embryos and adult animals. PSCA expression is upregulated in up to 70% of prostate tumors and metastases, and a subset of bladder and pancreatic cancers. However, its function is unknown. We studied the effect of targeted gene deletion of PSCA on normal organ development and prostate carcinogenesis. METHODS: PSCA +/+, PSCA +/-, and PSCA -/- mice were bred and aged to 22 months. A cohort of animals was treated with gamma-irradiation at 2 and 6 months of age. PSCA knockout mice were crossed to TRAMP mice and TRAMP+ PSCA +/+, TRAMP+ PSCA +/-, and TRAMP+ PSCA -/- mice and offspring aged to 10 months of age. Tissues were analyzed by RT-PCR, histology, and immunohistochemistry for markers of proliferation, apoptosis, angiogenesis, and tumor progression. RESULTS: PSCA knockout animals were viable, fertile and indistinguishable from wild-type littermates. Spontaneous or radiation-induced primary epithelial tumor formation was also similar in wild-type and PSCA knockout mice. We observed an increased frequency of metastasis in TRAMP+ PSCA heterozygous and knockout mice, compared to TRAMP+ wild-type mice. Metastases were largely negative for PSCA and androgen receptor. Cleaved-caspase 3 and CD31 staining was similar in all genotypes. Aurora-A and Aurora-B kinases were detected in the cytoplasm of PSCA heterozygous and knockout tumors, suggesting aberrant kinase function. CONCLUSION: These data suggest that PSCA may play a role in limiting tumor progression in certain contexts, and deletion of PSCA may promote tumor migration and metastasis. Prostate (c) 2007 Wiley-Liss, Inc. [Abstract]

van Wijngaarden E, Singer EA, Palapattu GS
Prostate-specific antigen levels in relation to cadmium exposure and zinc intake: results from the 2001-2002 national health and nutrition examination survey.
Prostate. 2007 Nov 28;
BACKGROUND: Cadmium exposure has been suggested as a risk factor for prostate cancer, and experimental literature suggests that the carcinogenic effect of cadmium is modified by the presence of zinc. We evaluated total prostate-specific antigen (PSA) levels in relation to urinary cadmium concentrations and dietary zinc intake. METHODS: PSA levels were determined in 1,320 men over the age of 40 in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Urinary cadmium concentrations were measured in about one-third of the sample population, whereas dietary zinc intake was based on participants' 24-hr recall. Information on all three variables was available for 422 men in the 2001-2002 NHANES survey. We performed linear regressions to evaluate the relationships these factors after accounting for age and other covariates. RESULTS: Little evidence for an association between cadmium and elevated PSA level was observed. However, the data provide suggestive evidence for an interaction between zinc intake and cadmium exposure (P for interaction = 0.09). Among men with zinc intake less than the median level of 12.67 mg/day, an increase in 1 microg/g creatinine cadmium exposure was associated with a 35% increase in PSA level. In contrast, among men with greater than median zinc intake, little evidence for an association between cadmium and PSA was found. CONCLUSIONS: These findings suggest a protective effect of zinc intake on cadmium-induced prostatic injury, and may provide further rationale for investigating the impact of these factors individually and jointly on the etiology of prostate cancer. Prostate (c) 2007 Wiley-Liss, Inc. [Abstract]

Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC
RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes.
Prostate. 2008 Jan 1;68(1):92-104.
BACKGROUND: Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kappaB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells. METHODS: Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro. RESULTS: OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix. CONCLUSION: These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner. Prostate 68: 92-104, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Chiu FL, Lin JK
Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts.
Prostate. 2008 Jan 1;68(1):61-71.
BACKGROUND: Androgen receptor (ARs) play a crucial role in the development and progression of prostate cancer. Recent studies have suggested that prostate cancer cell proliferation is inhibited by AR downregulation. Our aim was to investigate how luteolin, a natural flavonoid, affects cell growth and AR expression in prostate cancer cells and xenografts. METHODS: We assessed prostate cancer cell (LNCaP, DU145, and PC-3) proliferation and apoptosis by MTT assay, flow cytometric analysis, and Western analysis. AR function was measured by evaluating the AR target molecule, prostate-specific antigen (PSA), by RT-PCR, Western blotting, and enzyme-linked immunosorbent assay. We determined the mechanism of AR downregulation with cycloheximide chase assays, proteasome inhibitor, and coimmunoprecipitation experiments. The effects of luteolin on growth inhibition in vivo were examined by LNCaP xenografts in SCID mice. RESULTS: Luteolin significantly repressed prostate cancer cell proliferation and induced apoptosis in LNCaP cells. PC-3 and DU145 cells were less susceptible to luteolin-mediated growth inhibition. Luteolin simultaneously suppressed intracellular and secreted PSA levels and repressed AR mRNA and protein expression in a dose- and time-dependent manner. Luteolin reduced the association between AR and heat-shock protein 90, causing AR degradation through a proteasome-mediated pathway in a ligand-independent manner. Luteolin also suppressed LNCaP xenograft tumor growth in SCID mice. CONCLUSION: Luteolin-mediated AR downregulation contributes to the inhibition of cell proliferation and the induction of apoptosis in LNCaP human prostate cancer cells, suggesting that AR is a molecular target for luteolin-mediated anticancer activity. Luteolin may act as a chemopreventive or chemotherapeutic agent for prostate cancer. Prostate 68: 61-71, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Merseburger AS, Kramer MW, Hennenlotter J, Simon P, Knapp J, Hartmann JT, Stenzl A, Serth J, Kuczyk MA
Involvement of decreased Galectin-3 expression in the pathogenesis and progression of prostate cancer.
Prostate. 2008 Jan 1;68(1):72-7.
BACKGROUND: Altered expression or loss of function of Galectin-3 (Gal-3) was suggested to be involved in the pathogenesis and progression of various human cancer entities. The aim of the present study is to determine the expression of Gal-3 in prostate tissue emerging from a benign to a malignant, in the beginning hormone-sensitive and finally hormone-refractory status to further elucidate the role of this carbohydrate-binding protein for the pathogenesis and/or progression of malignant prostatic disease. MATERIALS AND METHODS: Five hundred and eighty three tissue samples from malignant, tumor adjacent benign, and histologically benign intra-prostatic areas, retrieved out of 25 whole mounted prostate cancer (CaP) specimens and additional 95 samples of hormone-refractory CaP, were processed to tissue microarrays. Immunohistochemical Gal-3 expression was correlated with clinicopathological parameters among the different tissue entities. RESULTS: Gal-3 expression was significantly decreased in the hormone-sensitive CaP specimens when compared with the respective benign tissue either localized far distant from the malignant lesion (P < 0.0001, Wilcoxon test) or directly neighboring the primary tumor (P < 0.0001). The staining reaction in the benign tissue areas directly neighboring the primary cancerous lesions differed significantly from the benign glands localized distant from the primary tumors (P < 0.001). A statistically highly significant, almost complete loss of Gal-3 was observed in the hormone-refractory when compared with the hormone-sensitive tumors (P < 0.0001; mean staining score: 27.7% vs. 8.5%). CONCLUSIONS: The present investigation clearly indicates decreased expression of Gal-3 to be substantially involved in the pathogenesis and further progression of CaP from benign prostate glands to a finally hormone-refractory malignant disease. Prostate 68: 72-77, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Saha B, Arase A, Imam SS, Tsao-Wei D, Naritoku WY, Groshen S, Jones LW, Imam SA
Overexpression of E-cadherin and beta-Catenin proteins in metastatic prostate cancer cells in bone.
Prostate. 2008 Jan 1;68(1):78-84.
BACKGROUND: The expression of E-cadherin in the intercellular adhesion of metastatic prostate cancer cells in bone, which is the most prevalent site of metastatic growth, remains elusive. METHODS: The aim of the study was to compare the concurrent membranous expression of E-cadherin and beta-catenin proteins, the state which is known to be associated with the cellular adhesion function of E-cadherin, in prostate biopsy tissue specimens by immunohistochemical staining method. The expression patterns of E-cadherin or beta-catenin were classified as homogeneous (most cells exhibiting positively), heterogeneous (a few scattered patches of cells with positivity) or negative. RESULTS: Benign prostate hyperplasia cells exhibited homogeneous expression of both E-cadherin and beta-catenin in 9 of 11 (82%), whereas the primary prostate cancer cells were homogeneously positive for both proteins only in 4 of 22 (18%) of the cases. The results are similar to those reported in literature. However, in contrast to the primary cancer, a significantly increased frequency of the metastatic prostate cancer cells in bone exhibited homogeneous expression of E-cadherin and beta-catenin in 12 of 17 (71%) of the cases. A statistically significant association was observed between the overexpression of both proteins and the metastatic prostate cancer cells in bone (Fisher's exact P < 0.001). CONCLUSIONS: The result of the study demonstrated for the first time that the membranous overexpression of E-cadherin and beta-catenin are significantly associated with the metastatic prostate cancer cells in bone and that the high frequency of expression suggest their involvement in the intercellular adhesion of the metastatic cells in bone. Prostate 68: 78-84, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Lee SO, Pinder E, Chun JY, Lou W, Sun M, Gao AC
Interleukin-4 stimulates androgen-independent growth in LNCaP human prostate cancer cells.
Prostate. 2008 Jan 1;68(1):85-91.
BACKGROUND: Clinical data showed that the levels of interleukin-4 (IL-4) are significantly elevated in serum of patients with ablation resistant prostate cancer. Previous studies demonstrated that IL-4 enhances androgen receptor (AR) activation mediated by NF-kappaB in the absence or in the very low levels of androgen in prostate cancer cells. In this study, the role of IL-4 in promoting the growth of androgen-independent prostate cancer cells was examined. METHODS: LNCaP cells were transfected with a full-length IL-4 cDNA and stable clones expressing IL-4 were selected. The growth of LNCaP cells expressing IL-4 was analyzed in vitro and in vivo both in the presence and absence of androgen. RESULTS: Overexpression of IL-4 enhances the growth of androgen-sensitive LNCaP cells in culture media containing charcoal-stripped FBS condition (CS-FBC), and increases the sensitivity of LNCaP cells in response to androgen stimulation. The DHT-mediated cell growth could not be blocked by bicalutamide in IL-4 overexpressing LNCaP cells, but can be neutralized by bicalutamide in parental LNCaP and neo control cells. Furthermore, overexpression of IL-4 stimulates tumor growth of androgen-sensitive LNCaP cells both in intact and castrated male mice. CONCLUSIONS: Overexpression of IL-4 increases the sensitivity of androgen-sensitive LNCaP prostate cancer cells in response to androgen stimulation and enhances the growth of LNCaP cells both in the presence and absence of androgen in vitro and in vivo. These studies suggest that IL-4 plays an important role in promoting androgen-independent prostate cancer growth. Prostate 68: 85-91, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Higuchi T, Nakamura M, Shimada K, Ishida E, Hirao K, Konishi N
HRK inactivation associated with promoter methylation and LOH in prostate cancer.
Prostate. 2008 Jan 1;68(1):105-13.
OBJECTIVES: Recent studies in selected human tumors have demonstrated reduced expression of HRK with hypermethylation. Because no similar study has been performed specifically in prostatic lesions, we examined whether the methylation status of HRK is altered in prostate cancers. METHODS: We chose to analyze the hypermethylation status of HRK, the expression of HRK protein and mRNA with 12q13.1 loss of heterozygosity (LOH) and with p53 mutation, and lesion apoptotic indices as determined by transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end-labeling (TUNEL) assays in 53 prostate cancers. RESULTS: Twenty of the 53 prostate cancers (38%) demonstrated hypermethylation in either the promoter or in exon 1 and, more significantly, the loss of HRK expression observed in 14 cancers by immunohistochemistry (IHC) was associated with promoter methylation. In addition, high apoptotic indices in tumors were related to positive HRK expression. Prostate cancers demonstrating HRK methylation also showed methylation of multiple other genes, such as p14(ARF), p16(INK4a), O(6)-MGMT, and GTS-P, but, with the exception of one case, p53 mutations were not detected. When compared to tumors having a Gleason score (GS) of 5-6, a significant difference in the apoptotic indices was found among prostate cancers of GS 7 (P < 0.001) or GS 8-9 (P = 0.007). We also detected a close correlation between the loss of HRK expression and decreased apoptosis in GS 5-6 and GS 7 tumors (P = 0.008, P < 0.001, respectively). CONCLUSIONS: HRK appears to be inactivated principally by promoter hypermethylation in prostate cancers. We further suggest that the decreased expression of HRK may play an important role in tumor progression by modulating apoptotic cell death. Prostate 68: 105-113, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Assinder SJ
Oxytocin increases 5alpha-reductase activity of human prostate epithelial cells, but not stromal cells.
Prostate. 2007 Nov 15;
BACKGROUND: Oxytocin is known to modulate 5-alpha-reductase expression and has, therefore, been implicated in the etiology and novel pharmacological treatments of benign prostatic hyperplasia (BPH). These suggestions have been made in the absence of any direct evidence that oxytocin regulates expression or activity of 5-alpha-reductase isoenzymes in the human prostate. This study evaluated the effects of oxytocin on the activity and expression of 5-alpha-reductase isoenzymes I and II of human prostate stromal (PrSC; primary site of BPH development) and epithelial (PrEC) cells. METHODS: Cell cultures were incubated with oxytocin, or oxytocin plus a specific oxytocin antagonist for 24 hr, and conversion of (3)H-Testosterone to dihydrotestosterone used to estimate total 5-alpha-reductase activity and to determine activity of both type I and type II isoenzymes. Fully quantitative real-time RT-PCR determined levels of expression of both isoenzymes following treatments. RESULTS: Oxytocin significantly increased the total 5-alpha-reductase activity of PrEC but not of PrSC. 5-alpha-Reductase I gene expression and enzyme activity were also increased (P < 0.05) in PrEC by oxytocin. Oxytocin significantly increased type II activity, but not expression, in PrEC. Oxytocin did not significantly affect 5-alpha-reductase activity or expression in PrSC. CONCLUSION: Both 5-alpha-reductase I and II are expressed in normal human prostate stromal and epithelial cells. Only 5-alpha-reductase isoenzymes of prostate epithelium are modulated by oxytocin. Prostate (c) 2007 Wiley-Liss, Inc. [Abstract]

Vykhovanets EV, Shukla S, Maclennan GT, Resnick MI, Carlsen H, Blomhoff R, Gupta S
Molecular imaging of NF-kappaB in prostate tissue after systemic administration of IL-1beta.
Prostate. 2008 Jan 1;68(1):34-41.
BACKGROUND: Activation of nuclear-factor kappaB (NF-kappaB) influences the transcription of number of genes, many of which participate in inflammatory responses and tumor development. A wide range of human cancers and inflammatory disorders express inappropriate regulation of NF-kappaB. The role of NF-kappaB in intraprostatic inflammation has not been elucidated. METHODS: Using transgenic NF-kappaB-Luciferase Tag mice coupled to the luciferase reporter gene, we performed serial, noninvasive in vivo and ex vivo molecular imaging of NF-kappaB activation in the mouse body after systemic administration of mouse pro-inflammatory cytokines: TNF-alpha, IL-6, and IL-1beta at 10 microg/kg body weights. In some experiments, pretreatment with dexamethasone (10 mg/kg) was used to modulate the cytokine-induced NF-kappaB-dependent luminescence in vivo. RESULTS: Treatment of NF-kappaB-Luc mice with cytokines increased luminescence in a time- and organ- specific manner. Highest levels of NF-kappaB-dependent luminescence were observed approximately 3-4 hr after IL-1beta administration. An important finding was the cumulative effect of IL-1beta to activate NF-kappaB in the prostate during chronic administration. CONCLUSIONS: The molecular imaging of NF-kappaB activity might be an attractive approach to distinguish the role of cytokine-induced NF-kappaB signaling in intraprostatic inflammation and prostate cancer development. Since dexamethasone, a known NF-kappaB inhibitor, could reduce the IL-1beta-induced NF-kappaB-dependent luminescence in the prostate, NF-kappaB-Luc mice might be useful tool to screen potential candidate drugs for treatment of inflammation and tumor associated with aberrant NF-kappaB activity. Prostate 68: 34-41, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Ellinger J, Haan K, Heukamp LC, Kahl P, Büttner R, Müller SC, von Ruecker A, Bastian PJ
CpG Island hypermethylation in cell-free serum DNA identifies patients with localized prostate cancer.
Prostate. 2008 Jan 1;68(1):42-9.
BACKGROUND: One of the earliest and most common epigenetic events in prostate carcinogenesis is DNA CpG island (CGI) hypermethylation. Our aim was to analyze the diagnostic and prognostic possibilities of multigene methylation analysis in cell-free serum DNA of prostate cancer (PCA) patients. METHODS: We analyzed serum samples from 226 consecutive patients (168 PCA; 42 benign prostatic hyperplasia (BPH); 5 incidental PCA; 11 healthy individuals). Cell-free DNA was digested with methylation-sensitive restriction endonucleases (HpaII and HinP1I). Subsequently, CGI hypermethylation at GSTP1, PTGS2, Reprimo, and TIG1 was assessed using real-time PCR. RESULTS: CGI hypermethylation at GSTP1, TIG1, PTGS2, and Reprimo was more frequent in PCA (42.3%, 9.5%, 2.4%, and 1.2%, respectively) compared to BPH (7.7%, 0%, 0%, and 0%, respectively) and healthy individuals (all 0%) with a statistical significant difference of GSTP1 (P < 0.0001) and TIG1 (P = 0.038). GSTP1 hypermethylation was also detected in four patients with incidental PCA. Hypermethylation in serum DNA at GSTP1 and hypermethylation at any gene site distinguished between PCA and BPH patients in a highly specific (92%) but less sensitive (42-47%) manner. Neither CGI hypermethylation at a single gene loci nor the combination of multiple gene sites was correlated to the pathological stage, grade or biochemical recurrence following radical prostatectomy. CONCLUSIONS: The detection of aberrant hypermethylation in cell-free serum DNA allows the highly specific diagnosis of PCA. A test based on GSTP1 hypermethylation in serum samples of patients with suspected PCA may help to identify men with increased risk of harboring PCA despite negative prostate biopsy. Prostate 68: 42-49, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Gupta A, Wang Y, Browne C, Kim S, Case T, Paul M, Wills ML, Matusik RJ
Neuroendocrine differentiation in the 12T-10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells.
Prostate. 2008 Jan 1;68(1):50-60.
BACKGROUND: Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy. METHODS: To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of beta-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10). RESULTS: Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic beta-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2. CONCLUSIONS: These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes that are required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic beta-cell differentiation is involved in NE differentiation of prostate cancer. Prostate 68: 50-60, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Locke JA, Wasan KM, Nelson CC, Guns ES, Leon CG
Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A: Cholesterol Acyltransferase (ACAT).
Prostate. 2008 Jan 1;68(1):20-33.
BACKGROUND: The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification in androgen-sensitive (AS) prostate cancer (LNCaP) cells. METHODS: We investigated the activity and expression of cholesterol metabolism enzymes, HMG-CoA-reductase and ACAT in the LNCaP and PC-3 (androgen-independent control) models. RESULTS: Microsomal PC-3 HMG-CoA-reductase activity was increased with R1881 despite having similar cholesterol levels while increased cholesterol levels in microsomes from LNCaPs treated with R1881 (L+) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (L+) were not associated with an increased ACAT1 activity. There was no effect from androgen treatment on ACAT1 protein expression in theses cells; however, ACAT2 expression was induced upon R1881 treatment. In contrast, we found an increase in the in vitro ACAT1 activity in PC-3 cells treated with androgen (P+). Only ACAT1 expression was induced in P+. We further assessed the expression of STAT1alpha, a transcriptional activator that modulates ACAT1 expression. STAT1alpha expression and phosphorylation were induced in P+. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PAR+). AR expression was decreased in PAR+ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1alpha expression was decreased in PAR+. CONCLUSIONS: Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1alpha in prostate cancer metabolism. Prostate 68: 20-33, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB
Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis.
Prostate. 2008 Jan 1;68(1):11-9.
BACKGROUND: Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model. METHODS: Seventy-five male SCID mice were fed a NCKD (84% fat-0% carbohydrate-16% protein kcal), low-fat (12% fat-72% carbohydrate-16% protein kcal), or Western diet (40% fat-44% carbohydrate-16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm(3). RESULTS: Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice. Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms. CONCLUSIONS: In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet. Prostate 68: 11-19, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Ebelt K, Babaryka G, Figel AM, Pohla H, Buchner A, Stief CG, Eisenmenger W, Kirchner T, Schendel DJ, Noessner E
Dominance of CD4(+) lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma.
Prostate. 2008 Jan 1;68(1):1-10.
BACKGROUND: Prostate cancer is the most common cancer of men in the Western world. Despite the over-expression of tumor-associated antigens, like PSA or PSMA, immune activation is inefficient. The goal of this investigation was to assess in situ characteristics of prostate cancer-infiltrating lymphocytes and to determine their activation status and effector function. METHODS: We compared 17 carcinoma containing tissues, four benign prostatic hyperplasia tissues and eight healthy prostate tissues regarding lymphocyte subset composition, locoregional distribution, and functional status using immunohistological staining of cryopreserved tissues. For determination of lymphocyte subsets, serial sections were stained with CD3, CD4, and CD8 antibodies. Activation status and effector function were studied using CD69, interferon-gamma (IFNgamma), perforin, and CD3 zeta chain antibodies. T-cell-receptor repertoire (TCR) analysis was made to determine the complexity of infiltrating lymphocytes. RESULTS: CD3(+), CD4(+), and CD69(+) T lymphocytes were prominent in tissues derived from patients with prostate carcinoma. CD8(+) lymphocytes were significantly less than CD4(+) lymphocytes. IFNgamma and perforin were downregulated on infiltrating lymphocytes compared to cells of healthy prostate tissue. Very few lymphocytes were detected within cancerous lesions whereas surrounding tissues showed extensive lymphocyte cluster formation. The TCR repertoire of infiltrating lymphocytes was broad and similar to that of healthy prostate tissue, giving no evidence for specific lymphocyte recruitment. CONCLUSIONS: In the prostate cancer microenvironment, CD4(+) T lymphocytes dominated while CD8(+) T cells were sparse. The lymphocytes exhibited signs of disturbed effector function. Consequently, the immune response against autologous tumor cells is likely to be inefficient in controlling tumor growth. Prostate 68: 1-10, 2008. (c) 2007 Wiley-Liss, Inc. [Abstract]

Wang D, Lu S, Dong Z
Regulation of TGF-beta1 gene transcription in human prostate cancer cells by nitric oxide.
Prostate. 2007 Dec 1;67(16):1825-33.
BACKGROUND: Overexpression of transforming growth factor (TGF)-beta1 is associated with advanced prostate cancer. Our previous studies showed an inverse correlation between the expressions of TGF-beta1 and inducible nitric oxide synthase (iNOS) in prostatic tumors in mice. The purpose of this study was to investigate regulation of TGF-beta1 expression in human prostate cancer cells by nitric oxide (NO). METHODS: Expression of TGF-beta1 in the three well-characterized lines of human prostate cancer cells (PC-3MM2, LNCaP, and DU145) was determined by using the enzyme-linked immunoabsorbance assay (ELISA), real-time reverse-transcriptase PCR (RT-PCR), nuclear run-on, and promoter activity analyses. RESULTS: Expression of both TGF-beta1 protein and mRNA was inhibited in both dose- and time-dependent manners by NO donors sodium nitroprusside (SNP), S-nitroso-N-acetylpenicilamine (SNAP), S-nitrosoglutathione (GSNO), and (+/-)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexeneamide (NOR-1) and by transfection of iNOS. The inhibitory effects of SNP and iNOS on TGF-beta1 expression were reduced in cells treated with NO scavengers N-dithiocarboxysarcosine (DTCS), 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), and hemoglobin, or with the iNOS inhibitor N-methyl-arginine (NMA). SNP downregulated the in vitro transcription of TGF-beta1 mRNA, inhibited TGF-beta1 promoter activity, but had no significant effects on TGF-beta1 mRNA stability. CONCLUSION: These results show that NO downregulates TGF-beta1 expression in prostate cancer cells at transcription level by suppressing the de novo synthesis of TGF-beta1 mRNA. Prostate 67: 1825-1833, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Tararova ND, Narizhneva N, Krivokrisenko V, Gudkov AV, Gurova KV
Prostate cancer cells tolerate a narrow range of androgen receptor expression and activity.
Prostate. 2007 Dec 1;67(16):1801-15.
BACKGROUND: The precise role of androgen receptor (AR) in the normal development of prostate and the progression of prostate cancer (CaP) remains controversial. While AR expression and activity is associated with growth arrest and differentiation of normal prostate cells, it is maintained in CaP cells that are characterized by continued proliferation. Our objective was to determine the importance of AR signaling for survival and growth of CaP cells, particularly those with a hormone-refractory phenotype. METHOD: AR expression was modulated in androgen-sensitive (AS) and androgen-insensitive (AI) CaP cells using RNAi and cDNA transduction. Resulting changes in AR transcriptional activity and cell growth were quantified. RESULTS: Interference with AR expression in both AS and AI CaP cells by shRNA transduction demonstrated a direct correlation between residual AR expression and cell viability. CaP cells lacking AR expression undergo apoptosis several days after AR down-regulation. This delayed response suggests that AR regulates apoptosis likely through an indirect mechanism. Overexpression of AR or hyper-stimulation of AR with high levels of androgen was also poorly tolerated by CaP cells. Cells with elevated AR had a growth disadvantage due to G1 cell cycle arrest and induction of p21 and GADD45 expression. CONCLUSIONS: CaP cells expressing endogenous AR are sensitive to both increases and decreases in AR expression levels and activity. AR in CaP cells is delicately regulated to provide a balance between cell death and continued proliferation. Thus, both approaches, inhibition and over-stimulation of AR activity, may have therapeutic value for treatment of prostate cancer. Prostate 67: 1801-1815, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Bosch JL, Tilling K, Bohnen AM, Bangma CH, Donovan JL
Establishing normal reference ranges for prostate volume change with age in the population-based Krimpen-study: Prediction of future prostate volume in individual men.
Prostate. 2007 Dec 1;67(16):1816-24.
BACKGROUND: We aim to establish the normal pattern of prostate volume change with age to provide a baseline from which accelerated prostate growth might be identified in patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). METHODS: In a community-based study, prostate volume was determined at baseline and after 2.1 and 4.2 years in men without prostate cancer. A bivariate multilevel growth curve model was used to estimate the pattern of change of prostate volume with age. RESULTS: The average percentage increase of total prostate volume and transition zone volume per year of follow-up was 2.2% and 3.5%, respectively. The final model showed that prostate volume was related to age only. The future prostate volume of an individual can be predicted based on his age and known history of prostate volume. The model was also used to calculate time needed for the prostate volume to increase with a certain percentage, for men with different baseline prostate volume values at different ages. CONCLUSIONS: This method establishes normal prostate volume values by age using prostate volume history in men without prostate cancer. The model provides baseline data from which disease progression might be detected. Prostate 67: 1816-1824, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Leiblich A, Cross SS, Catto JW, Pesce G, Hamdy FC, Rehman I
Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A.
Prostate. 2007 Dec 1;67(16):1761-9.
BACKGROUND: A proportion of men with prostate cancer will progress to develop metastatic disease involving the lymph-nodes and bone. To identify novel candidates associated with metastatic progression, we compared the proteomic profiles of LNCaP (lymph-node metastatic, androgen-dependant) and PC-3 (bone metastatic, androgen-independent), human prostate cancer cells. METHODS: Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), followed by electrospray ionisation tandem mass spectrometry (ESI-MS/MS), was used to identify differentially expressed proteins. Western blotting was used to validate the identity of any candidates. Immunohistochemistry was used to assess tissue expression. RESULTS: 2D-PAGE followed by ESI-MS/MS analyses identified the expression of glutathione S-transferase-pi (GST-pi) and protein gene product 9.5 (PGP 9.5) in PC-3 cells, but absent expression in LNCaP cells. PGP 9.5 expression in PC-3 cells was confirmed by Western blotting, in addition to expression in DU145 cells. Analysis of cell conditioned media showed that PGP 9.5 was secreted. Sequencing of the PGP 9.5 gene promoter region in bisulfite modified DNA, suggested that the regulation of expression involves promoter hypermethylation. RT-PCR analysis for Chromogranin A (ChA) mRNA (a marker of neuroendocrine cells), showed expression in PC-3 and DU145 cells but was undetectable in LNCaP cells. Immunohistochemistry localised PGP 9.5 expression exclusively within neuroendocrine cells and nerve fibres. CONCLUSIONS: Our unexpected finding that the neuroendocrine cell markers PGP 9.5 and ChA are expressed by PC-3 and DU145 cells, suggests that these cells may have been derived from metastatic adenocarcinomas which had undergone neuroendocrine differentiation or alternatively the expression occurred ectopically as a result of cell culture. Prostate 67: 1761-1769, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Bethel CR, Bieberich CJ
Loss of Nkx3.1 expression in the transgenic adenocarcinoma of mouse prostate model.
Prostate. 2007 Dec 1;67(16):1740-50.
BACKGROUND: The transgenic adenocarcinoma of mouse prostate (TRAMP) model has been extensively characterized at the histological and molecular levels, and has been shown to mimic significant features of human prostate cancer. However, the status of Nkx3.1 expression in the TRAMP model has not been elucidated. METHODS: Immunohistochemical analyses were performed using dorsal, lateral, and ventral prostate (VP) lobes from ages 6 to 30 weeks. Quantitative RT-PCR analyses were performed to determine relative mRNA expression. RESULTS: Heterogeneous loss of Nkx3.1 was observed in hyperplastic lesions of the ventral, dorsal, and lateral lobes. At 6 weeks of age, the ventral lobe displayed profound loss of Nkx3.1. Diminished Nkx3.1 protein was observed in well- to moderately-differentiated cancer lesions of all lobes. Poorly differentiated (PD) tumors stained negatively for Nkx3.1. Quantitative RT-PCR analyses revealed the presence of Nkx3.1 mRNA in each lobe at all ages, albeit reduced to variable levels. CONCLUSIONS: These data suggest that disease progression in the TRAMP model may be driven by loss of function of Nkx3.1, in addition to p53 and Rb. Lobe-specific disease progression in the TRAMP model correlates with the reduction of Nkx3.1 protein. Regulation of Nkx3.1 expression during tumorigenesis appears to occur by post-transcriptional and post-translational mechanisms. Prostate 67: 1740-1750, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Cao KY, Mao XP, Wang DH, Xu L, Yuan GQ, Dai SQ, Zheng BJ, Qiu SP
High expression of PSM-E correlated with tumor grade in prostate cancer: A new alternatively spliced variant of prostate-specific membrane antigen.
Prostate. 2007 Dec 1;67(16):1791-800.
BACKGROUND: Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer (PCa) has been targeted for therapy and diagnosis of PCa. In the current study, PSMA cDNA was cloned from PCa tissue by RT-PCR. After sequencing, a new spliced variant of PSMA (PSM-E) was discovered and its specificity in PCa was evaluated. METHODS: PSM-E and PSMA mRNA were measured in LNCaP, PC-3 and prostate or nonprostatic malignancies. Following transfection of PC-3 with PSM-E cDNA in the pcDNA3.0 vector, PSM-E expression was measured by immunofluorescence and Western-blot. PSM-E and PSMA mRNA levels were quantified by a real-time PCR assay in normal prostate (n = 7), benign prostatic hyperplasia (BPH) (n = 22) and PCa (n = 41). The correlation between their levels and tumor grade was analyzed. RESULTS: PSM-E cDNA is identical to PSMA except for a 97-nucleotide region and a 93-nucleotide region. PSM-E and PSMA mRNA were detected in PCa and LNCaP, not in PC-3; PSMA could be detected in some nonprostatic tumors whereas PSM-E not. The expression of PSM-E protein was detected in transfected cells. Significant difference of PSM-E mRNA levels was observed among normal prostate, BPH and PCa (P < 0.001), and PSM-E levels increased with increasing Gleason score (r = 0.514, P < 0.001). PSMA mRNA levels were higher in BPH and PCa than in normal prostate (P < 0.001), but no difference between BPH and PCa, no significant correlation was observed between PSMA levels and Gleason score (r = 0.229, P = 0.057). CONCLUSIONS: PSM-E may be a potential prognostic indicator for PCa progression and may be a new target antigen for therapy of PCa. Prostate 67: 1791-1800, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Dubovsky JA, McNeel DG
Inducible expression of a prostate cancer-testis antigen, SSX-2, following treatment with a DNA methylation inhibitor.
Prostate. 2007 Dec 1;67(16):1781-90.
BACKGROUND: Active immunotherapies are one approach being developed as novel treatments for prostate cancer. Critical to the success of these therapies is the identification of appropriate target antigens. We have been seeking to identify immunologically recognized proteins, cancer-testis antigens (CTA) in particular, in patients with prostate cancer that would be rational target antigens. METHODS: Using a previously reported panel of 29 different CTA, we used sera from 98 patients with prostate cancer and 50 healthy male blood donor controls to detect CTA-specific IgG. We then further evaluated the expression of one antigen, SSX-2, in prostate cancer cell lines and tissues. RESULTS: We identified IgG specific for NY-ESO-1, LAGE-1, NFX-2, and SSX-2 in at least 1/98 individuals with prostate cancer. We demonstrated that SSX-2 is a prostate CTA, and its expression is associated with metastatic prostate cancer. In addition, we report that the treatment of at least two human prostate cancer cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycytidine induced the expression of SSX-2. In contrast, treatment of a normal prostate epithelial cell line (RWPE-1) with 5-aza-2'-deoxycytidine did not induce SSX-2 expression. CONCLUSIONS: Our findings suggest that SSX-2 could be further pursued as an immunotherapeutic target in prostate cancer, and that treatment with 5-aza-2'-deoxycytidine could be exploited to modulate antigen expression in combination with immunotherapeutic approaches. Prostate 67: 1781-1790, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Wlazlinski A, Engers R, Hoffmann MJ, Hader C, Jung V, Müller M, Schulz WA
Downregulation of several fibulin genes in prostate cancer.
Prostate. 2007 Dec 1;67(16):1770-80.
BACKGROUND: Fibulins, encoded by FBLN genes, are extracellular matrix proteins influencing cell adhesion and migration. Altered expression of fibulins is associated with progression of several cancer types, but has not been studied in prostate cancer. METHODS: Expression of FBLN1 (major splice forms C and D), FBLN4, FBLN5, SPOCK1, and TENC was compared between 47 prostate cancer samples and 13 benign prostatic tissues by quantitative RT-PCR. Fibulin-1 and fibulin-5 expression was studied by immunohistochemistry. Effects of androgens and the DNA methylation inhibitor 5-aza-2'-deoxycytidine on fibulin expression were investigated in different prostate cancer cell lines. RESULTS: Our recent microarray analysis suggested downregulation of three fibulins, FBLN1, FBLN4, and FBLN5, in prostate cancer, while two further ECM genes, SPOCK1 (testican) and TENC (tenascin C), appeared upregulated or unchanged. These observations were corroborated by quantitative RT-PCR. Accordingly, FBLN1 and FBLN4 were weakly expressed in carcinoma lines compared to normal prostate epithelial cells (PrECs). Only FBLN4 was induced by 5-aza-2'-deoxycytidine, but its promoter was unmethylated. Androgen did not affect expression of FBLN genes. The FBLN1C and FBLN1D splice forms were coordinately expressed. Fibulin-1 protein was weakly detectable in benign PrECs, but tended to accumulate in cancer cells. Fibulin-5 was predominantly located in the stroma with a strong gradient from the periurethral to the peripheral zone, and lost in cancers. CONCLUSIONS: Three FBLN genes are significantly downregulated in prostate cancer, whereas SPOCK1 is often upregulated. FBLN5 downregulation fits its postulated anticancerous function, whereas FBLN1 and FBLN4 behave different than in certain other cancers. Prostate 67: 1770-1780, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Prowald A, Cronauer MV, von Klot C, Eilers T, Rinnab L, Herrmann T, Spindler KD, Montenarh M, Jonas U, Burchardt M
Modulation of beta-catenin-mediated TCF-signalling in prostate cancer cell lines by wild-type and mutant p53.
Prostate. 2007 Dec 1;67(16):1751-60.
BACKGROUND: Deregulation of the canonical Wnt/beta-catenin-pathway is known to play an important role in the progression of various tumour cell types including prostate cancer (PCa). Recently, the tumour-suppressor p53 was shown to down-regulate beta-catenin-signalling in colon cancer. As p53 is frequently mutated in late stage PCa we investigated the effect of wild-type p53 (p53wt) as well as p53-mutants on beta-catenin-signalling in PCa-cell lines. METHODS: The effects of p53wt and p53-mutants on Wnt/beta-catenin-signalling were studied using reporter gene assays. Expression of beta-catenin levels was monitored by Western blotting. RESULTS: Overexpression of p53wt as well as p53(249Ser) (a structural mutant) and p53(273His) (a DNA-contact-mutant) almost completely inhibited beta-catenin-mediated transcriptional activity of the T-cell factor (TCF) whereas p53(175His), a structural mutant, and a p53-mutant with a C-terminal deletion in the tetramerization domain (Deltap53) were unable to do so. Co-transfection experiments with p53wt and a dominant negative p53-mutant reversed the down-regulation of TCF-signalling, while Deltap53 was unable to interfere with p53wt-function. Down-regulation of TCF-signalling by p53wt and p53(273His) was accompanied by a reduction in beta-catenin protein level. CONCLUSIONS: p53wt, p53(273His)- and p53(249Ser)-mutants are able to down-regulate beta-catenin-signalling in PCa-cells probably via degradation of beta-catenin. The degradation of beta-catenin in PCa by p53 is not linked to transcriptional activity of p53. So far the mechanism how p53 interferes with beta-catenin-signalling is unknown. For the first time we provide experimental evidence that the C-terminus of p53 plays an important role in the down-regulation of beta-catenin-mediated TCF-signalling in PCa-cell lines possibly via p53 transrepressional function. Prostate 67: 1751-1760, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Bigler D, Gioeli D, Conaway MR, Weber MJ, Theodorescu D
Rap2 regulates androgen sensitivity in human prostate cancer cells.
Prostate. 2007 Oct 1;67(14):1590-9.
BACKGROUND: Progression of prostate cancer to a fatal androgen-independent disease is associated with activation of MAP kinase, consistent with chronic stimulation of the Ras-signaling pathway. We have previously shown that Ras activation is sufficient to induce androgen-independent growth of prostate cancer cells. One mechanism of MAP kinase regulation is modulation of Ras signaling by other Ras family members, the Rap gene paralogs Rap1a/b and Rap2a/b. Here we ask if Rap proteins play a role in determining androgen sensitivity of human prostate cancer cells either alone or in the context of an activated Ras. METHODS: To evaluate the role of Rap proteins in androgen responsiveness we use Rap over-expression with or without mutated Ras co-transfection and Rap siRNA knockdown to evaluate androgen-dependent prostate-specific antigen (PSA) promoter reporter expression and cell growth in androgen-dependent LNCaP and independent C4-2 human prostate cancer cells. RESULTS: Rap1 is equally expressed between LNCaP and C4-2 cells and thus we focused on Rap2 which is minimally expressed in C4-2. Rap2a affects androgen-dependent PSA reporter expression in a dose-dependent manner in LNCaP and C4-2 cells. Low levels of Rap2a enhance PSA reporter expression, whereas higher concentrations inhibit expression. We show that Rap2a antagonizes the enhanced PSA reporter expression conferred by an active RasV12 gene in prostate cancer cells. siRNA knockdown data indicate that Rap2 has a greater effect on androgen-stimulated growth in LNCaP than in C4-2 cells. CONCLUSIONS: We show that Rap2 is involved in androgen-mediated transcriptional and growth responses of human prostate cancer cells. [Abstract]

Leroux ME, Auzenne E, Evans R, Hail N, Spohn W, Ghosh SC, Farquhar D, McDonnell T, Klostergaard J
Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells.
Prostate. 2007 Nov 1;67(15):1699-717.
BACKGROUND: Elevated BCL-2 is one mechanism of therapeutic resistance in prostate cancer (PC), and new approaches are needed to overcome such resistance. METHODS: We evaluated the effects of BCL-2 over-expression in human prostatic adenocarcinoma cells on their susceptibility to sphingolipids (SLs) and to the sphingosine kinase (SpK) inhibitor, SKI II. RESULTS: In survival assays, no significant differences were observed in the responses to sphingosine or ceramide among parental PC-3 cells lacking detectable BCL-2 and BCL-2 over-expressing PC-3 transfectants; similarly, the responses to dimethyl-sphingosine (DMSP) of parental LNCaP cells and a BCL-2 over-expressing LNCaP transfectant were equivalent. SKI II induced protracted, BCL-2-independent survival loss in both PC-3 and LNCaP parental/transfectant pairs; in contrast, DMSP induced rapid cell shrinkage, caspase activation and caspase-dependent DNA fragmentation. DMSP-induced DNA fragmentation and loss of mitochondrial membrane potential were equivalent in BCL-2 transfectants and parental PC-3 cells and were not associated with BCL-2 downregulation. DMSP-mediated cytotoxicity was not associated with the enhanced production of reactive oxygen intermediates. SL analyses of parental and transfectant PC-3 cells did not reveal increased levels of sphingosine-1-phosphate in the BCL-2 transfectants; further, there only a modest early shift, corresponding to apoptotic onset, in pro- versus anti-apoptotic SLs in response to DMSP treatment. CONCLUSIONS: Thus, in contrast to the inhibitory effects of BCL-2 on apoptosis induced by various agents in tumor cells, SKI II and selected pro-apoptotic SLs appear atypical in their independence from such inhibition, and may have merits as new candidates for treatment of AI PC. [Abstract]

Olson BM, McNeel DG
Antibody and T-cell responses specific for the androgen receptor in patients with prostate cancer.
Prostate. 2007 Dec 1;67(16):1729-39.
BACKGROUND: The androgen receptor (AR) is a steroid hormone receptor that is an essential regulator of prostate development, and the primary molecular target for the treatment of metastatic prostate cancer. In this report, we evaluated whether patients with prostate cancer have pre-existing immune responses specific for the AR as evidence that the AR also might be pursued as an immunological target antigen. METHODS: The detection of auto-antibodies specific for the AR in patient sera was evaluated by ELISA and Western blotting. Peripheral blood mononuclear cells were analyzed for the presence of AR-specific T-cells, as measured by T-cell proliferation, interferon gamma (IFNgamma) and interleukin-10 secretion. RESULTS: We found that a significantly higher frequency of prostate cancer patients have AR LBD-specific antibody responses than do healthy male volunteers [18/105 cancer patients (17.1%) vs. 0/41 healthy volunteers, P = 0.0049], and that these responses were present regardless of the patients' disease stage [8/46 organ-confined prostate cancer patients (17.4%), 3/22 metastatic androgen-dependent patients (13.6%), and 7/37 metastatic, androgen-independent patients (18.9%)]. These antibodies were pre-dominantly of the IgG isotype, and furthermore of the IgG(2) sub-isotype. In addition, we found that patients with antibody responses also had concurrent antigen-specific CD4+ and CD8+ T-cell proliferation and IFNgamma secretion when compared to patients without antibody responses. CONCLUSIONS: These data demonstrate that some patients with prostate cancer have pre-existing humoral and cellular immune responses specific for the AR, suggesting that tolerance against the AR is not absolute and that the AR may be a potential immunotherapeutic target antigen. Prostate 67: 1729-1739, 2007. (c) 2007 Wiley-Liss, Inc. [Abstract]

Rohrmann S, Giovannucci E, Smit E, Platz EA
Association of IGF-1 and IGFBP-3 with lower urinary tract symptoms in the third national health and nutrition examination survey.
Prostate. 2007 Nov 1;67(15):1693-8.
BACKGROUND: Benign growth of the prostate is thought to contribute to lower urinary tract symptoms (LUTS) in older men. It is, however, unclear which factors induce prostate growth in these men. We examined the association of insulin-like growth factor (IGF)-1 and its major binding protein IGFBP-3 with LUTS in a representative US study. METHODS: We included men 60 years and older who participated in the morning session of the Third National Health and Examination Survey (NHANES III) between 1988 and 1994. Men were classified as cases (n = 91) if they reported at least three of four LUTS (nocturia, incomplete emptying, hesitancy, or weak stream) but had not had non-cancer prostate surgery in the past. Controls were men without symptoms and surgery (n = 220). All results were weighted to account for sampling probability in NHANES III. IGF-1 and IGFBP-3 were measured by ELISA and IRMA, respectively. RESULTS: After mutual adjustment, men in the highest tertile of serum IGF-1 concentration had a non-significantly higher odds of LUTS than men in the lowest tertile (odds ratio (OR) = 3.20; 95% confidence interval (CI) 0.89-11.4; p-trend = 0.09]. A high concentration of IGFBP-3 was inversely related to the odds of LUTS (OR = 0.25; 95% CI 0.08-0.81; p-trend = 0.02). CONCLUSION: A high IGFBP-3 level might affect LUTS by decreasing the bioavailability of IGF-1 or independent of IGF-1 by up-regulating apoptosis, and, thus, limiting its growth promoting effects on the prostate. [Abstract]

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Recent Articles in Current Opinion in Nephrology and Hypertension

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Bibliography. Current world literature. Pharmacology and therapeutics.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):491-7. [Abstract]

Sindi? A, Chang MH, Mount DB, Romero MF
Renal physiology of SLC26 anion exchangers.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):484-90.
PURPOSE OF REVIEW: The multifunctional anion exchanger family (Slc26) encompasses 11 identified genes, but only 10 encode real proteins (Slc26a10 is a pseudogene). Most of the Slc26 proteins function primarily as anion exchangers, exchanging sulfate, iodide, formate, oxalate, hydroxyl ion, and bicarbonate anions, whereas other Slc26 proteins function as chloride ion channels or anion-gated molecular motors. The aim of this review is to present recent studies on the molecular function of the Slc26 family and its role in renal physiology and pathophysiology. RECENT FINDINGS: In proximal tubules, Slc26a1 (Sat-1) mediates sulfate and oxalate transport across the basolateral membrane, while Slc26a6 (CFEX, Pat-1) mediates a variety of anion exchange at the apical membrane to facilitate transcellular sodium chloride absorption. Targeted deletion of murine Slc26a6 leads to intestinal hyperabsorption of oxalate, hyperoxaluria, and kidney stones. Slc26a4 (pendrin) and Slc26a7 are expressed in intercalated cells, and are involved in acid-base homeostasis and blood pressure regulation. Messenger RNA for Slc26a2, Slc26a9, and Slc26a11 is also present in the kidney, yet the roles of these family members in renal physiology or pathophysiology are not clear. SUMMARY: Members of this multifunctional anion transporter family play evolving roles in the etiology of nephrolithiasis (Slc26a6) and hypertension (Slc26a4 and Slc26a6). Other Slc26 family members (Slc26a2, Slc26a9, Slc26a11) express mRNA in the kidney but their roles in renal physiology are not yet known. [Abstract]

Palmer LG, Frindt G
Na+ and K+ transport by the renal connecting tubule.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):477-83.
PURPOSE OF REVIEW: The connecting tubule is emerging as a nephron segment critical to the regulation of Na+ and K+ excretion and the maintenance of homeostasis for these ions. The segment is difficult to study, however, and much of the available information we have concerning its functions is indirect. Here, we review the major transport mechanisms and transporters found in this segment and outline several unsolved problems in the field. RECENT FINDINGS: Recent electrophysiological and immunohistochemical measurements together with theoretical studies provide a more comprehensive view of ion transport in the connecting tubule. New signaling pathways governing Na+ and K+ transport have also been described. SUMMARY: Key questions about how Na+ and K+ transport are regulated remain unanswered. Is the connecting tubule the site of final regulation of both Na+ and K+ excretion? If so, how are the transport rates of these two ions independently controlled? [Abstract]

Wagner CA
Metabolic acidosis: new insights from mouse models.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):471-6.
PURPOSE OF REVIEW: Metabolic acidosis is a severe disturbance of extracellular pH homeostasis that can be caused both by inborn or acquired defects in renal acid excretion or metabolic acid production. Chronic metabolic acidosis causes osteomalacia with nephrocalcinosis and urolithiasis. In the setting of end-stage renal disease, metabolic acidosis is often associated with increased peripheral insulin resistance, and represents an additional independent morbidity risk factor. This review summarizes recent insight, gained primarily from mouse models, into the mechanisms whereby the kidney regulates and adapts acid excretion. RECENT FINDINGS: Human genetics and various mouse models have shed new light on mechanisms that contribute to the kidney's ability to excrete acid and adapt appropriately to metabolism. Progress in four specific areas will be highlighted: mechanisms contributing to the synthesis and excretion of ammonia; insights into adaptive processes during acidosis; mechanisms by which the kidney may sense acidosis; and the pathophysiology of acquired and inborn errors of renal acid handling. SUMMARY: Genetic mouse models and various messenger RNA and proteome profiling and screening technologies demonstrate the importance of various acid-base transporting proteins and a metabolic and regulatory network that contributes to the kidney's ability to maintain the systemic acid-base balance. [Abstract]

Capdevila JH
Regulation of ion transport and blood pressure by cytochrome p450 monooxygenases.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):465-70.
PURPOSE OF REVIEW: Past and recent studies of the cytochrome P450 monooxygenase branch of the arachidonate cascade establish a role for this metabolic pathway in the regulation of vascular tone and tubular ion transport. Functional and electrophysiology studies indicate that the P450 eicosanoids participate in the regulation of vascular potassium and renal sodium channels, and of systemic blood pressures. RECENT FINDINGS: Associations between genetically controlled alterations in blood pressure and the activity or transcriptional regulation of renal Cyp2c arachidonic acid epoxygenases and Cyp4a omega-hydroxylases document a role for these enzymes in the pathophysiology of hypertension--a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. Associations between a functional variant of the human CYP4A11 gene and hypertension suggest a potential role for this gene as a determinant of polygenic blood pressure control in humans. SUMMARY: These results provide new understandings of the role of P450s in renal physiology, as well as conceptually novel approaches for studies of the molecular basis of human hypertension that could lead to new strategies for the early diagnosis and clinical management of this devastating disease. [Abstract]

Angelow S, Yu AS
Claudins and paracellular transport: an update.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):459-64.
PURPOSE OF REVIEW: Claudins are tight junction proteins that form paracellular barriers and pores. The purpose of this timely review is to provide an update on the exciting new advances in our understanding of claudin biology and their relevance to renal physiology and pathophysiology. RECENT FINDINGS: Accumulating evidence from numerous studies indicates that the primary role of claudins is to determine the permeability and charge selectivity of the paracellular pathway to small ions. Studies in which claudins are overexpressed in cell lines have potential limitations and need to be interpreted cautiously. Ribonucleic acid interference is a novel approach to functional characterization. Claudins are believed to assemble into multimers by homophilic and heterophilic side-by-side and head-to-head interaction; however, there is still limited evidence for this. The roles of a few claudins in the renal tubule, including claudins 2, 8, 10, 16 and 19, have now been elucidated. SUMMARY: These findings reveal tantalizing clues to claudin biology and function. Much remains unknown, however, and these findings will hopefully encourage further research in this important area. [Abstract]

Cohen DM
The transient receptor potential vanilloid-responsive 1 and 4 cation channels: role in neuronal osmosensing and renal physiology.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):451-8.
PURPOSE OF REVIEW: To provide an overview of recent developments in the field of systemic osmoregulation, with attention to the brain and kidney. RECENT FINDINGS: A number of pivotal observations underscore the primary importance of transient receptor potential channels in systemic osmoregulation and their involvement constitutes the focus of this review. Recent data suggest that transient receptor potential vanilloid-responsive 4 is a central sensor or effector of systemic hypotonicity, whereas an unidentified variant of transient receptor potential vanilloid-responsive 1 potentially serves an analogous role in systemic hypertonicity. SUMMARY: Members of the transient receptor potential vanilloid-responsive subfamily of transient receptor potential channels are likely to serve as central sensors of systemic anisotonicity. [Abstract]

Hughey RP, Carattino MD, Kleyman TR
Role of proteolysis in the activation of epithelial sodium channels.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):444-50.
PURPOSE OF REVIEW: Epithelial sodium channels mediate Na+ transport across high resistance, Na+-transporting epithelia. This review describes recent findings that indicate that epithelial sodium channels are activated by the proteolytic release of inhibitory peptides from the alpha and gamma subunits. RECENT FINDINGS: Non-cleaved channels have a low intrinsic open probability that may reflect enhanced channel inhibition by external Na+--a process referred to as Na+ self-inhibition. Cleavage at a minimum of two sites within the alpha or gamma subunits is required to activate the channel, presumably by releasing inhibitory fragments. The extent of epithelial sodium channel proteolysis is dependent on channel residency time at the plasma membrane, as well as on the balance between levels of expression of proteases that activate epithelial sodium channels and inhibitors of these proteases. Regulated epithelial sodium channel proteolysis has been observed in rat kidney and in human airway epithelia. SUMMARY: Proteolysis of epithelial sodium channel subunits plays a key role in modulating epithelial sodium channel activity through changes in channel open probability. [Abstract]

Huang C, Miller RT
Regulation of renal ion transport by the calcium-sensing receptor: an update.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):437-43.
PURPOSE OF REVIEW: Extracellular calcium has profound effects on renal tubular transport, presumably via the calcium-sensing receptor, which is expressed in all nephron segments, but its effects in specific segments and the mechanism of regulation of transport are not fully understood. RECENT FINDINGS: Recognition that activating calcium-sensing receptor mutations result in a Bartter-like syndrome demonstrate that the transport effects of extracellular calcium are mediated by the calcium-sensing receptor. Its presence in the gills and solute and water-transporting organs of fish coupled with appropriate calcium-sensing receptor kinetics indicate that the calcium-sensing receptor was originally involved in the regulation of sodium chloride, calcium and magnesium transport. Based on its physiological effects on tubular transport and biochemical and genetic data, the calcium-sensing receptor appears to act by mechanisms that distinguish it from other G protein-coupled receptors. SUMMARY: The calcium-sensing receptor mediates the effects of extracellular calcium on the kidney, is an essential control point in the regulation of calcium balance and possibly the physiological regulation of sodium chloride balance. The thick ascending limb of Henle and distal convoluted tubule appear to be the nephron segments most responsible for the effects of the calcium-sensing receptor, although its mechanisms of action are not fully established. [Abstract]

Grimm PR, Sansom SC
BK channels in the kidney.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):430-6.
PURPOSE OF REVIEW: Large, BK (calcium-activated potassium) channels are now regarded as relevant players in many aspects of renal physiology, including potassium secretion. This review will highlight recent discoveries regarding the function and localization of BK in the kidney. RECENT FINDINGS: Patch clamp electrophysiology has revealed BK in cultured podocytes, glomerular mesangial cells, and in several tubule segments including principal cells (connecting tubules/principal cells), and intercalated cells of connecting tubules and cortical collecting ducts. Flow-induced potassium secretion is mediated by BK in the distal nephron and may be partly the result of shear stress-induced increases in cell calcium concentrations. ROMK-/- and wild-type mice on a high potassium diet exhibit BK-mediated potassium secretion, and studies of BK-alpha-/- and BK-beta1-/- mice suggest that flow-induced potassium secretion is mediated by BK-alpha/beta1, which is specifically localized in the apical membrane of the connecting tubule of the mouse and connecting tubule plus initial cortical collecting duct of the rabbit. SUMMARY: BK channels, located in glomerular cells and in many nephron segments, especially mediate potassium secretion in the combined condition of potassium adaptation and high flow. Understanding the molecular makeup of BK in specific renal cells and the dietary and physiological conditions for their expression can yield improved potassium-sparing compounds. [Abstract]

Mount DB
Collectrin and the kidney.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):427-9. [Abstract]

Segura J, García-Donaire JA, Ruilope LM
Are differences in calcium antagonists relevant across all stages of nephropathy or only proteinuric nephropathy?
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):422-6.
PURPOSE OF REVIEW: The main effects of classic calcium antagonists are mediated by the inhibition of L-type calcium channels broadly distributed within the renal vascular bed. Calcium antagonists act predominantly on the afferent arterioles, and dihydropyridines can favour the increase in glomerular hypertension and progression of kidney diseases, in particular when systemic blood pressure remains uncontrolled. RECENT FINDINGS: Calcium antagonists have been widely used in clinical practice because of their antihypertensive capacity. The prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease in the general population. Non-dihydropyridines such as verapamil have been shown to possess an antiproteinuric effect that could be particularly relevant. SUMMARY: Recent data from clinical trials have confirmed that, in hypertensive patients with preserved renal function or with chronic kidney disease, calcium antagonists are effective antihypertensive drugs to be considered alone or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In those patients presenting with proteinuric kidney disease, non-dihydropyridines could reduce proteinuria to a greater degree than dihydropyridines. [Abstract]

Weir MR
Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering?
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):416-21.
PURPOSE OF REVIEW: Direct renin inhibitors are the newest antihypertensive therapeutic class. The review describes their antihypertensive and antiproteinuric effects and possible renoprotective capabilities. RECENT FINDINGS: Clinical trials demonstrate direct renin inhibitors reduce systolic and diastolic blood pressure comparable with other commonly used antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. They also reduce proteinuria and are renoprotective in experimental models of kidney disease. Direct renin inhibitors, when used with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, offer incremental blood pressure reduction far greater than that observed when an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker are used together. This suggests that renin inhibitors possess a unique and distinct mechanism of action compared with the other two therapeutic classes. SUMMARY: Direct renin inhibitors, due to their antihypertensive and antiproteinuric effects, and the unique mechanism of action resulting in reduction in plasma renin activity and suppression of angiotensin II levels, may offer a unique opportunity to facilitate blood pressure reduction with both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as well as other commonly used therapeutic classes. More effective blood pressure and proteinuria reduction coupled with a unique means of suppressing the renin angiotensin system may offer improved opportunity for renoprotection. [Abstract]

Agarwal R
Antihypertensive agents and arterial stiffness: relevance to reducing cardiovascular risk in the chronic kidney disease patient.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):409-15.
PURPOSE OF REVIEW: Arterial stiffness is a sign of diffuse adventitial macrovascular disease. The purpose of the present review is to discuss, in patients with chronic kidney disease, the pathophysiology of increased arterial stiffness, the role of antihypertensive therapy on reduction of arterial stiffness, and the clinical ways by which the prognostication of cardiovascular disease in patients with chronic kidney disease can be refined using arterial stiffness monitoring. RECENT FINDINGS: Arterial stiffness is increased with increasing prevalence of traditional cardiovascular risk factors. In patients with chronic kidney disease some unique factors further increase the risk of arterial stiffness, and include volume overload, activation of the renin-angiotensin system, anemia, and dysregulated mineral metabolism. Arterial stiffness is increased even in patients with early-stage chronic kidney disease. Blood pressure reduction when accompanied by a reduction in arterial stiffness is associated with improved prognosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can preferentially improve arterial stiffness, which may be an additional mechanism of cardiovascular protection with these agents. SUMMARY: The impact of improvement in arterial stiffness with antihypertensive agents on cardiovascular outcomes needs well designed clinical trials. [Abstract]

Filippone JD, Bisognano JD
Baroreflex stimulation in the treatment of hypertension.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):403-8.
PURPOSE OF REVIEW: It is not uncommon for hypertension to be resistant to the effects of medical therapy, and this poses a significant risk of adverse cardiovascular events. Electrical stimulation of the carotid sinus is a novel treatment for hypertension, and has been shown to reduce blood pressure by activating the baroreflex and reducing sympathetic tone. RECENT FINDINGS: Evidence suggests that the baroreceptors play a more important role in long-term blood pressure regulation than was once believed. It appears that the baroreflex attenuates chronic hypertension in large part by inhibiting renal sympathetic tone. Animal and human studies have demonstrated a safe and effective lowering of blood pressure with chronic electrical stimulation of the carotid sinus, and have generated enthusiasm for implantable carotid sinus stimulators in the treatment of hypertension. SUMMARY: Electrical baroreflex stimulation appears safe and effective, and may represent a useful adjunct to medical therapy in patients with resistant hypertension. [Abstract]

Anderson PW, McGill JB, Tuttle KR
Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):397-402.
PURPOSE OF REVIEW: The prevalence of diabetes mellitus is increasing rapidly worldwide. The number of patients with diabetic nephropathy is also expected to increase considerably in the future despite currently available treatments that may prevent or slow kidney disease progression. Additional therapeutic agents are therefore urgently needed. RECENT FINDINGS: Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta-isoform of protein kinase C. In animal models of diabetic nephropathy, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved renal function and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. In humans with type 2 diabetes and nephropathy already treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, treatment with ruboxistaurin for 1 year reduced albuminuria and urinary transforming growth factor-beta, and maintained estimated glomerular filtration rate. Ruboxistaurin has so far been shown to be well tolerated at the doses tested. SUMMARY: Inhibition of protein kinase C beta may represent a novel strategy to improve kidney outcomes in patients with diabetes mellitus. Large-scale, prospective trials are needed to confirm the safety and potential benefits of ruboxistaurin in patients with diabetic nephropathy. [Abstract]


Bibliography. Current world literature. Molecular cell biology and physiology of solute transport.
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):497-502. [Abstract]


Bibliography. Current world literature. Renal pathophysiology.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):393-6. [Abstract]


Bibliography. Current world literature. Mineral metabolism.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):388-93. [Abstract]

Ambühl PM
Posttransplant metabolic acidosis: a neglected factor in renal transplantation?
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):379-87.
PURPOSE OF REVIEW: The occurrence and pathogenesis of metabolic acidosis after renal transplantation is reviewed. Posttransplant acidosis is shown to be a key mechanism for major metabolic complications in mineral and muscle metabolism, and for anemia, discussed in the context of both acidosis and renal transplantation. RECENT FINDINGS: Continuous improvement in kidney transplant survival has shifted attention to long-term outcomes, specifically to disorders linked to cardiovascular disease, physical capacity and quality of life. Metabolic acidosis is gaining growing acceptance as a clinical entity and has occasionally come into focus in the context of renal transplantation. The possible link to metabolic disturbances resulting in impairment of musculoskeletal disorders and physical limitations, however, has not been considered specifically. SUMMARY: Available evidence suggests a high prevalence of (compensated) metabolic acidosis after renal transplantation, presenting as low serum bicarbonate and impaired renal acid excretion. This condition is associated with relevant disorders in mineral metabolism and muscle function. Current knowledge about the effects of acidosis on renal electrolyte handling, mineral metabolism and protein synthesis suggests that acid/base derangements contribute to the muscle and bone pathology, as well as anemia, encountered after kidney transplantation. Consequently, posttransplant acidosis may be a relevant factor in the causal pathway of impaired physical capacity observed in this patient group. [Abstract]

Xu J, Desir GV
Renalase, a new renal hormone: its role in health and disease.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):373-8.
PURPOSE OF REVIEW: Renalase is a secreted amine oxidase that metabolizes catecholamines. The approach used to identify this novel renal hormone will be discussed, as will the experimental data suggesting it regulates cardiovascular function, and its deficiency contributes to heightened cardiovascular risks in patients with chronic kidney disease. RECENT FINDINGS: The sympathetic nervous system is activated in chronic kidney disease and end-stage renal disease, and patients have a significant increase in cardiovascular disease. Parenteral administration of either native or recombinant renalase lowers blood pressure and heart rate by metabolizing circulating catecholamines. Plasma levels are markedly reduced in patients with chronic kidney disease and end-stage renal disease. Renalase deficiency occurs in salt-sensitive Dahl rats as they develop hypertension. Renalase inhibition by antisense RNA increases baseline blood pressure, and leads to an exaggerated blood pressure response to adrenergic stress. Most recently, two single nucleotide polymorphisms in the renalase gene were found to be associated with essential hypertension in humans. SUMMARY: The renalase pathway is a previously unrecognized mechanism for regulating circulating catecholamines, and, therefore, cardiac function, and blood pressure. Abnormalities in the renalase pathway are evident in animal models of chronic kidney disease and hypertension. Collectively, these data suggest that renalase replacement may be an important therapeutic modality. [Abstract]

Meima ME, Mackley JR, Barber DL
Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):365-72.
PURPOSE OF REVIEW: The sodium-hydrogen exchanger isoform-1 (NHE1) functions in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Recent studies have revealed the structural functions of NHE1 as an anchor for actin filaments and a scaffold for an ensemble of signaling proteins. This review highlights how these functions contribute to NHE1 regulation of biochemical events and cell behaviors. RECENT FINDINGS: New data confirming nontransport structural functions of NHE1 suggest reexamining how NHE1 regulates cell functions. Cell survival, cell substrate adhesion, and organization of the actin cytoskeleton are confirmed to be regulated through actin anchoring by NHE1 and likely by NHE1-dependent scaffolding of signaling proteins. A role for NHE1 in mechanotransduction is emerging and a challenge of future studies is to determine whether structural functions of NHE1 are important for mechanoresponsiveness. SUMMARY: This review highlights evidence for the nontransport functions of NHE1 and describes how the structural functions are integrated with ion translocation to regulate a range of cellular processes. Nontransporting features of NHE1 are analogous to recently observed nonconducting actions of ion channels in regulating cell behaviors and represent an emerging paradigm of ion transporters as multifunctional proteins. [Abstract]

Pollock CA, Poronnik P
Albumin transport and processing by the proximal tubule: physiology and pathophysiology.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):359-64.
PURPOSE OF REVIEW: Significant epidemiological and clinical trial evidence supports the association between increased urinary albumin excretion, cardiovascular events and renal failure. An increase in albumin excretion has traditionally been considered to reflect a 'glomerular' leak of protein; however, it is now recognized that significant tubular reabsorption of albumin occurs under physiological conditions that may be modified by genetic determinants, systemic disease and drug therapies. RECENT FINDINGS: The endocytosis of albumin by the proximal tubule is a highly regulated process depending on protein-protein interactions between several membrane proteins and scaffolding and regulatory molecules. The elucidation of these interactions is an ongoing research focus. There is also mounting evidence for a transcytotic pathway for retrieval of albumin from the tubular filtrate. The molecular basis for the role of albuminuria in both interstitial renal disease and cardiovascular pathology continues to be defined. The clinical implications of albuminuria due to a glomerular leak vs. reduced tubular reabsorption of albumin are, however, now under consideration. In particular, the prognostic implication of microalbuminuria induced by the more potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors is under study. SUMMARY: The currently defined mechanisms underpinning the tubular reabsorption of albumin, how these are modified by pathology and pharmacology, and the clinical implications are the subject of this review. [Abstract]

Caplan MJ, Kamsteeg EJ, Duffield A
Tetraspan proteins: regulators of renal structure and function.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):353-8.
PURPOSE OF REVIEW: Members of the tetraspan family are widely expressed and poorly understood. An emerging literature suggests that through their interactions with other membrane proteins they play central or regulatory roles in a wide variety of physiological processes. This review will discuss selected tetraspan complexes and highlight their relevance to epithelial cells and the kidney. RECENT FINDINGS: Tetraspans regulate the signaling and trafficking properties of their partner proteins. Tetraspan complexes with integrin molecules, for example, modulate cell adhesion and mobility. Perturbations of tetraspan-integrin assemblies can have dramatic impacts on renal tissue morphogenesis, resulting in a disruption of normal glomerular architecture and selectivity. Tetraspan interactions with renal ion transport proteins appear to affect transporter function by enhancing or inhibiting the endocytic internalization of their transport protein partners. SUMMARY: Tetraspans constitute a novel class of proteins whose capacity to alter the cell biological and functional properties of their membrane protein partners is likely to have wide ranging and important physiological ramifications. [Abstract]

Sasaki S, Noda Y
Aquaporin-2 protein dynamics within the cell.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):348-52.
PURPOSE OF REVIEW: Aquaporin-2 is an aquaporin water channel protein present at the apical membrane of kidney collecting duct cells and plays a key role in urine concentrating ability. Like other membrane proteins, aquaporin-2 undergoes dynamic processes within the cells: synthesized, targeted to the subapical region, exocytosed to the apical membrane, endocytosed, recycled and finally degraded. The understanding of the molecular and cellular mechanisms of these events is advancing rapidly, and recent new findings characterizing such processes are reviewed. RECENT FINDINGS: Hypertonicity itself stimulates aquaporin-2 expression through the tonicity-responsive enhancer and its transcription factors. Gene targeted mouse models for human nephrogenic diabetes insipidus show the importance of the C-terminus of aquaporin-2 in apical sorting and provide mechanistic insights. Evidence for the importance of actin cytoskelton in exocytosis of aquaporin-2 to the apical membrane is accumulating. Actin and other proteins bind to aquaporin-2 and make a multiprotein complex. New proteomic analyses indicate the involvement of a large series of proteins in aquaporin-2 dynamics. SUMMARY: The protein-level understanding of aquaporin-2 dynamics has advanced considerably over the past few years, and continuing studies will open a new way in developing new manoeuvres or drugs to manipulate kidney water homeostasis. [Abstract]

Van Praet JT, De Vriese AS
Prevention of contrast-induced nephropathy: a critical review.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):336-47.
PURPOSE OF REVIEW: Although contrast-induced nephropathy (CIN) is common and portends a significant morbidity and mortality, only few large and well designed trials have assessed the available prophylactic measures and there are no clear evidence-based guidelines that can easily be adopted by the clinician. We critically discuss the evidence for periprocedural hydration, pharmacological agents, periprocedural withdrawal of medication, application of renal replacement therapy and the use of contrast media. RECENT FINDINGS: Pending confirmation of the superiority of sodium bicarbonate, NaCl 0.9% remains the fluid of choice for periprocedural hydration. A recent trial found a dose-dependent beneficial effect of acetylcysteine on CIN and mortality, adding to the controversy on the prophylactic use of this agent. Publication bias of acetylcysteine trials may have confounded the results of the meta-analyses, since negative results were more likely to be published as an abstract only. Periprocedural haemofiltration protected against CIN in a high-risk population, but the results require confirmation before the technique can be recommended. SUMMARY: Pending randomized controlled trials with rigorous scientific design, we propose practical mixed evidence-based and opinion-based guidelines for the prevention of CIN, using a stratification of patients into three risk groups, based on their renal function and a risk-prediction model. [Abstract]

Liu S, Gupta A, Quarles LD
Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):329-35.
PURPOSE OF REVIEW: To describe emerging understanding of fibroblast growth factor 23 (FGF23) - a bone-derived hormone that inhibits phosphate reabsorption and calcitriol production by kidney and participates as the principle phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization. RECENT FINDINGS: FGF23 (a circulating factor made by osteocytes in bone) inhibits phosphate reabsorption and 1,25(OH)2D production by kidney. Physiologically, FGF23 is a counter-regulatory phosphaturic hormone for vitamin D and coordinates systemic phosphate homeostasis with skeletal mineralization. Pathologically, high circulating FGF23 levels cause hypophosphatemia, decreased 1,25(OH)2D production, elevated parathyroid hormone and rickets/osteomalacia. FGF23 mutations impairing its degradation cause autosomal dominant hypophosphatemic rickets. Respective loss-of-function mutations of osteocyte gene products DMP1 and Phex cause autosomal recessive hypophosphatemic rickets and X-linked hypophosphatemic rickets, initiating increased FGF23 production. Low FGF23 levels lead to hyperphosphatemia, elevated 1,25(OH)2D, and soft-tissue calcifications. FGF23 is markedly increased in chronic renal disease, but its role remains undefined. SUMMARY: FGF23 discovery has uncovered primary regulatory pathways and new systems biology governing bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. FGF23 assessment will become important in diagnosing hypophosphatemic and hyperphosphatemic disorders, for which pharmacological regulation of FGF23 levels may provide novel treatments. [Abstract]

Li X, Giachelli CM
Sodium-dependent phosphate cotransporters and vascular calcification.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):325-8.
PURPOSE OF REVIEW: Vascular calcification is associated with cardiovascular events in patients with end-stage renal disease and diabetes. Hyperphosphatemia is a risk factor for vascular calcification in these patients. Sodium-dependent phosphate cotransporters are required for cellular phosphate uptake. This review focuses on the potential role of phosphate transport and type III sodium-dependent phosphate cotransporters in the process of vascular calcification. RECENT FINDINGS: Consistent with clinical and animal studies, elevated phosphate induces mineralization of cultured smooth muscle cells in vitro. Calcification is concomitant with osteochondrogenic phenotype change in smooth muscle cells characterized by induction of osteochondrogenic differentiation marker, Runx2, and inhibition of smooth muscle cell lineage marker, SM22. Inhibition of the type III sodium-dependent phosphate cotransporter, Pit-1, blocks phosphate-induced smooth muscle cell calcification. Moreover, the phosphate-induced osteochondrogenic phenotype modulation is also abrogated by Pit-1 inhibition. Pit-1 is upregulated by several calcification-promoting factors, including tumor necrosis factor-alpha, bone morphogenetic protein 2, platelet-derived growth factor and elevated calcium. SUMMARY: Phosphate uptake via Pit-1 is required for osteochondrogenic phenotypic change and calcification of vascular smooth muscle cells in vitro. Modulation of Pit-1 expression or its transport activity may provide a novel therapeutic target for intervention of vascular calcification. [Abstract]

Topala CN, Bindels RJ, Hoenderop JG
Regulation of the epithelial calcium channel TRPV5 by extracellular factors.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):319-24.
PURPOSE OF REVIEW: Recent studies have greatly increased our knowledge concerning the regulation of renal calcium handling. This review focuses on newly identified calciotropic factors present in the pro-urine and the mechanisms by which they control the transient receptor potential channel vanilloid subtype 5 (TRPV5) which forms the gatekeeper of active renal calcium reabsorption. RECENT FINDINGS: The antiaging hormone klotho regulates TRPV5 activity via a novel mechanism modifying its glycosylation status, thereby entrapping the channel at the cell surface. Functional characterization of tissue kallikrein knockout mice revealed that these animals exhibit a pronounced hypercalciuria, comparable to the calcium leak observed in TRPV5 knockout mice. Recently, it has been demonstrated that tissue kallikrein stimulates active calcium reabsorption via the bradykinin receptor type 2 pathway involving protein kinase C-dependent activation of TRPV5. Finally, the extracellular pH appears to act as a dynamic switch controlling cell surface expression of TRPV5. SUMMARY: Unraveling the molecular mechanisms of TRPV5 channel regulation by the antiaging hormone klotho, tissue kallikrein and extracellular pH demonstrated the existence of novel regulatory mechanisms of active calcium reabsorption acting from the tubular lumen. [Abstract]

Lanske B, Razzaque MS
Mineral metabolism and aging: the fibroblast growth factor 23 enigma.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):311-8.
PURPOSE OF REVIEW: The regulation of phosphate homeostasis was thought to be passively mediated by the calciotrophic hormones parathyroid hormone and 1,25(OH)2D3. This article summarizes the emerging trends that show an active regulation of phosphate homeostasis by fibroblast growth factor 23 (FGF-23) - a process fairly independent of calcium homeostasis - and how altered mineral ion metabolism may affect the aging process. RECENT FINDINGS: A major breakthrough in FGF-23 biology has been achieved by the demonstration of strikingly similar physical/biochemical phenotypes of Fgf-23(-/-) and klotho hypomorph mice, which eventually led to the identification of klotho as a cofactor in FGF-23 and its receptor interactions. Furthermore, FGF-23 has emerged as a counter regulator of the renal 1alpha(OH)ase and sodium-phosphate cotransporter activities to modulate phosphate homeostasis. Finally, studies point towards a role of dentine matrix protein 1 in affecting phosphate homeostasis, in coordination with FGF-23. SUMMARY: Recent mouse genetic studies have broadened our understanding of biochemical/molecular pathways involved in phosphate homeostasis, and linked FGF-23 to such regulation. Understanding the molecular interactions of essential calcium and phosphate regulators will enhance our knowledge of the coordinated regulation of mineral ion metabolism, and will help to redefine the molecular pathology of age-associated lesions accompanied by abnormal mineral ion metabolism such as vascular calcifications and osteoporosis. [Abstract]

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Recent Articles in The Journal of Urology

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Proceedings of the Annual Meeting of the Section on Urology, American Academy of Pediatrics, Atlanta, Georgia, USA, October 7-9, 2006.
J Urol. 2007 Oct;178(4 Pt 2): . [Abstract]

Smith JA
This Month in Clinical Urology.
J Urol. 2007 Nov 13; [Abstract]

Borawski KM, Sur RL, Miller OF, Pak CY, Preminger GM, Kolon TF
Urinary Reference Values for Stone Risk Factors in Children.
J Urol. 2007 Nov 13;
PURPOSE: Reference values for stone risk factors in 24-hour urine samples for nonstone forming children are limited. We measured urinary stone risk factors in healthy children 3 to 18 years old, and sought to determine whether the risk factors are affected by age. MATERIALS AND METHODS: A total of 48 healthy subjects with no history of stone disease, endocrine abnormalities or urological surgery were recruited from the Naval Medical Center in San Diego. Subjects were then further divided into 4 age groups, each separated by 5 years. A single outpatient 24-hour urine sample was obtained and analyzed. Urine chemistries were adjusted for urinary creatinine and body weight. RESULTS: After excluding under collected samples 46 urine samples were analyzed. Urinary pH and volume decreased with increasing age, although the difference in pH did not reach statistical significance. Unadjusted urinary parameters failed to show statistical difference among the age groups. When adjusted for urinary creatinine and body weight all urinary parameters (calcium, oxalate, uric acid, citrate, magnesium, sodium, phosphorus and potassium) decreased with increasing age (statistically significant except for calcium). CONCLUSIONS: Stone risk factors in 24-hour urine samples decrease with increasing age in healthy, nonstone forming children. Normative data, derived by adjustment with urinary creatinine or body weight and stratified according to quintiles of age, should be useful in defining abnormal stone risk factors in children with stones. [Abstract]

Zink S, Freitag CM, Gontard AV
Behavioral Comorbidity Differs in Subtypes of Enuresis and Urinary Incontinence.
J Urol. 2007 Nov 13;
PURPOSE: The aim of this prospective study is to describe the association of comorbid behavioral and somatic factors in children with different forms of nocturnal enuresis and daytime incontinence referred to a tertiary center. MATERIALS AND METHODS: A total of 166 consecutive children 5.1 to 16.4 years old were referred for detailed assessment between January 2004 and July 2006. Evaluation included a detailed history, pediatric examination, 24 to 48-hour voiding protocols, sonography and uroflow. Parents filled out the Child Behavior Checklist, a standardized parental questionnaire consisting of 113 problem items. ICD-10 diagnoses were given based on standardized mental state examination and mutual consensus conferences. RESULTS: In the full sample externalizing disorders were more than twice as common as internalizing disorders. Differences were found between children with nocturnal enuresis and daytime incontinence regarding parent reported externalizing behavior scores as well as rates of "at least 1 ICD-10 psychiatric diagnosis" and comorbid encopresis. Children with monosymptomatic nocturnal enuresis showed fewer internalizing disorders and lower rates of "at least 1 ICD-10 psychiatric diagnosis" and comorbid encopresis compared to those with nonmonosymptomatic nocturnal enuresis, urge incontinence and voiding postponement. The results of sonography and uroflow measures also differed between groups. CONCLUSIONS: Different subtypes of enuresis and urinary incontinence demonstrate differences in behavioral problems and psychiatric comorbidity. The highest rates of psychiatric comorbidity were found in the group of children with voiding postponement and the lowest were in children with monosymptomatic nocturnal enuresis. We recommend screening for comorbid psychiatric disorders in children with enuresis and urinary incontinence. Further investigations in a larger group of children are necessary. [Abstract]

Nanigian DK, Kurzrock EA
Intermediate-Term Outcome of the Simplified Laparoscopic Antegrade Continence Enema Procedure: Less is Better.
J Urol. 2007 Nov 13;
PURPOSE: The Malone antegrade continence enema procedure revolutionized the surgical management of fecal incontinence. Open and laparoscopic antegrade continence enemas are often performed with cecoplication and mesenteric manipulation. Since our initial laparoscopic antegrade continence enema description, we have simplified our technique. We present our series of laparoscopic antegrade continence enema procedures, discuss technique and outcomes, and review the literature. MATERIALS AND METHODS: We retrospectively reviewed children who underwent laparoscopic antegrade continence enema between 2001 and 2007. Outcome measures included operative time, length of stay, stomal complications and resolution of incontinence or constipation. Using an umbilical port and 1 to 2 additional ports, the appendix was mobilized to allow transposition to the umbilicus. No cecoplication was performed. The appendix was not straightened unless catheterization was difficult. RESULTS: A total of 22 patients (mean age 7.8 years) underwent laparoscopic antegrade continence enema. Of the patients 21 were discharged home on postoperative day 1. Mean operative time was 65 minutes (range 30 to 116). In the last 10 patients only 1 working port was used. No perioperative complications were encountered. Mean followup was 24 months (range 1 to 68). Constipation and fecal incontinence resolved in all cases. No patient experienced stomal complications. One obese patient with kyphosis could not pass the catheter beyond the mid appendix at 1 month postoperatively. She had the same problem 1 month following open antegrade continence enema with cecoplication. CONCLUSIONS: Laparoscopic antegrade continence enema is an effective means of treating intractable fecal incontinence and constipation. Our technique of using in situ appendix without cecoplication requires minimal mobilization and manipulation of the blood supply. Secondary ischemia, adhesions and scar formation are reduced, alleviating the most common complication, stomal stenosis. Our results show that cecoplication is not necessary to maintain stomal continence. [Abstract]

Cervellione RM, Bianchi A, Fishwick J, Gaskell SL, Dickson AP
Salvage Procedures to Achieve Continence After Failed Bladder Exstrophy Repair.
J Urol. 2007 Nov 13;
PURPOSE: We assessed the results from a single exstrophy center of salvage continence surgery after failed staged reconstruction for bladder exstrophy. MATERIALS AND METHODS: A total of 32 patients with bladder exstrophy had undergone salvage continence procedures. Indications for surgery included incontinence due to poor bladder capacity or failed bladder neck repair, and upper tract deterioration. Continence was defined according to the International Children's Continence Society as continent, intermittently incontinent and continuously incontinent. RESULTS: A total of 29 patients (91%) are continent, 3 (9%) are intermittently incontinent and none is continuously incontinent. One patient is continent after bladder augmentation and urethral clean intermittent catheterization. Two patients are continent and 1 is intermittently incontinent after bladder augmentation and modified Young-Dees bladder neck repair using urethral clean intermittent catheterization. One patient is continent using clean intermittent catheterization through a continent cutaneous diversion into a bladder substitution. A total of 19 patients are continent after bladder neck closure, bladder augmentation and continent cutaneous diversion using clean intermittent catheterization. Four patients are continent after cutaneous urinary diversion. Two are continent and 2 are intermittently incontinent after a Mainz II pouch. CONCLUSIONS: The majority of patients can still achieve continence following failed staged repair. Patients who have a low bladder leak pressure and who tolerate urethral catheterization can be consistently dry with bladder augmentation and bladder neck repair, which is a viable alternative to bladder neck closure, bladder augmentation and continent cutaneous diversion. Cutaneous urinary diversion has a role in selected patients. Mainz II pouch has not yielded consistent results. With better patient selection and increasing experience within specialist exstrophy centers fewer patients should require salvage continent surgery in the future. [Abstract]

Sarhan O, Zaccaria I, Macher MA, Muller F, Vuillard E, Delezoide AL, Sebag G, Oury JF, Aigrain Y, El-Ghoneimi A
Long-Term Outcome of Prenatally Detected Posterior Urethral Valves: Single Center Study of 65 Cases Managed by Primary Valve Ablation.
J Urol. 2007 Nov 13;
PURPOSE: Management of posterior urethral valves is significantly modified by the prenatal diagnosis. Our aim was to assess long-term outcome of children with prenatally detected posterior urethral valves treated at our institution by primary valve ablation without routine urinary drainage or diversion. MATERIALS AND METHODS: A total of 79 cases of posterior urethral valves were detected prenatally at our hospital between 1987 and 2004. Of these cases 65 were managed postnatally, while pregnancy was terminated in 14. We studied the prenatal parameters of gestational age at diagnosis, renal parenchyma on ultrasound and amniotic fluid volume. Fetal urine was analyzed when indicated. Long-term outcome was assessed. RESULTS: Primary valve ablation was done in all cases except 2. Median followup was 6.8 years (range 1 to 14.3). At the end of followup there were 11 cases of renal failure (17%) with 5 detected before 24 weeks of gestation, 6 cases of oligohydramnios and 9 cases of abnormal parenchyma. Gestational age at diagnosis and oligohydramnios were statistically significant predictors of final renal outcome (p = 0.003 and p = 0.02, respectively), while renal parenchymal changes were not (p = 0.23). When fetal urinalysis detected good prognosis (12 cases) renal failure developed in none, compared to 2 of the 3 cases with a bad prognosis. Continence was achieved in 42 of 55 toilet trained children (76%), 3 had nocturnal enuresis and 10 (18%) were incontinent. CONCLUSIONS: Our long-term results of prenatally detected posterior urethral valves confirm that early valve ablation can be considered as the primary treatment in the majority of patients, without the need for preoperative drainage or diversion. Gestational age at diagnosis and volume of amniotic fluid are significant predictors of postnatal renal outcome. [Abstract]

Cortes D, Kjellberg EM, Breddam M, Thorup J
The True Incidence of Cryptorchidism in Denmark.
J Urol. 2007 Nov 13;
PURPOSE: Considerable controversy exists regarding the recently published high prevalence of cryptorchidism and the actual orchiopexy rate in Denmark. Therefore, we carried out another prevalence study. MATERIALS AND METHODS: The study population included 1,094 consecutive males delivered alive at Glostrup University Hospital during 2002, with a 4-year review of patient data and telephone contact with primary physicians. RESULTS: At birth the overall frequency of cryptorchidism was 2.4% (26 of 1,088 cases, 23% bilateral). The frequency of cryptorchidism in singletons was 2.4% (24 of 1,012 patients). The frequency of cryptorchidism in patients with a birth weight of 2,500 gm or more was 2.1%, compared to 8.2% in those with a birth weight of less than 2,500 gm (chi-square p <0.05). The frequency of cryptorchidism in twins was 2.6% (2 of 76). The frequency of birth weight below 2,500 gm was 51% (39 of 76) in twins and 4.9% (50 of 1,012) in singletons (chi-square p <0.00005). The weight of the placenta was higher in twins (median 1,000 gm) than in singletons (650 gm). At age 4 years 1.6% of the boys had undergone or were waiting to undergo surgery for cryptorchidism, and 0.6% had a diagnosis of retractile testes. CONCLUSIONS: In a small cohort of newborns the incidence of cryptorchidism in Denmark has not changed, and is similar to previous reports from the 1950s. The risk is higher in low birth weight singleton neonates but does not appear to be higher in twins, despite lower birth weight and prematurity. [Abstract]

Chouairy CJ, Abdul-Karim F, Maclennan GT
Adrenocortical Carcinoma.
J Urol. 2007 Nov 13; [Abstract]

Derosa A, Hellstrom WJ, Lang E
Magnetic Resonance Imaging for the Diagnosis and Management of Perineal Hemangiomas in Children.
J Urol. 2007 Nov 13; [Abstract]

Bartsch G, Eggert K, Soker S, Bokemeyer C, Hautmann R, Schuch G
Combined Antiangiogenic Therapy is Superior to Single Inhibitors in a Model of Renal Cell Carcinoma.
J Urol. 2007 Nov 13;
PURPOSE: Similar to cytotoxic drugs, a combination of antiangiogenic factors may lead to an improved treatment response and minimize resistance by targeting different pathways. Therefore, we investigated the effects of a combination of endogenous inhibitors using endostatin, soluble neuropilin-1 and thrombospondin-2 in a renal cell carcinoma model. MATERIALS AND METHODS: Microencapsulated porcine aortic endothelial cells producing endostatin, soluble neuropilin-1 or thrombospondin-2 were tested in vitro and in a murine renal cell carcinoma alone or as a combination of the all 3 factors. Renca cells were applied subcutaneously for local therapy or injected intravenously in a metastatic model. RESULTS: Factors released from microbeads inhibited endothelial cell function but did not affect tumor cell proliferation in vitro. In vivo tumor growth was inhibited similarly by each angiogenic inhibitor alone (0.17, 0.18 and 0.18 gm in endostatin, soluble neuropilin-1 and thrombospondin-2 treated mice vs 1.3 gm in controls). The combination of all 3 inhibitors further decreased tumor weight (0.03 gm). In the metastatic model treatment with angiogenic inhibitors induced a significant reduction in the size and number of lung metastases with additive effects when factors were used in combination. CONCLUSIONS: The combination of angiogenic inhibitors was superior to single factors, suggesting additive activity. These data support the strategy of combining angiogenic inhibitors to accomplish a complete angiogenic blockade. [Abstract]

Breda A, Lam JS, Riggs S, Leppert JT, Gui D, Said JW, Schulam PG, Belldegrun AS
In Vivo Efficacy of Laparoscopic Assisted Percutaneous Renal Cryotherapy: Evidence Based Guidelines for the Practicing Urologist.
J Urol. 2007 Nov 13;
PURPOSE: The treatment of small renal tumors continues to evolve in parallel with advances in ablative technology. We compared the lesion geometry of 3, 17 gauge cryoneedles to determine the most effective distance and configuration of the cryoneedles in an in vivo porcine kidney model. MATERIALS AND METHODS: Argon gas based renal cryoablation was performed in 6 pigs using a laparoscopically assisted percutaneous approach. Cryoablation using a single cryoneedle and a template of 3 cryoneedles with various ice ball shapes, including elliptical, bulb-shaped and standard 17 gauge cryoneedles (Galil Medical, Plymouth Meadow, Pennsylvania) was performed in 3 pigs. Three additional pigs underwent renal cryoablation using elliptical cryoneedles in 3 triangular template configurations with the cryoneedles spaced 1, 1.5 and 2 cm apart, respectively. The animals were sacrificed a minimum of 2 weeks following treatment. RESULTS: Elliptical cryoneedles achieved the largest area of necrosis when used in single and template configurations. When used in a template configuration of 3 needles 1, 1.5 and 2 cm apart from each other the calculated volume of necrosis was 4.3 x 4.5 x 2.5, 4.9 x 4.1 x 2.5 and 4.0 x 4.5 x 2.5 cm, respectively. CONCLUSIONS: Using a single 17 gauge cryoneedle is inadequate for treating most small renal tumors. Cryoneedles with an elliptical ice ball are most effective for achieving consistent and reliable tissue destruction. The 1.5 cm template configuration generated the largest area of necrosis. Our data suggest that with the current technology renal cryoablation should be limited to lesions not greater than 4 cm. [Abstract]

Seligson DB, Rajasekaran SA, Yu H, Liu X, Eeva M, Tze S, Balljr W, Horvath S, Dekernion JB, Rajasekaran AK
Na,K-Adenosine Triphosphatase alpha(1)-Subunit Predicts Survival of Renal Clear Cell Carcinoma.
J Urol. 2007 Nov 13;
PURPOSE: Na,K-adenosine triphosphatase, which is composed of a catalytic alpha-subunit and a regulatory beta-subunit, generates an electrochemical gradient across the plasma membrane. Previous studies demonstrated altered Na,K-adenosine triphosphatase subunit expression in renal clear cell carcinoma and an association of subunit levels with the prediction of recurrent bladder cancer. We determined the clinical association of protein expression patterns of the Na,K-adenosine triphosphatase alpha(1) and beta(1)-subunits in renal clear cell carcinoma using tissue microarrays with linked clinicopathological data. MATERIALS AND METHODS: The UCLA kidney cancer tissue microarray was used to investigate the protein expression of Na,K-adenosine triphosphatase alpha(1) and beta(1)-subunits by immunohistochemistry in 342 patients with renal clear cell carcinoma who were treated with radical nephrectomy. Of these patients clinical outcomes studies were performed in 317. The resultant expression reactivity was correlated with clinicopathological variables. RESULTS: We found that the alpha(1)-subunit was a significant and independent predictor of disease specific death from renal clear cell carcinoma on multivariate Cox proportional hazards analysis that included established prognostic factors Eastern Cooperative Oncology Group performance status, pT status, metastasis status and tumor grade. Significance was found when examining all patients with clear cell renal cell carcinoma as well as patient substrata with low or high grade tumors and localized or metastatic disease, suggesting that the Na,K-adenosine triphosphatase alpha(1)-subunit could be used as a new prognosticator for disease specific death from renal clear cell carcinoma. CONCLUSIONS: These results suggest that Na,K-adenosine triphosphatase alpha(1)-subunit expression patterns may be a useful clinical prognosticator for renal clear cell carcinoma. The Na,K-adenosine triphosphatase beta(1)-subunit was not found to be a useful prognosticator in this setting. [Abstract]

Ellinger J, El Kassem N, Heukamp LC, Matthews S, Cubukluoz F, Kahl P, Perabo FG, Müller SC, von Ruecker A, Bastian PJ
Hypermethylation of Cell-Free Serum DNA Indicates Worse Outcome in Patients With Bladder Cancer.
J Urol. 2007 Nov 13;
PURPOSE: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer. MATERIALS AND METHODS: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment. RESULTS: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%), PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including APC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and APC, or APC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation. CONCLUSIONS: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker. [Abstract]

Kassouf W, Black PC, Tuziak T, Bondaruk J, Lee S, Brown GA, Adam L, Wei C, Baggerly K, Bar-Eli M, McConkey D, Czerniak B, Dinney CP
Distinctive Expression Pattern of ErbB Family Receptors Signifies an Aggressive Variant of Bladder Cancer.
J Urol. 2007 Nov 13;
PURPOSE: Expression of various members of the ErbB family (epidermal growth factor receptor/ErbB-1, ErbB-2, ErbB-3 and ErbB-4) is associated with disease stage and survival in patients with urothelial carcinoma. We examined the correlation of ErbB family receptor expression with the progression of urothelial carcinoma and survival. MATERIALS AND METHODS: A urothelial carcinoma tissue array was constructed from 248 archival paraffin blocks and quality control studies were ascertained. The tissue microarray was stained for epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4, and analyzed using an automated reader. Patient data included grade, stage, growth pattern, recurrence and survival. RESULTS: Kaplan-Meier estimates of 5-year overall and recurrence-free survival were 58% and 27%, respectively. Patients with high grade, invasive or nonpapillary disease had a worse prognosis than patients with low grade, superficial or papillary disease (p <0.0001). High epidermal growth factor receptor or low ErbB-4 expression was associated with nonpapillary, high grade and invasive tumors as well as with significantly shorter recurrence-free and overall survival (p <0.002, 0.028 and 0.047, respectively). Levels of ErbB-2 and ErbB-3 expression were not associated with overall or recurrence-free survival. CONCLUSIONS: The expression profiles of ErbB-4 and epidermal growth factor receptor are prognostic in urothelial carcinoma. They may help in selecting patients at high risk with bladder cancer for more aggressive therapy. [Abstract]

Saitoh C, Chancellor MB, de Groat WC, Yoshimura N
Effects of Intravesical Instillation of Resiniferatoxin on Bladder Function and Nociceptive Behavior in Freely Moving, Conscious Rats.
J Urol. 2007 Nov 13;
PURPOSE: A new animal model in which to concurrently evaluate bladder function and nociceptive behavior was developed using freely moving, noncatheterized, conscious rats to assess the nociceptive behavior responses induced by intravesical instillation of resiniferatoxin (Sigma(R)) and its relationship with bladder dysfunction. MATERIALS AND METHODS: In female Sprague-Dawley rats resiniferatoxin (0, 0.3 and 3 muM) was instilled via a catheter that was temporarily inserted into the bladder through the urethra. After removing the catheter the incidence of nociceptive behavior (lower abdominal licking and freezing) was scored. Voided urine was collected continuously to measure bladder capacity. In some rats the pudendal nerves were transected bilaterally to eliminate the activation of urethral afferents by resiniferatoxin. RESULTS: Intravesical instillation of resiniferatoxin induced decreased bladder capacity and increased nociceptive behaviors, such as licking and freezing, which were blocked by the transient receptor potential vanilloid receptor 1 antagonist BCTC (Biomoltrade mark). In rats with pudendal nerve transection the early phase of resiniferatoxin induced licking was decreased without affecting the resiniferatoxin induced decrease in bladder capacity and late phase licking behavior. Resiniferatoxin induced late phase licking in the water unloaded group was observed to a lesser extent than in the water loaded diuresis group. CONCLUSIONS: The intravesical instillation of resiniferatoxin, which decreases bladder capacity, acts by at least 3 distinct mechanisms to induce licking behavior, including 1) an immediate response mediated by the activation of urethral afferents in the pudendal nerve, 2) a late response evoked by the direct stimulation of C-fiber afferents in the bladder and 3) gradual facilitation of the response elicited by the bladder wall distention induced by rapid bladder filling. [Abstract]

Giuliani S, Perin L, Sedrakyan S, Kokorowski P, Jin D, Filippo RD
Ex Vivo Whole Embryonic Kidney Culture: A Novel Method for Research in Development, Regeneration and Transplantation.
J Urol. 2007 Nov 13;
PURPOSE: Whole metanephric organ culture represents a novel investigatory approach with potential application in many aspects of research in kidney regeneration and transplantation. We report the current status of embryonic kidney culture, discussing issues such as the appropriate culture conditions and methods, histological results, values of and limitations to the different techniques used today. To optimize this system in vitro for the benefit of future studies we focused our efforts on evaluating and developing a new durable 3-dimensional organ culture system using a uniquely modified approach. MATERIALS AND METHODS: Metanephric kidneys were microdissected from the embryos of timed pregnant WT C57BL/C6 mice on days 12 to 16 of gestation (embryonic days 12 to 16). Novel perfusion channels were created in the harvested embryonic kidneys before placing them in culture. Embryonic kidneys were placed on a 0.4 mum pore size Transwell(R) membrane, cultured in base medium at a medium gas interphase and incubated at 37C with fully humidified 5% CO(2). Histological and immunocytochemical analysis was performed to evaluate for signs of necrosis, and the structural integrity and functionality of organs during culture. RESULTS: We confirmed histologically that our organ culture system was capable of maintaining normal kidney structures significantly longer (mean 10 days) than previously reported standard protocols. Condensation and aggregation of the metanephric mesenchyma at the tips of the ureteral bud were observed, including the formation of well developed nephrons and glomeruli without evidence of necrosis. Organ maturation occurred in a developmentally appropriate centrifugal pattern and the expression of key regulatory factors was demonstrated. CONCLUSIONS: Our in vitro model replicates closely the in vivo processes involved in normal kidney development. We also present what is to our knowledge the first demonstration of a durable 3-dimensional kidney culture system reported in the literature. This system may represent an uncomplicated method for in vitro kidney culture that we hope will serve as an effective adjunct to research focused on signaling pathways, development and regeneration as applied to the kidney. [Abstract]

Keller AK, Jorgensen TM, Olsen LH, Stolle LB
Early Detection of Renal Ischemia by In Situ Microdialysis: An Experimental Study.
J Urol. 2007 Nov 13;
PURPOSE: Acute vascular thrombosis of the renal artery or vein is a feared and devastating complication after renal operations, especially transplantation. We evaluated microdialysis as a possible new tool for the rapid and reliable detection of renal ischemia in a porcine model. MATERIALS AND METHODS: A total of 20 healthy anesthetized pigs were randomized to experiments on the left or right kidney and into 3 groups, including arterial ischemia in 8, venous ischemia in 8 and 4 controls. One microdialysis catheter was inserted superficially in the renal cortex and 1 was placed outside on the renal capsule. The contralateral kidney was removed. After 2 hours of baseline measurements ischemia was introduced by clamping the renal artery or vein in the first 2 groups. Microdialysis samples were taken every 30 minutes during baseline and the following 5 hours. The samples were analyzed for glucose, lactate, glutamate and glycerol. The mean change from baseline was analyzed for each metabolite in all groups. RESULTS: At 30 minutes after the introduction of arterial or venous ischemia there was a significant increased mean change from baseline of glutamate, glycerol and lactate in the cortex and of glutamate extracapsularly. The mean change from baseline of glucose in the cortex decreased significantly 60 minutes after venous ischemia and 90 minutes after arterial ischemia. In controls these metabolites did not change significantly from baseline with time. CONCLUSIONS: Microdialysis from just outside the renal capsule is a reliable tool for the early detection of acute renal ischemia. It may be used to detect acute vascular complications in the first days after renal transplantation. [Abstract]

Stahl BC, Ratliff TL, De Young BR, Wald M
Involvement of Growth Factors in the Process of Post-Vasectomy Micro-Recanalization.
J Urol. 2007 Nov 13;
PURPOSE: We investigated the role of growth factors in the process of post-vasectomy micro-recanalization using real-time polymerase chain reaction, enzyme-linked immunosorbent assay and histopathological analyses of the vasectomy sites and controls at different time points in a rat model. MATERIALS AND METHODS: Unilateral vasectomies were performed in 18 rats with sham surgery on the contralateral side. Vasectomy sites and vas segments of similar length from the sham operated sides were taken for analysis at 2, 8 and 12 weeks. Real-time polymerase chain reaction was used to test the expression of mRNA of 7 common growth factors and select growth factor receptors. Enzyme-linked immunosorbent assay was performed for growth factors with strong positive polymerase chain reaction findings. Histopathological examination was performed by a staff pathologist (BRD) to detect micro-recanalization, defined as tubules visible on hematoxylin and eosin staining with an epithelial lining of cuboidal or columnar cells. RESULTS: Micro-canals were found in 2 of 18 rat specimens. Real-time polymerase chain reaction of all specimens demonstrated a 12-fold increase in platelet-derived growth factor-beta, a 6-fold increase in platelet-derived growth factor-beta receptor, an 11-fold increase in platelet-derived growth factor-alpha, a 7-fold increase in platelet-derived growth factor-alpha receptor and a 9-fold increase in transforming growth factor-beta compared to the sham operated side. All increases were sustained and statistically significant (p <0.05). Enzyme-linked immunosorbent assay revealed statistically significantly increased expression of platelet-derived growth factor-beta protein. CONCLUSIONS: The demonstrated micro-recanalization and sustained growth factor up-regulation at vasectomy sites suggest a possible mechanism for post-vasectomy ejaculate sperm identification. There is a need for further research on the potential role of select growth factors in reconstruction of the male reproductive tract. [Abstract]

Saade RD, Neves PA, Glina S, D'Ancona CA, Dambros M, Lúcio MA
Quantitative (Stereological) and Qualitative Study of Rat Epididymis After Vasectomy and Percutaneous Epididymal Sperm Aspiration.
J Urol. 2007 Nov 13;
PURPOSE: We investigated whether viable spermatozoa could be obtained from the rat epididymis after vasectomy by up to 5 percutaneous epididymal sperm aspiration punctures. We analyzed the inflammatory and scar forming histological alterations to the epididymis due to these punctures. Epididymal smooth muscle fiber and collagen density were also analyzed. MATERIALS AND METHODS: A total of 50 rats that underwent bilateral vasectomy were divided into 5 groups of 10 each. Groups 1 to 5 underwent 1 to 5 right transscrotal percutaneous epididymal sperm aspiration punctures, respectively. Sperm quantification, and histological and stereological analyses were done on the punctured epididymides. RESULTS: A mean of 48.78 x 10(6), 37.55 x 10(6), 26.33 x 10(6), 33.90 x 10(6) and 41.34 x 10(6)/ml spermatozoa were recovered in groups 1 to 5, respectively. A cumulative effect of the punctures was only observed in the variables of lymphoplasmacytic infiltrate and fibrosis, thus, showing that groups 1 and 2 differed significantly from groups 3 to 5. Stereological analysis revealed that conjunctive tissue volumetric density was 21.56%, 27.60%, 35.67%, 37.56%, 38.60% and 22.30% on the punctured side in groups 1 to 5 and controls, respectively (p <0.05). CONCLUSIONS: Spermatozoa were obtained from all groups. All animals showed significant histological alterations in the epididymides from the second puncture and thereafter except with regard to necrosis. The cumulative effect of percutaneous epididymal sperm aspiration was only shown by lymphoplasmacytic infiltrate and fibrosis. Stereological analysis showed increased conjunctive tissue volumetric density from the second puncture and thereafter. [Abstract]

Loughlin KR, Ganatra A
Re: Malignant Ureteral Obstruction: Outcomes After Intervention. Have Things Changed? L. M. Wong, L. K. Cleeve, A. D. Milner and A. G. PitmanJ Urol 2007; 178: 178-183.
J Urol. 2007 Nov 13; [Abstract]

Rushton HG
This Month in Pediatric Urology.
J Urol. 2007 Nov 13; [Abstract]

Atala A
This Month in Investigative Urology.
J Urol. 2007 Nov 13; [Abstract]

Herz DB
Editorial Comment.
J Urol. 2007 Nov 13; [Abstract]

Wan J
Editorial Comment.
J Urol. 2007 Nov 13; [Abstract]

Hensle TW
Editorial Comment.
J Urol. 2007 Nov 13; [Abstract]

Smith MR, Malkowicz SB, Chu F, Forrest J, Price D, Sieber P, Barnette KG, Rodriguez D, Steiner MS
Toremifene Increases Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer: Interim Analysis of a Multicenter Phase 3 Clinical Study.
J Urol. 2007 Nov 12;
PURPOSE: We evaluated the effects of toremifene on bone mineral density, a surrogate for fracture risk, in men receiving androgen deprivation therapy for prostate cancer. MATERIALS AND METHODS: In an ongoing, multicenter, phase 3 fracture prevention study 1,392 men 50 years or older with prostate cancer receiving androgen deprivation therapy were randomized to 80 mg toremifene per day or placebo. Bone mineral density of the lumbar spine, total hip and femoral neck was assessed using dual energy x-ray absorptiometry. In this planned interim analysis of the first 197 subjects we compared bone mineral density changes from baseline to month 12 between the placebo and toremifene groups. RESULTS: Compared with the placebo group men in the toremifene group had significant increases in bone mineral density at each evaluated skeletal site. Lumbar spine bone mineral density decreased 0.7% in the placebo group and increased 1.6% in the toremifene group (between group comparison p <0.001). Total hip bone mineral density decreased 1.3% in the placebo group and increased 0.7% in the toremifene group (p = 0.001). Femoral neck bone mineral density decreased 1.3% in the placebo group and increased 0.2% in the toremifene group (p = 0.009). Between group differences in the change in bone mineral density from baseline to month 12 were 2.3%, 2.0% and 1.5% for the lumbar spine, total hip and femoral neck, respectively. CONCLUSIONS: Toremifene significantly increased hip and spine bone mineral density in men receiving androgen deprivation therapy for prostate cancer. The effect of toremifene on the fracture risk is being assessed in the ongoing randomized, controlled trial. [Abstract]

Makarov DV, Humphreys EB, Mangold LA, Carducci MA, Partin AW, Eisenberger MA, Walsh PC, Trock BJ
The Natural History of Men Treated With Deferred Androgen Deprivation Therapy in Whom Metastatic Prostate Cancer Developed Following Radical Prostatectomy.
J Urol. 2007 Nov 12;
PURPOSE: We report on the natural history and factors influencing the prognosis of a cohort of hormone naïve, prostate specific antigen era patients in whom metastatic prostate cancer developed after radical prostatectomy who were followed closely and treated with deferred androgen deprivation therapy at the time of metastasis. MATERIALS AND METHODS: A total of 3,096 men underwent radical prostatectomy performed by a single surgeon at Johns Hopkins Hospital between 1987 and 2005. Of these men 422 had prostate specific antigen failure. Distant metastasis developed in 123 patients, of whom 91 with complete data formed the study cohort initially treated during the prostate specific antigen era (1987 to 2005) and receiving androgen deprivation therapy after documented metastasis. A total of 41 men died of prostate cancer. Median survival times were estimated by Kaplan-Meier analysis. Prognostic impact was estimated as the hazard ratio derived from the Cox proportional hazards model. RESULTS: Median followup from radical prostatectomy was 120 months (range 24 to 216). Kaplan-Meier median (range) times to failure were 24 months (12 to 144) from radical prostatectomy to prostate specific antigen failure, 36 months (0 to 132) from prostate specific antigen failure to metastasis, 84 months (12 to 180) from metastasis to death and 168 months (24 to 216) from radical prostatectomy to death. Statistically significant univariate risk factors for prostate cancer specific mortality at the time of metastasis were pain at diagnosis of metastases (p = 0.002), time from radical prostatectomy to metastasis (p = 0.024) and prostate specific antigen doubling time less than 3 months during the 24 months before metastasis (p = 0.016). Multivariable analysis demonstrated independent predictors of prostate cancer specific mortality at the time of metastasis, namely pain (HR 3.5, p = 0.003) and prostate specific antigen doubling time less than 3 months (HR 3.4, p = 0.017). CONCLUSIONS: Men treated with deferred androgen deprivation therapy for the development of metastasis after radical prostatectomy may have a long life span, 169 months after radical prostatectomy (range 24 to 216). The presence of pain and short prostate specific antigen doubling time predicted an unfavorable outcome. [Abstract]

Westermann DH, Schefer H, Thalmann GN, Karamitopoulou-Diamantis E, Fey MF, Studer UE
Long-Term Followup Results of 1 Cycle of Adjuvant Bleomycin, Etoposide and Cisplatin Chemotherapy for High Risk Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis.
J Urol. 2007 Nov 12;
PURPOSE: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. RESULTS: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. CONCLUSIONS: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection. [Abstract]

Abreu DA, Osorio F, Guido LG, Carvalhal GF, Mouro L
Retroperitoneal Infections by Community Acquired Methicillin Resistant Staphylococcus Aureus.
J Urol. 2007 Nov 12;
PURPOSE: We describe the clinical presentation and response to treatment of community acquired, methicillin resistant Staphylococcus aureus retroperitoneal infections. MATERIALS AND METHODS: A total of 13 patients with unusual retroperitoneal infections who fulfilled Centers for Disease Control criteria for community acquired, methicillin resistant S. aureus were included in this multicenter study, which was done from May 2004 to June 2005. Distinctive features of these infections were noted and treatment alternatives are proposed. RESULTS: Mean patient age was 32 years and 85% of the patients were male. All 13 patients presented with back pain and fever. Infected skin lesions were the presumed portals of entry for bacteria in all cases. Mean time between skin infection and lumbar pain was 48 days. After lumbar pain was established a retroperitoneal abscess was diagnosed at a mean delay of 11 days. An association of foci (kidney, perinephric tissue and psoas) occurred in 85% of cases. Perinephric tissue was the most affected site. Of note, all patients presented with anemia and low serum prothrombin, and required drainage of the retroperitoneal collection. Open drainage was performed in all except 1 patient, in whom percutaneous drainage and antibiotic treatment were sufficient. In 1 patient nephrectomy was necessary. Specific antibiotics were administered as soon as culture results were obtained. Sensitivity was 100% to vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin and gentamicin. There were no deaths. CONCLUSIONS: Three characteristics shared by our patients should be given special consideration, including an infected skin lesion as the possible portal of entry, anemia plus hypoprothrombinemia and frequent involvement of the perinephric region. Treatment with drainage and antibiotic therapy was effective in all cases. [Abstract]

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Recent Articles in Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association

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Delanaye P, Cavalier E, Krzesinski JM, Mariat C
Cystatin C-based Equations: Don't Repeat the Same Errors with Analytical Considerations.
Nephrol Dial Transplant. 2007 Dec 9; . [Abstract]

Lankisch PG, Weber-Dany B, Maisonneuve P, Lowenfels AB
Frequency and Severity of Acute Pancreatitis in Chronic Dialysis Patients.
Nephrol Dial Transplant. 2007 Dec 9;
BACKGROUND: The incidence and severity of acute pancreatitis in patients undergoing dialysis treatment are unknown. METHODS: A questionnaire asking for the incidence and the severity of a first attack of acute pancreatitis in chronic dialysis patients in the year 2002 was sent to the members of QuaSi-Niere gGmbH, an organization representing almost all dialysis centres in Germany. A second questionnaire was sent to those who reported such patients. Results. Response rates for the first and second questionnaire were 72% (832 out of 1150 centres) and 100% (72 out of 72 centres), respectively. After the exclusion of patients with invalid data, 55 patients with acute pancreatitis remained: 46 patients out of 68 715 haemodialysis (HD) patients (incidence rate 67/100 000/year; 95% confidence interval, 49 to 89/100 000/year) and 9 out of 3386 peritoneal dialysis (PD) patients (incidence rate 266/100 000/year; 95% confidence interval, 122 to 504/100 000/year; Fisher's exact test: P = 0.002). Twenty-eight patients (51%) had a known risk factor for acute pancreatitis. When these were excluded, the incidence of pancreatitis of unknown aetiology was 32/100 000/year (20-48) for HD patients (n, 22) and 148/100 000/year (48-345) for PD patients (n, 3; Fisher's exact test: P = 0.016). PD patients required hospital admission more frequently than HD patients (100% versus 76%) and suffered more frequently from necrotizing pancreatitis (50% versus 19%). CONCLUSIONS: Dialysis-especially PD-is another risk factor that increases the susceptibility of the pancreas to acute pancreatitis. Acute pancreatitis in patients undergoing PD is more frequent and seems to be more severe than in those receiving HD treatment. [Abstract]

Majchrzak KM, Pupim LB, Flakoll PJ, Ikizler TA
Resistance Exercise Augments the Acute Anabolic Effects of Intradialytic Oral Nutritional Supplementation.
Nephrol Dial Transplant. 2007 Dec 9;
Background. An intriguing strategy to further enhance the anabolic effects of nutritional supplementation is to combine the administration of nutrients with resistance exercise. We hypothesized that the addition of resistance exercise to oral nutrition supplementation would lead to further increases in skeletal muscle protein accretion when compared to nutritional supplementation alone in chronic haemodialysis (CHD) patients. Methods. We performed stable isotope protein kinetic studies in eight CHD patients during two separate settings: with oral nutritional supplementation alone (PO) and oral nutritional supplementation combined with a single bout of resistance exercise (PO + EX). Metabolic assessment was performed before, during and after haemodialysis. Both interventions resulted in robust protein anabolic response. Results. There were no differences in metabolic hormones, plasma amino acid and whole-body protein balance between the interventions. During the post-HD phase, PO + EX retained a positive total amino acid (TAA) balance (primarily due to essential amino acid) while PO returned to a negative TAA balance although this difference did not reach statistical significance (78 +/- 109 versus -128 +/- 72 nmol/100 ml/min, respectively; P = 0.69). In the post-HD phase, PO + EX had significantly higher net muscle protein balance when compared to PO (19 +/- 16 versus -24 +/- 10 mug/100 ml/min, respectively; P = 0.036) We conclude that a single bout of resistance exercise augments the protein anabolic effects of oral intradialytic nutritional supplementation when examining skeletal muscle protein turnover. [Abstract]

Hohenstein B, Hugo CP, Hausknecht B, Boehmer KP, Riess RH, Schmieder RE
Analysis of NO-Synthase Expression and Clinical Risk Factors in Human Diabetic Nephropathy.
Nephrol Dial Transplant. 2007 Dec 9;
Background. Changes of renal nitric oxide (NO) production have been associated with glomerular hyperfiltration, vascular permeability, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Several studies demonstrated an up- as well as downregulated expression of NO-synthases (NOS) in experimental diabetic nephropathy. It is still not yet specified whether the regulation and activity of NOS is changed in human diabetic nephropathy. Methods. Renal biopsies and clinical data of 45 patients with diabetic nephropathy and of 10 control subjects were investigated. Glomerular and cortical endothelial NOS (eNOS) and inducible NOS (iNOS) expression were assessed by immunohistochemical staining and related to clinical data such as the duration of diabetes, insulin therapy and arterial hypertension, albuminuria/proteinuria, eGFR according to the formula modification of diet in renal disease (MDRD), presence of vascular complications or diabetic retinopathy. Results. The mean age of patients at biopsy was 60.3 years and the mean duration of diabetes 12.9 years. Expression of cortical and glomerular eNOS was increased in type 2 diabetes (P < 0.05). Increased expression of glomerular and cortical eNOS correlated with more severe vascular complications (r = 0.44; P < 0.05). Glomerular eNOS was strongly increased among different degrees of proteinuria (P < 0.01). In contrast to expression levels of eNOS, the glomerular expression pattern of iNOS changed from an endothelial pattern in glomeruli with preserved morphology towards expression predominantly by inflammatory cells. Conclusions. Thus, increased eNOS expression by the renal endothelium could be demonstrated in type 2 diabetic nephropathy, whereas iNOS was unchanged but spatially differentially expressed. The eNOS expression was related to vascular lesions and the degree of proteinuria. [Abstract]

Hoorn EJ, Betjes MG, Weigel J, Zietse R
Hypernatraemia in Critically Ill Patients: Too Little Water and Too Much Salt.
Nephrol Dial Transplant. 2007 Dec 9;
Background. Our objective was to study the risk factors and mechanisms of hypernatraemia in critically ill patients, a common and potentially serious problem. Methods. In 2005, all patients admitted to the medical, surgical or neurological intensive care unit (ICU) of a university hospital were reviewed. A 1:2 matched case-control study was performed, defining cases as patients who developed a serum sodium >/=150 mmol/l in the ICU. Results. One hundred and thirty cases with ICU-acquired hypernatraemia (141 +/- 3 to 156 +/- 6 mmol/l) were compared to 260 controls. Sepsis (9% versus 2%), hypokalaemia (53% versus 34%), renal dysfunction (53% versus 13%), hypoalbuminaemia (91% versus 55%), the use of mannitol (10% versus 1%) and use of sodium bicarbonate (23% versus 0.4%) were more common in cases (P < 0.05 for all) and were independently associated with hypernatraemia. During the development of hypernatraemia, fluid balance was negative in 80 cases (-31 +/- 2 ml/kg/day), but positive in 50 cases (72 +/- 3 ml/kg/day). Cases with a positive fluid balance received more sodium plus potassium (148 +/- 2 versus 133 +/- 3 mmol/l, P < 0.001). On average, cases were polyuric (40 +/- 5 ml/kg). Mortality was higher in cases (48% versus 10%, P < 0.001), for which hypernatraemia was an independent predictor (odds ratio 4.3, 95% confidence interval 2.5 to 7.2). Conclusions. Hypernatraemia seems to develop in the ICU because various factors promote renal water loss, which is then corrected with too little water or overcorrected with relatively hypertonic fluids. Therapy should therefore rely on adding electrolyte-free water and/or creating a negative sodium balance. Adjustments in intravenous fluid regimens may prevent hypernatraemia. [Abstract]

Richards N, Harris K, Whitfield M, O'Donoghue D, Lewis R, Mansell M, Thomas S, Townend J, Eames M, Marcelli D
Primary Care-Based Disease Management of Chronic Kidney Disease (CKD), Based on Estimated Glomerular Filtration Rate (eGFR) Reporting, Improves Patient Outcomes.
Nephrol Dial Transplant. 2007 Dec 9;
BACKGROUND: The majority of patients with chronic kidney disease (CKD) stages 3-5 are managed within primary care. We describe the effects, on patient outcomes, of the introduction of an algorithm-based, primary care disease management programme (DMP) for patients with CKD based on automated diagnosis using estimated glomerular filtration rate (eGFR) reporting. METHODS: Patients within West Lincolnshire Primary Care Trust, UK, population 223, 287 with CKD stage 4 or 5 were enrolled within the DMP between March 2005 and October 2006. We have analysed the performance against clinical targets looking at a change in renal function prior to and following joining the DMP and the proportion of patients achieving clinical targets for blood pressure control and lipid abnormalities. RESULTS: Four hundred and eighty-three patients with CKD stage 4 or 5 were enrolled in the programme. There were significant improvements in the following parameters, expressed as median values (interquartile range) after 9 months in the programme, compared to baseline and percentage values patients achieving target at 9 months: total cholesterol 4.2 (3.45-5.0) mmol/l versus 4.6 (3.9-5.4) mmol/l (P < 0.01), 75.0% versus 64.5% (P < 0.001); LDL 2.2 (1.6-2.8) mmol/l versus 2.5 (1.9-3.2) mmol/l (P < 0.01), 81.9% versus 69.2% (P < 0.05); systolic blood pressure 130 (125-145) mmHg versus 139 (124-154) mmHg (P < 0.05), 56.2% versus 37.1% (P < 0.05) and diastolic blood pressure 71 (65-79) mmHg versus 76 (69-84) mmHg (P < 0.01), 68.4% versus 90.3% (P < 0.01). The median fall (interquartile range) in eGFR in the 9 months prior to joining the programme was 3.69 (1.49-7.46) ml/min/1.73 m(2) compared to 0.32 (-2.61-3.12) ml/min/1.73 m(2) in the 12 months after enrolment (P < 0.001). One hundred and twenty-two patients experienced a fall in eGFR of >/=5 ml/min/1.73 m(2), median 9.90 (6.55-12.36) ml/min/1.73 m(2) in the 9 months prior to joining the programme, whilst in the 12 months after enrolment, their median fall in eGFR was -1.70 (-6.41-1.64) ml/min/1.73 m(2) (P < 0.001). In the remaining patients, the median fall in eGFR was 1.92 (0.41-3.23) ml/min/1.73 m(2) prior to joining the programme and 0.86 (-1.03-3.53) ml/min/1.73 m(2) in the 12 months after enrolment (P = 0.082). CONCLUSIONS: These data suggest that chronic disease management in this form is an effective method of identifying and managing patients with CKD within the UK. The improvement in cardiovascular risk factors and reduction in the rate of decline of renal function potentially have significant health benefits for the patients and should result in cost savings for the health economy. [Abstract]

Ahmed MS, Wong CF
Rituximab and Nephrotic Syndrome: a New Therapeutic Hope?
Nephrol Dial Transplant. 2007 Dec 9; [Abstract]

Hu W, Liu C, Xie H, Chen H, Liu Z, Li L
Mycophenolate Mofetil Versus Cyclophosphamide for Inducing Remission of ANCA Vasculitis with Moderate Renal Involvement.
Nephrol Dial Transplant. 2007 Dec 8;
Objective. We performed a single-centre non-blinded clinical trial to compare the clinical efficacies of mycophenolate mofetil (MMF) and intermittent cyclophosphamide (CTX) pulse therapy as induction treatments in patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis (AAV) and moderate renal involvement. Methods. Patients with active AAV and serum creatinine <500 mumol/L received either MMF treatment (MMF group) or monthly CTX pulse therapy (CTX group) for 6 months. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). The disease activity, remission rate, renal function and adverse reactions were compared between the two groups. Results. A total of 35 patients (15 male, 20 female: aged 49.1 +/- 12.2 years) were enrolled, with 18 in the MMF group and 17 in the CTX group. Of the 35 patients, 28 were MPO-ANCA positive and 2 were PR3-ANCA positive. Four patients were lost to follow-up in the CTX group. At Month 6, BVAS scores were much lower in the MMF group than in the CTX group (0.2 +/- 0.89 versus 2.6 +/- 1.7, P < 0.05). In the intent-to-treatment analysis, 14 of 18 patients (77.8%) treated with MMF and 8 of 17 patients receiving CTX (47.1%) had complete remission with an absolute difference of 30.7%. Eight of 18 patients (44.4%) in the MMF group and 2 of 17 patients (15.4%) in the CTX group recovered renal function. Serum ANCA decreased to normal in 41.7% of patients in the MMF group and in 16.7% in the CTX group. Side effects in the MMF group were pneumonia (1), herpes zoster (1) and gastrointestinal symptoms (2), and in the CTX group were leukocytopenia (1), gastrointestinal distress (4) and pneumonia (1). Conclusion. Our study suggests that MMF effectively ameliorates disease activity and considerably improves renal function in patients with AAV. Further large-scale multicentre prospective randomized controlled trials will be needed to confirm these findings. [Abstract]

Paulsen L, Holm C, Bech JN, Starklint J, Pedersen EB
Effects of Statins on Renal Sodium and Water Handling: Acute and short-term effects of atorvastatin on renal haemodynamics, tubular function, vasoactive hormones, blood pressure and pulse rate in healthy, normocholesterolemic humans.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: Statins have a beneficial effect on cardiovascular morbidity and mortality due to a reduction in plasma cholesterol. However, statins seem to have effects beyond the lowering of plasma cholesterol. We hypothesize that these effects are caused by an effect on renal function. METHODS: We measured the effects of atorvastatin (AS) on renal function in two randomized, placebo-controlled, double-blinded and crossover studies in healthy man. In an acute trial (Study 1), 19 subjects received either 80 mg AS as a single dose or placebo. In a short-term trial (Study 2), 20 subjects received either 80 mg AS or placebo daily for 4 weeks. In both studies glomerular filtration rate (GFR), renal plasma flow (RPF), plasma concentrations of angiotensin II (Ang II), renin (PRC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP) and blood pressure (BP) were determined. RESULTS: In Study 1 AS decreased fractional excretion of sodium (FE(Na)) significantly (P = 0.035), but very modestly, and reduced diastolic BP (P = 0.024). Apart from this, we found no significant differences in GFR, RPF, tubular function and vasoactive hormones in either Study 1 or 2. CONCLUSIONS: An acute dose of AS decreased FE(Na) and DBP in healthy humans. The reduction in fractional urinary sodium excretion was very modest and transitory, and most likely secondary to the fall in diastolic blood pressure (DBP). However, renal haemodynamics, tubular function, vasoactive hormones and blood pressure were unchanged during short-term statin treatment in healthy man. [Abstract]

Hoek FJ, Korevaar JC, Dekker FW, Boeschoten EW, Krediet RT
Reply-Cystatin C for Estimation of Residual GFR.
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Emem CP, Arogundade F, Sanusi A, Adelusola K, Wokoma F, Akinsola A
Renal Disease in HIV-Seropositive Patients in Nigeria: an Assessment of Prevalence, Clinical Features and Risk Factors.
Nephrol Dial Transplant. 2007 Dec 8;
In order to determine the pattern of renal disease and risk factors for renal disease in HIV-infected Nigerians, we studied 400 consecutive HIV/AIDS patients (210 males, 190 females) aged between 18 and 65 years (mean +/- SD; 34.6 +/- 9.4 years), and examined renal disease factors attributable to the infection. Diagnosis of renal disease was based on the consistent presence of at least 1+ albuminuria and/or elevated serum creatinine (>132 mumol/l) as well as the absence of other identifiable causes of chronic kidney disease (CKD). We determined socio-demography and clinical findings, as well as full laboratory work-ups including haemogram, CD4+ cell count, serum electrolytes, urea, creatinine, protein, cholesterol and urine analysis. Renal biopsies were taken in 10 patients who had moderate to massive proteinuria and had consented to the procedure. Finally, we compared HIV/AIDS cases with and without renal disease to determine the risk factors for nephropathy. We observed a high prevalence of renal disease (proteinuria and/or elevated serum creatinine), which was present in 152 (38%) of the patients. This subgroup included 74 males and 78 females with a M:F ratio of 1:1. The mean age (+/-SD) was 35.8 (+/-10.01) years. Systolic and/or diastolic hypertension was seen in 13.2% of these patients while the mean (+/- SD) body mass index (BMI) and packed cell volume (PCV) were 18.5 (+/-3.1) kg/m(2) and 25.26 (+/-6.81)%, respectively. The mean (+/-SD) CD4+ count was 246.49 (+/-192.8) cells/mul, while the mean (+/-SD) serum creatinine and 24-h urine protein excretion rates were 210.11 (+/-337.8) mumol/l and 2.57 (+/- 2.42) g/day, respectively. In subjects with and without nephropathy, there were significant differences in age, BMI, serum cholesterol, serum albumin and CD4+ counts, suggesting that these parameters may be risk factors for nephropathy. Histology revealed mainly focal glomerulosclerosis (FGS) with glomerular collapse. We conclude that the prevalence of proteinuria in HIV-seropositive patients is high in Nigeria. Such subjects show an equal male:female distribution, and glomerular histology revealed that a majority of biopsied patients had the collapsing FSGS variant. The risk factors for renal disease included severity of the HIV infection (inferred from the generally low CD4+ count), anaemia, malnutrition and increasing age. [Abstract]

Feinstein S, Rinat C, Becker-Cohen R, Ben-Shalom E, Schwartz SB, Frishberg Y
The Outcome of Chronic Dialysis in Infants and Toddlers Advantages and Drawbacks of Haemodialysis.
Nephrol Dial Transplant. 2007 Dec 8;
Background. Improvements in dialysis technology allow replacement therapy for even the youngest of children with end stage renal disease. Nevertheless, the cumulative experience in this age group is limited. Methods. We compared the outcome of 20 children who initiated chronic dialysis before the age of 1 year (weight 4.9 +/- 2 kg, Group 1), with a particular focus on those under the age of 1 month (eight children, weight 2.9 +/- 0.34), to that of 14 patients, aged 1.1-3 years when starting dialysis (weight 10.1 +/- 1.7, Group 2). Results. The outcome was poor in the youngest age group; only 3/8 survived to 3 years. Of those who started dialysis between the ages of 0.3 and 3 years, 84% underwent kidney transplantation. The survival of 1-, 3-, 5- and 8-year-old patients was 96%, 88%, 84% and 84% respectively. Severe co-morbidities were present in almost half of those who died. Hospital stay was 3.5 times longer in Group 1 than in Group 2 during the first 3 months of dialysis. Permanent central venous catheters inserted under ultrasound guidance resulted in a 4.4-fold increase in catheter survival compared to non-cuffed catheters. Marked blood loss at beginning of haemodialysis (HD) is attributable to residual volume in the dialysis system (15.7 mL/kg/month) and frequent blood tests (12.1 +/- 5.9 mL/kg/month). These values decreased 2-fold after 8 months of treatment. Conclusions. The main factors determining the poor outcome of infants on dialysis are extremely young age at initiation and severe co-morbidities. Despite some disadvantages, HD may be successfully implemented in infants and toddlers, in highly specialized centres with a well-trained nursing staff. [Abstract]

Ranjan P, Nada R, Jha V, Sakhuja V, Joshi K
The Role of C4d Immunostaining in the Evaluation of the Causes of Renal Allograft Dysfunction.
Nephrol Dial Transplant. 2007 Dec 8;
Background. Renal biopsy is the gold standard for diagnosis of acute rejection in renal transplant recipients. The Banff (1997) classification was revised in 2003 incorporating morphological criteria and C4d immunostaining for the diagnosis of acute antibody-mediated rejection. Aims. The aim of this study was to evaluate the role of histomorphology and C4d immunostaining in indicated renal allograft biopsies with a clinical follow-up for a minimum duration of 1 year. Material and methods. Histological analysis and C4d immunostaining were performed on 132 needle core biopsies and 2 nephrectomy specimens from 107 patients from July 2004 to June 2005. Results. Histological analysis revealed 59 cases of acute rejection, 10 biopsies of acute tubular necrosis, 41 cases of chronic allograft nephropathy (CAN), either alone or in combination with other diseases, and 18 biopsies of normal morphology. There were four cases of BK nephropathy (BK N) and eight cases had miscellaneous diagnoses. C4d immunostaining was performed on 126 biopsies. Overall, the prevalence of C4d positivity was 45% (57 of 126). Fifty-five percent (28 of 51) of the cases of acute rejection showed C4d positivity including 81% of presumptive antibody-mediated rejection (P-AbAR), 20% acute cellular rejection and 58% acute cellular rejection + P-AbAR. Overall C4d positivity was 37% in chronic allograft nephropathy. Acute tubular necrosis and borderline rejection showed 25 and 50% C4d positivity, respectively. Amongst various histological features, capillary margination of polymorphs and dilatation of peritubular capillaries (PTC-D) showed significant association with C4d positivity (P < 0.005). In cases of CAN, transplant glomerulopathy had significant association with C4d positivity. C4d-positive cases had a higher mean value of serum creatinine at the time of biopsies. Conclusion. It is concluded that C4d staining is a useful adjunct marker of the humoral limb of rejection, both in early and late post-transplant periods. [Abstract]

Janus N, Vacher LV, Karie S, Ledneva E, Deray G
Vaccination and Chronic Kidney Disease.
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, Loirat C, Ozaltin F, Hashmi S, Ulmer F, Cleper R, Ettenger R, Antignac C, Wiggins RC, Zenker M, Hildebrandt F
Mutations in PLCE1 are a Major Cause of Isolated Diffuse Mesangial Sclerosis (IDMS).
Nephrol Dial Transplant. 2007 Dec 8;
Background and objectives. Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort. METHODS: We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2. RESULTS: The median (range) age at onset of NS was 11 (1-72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2. CONCLUSIONS: PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment. [Abstract]

Ishani A, Solid CA, Weinhandl ED, Gilbertson DT, Foley RN, Collins AJ
Association Between Number of Months Below K/DOQI Haemoglobin Target and Risk of Hospitalization and Death.
Nephrol Dial Transplant. 2007 Dec 8;
Background. A proportion of haemodialysis patients experience periods below target haemoglobin levels due to longer time required to reach the target or to haemoglobin level variability. We aimed to determine the consequences associated with cumulative number of months below target haemoglobin concentrations. Methods. We constructed an incident cohort including patients whose day 91 after dialysis initiation fell between 1 January and 31 December 2002. Haemoglobin concentration, erythropoiesis-stimulating agent dose, comorbid condition and hospitalization data were obtained from Medicare claims. Patients were classified by 0, 1, 2 or 3 months with haemoglobin concentration below the K/DOQI target (11 g/dL). Using an inverse probability weighted marginal structural model to adjust for time-varying factors associated with haemoglobin concentration, we determined the association between number of months below target and subsequent risk for hospitalization and mortality. Results. The final cohort included 54 328 patients who met criteria. Those with more months below haemoglobin target were less likely to have received intravenous iron. More months below target were associated with increased risk of hospitalization (RR 1.70, 95% CI 1.63-1.76) and mortality (RR 2.48, 95% CI 2.28-2.69). Conclusions. Future interventions should focus on modifiable factors associated with greater time below target haemoglobin concentrations to determine whether altering the time below target can alter the risk of hospitalizations or mortality. [Abstract]

Gelb S, Shapiro RJ, Hill A, Thornton WL
Cognitive Outcome Following Kidney Transplantation.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: While a handful of studies have assessed cognition in kidney transplant (TX) recipients, the neuropsychological presentation of this population is not yet clear. Kidney transplantation typically leads to improvement of metabolic factors associated with chronic kidney disease (CKD). However, comorbid diseases independently linked with cognitive compromise often persist, and for this reason, cognitive difficulties may still be present following transplantation. METHODS: In this cross-sectional study, we assessed cognition in 42 kidney TX recipients, 45 outpatients with pre-dialysis CKD and 49 healthy controls using measures of verbal learning and memory and executive functioning. RESULTS: Findings indicated that TX and CKD patients demonstrated significantly worse verbal learning and memory in comparison to controls. While both CKD and TX patients exhibited significantly worse performance than controls on a response inhibition measure, only CKD patients performed significantly worse on a set-shifting task. CONCLUSIONS: Results suggest that, in comparison to controls, verbal memory and executive functioning skills are worse in both CKD and TX patients. Further research is needed to determine the etiology and extent of cognitive compromise, as well as to assess the clinical implications of these findings. [Abstract]

Zhou H, Tan KC, Shiu SW, Wong Y
Increased Serum Advanced Glycation End Products is Associated with Impairment in Hdl Antioxidative Capacity in Diabetic Nephropathy.
Nephrol Dial Transplant. 2007 Dec 8;
Background. Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications. Recent data suggest that AGEs may also interfere with the function of HDL and the reverse cholesterol transport pathway. We have investigated whether serum AGE level is associated with impairment in the antioxidative capacity of HDL and in the ability of serum to induce cholesterol efflux in type 2 diabetic patients with and without nephropathy. Methods. A total of 167 controls and 264 diabetic patients was recruited. The ability of serum to induce cellular cholesterol efflux and the capacity of HDL to inhibit LDL oxidation ex vivo was determined. Serum AGEs were assayed by competitive ELISA using a polyclonal rabbit antisera raised against AGE-RNase. Results. Diabetic subjects were subdivided into three groups (normoalbuminuria, microalbuminuria and proteinuria). Serum AGEs were significantly increased in diabetic patients with microalbuminuria or proteinuria (P < 0.001). Cholesterol efflux was significantly decreased in all three groups of diabetic patients compared to controls (P < 0.001) whereas the antioxidative capacity of HDL was significantly impaired in patients with microalbuminuria or proteinuria (P < 0.01). No relationship between serum AGEs and cholesterol efflux was found. However, serum AGE concentration was significantly associated with the antioxidative capacity of HDL and this was partly due to the adverse effect of AGEs on paraoxonase-1 activity. Conclusion. In type 2 diabetic patients with incipient or overt nephropathy, increased serum concentration of AGEs was associated with impairment in the antioxidative capacity of HDL. Cholesterol efflux to serum was also reduced but was not related to serum AGEs. [Abstract]

Hoskins BE, Cramer CH, Tasic V, Kehinde EO, Ashraf S, Bogdanovic R, Hoefele J, Pohl M, Hildebrandt F
Missense Mutations in EYA1 and TCF2 are a Rare Cause of Urinary Tract Malformations.
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Moyses ZP, Nakandakari FK, Magaldi AJ
Fluoxetine Effect on Kidney Water Reabsorption.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: The pathogenesis of hyponatraemia caused by fluoxetine(Fx) use in the treatment of depression is not well understood. It has been attributed to a SIADH, although ADH-enhanced plasma level has not yet been demonstrated in all the cases reported in humans. This experiment aimed at investigating the effect of fluoxetine on the kidney and more specifically in the inner medullary collecting duct (IMCD). METHODS: (1) In vivo study: (a) 10 rats were injected daily i.p. with 10 mg/kg fluoxetine doses. After 10 days, rats were sacrificed and blood and kidneys were collected. (b) Immunoblotting studies for AQP2 protein expression in the IMCD from injected rats and in IMCD tubules suspension from 10 normal rats incubated with 10(-7) M fluoxetine. (2) In vitro microperfusion study: The osmotic water permeability (P(f), mum/s) was determined in normal rats IMCD (n = 6), isolated and perfused by the standard methods. RESULTS: In vivo study: (a) Injected rats with fluoxetine lost about 12% body weight; Na(+) plasma level decreased from 139.3 +/- 0.78 mEq/l to 134.9 +/- 0.5 mEq/l (p < 0.01) and K(+) and ADH plasma levels remained unchanged. (b) Immunoblotting densitometric analysis of the assays showed an increase in AQP2 protein abundance of about 40%, both in IMCDs from injected rats [control period (cont) 99.6 +/- 5.2 versus Fx 145.6 +/- 16.9, p < 0.05] and in tubule suspension incubated with fluoxetine (cont 100.0 +/- 3.5 versus 143.0 +/- 2.0, p < 0.01). In vitro microperfusion study fluoxetine increased P(f) in the IMCD in the absence of ADH from the cont 7.24 +/- 2.07 to Fx 15.77 +/- 3.25 (p < 0.01). CONCLUSION: After fluoxetine use, the weight and plasma Na(+) level decreased, and the K(+) and ADH plasma levels remained unchanged, whereas the AQP2 protein abundance and water absorption in the IMCD increased, leading us to conclude that the direct effect of fluoxetine in the IMCD could explain at least in part, the hyponatraemia found sometime after this drug use in humans. [Abstract]

Topham P, Barratt J, Feehally J
A Spoonful of Sugar Helps the Proteinuria Go Down?
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Santoro A, Mancini E, London G, Mercadal L, Fessy H, Perrone B, Cagnoli L, Grandi E, Severi S, Cavalcanti S
Patients with Complex Arrhythmias During and after Haemodialysis Suffer from Different Regimens of Potassium Removal.
Nephrol Dial Transplant. 2007 Dec 8;
Background. Although sudden death is one of the most frequent causes of death in haemodialysis (HD) patients, the problem of cardiac arrhythmias, the major cause of these outcomes, has been little discussed. Methods. In 30 arrhythmia-prone HD patients, we compared the arrhythmogenic effects of two dialysis techniques differing in dialysate potassium (K) content. Each patient underwent Acetate-Free Biofiltration sessions with constant (2.5 mEq/l) K (AFB) and sessions with decreasing intra-HD K (AFBK), according to a crossover single blind design. Holter ECG recording and plasma electrolyte measurements were performed during each dialysis session. Results. There was a tendency in the whole sample for arrhythmia appearance in AFBK to be reduced as compared to AFB throughout the 24 hr period, although this reduction was not statistically significant. In the subset of patients sensitive to dialysis as far as arrhythmia onset is concerned, AFBK was systematically less arrhythmogenic than AFB (P < 0.01). The highest difference was achieved around the 14th hour after the end of dialysis, when the premature ventricular contractions in AFB were 3.9 times higher than in AFBK (P < 0.05). Potassium kinetics differed between the two procedures. At the first hour of treatment, the plasma K concentration was lower in AFB than in AFBK (3.67 +/- 0.15 mEq/l in AFB vs 4.06 +/- 0.13 mEq/l in AFBK, P = 0.05). Conclusions. Our study shows a greater arrhythmogenic activity with the use of a constant and relatively low K concentration as compared to decreasing K profiling in dialysis-sensitive arrhythmic patients. Smoother K removal may well engender a kind of protective effect. [Abstract]

Cohen E
Cinacalcet: Benefit and Cost.
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Banas MC, Banas B, Wolf J, Hoffmann U, Krüger B, Böger CA, Orth SR, Krämer BK
Smoking Behaviour of Patients Before and After Renal Transplantation.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: Smoking is the most important remediable cardiovascular risk factor, and an independent risk factor for the progression of renal diseases. To date, only limited information about changes in cigarette-smoking habits before and after renal transplantation is available. METHODS: In a comprehensive cross-sectional single centre study, we analysed smoking habits of patients registered on the waiting list for renal transplantation and patients that had received an allograft. RESULTS: Of 230 patients (76.1%), 175 on the waiting list and of 264 allograft recipients (87.5%), 231 were non-smokers at the time of investigation (P <0.01). Among the non-smoking waiting list patients, only 71 (30.9%) had never smoked, whereas 108 (40.9%) patients of the allograft recipients were never-smokers. Of former smoking patients, 27.6% (n = 34) had stopped smoking after transplantation. Patients <55 years of age and females were more likely to stop smoking than patients >55 years of age or males. A data analysis revealed that smokers had a significantly lower probability to attain renal transplantation. CONCLUSION: We conclude that renal transplantation is a strong incentive for patients to stop smoking. Reasons for changes in smoking behaviour after renal transplantation may be an intense contact of the patients with their physicians, the fear of a premature loss of the transplanted organ with continued smoking and the psychological support during post-transplantation patient care. [Abstract]

Velikonja NK, Coer A, Gorensek M, Knezevic M, Kmetec A
Tissue Formation Following Implantation of Cultured Elastic Chondrocytes for Treatment of Vesicoureteral Reflux.
Nephrol Dial Transplant. 2007 Dec 8; [Abstract]

Teeninga N, Schreuder MF, Bökenkamp A, Waal HA, Wijk JA
Influence of Low Birth Weight on Minimal Change Nephrotic Syndrome in Children, Including a Meta-Analysis.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: Low birth weight (LBW) has been shown to lead to a low nephron endowment with subsequent glomerular hyperfiltration. Additional renal disease can therefore be expected to have a more severe course. Minimal change nephrotic syndrome (MCNS) is a common chronic illness in childhood. As it is important to be able to predict prognosis in MCNS, we set out to study the effect of LBW on MCNS in a cohort of patients from our University Medical Center, and performed a meta-analysis. METHODS: A retrospective chart review of children with MCNS treated at the VU University Medical Center was performed, identifying 55 patients of whom 4 had LBW. The meta-analysis was performed using Review Manager (The Cochrane Collaboration). RESULTS: The meta-analysis consisted of 201 patients (25 LBW, 176 normal birth weight). More LBW patients were classified as steroid resistant [odds ratio (OR) 6.97 (95% confidence interval [CI] 2.02-24.04), P = 0.002]. The number of relapses per year of follow-up was significantly higher in the LBW patients with MCNS [weighted mean difference 0.93 (95% CI 0.71-1.15) relapse per year, P < 0.0001]. MCNS patients with LBW were significantly more likely to be treated with cyclosporine [OR 4.4 (95% CI 1.7-11.8), P = 0.003] or cytotoxic agents [OR 4.2 (95% CI 1.8-10.2), P = 0.001] during the course of their disease, and they had a higher chance of developing several complications during the follow-up period, including hypertension. CONCLUSIONS: This meta-analysis provides support for an adverse effect of LBW on the course and prognosis of MCNS in children, which can aid clinicians and parents in assessing the expected clinical course. [Abstract]

Gupta K, Iskandar SS, Daeihagh P, Ratliff HL, Bleyer AJ
Distribution of Pathologic Findings in Individuals with Nephrotic Proteinuria According to Serum Albumin.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: Previous studies of the nephrotic syndrome have not carefully examined the relationship between serum albumin and the distribution of pathologic diagnoses found at the time of biopsy. The spectrum of pathologic findings in individuals with nephrotic proteinuria and a normal serum albumin has not been determined. Knowledge regarding the spectrum of findings in nephrotic proteinuria according to serum albumin levels may help nephrologists in the clinical decision making of when to perform a renal biopsy and in determining proper management of these patients. METHODS: Pathologic reports of native kidney biopsies performed for idiopathic proteinuria >3 g/24 h were reviewed. Clinical characteristics and biopsy findings were compared for individuals with serum albumin <30 g/L (Group I), 30 to <35 g/L (Group II) and >/=35 g/L (Group III). RESULTS: There were 57 patients in Group I, 20 in Group II and 35 in Group III. The proportion of individuals with focal and segmental glomerulosclerosis (FSGS) increased according to group: 26% in Group I, 45% in Group II and 74% in Group III. Of 35 patients in Group III, 34 had FSGS or advanced nephrosclerosis from another cause. Seven of 17 Group III patients with follow-up required dialysis after a mean interval of 6 years. Few of these patients received immunosuppressive therapy. CONCLUSIONS: As serum albumin increases in the nephrotic syndrome, the proportion of patients with FSGS increases. Patients with nephrotic proteinuria and a serum albumin >35 g/L suffer from FSGS, nephrosclerosis and have poor renal survival. When evaluating nephrotic patients, nephrologists should use this knowledge about the spectrum of disease in the clinical decision making of when to perform a biopsy and in providing the patient more precise information regarding risks, benefits and alternatives of the kidney biopsy procedure. [Abstract]

Richards N, Harris K, Whitfield M, O'Donoghue D, Lewis R, Mansell M, Thomas S, Townend J, Eames M, Marcelli D
The impact of population-based identification of chronic kidney disease using estimated glomerular filtration rate (eGFR) reporting.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: The object of this study was to determine the impact of estimated glomerular filtration rate (eGFR) reporting, as part of a disease management programme (DMP), and clarify the prevalence of chronic kidney disease (CKD) and the level of un-met need in a UK Primary Care Trust. METHODS: Our approach was to prospectively identify patients with an eGFR <60 ml/min/1.73 m(2) using the four-variable MDRD equation in all patients from West Lincolnshire PCT (population 185 434 over the age of 15 years) having a routine estimation of serum creatinine. RESULTS: During the first 12 months of the programme 25.4% of the population had an eGFR reported. The likelihood of having an eGFR reported increased markedly with age. The prevalence of CKD stages 3-5 within primary care was 7.3%. Only 3.7% of patients with CKD stages 3-5 were under nephrology care compared to 13.7% in non-nephrology secondary care and 82.6% in primary care. There were marked differences in the male to female ratio between primary care and nephrology care, 1:1.9 versus 0.6:1, respectively (P < 0.001). The incidence of newly identified patients with CKD stages 4 and 5 was 0.16%. Initially there was a marked (up to 7-fold month on month) rise in nephrology referrals following institution of eGFR reporting which was reversed by the introduction of a referral management service as part of the DMP. Only 33% of patients with CKD stage 4 or 5, identified from within primary care, went on to have a nephrology referral in the subsequent 12 months compared with 44% and 78% respectively identified from non-nephrology secondary care (P < 0.001). CONCLUSIONS: The reporting of the eGFR in association with this DMP effectively identified patients with CKD. A referral assessment programme can effectively ensure appropriate nephrology referral and avoids exceeding the capacity of nephrology services. The vast majority of patients with CKD stages 3-5 are cared for within primary care. There are marked gender differences in the prevalence of CKD stages 3-5 that are not reflected by referral patterns to nephrology services. There are significant differences in referral practices between primary and secondary care. In a steady state the burden of incident patients with CKD stages 4-5 should not exceed the capacity of the local nephrology service. [Abstract]

Labriola L, Crott R, Jadoul M
Preventing Haemodialysis Catheter-Related Bacteraemia with an Antimicrobial Lock Solution: a Meta-Analysis of Prospective Randomized Trials.
Nephrol Dial Transplant. 2007 Dec 8;
Background. Catheter-related bacteraemia (CRB) is a major cause of morbidity and mortality in haemodialysis patients. Interdialytic locking of catheters with antimicrobial agents has recently been investigated for the prevention of CRB. We performed a meta-analysis of randomized controlled trials (RCT) to determine the efficacy of antimicrobial lock solutions (ALS) in the prevention of CRB in haemodialysis patients. Methods. We collected from Medline, Web of Science, the Cochrane Library and major nephrology journals, all relevant references (January 1990-March 2007). We selected RCT comparing an ALS to a standard heparin lock in CRB prevention. We extracted data concerning study quality, patient characteristics and CRB incidence. The relative risk (RR) of CRB was calculated as Ln (CRB incidence control/CRB incidence experimental) using both a fixed- and a random-effects model. Results. Eight studies were included, involving 829 patients, 882 catheters and 90 191 catheter-days. The use of an ALS significantly decreased the risk of CRB (RR 0.32; 95% CI 0.10-0.42). Borderline heterogeneity was observed in the fixed-effects model (Q = 14.42; P = 0.071). Despite the under-representation of small negative studies, the high number of additional trials necessary to reverse the final effect strengthens the confidence in the overall results. Subgroup analyses stratified by the presence of diabetes, duration of follow-up, biochemical markers, proportion of tunnelled cuffed catheters, intranasal mupirocin use and citrate use in the ALS did not show significant differences, except a higher efficacy of gentamicin-containing lock solutions (P = 0.003). Conclusions. The use of ALS reduces by about a factor 3 the risk of CRB in haemodialysis patients. The achieved absolute incidence is similar to the best-published figures (presumably related to stricter hygienic measures). The limited follow-up of the studies does not exclude the onset of adverse events or bacterial resistance with longer use of ALS. [Abstract]

Melamed ML, Eustace JA, Plantinga LC, Jaar BG, Fink NE, Parekh RS, Coresh J, Yang Z, Cantor T, Powe NR
Third-generation parathyroid hormone assays and all-cause mortality in incident dialysis patients: the CHOICE study.
Nephrol Dial Transplant. 2007 Dec 8;
BACKGROUND: There has been controversy about the utility of new third-generation parathyroid hormone (PTH) assays measuring only 1-84 PTH, with few large studies comparing second- and third-generation PTH measurements in patients with ESRD. METHODS: We measured 1-84 PTH ('biointact' or 'whole' PTH) and total PTH ('intact' PTH) in a national cohort of 515 incident dialysis patients from banked frozen EDTA plasma (median follow-up, 35 months) and examined the accuracy of estimating 1-84 PTH from total PTH and the associations of these levels with patient characteristics and mortality. RESULTS: The 1-84 PTH and total PTH levels were closely correlated. Higher 1-84 PTH was associated with African-American race and higher serum phosphate and lower calcium levels. The percentage of total PTH represented by 1-84 PTH was, on average, 53%, but with a wide range (25-89%). Calculating 1-84 PTH from total PTH using a proposed standard conversion factor (54%) led to misclassification of 8% of the population compared with measured 1-84 PTH. In a multivariate Cox proportional hazards model for all-cause mortality, a 1-84 PTH value >160 pg/ml was associated with increased risk of mortality (HR = 1.62, 95% CI, 1.03-2.54) compared to a level of 80-160 pg/ml. Elevated total PTH, 7-84 PTH and the 1-84 PTH/7-84 PTH ratio were not significantly associated with mortality. CONCLUSIONS: The 1-84 PTH and total PTH are highly correlated. Elevated 1-84 PTH was significantly associated with increased mortality, whereas total PTH did not reach statistical significance. Thus, although in other respect they are similar, there may be utility in measuring 1-84 PTH for its associations with mortality. [Abstract]

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Recent Articles in International Journal of Impotence Research: Official Journal of the International Society for Impotence Research

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Yang CC, Cao YY, Guan QY, Heiman JR, Kuffel SW, Peterson BT, Maravilla KR
Influence of PDE5 inhibitor on MRI measurement of clitoral volume response in women with FSAD: a feasibility study of a potential technique for evaluating drug response.
Int J Impot Res. 2007 Dec 6; .
The purpose of this study was to determine if magnetic resonance imaging (MRI) could quantify a difference in clitoral response following administration of a vasoactive medication, in 12 women with female sexual arousal disorder (FSAD). Subjects were entered into a double-blind, randomized two-way crossover study of sildenafil 50 mg vs placebo administered 1 h prior to genital MRI. Each subject underwent two MR studies, performed while subjects viewed alternating segments of nonerotic and erotic video. MR images were analyzed for change in clitoral volume during each session. The mean change in clitoral volume for the entire group was higher in the sildenafil MRI session (1282 mm(3)) compared with placebo (849 mm(3)) but did not reach statistical significance (P=0.064). Comparison using analysis of variance between the two sessions for each individual subject revealed a significant increase in clitoral volume following sildenafil compared with placebo in 6 of 12 subjects, no significant change in either imaging session in three subjects and in three subjects, there was a robust clitoral response in both MR sessions. In conclusion, MR measurements of clitoral volume can provide an objective measure of engorgement change following a vasoactive medication in women with FSAD.International Journal of Impotence Research advance online publication, 6 December 2007; doi:10.1038/sj.ijir.3901625. [Abstract]

Bekkering GE, Abou-Setta AM, Kleijnen J
The application of quantitative methods for identifying and exploring the presence of bias in systematic reviews: PDE-5 inhibitors for erectile dysfunction.
Int J Impot Res. 2007 Dec 6;
A systematic review of PDE-5 inhibitors for erectile dysfunction was performed to evaluate the utility of quantitative methods for identifying and exploring the influence of bias and study quality on pooled outcomes from meta-analyses. We included 123 randomized controlled trials (RCTs). Methodological quality was poorly reported. All three drugs appeared highly effective. Indirect adjusted analyses showed no differences between the three drugs. Funnel plots and statistical tests showed no evidence of small-study effects for sildenafil whereas there was evidence of such bias for tadalafil and vardenafil. Adjustment for missing studies using trim and fill techniques did not alter the pooled estimates substantially. The exclusion of previous sildenafil nonresponders was associated with larger treatment effects for tadalafil. This investigation was hampered by poor reporting of methodological quality, a low number of studies, heterogeneity and large effect sizes. Despite such limitations, a comprehensive assessment of biases should be a routine in systematic reviews.International Journal of Impotence Research advance online publication, 6 December 2007; doi:10.1038/sj.ijir.3901626. [Abstract]

Nimmegeers S, Sips P, Buys E, Decaluwé K, Brouckaert P, Van de Voorde J
Role of the soluble guanylyl cyclase alpha(1)-subunit in mice corpus cavernosum smooth muscle relaxation.
Int J Impot Res. 2007 Dec 6;
Soluble guanylyl cyclase (sGC) is the major effector molecule for nitric oxide (NO) and as such an interesting therapeutic target for the treatment of erectile dysfunction. To assess the functional importance of the sGCalpha(1)beta(1) isoform in corpus cavernosum (CC) relaxation, CC from male sGCalpha(1)(-/-) and wild-type mice were mounted in organ baths for isometric tension recording. The relaxation to endogenous NO (from acetylcholine, bradykinin and electrical field stimulation) was nearly abolished in the sGCalpha(1)(-/-) CC. In the sGCalpha(1)(-/-) mice, the relaxing influence of exogenous NO (from sodium nitroprusside and NO gas), BAY 41-2272 (NO-independent sGC stimulator) and T-1032 (phosphodiesterase type 5 inhibitor) were also significantly decreased. The remaining exogenous NO-induced relaxation seen in the sGCalpha(1)(-/-) mice was significantly decreased by the sGC-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The specificity of the impairment of the sGC-related responses was demonstrated by the unaltered relaxations seen with forskolin (adenylyl cyclase activator) and 8-pCPT-cGMP (cGMP analog). In conclusion, the sGCalpha(1)beta(1) isoform is involved in corporal smooth muscle relaxation in response to NO and NO-independent sGC stimulators. The fact that there is still some effect of exogenous NO in the sGCalpha(1)(-/-) mice suggests the contribution of (an) additional pathway(s).International Journal of Impotence Research advance online publication, 6 December 2007; doi:10.1038/sj.ijir.3901627. [Abstract]

Campos AR, Cunha KM, Santos FA, Silveira ER, Uchoa DE, Nascimento NR, Rao VS
Relaxant effects of an alkaloid-rich fraction from Aspidosperma ulei root bark on isolated rabbit corpus cavernosum.
Int J Impot Res. 2007 Nov 29;
We described earlier that an alkaloid-rich fraction (F(3-5)) from Aspidosperma ulei (Markgr) induces penile erection-like behavioral responses in mice. This study verified a possible relaxant effect of this fraction on isolated rabbit corpus cavernosum (RbCC) strips precontracted by phenylephrine (1 muM) or K(+) 60 mM. F(3-5) (1-300 mug ml(-1)) relaxed the RbCC strips in a concentration-dependent and reversible manner. The relaxant effect of F(3-5) (100 mug ml(-1)) on phenylephrine contraction was unaffected in the presence of atropine, N-omega-nitro-L-arginine methyl ester or 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one and by preincubation with tetrodotoxin, glibenclamide, apamine and charybdotoxin suggesting that mechanisms other than cholinergic, nitrergic, sGC activation or potassium channel opening are probably involved. However, the phasic component of the contraction induced by K(+) 60 mM as well as the maximal contraction elicited by increasing external Ca(2+) concentrations in depolarized corpora cavernosa was inhibited by F(3-5). We conclude that F(3-5) relaxes the RbCC smooth muscle, at least in part, through a blockade of calcium influx or its function.International Journal of Impotence Research advance online publication, 29 November 2007; doi:10.1038/sj.ijir.3901624. [Abstract]

Meadows WA, Hollowell BD
'Off-label' drug use: an FDA regulatory term, not a negative implication of its medical use.
Int J Impot Res. 2007 Nov 15;
As physicians continue to prescribe more and more drugs, plaintiff's attorneys in the wake of tort reform are attempting to carve out or create informed consent cases based on the Food and Drug Administration's (FDA) labeling requirements and the doctors' communications with their patients as it relates to those requirements. The theory of tort litigation revolves around whether the doctor disclosed to his patient the fact that he prescribed a drug in an 'off-label' manner, or for a purpose not approved by the FDA's testing process. This article argues that the doctor's decision to inform the patient of the 'off-label' status of the prescription is not relevant to the physician's standard of care for an informed consent case. First, the FDA has specifically stated that its procedures and requirements have no effect on the practice of medicine and that the FDA does not prohibit doctors from prescribing drugs in an 'off-label' manner. Second, the FDA's approval of a drug is immaterial to the effectiveness in the drug's 'off-label' use. In fact, prescribing medication in an 'off-label' manner can constitute the standard of care in many cases. Third, a doctor's duty is to practice medicine and treat his patient, not inform the patient of the FDA's non-medically related labeling. Therefore, doctors should not be branded with the additional duty of disclosing non-pertinent information, such as the FDA's medically irrelevant distinction, to their patients.International Journal of Impotence Research advance online publication, 15 November 2007; doi:10.1038/sj.ijir.3901619. [Abstract]


The relationship between lipid profile and erectile dysfunction.
Int J Impot Res. 2007 Nov-Dec;19(6): [Abstract]

Nikoobakht M, Nasseh H, Pourkasmaee M
The relationship between lipid profile and erectile dysfunction.
Int J Impot Res. 2005 Nov-Dec;17(6):
The objective of this study is to investigate the relation between serum lipids (cholesterol, LDL, HDL, triglyceride (TG)) and erectile dysfunction (ED). The experimental methods involved comparison of 100 patients with organic ED (mean age of 43.59+/-10.51 y), with 100 healthy individuals (mean age of 43.72+/-9.76 y) regarding their lipid profile from January 2000 to June 2003 (cholesterol, TG, HDL, LDL). The results showed that there was a significant difference between mean plasma cholesterol and LDL levels in the individuals suffering from ED and the control group (P=0.04 and 0.02, respectively). The TG and HDL mean plasma level differences were not significant (P=0.583 and 0.299, respectively). Odds ratios for high plasma cholesterol level (>240 mg/dl) and high plasma LDL level (>160 mg/dl) were 1.74 and 1.97. The R2 was 0.04 for both cholesterol and LDL. Applying linear regression, the coefficient for cholesterol and LDL reduced the International Index of Erectile Function questionnaire scores by -0.036 and -0.035. In conclusion, this study, the correlation of cholesterol and LDL levels with ED strongly supports the role of hyperlipidemia treatment in both the prevention and management of ED. [Abstract]

Armagan A, Hatsushi K, Toselli P
The effects of testosterone deficiency on the structural integrity of the penile dorsal nerve in the rat.
Int J Impot Res. 2007 Sep 27;
Androgens play a vital role in erectile function and are known to have a neuroprotective role in the nervous system. This study investigated, in a rat model, the effects of testosterone deprivation and replacement on the morphology of the dorsal nerve of the rat penis at the light microscopy level. Two weeks after castration, male rats were infused with vehicle alone or 44 mug of testosterone for 2 weeks. Age-matched, sham-operated control animals were used for comparisons. Penile tissue samples were removed for histological analyses. The following parameters were assessed: (1) total myelin sheath thickness; (2) density of nerve fibers; and (3) axon cross-sectional area per nerve fiber. Castration resulted in a significant increase in axon cross-sectional area compared to that of the control and testosterone-treated animals (6.97+/-0.59 mum(2) per fiber in control animals to 14.32+/-0.44 mum(2) per fiber in castrated animals). Qualitatively, there were signs of nerve degeneration, particularly myelin sheath degeneration, in all sample groups. We did not observe statistically significant changes in myelin sheath thickness. There was a trend of reduced nerve density. Nerve degeneration was not quantified since this study was performed at the light microscopic level. This study suggests that testosterone has a neuroprotective role in the nerve fibers of the dorsal nerve and testosterone deficiency may lead to different forms of nerve degeneration resulting in anatomic alterations, thus contributing to erectile dysfunction.International Journal of Impotence Research advance online publication, 27 September 2007; doi:10.1038/sj.ijir.3901614. [Abstract]

Ghanem H, Shamloul RM
Incisional corporoplasty for the correction of congenital penile curvature: a review of two suturing techniques.
Int J Impot Res. 2007 Sep 27;
This retrospective study was designed to evaluate the surgical outcome of correction of congenital penile curvature, via multiple vertical incisions in the tunica albuginea using two different types of suture material, simple inverted 2-0 PDS sutures versus Proline 2-0 suture followed by closure with 3-0 vicryl. The study included 45 men with congenital penile curvature and surgeries were performed in four general hospitals. Patients were divided into two groups; Group A (n=24) included patients undergoing penile curvature correction using 2-0 PDS sutures; and Group B (n=21) patients undergoing the same procedure by placing an inverted Proline 2-0 suture in the middle of the suture line and completing the closure of the incision line with 3-0 vicryl. The procedures straightened the penile shaft in all cases but a degree of curvature recurred in three cases (all Group A). No operative or postoperative complications occurred and no reoperations were needed. Four patients complained of penile shortening (all Group A). No recurrence was observed in the proline group (difference not statistically significant). Horizontal plication after vertical corporal incisions is safe and effective in the treatment for congenital penile curvature without hypospadias. We advise avoiding overcorrection to prevent penile shortening.International Journal of Impotence Research advance online publication, 27 September 2007; doi:10.1038/sj.ijir.3901617. [Abstract]

Grober ED, Khera M, Soni SD, Espinoza MG, Lipshultz LI
Efficacy of changing testosterone gel preparations (Androgel or Testim) among suboptimally responsive hypogonadal men.
Int J Impot Res. 2007 Sep 27;
The study objective was to evaluate the efficacy of changing testosterone gel preparations among suboptimally responsive hypogonadal men. The records of all hypogonadal men on gel (Testim or Androgel) testosterone replacement therapy (TRT) were reviewed to identify men who underwent a brand substitution in gel TRT due to initial suboptimal response. Total and free serum testosterone levels and the presence of hypogonadal symptoms (ADAM) were compared pre- and post-gel substitution. Of the 370 hypogonadal men on testosterone gel replacement therapy, 75 (20%) underwent a brand substitution. Prior to substitution, among patients initially treated with Androgel, the mean total and free testosterone levels were 311 ng dl(-1) and 10.4 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 58% of these patients. Following a change to Testim, mean total and free testosterone levels increased to 484 ng dl(-1) (P<0.001) and 14.6 pg ml(-1) (P=0.01), respectively. Total testosterone levels remained below 300 ng dl(-1) in only 17% of these patients. Among patients initially treated with Testim, the mean total and free testosterone levels were 544 ng dl(-1) and 18.0 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 15% of men. Following testosterone gel change to Androgel, mean total and free testosterone levels were 522 ng dl(-1) (P=0.7) and 16.1 pg ml(-1) (P=0.6), respectively. Total testosterone levels remained below 300 ng dl(-1) in 27% of these patients. Hypogonadal symptoms improved in a significant proportion of men who underwent a brand substitution following an initial suboptimal biochemical or symptomatic response. A change in testosterone gel preparation among initially unresponsive hypogonadal men is justified prior to abandoning or considering more invasive TRT. Changing from Androgel to Testim offers hypogonadal men the potential for improved clinical and biochemical responsiveness. Changing from Testim to Androgel is indicated to eliminate or minimize unwanted side effects.International Journal of Impotence Research advance online publication, 27 September 2007; doi:10.1038/sj.ijir.3901618. [Abstract]

Ponholzer A, Temml C, Rauchenwald M, Marszalek M, Madersbacher S
Is the metabolic syndrome a risk factor for female sexual dysfunction in sexually active women?
Int J Impot Res. 2007 Sep 20;
Despite of the high prevalence, pathogenesis of female sexual dysfunction (FSD) is still poorly understood. A consecutive series of sexually active women underwent a health investigation and completed a questionnaire on FSD. Metabolic syndrome (MS) was defined according to the International Diabetes Federation definition. A total of 538 women with a mean age of 44 years (range: 30-69) was analysed. The premenopausal group comprised 329 women (61.2%) with a mean age of 38.5 years; the postmenopausal cohort contained 209 women (38.8%) with a mean age of 52.7 years. In the total cohort (n=538) MS was present in 17.6%, 8.5% in the premenopausal group and 32.6% in the postmenopausal women. In premenopausal women, the MS was an independent risk factor for impaired sexual desire (P=0.03) with an age-adjusted odds ratio of 3.3 (95% confidence interval: 1.5-7.3). In premenopausal female sexual life, the MS represents an independent role via its correlation to impaired desire.International Journal of Impotence Research advance online publication, 20 September 2007; doi:10.1038/sj.ijir.3901605. [Abstract]

Kovanecz I, Rambhatla A, Ferrini M, Vernet D, Sanchez S, Rajfer J, Gonzalez-Cadavid N
Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats.
Int J Impot Res. 2007 Sep 20;
It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal veno-occlusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N=10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg(-1) day(-1)) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg(-1) day(-1)) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.International Journal of Impotence Research advance online publication, 20 September 2007; doi:10.1038/sj.ijir.3901612. [Abstract]

Schwarz ER, Kapur V, Bionat S, Rastogi S, Gupta R, Rosanio S
The prevalence and clinical relevance of sexual dysfunction in women and men with chronic heart failure.
Int J Impot Res. 2007 Sep 20;
Sexual dysfunction is a common problem of increasing incidence that is associated with multiple co-morbid conditions and chronic diseases. In heart failure, however, exact numbers are unknown, in part secondary to under-reporting and under-interrogating by health care providers. A gender-specific questionnaire was modified from established sexual dysfunction questionnaires to correspond to a non-randomized outpatient heart failure population, to assess the prevalence and demographic distribution of sexual dysfunction and potential treatments expectations. One-hundred patients in a stable hemodynamic condition in New York Heart Association classes I-III participated. Eighty-seven percent of women were diagnosed with female sexual dysfunction compared to 84% of men with erectile dysfunction. Eighty percent of women reported reduced lubrication, which resulted in frequent unsuccessful intercourse in 76%. Thirty-six percent of patients thought that sexual activity could harm their current cardiac condition; 75% of females and 60% of men stated that no physicians ever asked about potential sexual problems. Fifty-two percent of men considered sexual activity in their current condition as an essential aspect of quality of life and 61% were interested in treatment to improve sexual function. Sexual dysfunction appears to be high in prevalence in both men and women with chronic compensated heart failure and represents a reduction in quality of life for most. Despite the fact that most patients are interested in receiving therapy to improve sexual dysfunction, treatment options are rarely discussed or initiated.International Journal of Impotence Research advance online publication, 20 September 2007; doi:10.1038/sj.ijir.3901613. [Abstract]

Dogan S, Dogan M
The frequency of sexual dysfunctions in male partners of women with vaginismus in a Turkish sample.
Int J Impot Res. 2007 Sep 20;
The aim of this investigation is to determine the sexual history traits, sexual satisfaction level and frequency of sexual dysfunctions in men whose partners have vaginismus. The study included 32 male partners of vaginismic patients, who presented at a psychiatry department. Subjects were evaluated by a semi-structured questionnaire. The questionnaire was developed by researchers for assessing sexually dysfunctional patients and included detailed questions with regard to socio-demographic variables, general medical and sexual history. All participants also received the Golombok Rust Inventory of Sexual Satisfaction (GRISS). According to DSM-IV-TR criteria, 65.6% of the investigated males were diagnosed with one or more sexual dysfunctions. The most common problem was premature ejaculation (50%) and the second one was erectile dysfunction (28%). The transformed GRISS subscale scores provided similar data. It is concluded that the assessment of sexual functions of males who have vaginismic partners should be an integral part of the management procedure of vaginismus for optimal outcome.International Journal of Impotence Research advance online publication, 20 September 2007; doi:10.1038/sj.ijir.3901615. [Abstract]

El Atat R, Derouiche A, Kourda N, Hammami A, Chebil M, Ben Jilani S, Ayed M
Segmental infarction of the testis: an exceptional complication of diabetes microangiopathy.
Int J Impot Res. 2007 Nov-Dec;19(6):
We report a case of segmental infarction of the testis in a 55-year-old man. Past medical history included 12 years of type II diabetes and hypertension. The patient presented with a 2-month history of testicular pain and was found clinically and sonographically to have a testicular tumour. The pathological examination of the partial orchiectomy specimen revealed segmental infarction of the testicle secondary to diabetes microangiopathy. We propose diabetes microangiopathy as a localization and aetiology of segmental testicular infarction. A possible testicular sparing procedure through an inguinal approach may be considered in cases of testicular masses for which the clinical and imaging findings are suggestive of focal testicular infarction. [Abstract]

Fallon B
'Off-label' drug use in sexual medicine treatment.
Int J Impot Res. 2007 Sep 13;
Phosphodiesterase type 5 inhibitors are the only drugs approved for a specific sexual function disorder. All other drugs used in the treatment of sexual disorders are used 'off-label.' This paper reviews the use of drugs in the treatment of premature ejaculation, Peyronie's disease and female hypoactive sexual desire disorder (HSDD). While the treatment of premature ejaculation is quite well documented and supported by evidence of good quality in the medical literature, there is little evidence for the use of the variety of medications in use for the treatment of Peyronie's disease. In particular, the use of verapamil is not supported by any double-blind studies whatsoever. The use of testosterone patch for treatment of HSDD in postmenopausal women is well documented, but not in premenopausal women.International Journal of Impotence Research advance online publication, 13 September 2007; doi:10.1038/sj.ijir.3901610. [Abstract]

Raza S, Baig M, Ali J, Rizvi S
To study hypoactive sexual desire disorder in a fragile X carrier female successfully treated with local testosterone application.
Int J Impot Res. 2007 Sep 13;
There is still considerable controversy concerning the role of androgen therapy for hypoactive sexual desire disorder in females. Clinical trials have shown that exogenous testosterone therapy improves arousability, sexual desire and fantasy, frequency of sexual activity and orgasm, and satisfaction and pleasure from the sexual act. We report our experience of 36-year-old fragile X carrier female presented to our department with low sex drive and subjectively poor arousal for the past 1 year. We decided to treat her with local testosterone in a pump form (1% 5 g twice a week). She responded very well to the treatment, and in 3 weeks her libido and sexual functions improved dramatically. We decided to continue the same treatment for almost 1 year following up her free and total testosterone, complete lipid profiles, liver functions and complete blood picture every 3 months. During the whole course of treatment, she had mild facial acne, which was resolved in 2 months after completing treatment with testosterone. This is our first and only case of this syndrome with low sexual desire disorder treated with local testosterone in a pump form. Based upon our 1 year follow-up, low-dose testosterone is a safe and effective approach in treating hypoactive sexual desire disorder in a fragile X carrier female, provided the patient is monitored every 3 months for blood counts, lipid profiles, liver functions and free and total testosterone levels.International Journal of Impotence Research advance online publication, 13 September 2007; doi:10.1038/sj.ijir.3901611. [Abstract]

Singh M, Seftel AD
The impact of formulary replacement of sildenafil by vardenafil at a local VA hospital.
Int J Impot Res. 2007 Sep 6;
The National Veterans Administration (VA) changed its formulary agent for the treatment of erectile dysfunction from sildenafil to vardenafil in January 2006 for economic reasons. The objective of this study was to assess the impact of this formulary change on the patients at a local VA hospital. All non-formulary requests for sildenafil between January 2006 and September 2006 were reviewed. A total of 169 non-formulary requests were made for sildenafil while 7657 patients filled vardenafil prescriptions. Overall, the formulary change from sildenafil to vardenafil appeared to be well tolerated by the vast majority of patients at this local VA hospital. The substantial cost savings to the VA seem to be justified by the minimal adverse effects on men treated for erectile dysfunction.International Journal of Impotence Research advance online publication, 6 September 2007; doi:10.1038/sj.ijir.3901606. [Abstract]

Kurbatov DG, Kuznetsky YY, Kitaev SV, Brusensky VA
Magnetic resonance imaging as a potential tool for objective visualization of venous leakage in patients with veno-occlusive erectile dysfunction.
Int J Impot Res. 2007 Sep 6;
Duplex Doppler ultrasonography (DDU) and dynamic infusion pharmacocavernosometry are the conventional diagnostic methods currently used to assess veno-occlusive hemodynamic status of patients with erectile dysfunction (ED). Dynamic infusion pharmacocavernosography is the standard method for demonstrating and visualization of venous leakage. To assess the potential application and utility of magnetic resonance imaging (MRI) in demonstrating and visualizing veno-occlusive dysfunction in patients with ED. A total of 28 patients, (32-56 years of age; mean 43.4+/-7.2 years), with clinical symptoms of veno-occlusive ED participated in this study. All patients have undergone DDU and dynamic infusion pharmacocavernosometry and pharmacocavernosography to assess presence of venous leakage. Patients were then evaluated with MRI and enhancement by intracavernous injection of paramagnetic contrast agent and erection was induced by intracavernosal injection of pharmacological agents. Diagnosis of ED patients with venous leakage was confirmed in all 28 patients using DDU and dynamic infusion cavernosometry-cavernosography (DICC). Venous leakage was documented by conventional DICC in 21 of 28 patients (75%). Veno-occlusive dysfunction in all patients was also assessed by MRI to localize distal, proximal or mixed locations of draining veins from the corpora cavernosa. MRI visualized venous leakage patients, in which DICC did not confirm venous leakage. MRI may be a useful diagnostic tool for assessing veno-occlusive dysfunction in ED patients and may improve diagnosis of venous leakage visualization.International Journal of Impotence Research advance online publication, 6 September 2007; doi:10.1038/sj.ijir.3901607. [Abstract]

Günzler C, Kriston L, Stodden V, Leiber C, Berner MM
Can written information material help to increase treatment motivation in patients with erectile dysfunction? A survey of 1188 men.
Int J Impot Res. 2007 Sep-Oct;19(5): [Abstract]

Strong TD, Champion HC, Kadowitz PJ, Bivalacqua TJ
Reply: potential differentiation of human mesenchymal stem cell transplanted in rat corpus cavernosum toward endothelial or smooth muscle cells.
Int J Impot Res. 2007 Sep-Oct;19(5): [Abstract]

Fourcroy JL
Regulatory issues in female sexual dysfunction.
Int J Impot Res. 2007 Sep-Oct;19(5):
Female sexual dysfunction (FSD) remains an enigmatic area to some, a controversial area to others and the subject of continued, intense debate in the literature. Questions remain regarding the legitimacy of FSD as a bona fide disease; the definition of FSD; the methods of diagnosis; and, the treatment of FSD. In this timely perspective, Jean Fourcroy, Consultant in Urology, Endocrinology and Regulatory Issues, discusses the controversies that continue to plague FSD. [Abstract]

Chien CV, Schwarz ER
Erectile dysfunction: risk factor or manifestation of cardiovascular disease?
Int J Impot Res. 2007 Sep-Oct;19(5): [Abstract]

Falagas ME, Alexiou VG
Editors may inappropriately influence authors' decisions regarding selection of references in scientific articles.
Int J Impot Res. 2007 Sep-Oct;19(5): [Abstract]

Seftel AD
A bag of pretzels.
Int J Impot Res. 2007 Sep-Oct;19(5): [Abstract]

Schouten BW, Bohnen AM, Bosch JL, Bernsen RM, Deckers JW, Dohle GR, Thomas S
Erectile dysfunction prospectively associated with cardiovascular disease in the Dutch general population: results from the Krimpen Study.
Int J Impot Res. 2007 Aug 30;
The possible relationship between erectile dysfunction and the later occurrence of cardiovascular disease while biologically plausible has been evaluated in only a few studies. Our objective is to determine the relation between ED as defined by a single question on erectile rigidity and the later occurrence of myocardial infarction, stroke and sudden death in a population-based cohort study. In Krimpen aan den IJssel, a municipality near Rotterdam, all men aged 50-75 years, without cancer of the prostate or the bladder, without a history of radical prostectomy, neurogenic bladder disease, were invited to participate for a response rate of 50%. The answer to a single question on erectile rigidity included in the International Continence Society male sex questionnaire was used to define the severity of erectile dysfunction at baseline. Data on cardiovascular risk factors at baseline (age smoking, blood pressure, total- and high-density lipoprotein cholesterol, diabetes) were used to calculate Framingham risk scores. During an average of 6.3 years of follow-up, cardiovascular end points including acute myocardial infarction, stroke and sudden death were determined. Of the 1248 men free of CVD at baseline, 258 (22.8%) had reduced erectile rigidity and 108 (8.7%) had severely reduced erectile rigidity. In 7945 person-years of follow-up, 58 cardiovascular events occurred. In multiple variable Cox proportional hazards model adjusting for age and CVD risk score, hazard ratio was 1.6 (95% confidence interval (CI): 1.2-2.3) for reduced erectile rigidity and 2.6 (95% CI: 1.3-5.2) for severely reduced erectile rigidity. The population attributable risk fraction for reduced and severely reduced erectile rigidity was 11.7%. In this population-based study, a single question on erectile rigidity proved to be a predictor for the combined outcome of acute myocardial infarction, stroke and sudden death, independent of the risk factors used in the Framingham risk profile.International Journal of Impotence Research advance online publication, 30 August 2007; doi:10.1038/sj.ijir.3901604. [Abstract]

Rosen R, Seftel A, Roehrborn CG
Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia.
Int J Impot Res. 2007 Sep-Oct;19(5):
We evaluated the effects of extended-release alfuzosin HCl 10 mg once daily (q.d.) on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). In a randomized, double-blind, placebo-controlled study of men aged > or = 50 years, after a 28-day placebo run-in period, patients were randomized to receive alfuzosin 10 mg q.d. or matching placebo for 28 days. The mean change from baseline (day 1) in sexual function on day 29 was assessed using the Danish Prostate Symptom Score Sex (DAN-PSSsex) questionnaire. A total of 372 patients were randomized to receive alfuzosin (n=186) or placebo (n=186), with 355 completing the study. At baseline, 64% of the patients reported erectile dysfunction (ED) and 63% reported ejaculatory dysfunction (EjD). For the 320 patients who completed the DAN-PSSsex, alfuzosin treatment was associated with a significant improvement in the mean change from baseline in erectile function on day 29 compared with placebo (P=0.02). No significant difference was observed between the two treatment groups in the mean change from baseline in ejaculatory function on day 29. For patients with ED at baseline, a marginal improvement in erectile function was demonstrated with alfuzosin treatment (P=0.09 vs placebo). For patients with EjD at baseline, the mean change from baseline in ejaculatory function with alfuzosin was comparable to that with placebo. Dizziness was the most common adverse event with alfuzosin treatment (5 vs 0% with placebo), with other adverse events reported with comparable frequency in both treatment groups. After 1 month of treatment, alfuzosin 10 mg q.d. significantly improved erectile function in men with lower urinary tract symptoms/ benign prostatic hypertrophy and had no adverse effect on ejaculatory function. [Abstract]

Brading AF, Heaton JP, Hashitani H
A survey of commonalities relevant to function and dysfunction in pelvic and sexual organs.
Int J Impot Res. 2007 Aug 23;
Micturition, defecation and sexual function are all programmed through spinal reflexes that are under descending control from higher centres. Interaction between these reflexes can clearly be perceived, and evidence is accumulating the dysfunction in one reflex is often associated with dysfunction in another. In this article, we describe some of the basic properties and neural control of the smooth muscles mediating the reflexes, reviewing the common features that underlie these reflex functions, and what changes may be responsible for dysfunction. We propose that autonomic control within the pelvis predisposes pelvic and sexual organs to crosstalk, with the consequence that diseases and conditions of the pelvis are subject to convergence on a functional level. It should be expected that disturbance of the function of one system will inevitably impact adjacent systems.International Journal of Impotence Research advance online publication, 23 August 2007; doi:10.1038/sj.ijir.3901568. [Abstract]

Berner MM, Plöger W, Burkart M
A typology of men's sexual attitudes, erectile dysfunction treatment expectations and barriers.
Int J Impot Res. 2007 Nov-Dec;19(6):
In total, 1122 men completed non-validated structured interviews on sexual attitudes and on erectile dysfunction treatment expectations and barriers. Dimensions of sexual attitudes and treatment expectations and barriers were extracted by factor analysis and subjects were grouped into types by cluster analysis. Five types emerged: the sensation seeker, the sensuous, the anxious, the confident and the abstinent. The majority of men agreed on the importance of sex for the partnership. For the majority of anxious, sensuous and sensation-seeking men, sex was important for self-esteem. Expecting quality of life, enjoyment, self-esteem and hard reliable erections from treatment with phosphodiesterase-5 inhibitors, anxieties for side effects and loss of control, sexual abstinence and desire for an intensive sex life had the strongest impact on the likelihood of use. Men's sexual attitudes vary considerably and impact reactions to erection difficulties. A typology of five groups was developed, which will contribute to research on and understanding of men's sexual and treatment-seeking behaviors. [Abstract]

Powell CR, Desai RA, Makhlouf AA, Sigman M, Jarow JP, Ross LS, Niederberger CS
Computational models for detection of endocrinopathy in subfertile males.
Int J Impot Res. 2007 Aug 23;
The observation that men with sperm density greater than 10 million/ml had low probability of endocrinopathy led to a refinement in the evaluation of subfertility. Using statistical methods, we sought to provide a more accurate prediction of which patients have an endocrinopathy, and to report the outcome as the odds of having disease. In addition, by examining the parameters that influenced the model significantly, the underlying pathophysiology might be better understood. Records of 1035 men containing variables including testis volume, sperm density, motility as well as the presence of endocrinopathy were randomized into 'training' and 'test' data sets. We modeled the data set using linear and quadratic discriminant function analysis, logistic regression (LR) and a neural network. Wilk's regression analysis was performed to determine which variables influenced the model significantly. Of the four models investigated, LR and a neural network performed the best with receiver operating characteristic areas under the curve of 0.93 and 0.95, respectively, correlating to a sensitivity of 28% and a specificity of 99% for the LR model, and a sensitivity and specificity of 56 and 97% for the neural network model. Reverse regression yielded P-values for the testis volume and sperm density of <0.0001. The neural network and LR models accurately predicted the probability of an endocrinopathy from testis volume, sperm density and motility without serum assays. These models may be accessed via the Internet, allowing urologists to select patients for endocrinologic evaluation at http://www.urocomp.org.International Journal of Impotence Research advance online publication, 23 August 2007; doi:10.1038/sj.ijir.3901593. [Abstract]

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Recent Articles in Neurourology and Urodynamics

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Rosario DJ, Woo HH, Chapple CR
Definition of normality of pressure-flow parameters based on observations in asymptomatic men.
Neurourol Urodyn. 2007 Dec 6; .
AIMS: Clinical nomograms for differentiating obstructed from unobstructed voiding and poor detrusor contractility from normal contractility have traditionally been drawn on the basis of symptomatic response to outflow tract surgery or on urodynamic changes in men with LUTS before and after surgery. The aim of this study was to examine pressure-flow parameters in asymptomatic male volunteers before age-related changes in the lower urinary tract had taken place and to assess detrusor contractility and outflow conditions during physiological bladder filling against clinically used pressure-flow nomograms. METHODS: Thirty-seven healthy male subjects between the ages of 18 and 40 years volunteered to undergo AUM. A total of 66 fill-void cycles in 25 individuals were evaluable. RESULTS: Mean p(det.Qmax) for the group was 53 +/- 3 cmH(2)O with a mean Q(max) of 24 +/- 2 ml sec(-1). URA of 21 cmH(2)O defined the upper border of normality for the outflow condition. Schäfer's OCO showed the most consistent relationship between estimated urethral pressure at minimal flow and true measured urethral closure pressure. From a clinical perspective, the linear nomograms (ICS and Schäfer) are more easily accessible with the ICS BOOI and obstruction index being the simplest to calculate manually. Minimal differences found between these urodynamic nomograms confirm the clinical value of recommending a single method to facilitate future comparisons between studies. CONCLUSIONS: An upper limit of normality for the male outflow condition can be defined by an URA of 21 cmH(2)O, AGN of 40 cmH(2)O or OCO of 1. Results above these reference values should be considered abnormal in this age group and where identified in a different age-group should be explained by physiological or pathophysiological events. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Hill SR, Fayyad AM, Jones GR
Diabetes mellitus and female lower urinary tract symptoms: A review.
Neurourol Urodyn. 2007 Nov 27;
Diabetes mellitus (DM) has reached epidemic proportions world wide. Many chronic complications of DM, including neuropathy, retinopathy and nephropathy, have been well studied and although urologic complications have been recognized since 1935, little is known about DM as a pathophysiological risk factor for development of lower urinary tract symptoms (LUTS) in women. Diabetic nephropathy, a life-threatening condition, has received considerable attention in the last few years. Diabetic cystopathy, on the other hand, has received far less attention despite having a significant impact on quality of life, and with significant individual health risks. Initial studies suggested that long standing DM causes paralysis of the detrusor muscle leading to voiding difficulties and this has been the received wisdom regarding diabetic cystopathy for many years. In this review, we discuss what is currently known about lower urinary tract function and urinary incontinence in diabetic females, with a critical analysis of the available evidence and suggest areas for future research. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Boger A, Bhadra N, Gustafson KJ
Bladder voiding by combined high frequency electrical pudendal nerve block and sacral root stimulation.
Neurourol Urodyn. 2007 Nov 27;
AIMS: Uncoordinated contraction of the external urethral sphincter is prevalent in individuals with spinal cord injury and can prevent bladder voiding. The aim of this study was to demonstrate that complete and reversible sinusoidal high frequency alternating current (HFAC) conduction block of the pudendal nerves (PN) can eliminate external urethral sphincter activation and produce low residual bladder voiding. METHODS: In four cats, tripolar nerve cuff electrodes were implanted bilaterally on both pudendal nerves and on both extradural S2 roots. Bladder and urethral pressures, bladder volumes and flow were recorded. Bilateral HFAC was applied to determine voltage and frequency parameters resulting in bilateral PN conduction block. Sacral root stimulation provided bladder activation. Randomized sets of voiding trials were conducted with and without HFAC PN block. Additional voiding trials were conducted following bilateral PN neurotomy to eliminate somatic sphincter resistance and provide an estimate of voiding with complete block. RESULTS: Effective bilateral PN block and voiding was obtained in three of four animals. Application of bilateral PN HFAC stimulation improved voiding from 2 +/- 4% to 77 +/- 18% of the initial bladder volume and significantly (P < 0.001) reduced maximum bladder pressure during voiding. Voiding in trials with PN block was not significantly different from voiding following PN neurotomy (82 +/- 19%, P = 0.51). CONCLUSIONS: These results demonstrate that bilateral HFAC block of the PN can produce effective voiding. Neural prostheses using this approach may provide an alternative method for producing micturition for people with spinal cord injury. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Gard G, Tibaek S
Erratum.
Neurourol Urodyn. 2007 Nov 13;
Gunvor Gard and Sigrid Tibaek want it to be known that in the following two publications Sigrid Tibaek has an affiliation to both Department of Geriatrics and Rheumatology, Copenhagen University Hospital, Glostrup, Denmark and Department of Health Sciences, Division of Physiotherapy, Lund University, Lund, Sweden. [Abstract]

Alperin M, Abrahams-Gessel S, Wakamatsu MM
Development of de novo urge incontinence in women post sling: The role of preoperative urodynamics in assessing the risk.
Neurourol Urodyn. 2007 Nov 5;
AIMS: The study was undertaken to investigate if there are specific identifiable risk factors on the preoperative history or urodynamics testing associated with an increased risk for the development of symptoms of de novo urge urinary incontinence after a minimally invasive sling procedure. METHODS: Two hundred eighty-one women who had undergone minimally invasive sling surgery for stress urinary incontinence between January 2000 and December 2003 were identified. The records of 92 patients were included in this review. RESULTS: Twenty-five patients (27%) reported urge urinary incontinence on postoperative questioning. Clinical and urodynamic parameters were correlated with the development of de novo urge urinary incontinence. Preoperative history parameters were not predictive of the increased risk of de novo urge urinary incontinence, with the exception of increased preoperative daytime frequency (OR 3.3 (1.2, 9.1)). Of 16 women whose detrusor pressure during the filling phase of cystometry exceeded 15 cm H(2)O, de novo urge urinary incontinence developed in 9 (56%) vs. 16 (21%) of 76 women, whose detrusor pressure was </= 15 cm H(2)O (OR 4.6 (1.4, 15.0)). CONCLUSIONS: Directed patient history is only minimally helpful in the identification of women at increased risk for the development of de novo urge urinary incontinence, with the exception of the complaint of increased daytime frequency. Women with elevated detrusor pressure during the filling phase of cystometry were more likely to develop urge urinary incontinence postoperatively. Therefore, we suggest that preoperative urodynamic evaluation, and specifically detrusor pressure > 15 cm H(2)O may help identify patients at increased risk of developing de novo urge urinary incontinence following the minimally invasive sling procedure. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Kuschel S, Schuessler B
Results on function and safety of the Safyre-t, a hybrid transobturator vaginal sling for the treatment of stress urinary incontinence.
Neurourol Urodyn. 2007 Nov 5;
AIMS: To examine the efficacy and safety of the Safyre-t vaginal sling. METHODS: 108 women with a Safyre-t were invited for a gynecological follow up examination. RESULTS: 79/108 patients showed up for an examination at 20 +/- 4 months 59.5% stated that they were subjectively dry. Vaginal sling erosion was found in 8.8% of the patients and a pre-erosive state in another 13.9%. The lateral silicone column could be palpated medial to the pubic bone in 47% of the patients indicating dislocation. 6/53 sexually active women complained of dyspareunia and one women stated that her partner had felt discomfort during sexual intercourse since her vaginal sling surgery. CONCLUSIONS: This study shows that despite high patient satisfaction and acceptable subjective continence rates, the Safyre-t was associated with a comparatively high rate of vaginal sling erosions and dislocations. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Juhasz Z, Somogyi R, Vajda P, Oberritter Z, Fathi K, Pinter AB
Does the type of bladder augmentation influence the resolution of pre-existing vesicoureteral reflux? Urodynamic studies.
Neurourol Urodyn. 2007 Nov 5;
AIMS: The type of bladder augmentation on pre-existing vesicoureteral reflux (VUR) was assessed. The effects of urodynamic changes on the resolution of VUR following augmentation cystoplasty performed with various gastrointestinal segments were examined. It was queried whether elimination of high-pressure bladder is sufficient to resolve pre-existing reflux. METHODS: A retrospective record review of patients who underwent bladder augmentation between 1987 and 2004. Patients were divided into two groups. Group I included patients who had a simultaneous augmentation and ureteral reimplantation. Group II included patients with reflux in whom only a bladder augmentation was performed. Pre-and post-augmentation urodynamic results were compared in both groups. The outcome of VUR and the role of various gastrointestinal (GI) segments on the resolution of VUR were studied. RESULTS: Sixty-three patients underwent bladder augmentation during the study period. Twenty-six of them had VUR before augmentation. There were 10 patients in Group I and 16 patients in Group II. In Group I, VUR ceased in all patients, while in group II, VUR resolved in 14 patients and persisted in two patients. Small and large bowel segments used for augmentation had no effect on the resolution of VUR but the results of gastrocystoplasties were less favorable. Urodynamically there was no significant difference between the various augmentation cystoplasties. CONCLUSIONS: Bladder augmentation alone without simultaneous antireflux repair is usually sufficient for the resolution of pre-existing reflux. The various GI segments used for augmentation have no effect on urodynamic results and the resolution of VUR. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Rickey LM, Sarkey S, Doncarlos LL
Estrogen-sensitive projections from the medial preoptic area to the dorsal pontine tegmentum, including Barrington's nucleus, in the rat.
Neurourol Urodyn. 2007 Oct 23;
AIM: Urinary incontinence affects a significant number of post-menopausal women. There is conflicting evidence whether voiding symptoms in these women are related to hypoestrogenism or aging itself. This neuroanatomical study was designed to determine whether a specific central nervous system (CNS) pathway that projects to the pontine micturition center (PMC, also known as "Barrington's nucleus") is estrogen sensitive in a rat model. METHODS: A fluorescent retrograde tracer was injected into the dorsal pontine tegmentum of adult female Sprague-Dawley rats to identify neurons in the medial preoptic area (MPA) that project to the PMC. Immunohistochemistry was performed using antibodies directed against estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) to identify estrogen-sensitive neurons. The brain sections were examined using fluorescence microscopy to identify cells that project to the PMC (contain fluorescent tracer) and also express ER (are immunoreactive for ER). RESULTS: There are neurons in the MPA that are double labeled (contain fluorescent tracer and express ERalpha, but not ERbeta), showing that a subset of neurons projecting from the MPA to the PMC is estrogen sensitive. CONCLUSIONS: A subset of estrogen-sensitive neurons projects from the MPA to the PMC in rats, raising the possibility that indirect estrogenic regulation of forebrain neuronal function may modulate the micturition reflex. Future development of drugs that alter the function of this estrogen-sensitive CNS pathway may provide therapeutic strategies to treat post-menopausal incontinence. Neurourol. Urodynam. (c) Wiley-Liss, Inc. [Abstract]


Abstracts from the Society of Urodynamics and Female Urology (SUFU) Annual Meeting, 21-24 February 2007, San Diego, California, USA.
Neurourol Urodyn. 2007;26(7 Suppl): [Abstract]

Patel AK, Chapple CR
What's hot from the ICS Annual Meeting 2007.
Neurourol Urodyn. 2007;26(7): [Abstract]

Chapple C
Editorial.
Neurourol Urodyn. 2007;26(7): [Abstract]

Digesu GA, Salvatore S, Fernando R, Khullar V
Mixed urinary symptoms: What are the urodynamic findings?
Neurourol Urodyn. 2007 Oct 17;
AIM: To define the urodynamic diagnoses of women with mixed urinary incontinence (MUI) symptoms. MATERIALS AND METHODS: Women with MUI symptoms were studied. They were divided into stress predominant MUI; urge predominant MUI; or equal severity of stress and urge MUI on the basis of the most severe symptom scored on the King's Health Questionnaire. The frequency of different urodynamic diagnoses for the all women with MUI and in each of the above groups was calculated. RESULTS: Overall 3,338 women were studied. Of these 49% (1,626/3,338) reported MUI symptoms and were included. In this group 29% (464/1,626) had stress predominant MUI, 15% (248/1,626) had urge predominant MUI and 56% (912/1,626) had equal severity of urge and stress MUI. On urodynamics 42% (665/1,626) had pure urodynamic stress incontinence, 25% (414/1,626) had pure detrusor overactivity, 18% (299/1,626) had both detrusor overactivity and urodynamic stress incontinence and 15% (248/1,626) had normal urodynamic studies. In those with stress predominant MUI, 82% had urodynamic stress incontinence; in those with urge predominant MUI, 64% had detrusor overactivity. The urodynamic diagnoses were significantly different for the different balance of symptoms (P < 0.05, Chi-Square test). In women with equal severity of urge and stress incontinence, 46% had detrusor overactivity while 54% had urodynamic stress incontinence. CONCLUSIONS: The relative severity of MUI symptoms from a symptom questionnaire significantly distinguishes between different urodynamic diagnoses. Women with urge predominant MUI are more likely to have detrusor overactivity while those with stress predominant MUI are more likely to have urodynamic stress incontinence. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Digesu GA, Khullar V, Panayi D, Calandrini M, Gannon M, Nicolini U
Should we explain lower urinary tract symptoms to patients?
Neurourol Urodyn. 2007 Oct 17;
AIM: The aim of our study was to evaluate the understanding of lower urinary tract symptom (LUTS) terminology used by patients. MATERIALS AND METHODS: Women attending urodynamic clinics in United Kingdom, Australia, and Italy were asked to complete a questionnaire testing the women's understanding of stress urinary incontinence, urge urinary incontinence, frequency, urgency, nocturia, and hesitancy. Five possible explanations for the meaning of each symptom were given. RESULTS: A total of 138 consecutive women were prospectively recruited. The terms of daytime frequency, nocturia, urgency, urge urinary incontinence, stress urinary incontinence, and hesitancy were defined correctly, according to the International Continence Society terminology, only by 33% (45/138), 44% (61/138), 46% (64/138), 39% (54/138), 37% (51/138), and 41% (57/138) of women, respectively. Over 20% of women were unsure about the meaning of each symptom. We did not find any statistical difference between the three groups in determining the correct definition (P = 0.5). CONCLUSIONS: Our findings showed that most women do not know the correct meaning of LUTS terminology currently used by physicians. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Greenberg P, Brown J, Yates T, Brown V, Langenberg P, Warren JW
Voiding urges perceived by patients with interstitial cystitis/painful bladder syndrome.
Neurourol Urodyn. 2007 Oct 11;
AIMS: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a symptom-based diagnosis. We studied the IC/PBS symptom commonly referred to as "urgency" and its relationship to IC/PBS pain in a group of women with recent onset of the disease. METHODS: As part of a case control study to identify risk factors for IC, cases completed a questionnaire including two statements regarding the perceived cause of their urge to void. One was related to fear of incontinence and the other was linked with relief of pain. A Likert scale indicating level of agreement/disagreement comprised the response options. RESULTS: Most respondents (65%) agreed with the statement linking urge with pain relief. A minority (21%) concurred with the fear of incontinence statement. Disagreement for both was found in 19%. A substantial proportion (46%) agreed with pain relief but also disagreed that urge is related to fear of incontinence. Those who reported urge to relieve pain were significantly more likely to report worsened pain with bladder filling and/or improved pain with voiding. There were no such associations with urge to prevent incontinence. Overactive bladder or diabetes prior to IC onset did not confound these results. CONCLUSIONS: At least two distinct experiences of urge to urinate are evident in this population. For most, urge is linked with pain relief and is associated with bladder filling/emptying. About 1/5 reported urge to prevent incontinence. A similar portion did not agree with either urge, indicating that they may experience something altogether different, which requires further inquiry. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Yanai Y, Hashitani H, Hayase M, Sasaki S, Suzuki H, Kohri K
Role of nitric oxide/cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder.
Neurourol Urodyn. 2007 Oct 10;
AIMS: The role of nitric oxide (NO)/cyclic GMP (cGMP) pathway in regulating detrusor smooth muscle (DSM) function is still to be elucidated. We have investigated the effects of NO donors and phosphodiesterase-5 (PDE5) inhibition on spontaneous excitations in DSM. METHODS: Multibundle DSM of the guinea-pig bladder generated spontaneous phasic contractions. The effects of sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), NO donors, 8-bromo-cyclicGMP (8-Br-cGMP), a cell-permeable cGMP analog and sildenafil, a PDE5 inhibitor on these contractions were examined. The effects of these agents on spontaneous action potentials were also studied using intracellular recording technique in single-bundle DSM. RESULTS: SNP and SIN-1 enhanced spontaneous contractions in multibundle DSM and increased the frequency of spontaneous action potentials in single-bundle DSM. These excitatory effects were not antagonized by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor for guanylate cyclase, but were attenuated by cyclopiazonic acid (CPA), an inhibitor of sarco- and endoplasmic Ca ATPase (SERCA). 8-Br-cGMP invariably suppressed spontaneous contractility. Sildenafil inhibited spontaneous contractions in about 65% of multibundle DSM but had no effects on the remainder. In single-bundle DSM, sildenafil had no effect on spontaneous action potentials. CONCLUSIONS: These results suggested that NO caused an enhancement of spontaneous contractions in DSM by accelerating spontaneous action potentials through cGMP-independent mechanisms, which may involve the Ca release from intracellular stores, whilst cGMP itself has inhibitory effects on DSM contractility. Sildenafil may indirectly suppress DSM contractility by diminishing synchronicity between functional units of DSM bundles without inhibiting excitability of DSM themselves. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Valentini F, Marti B, Robain G, Nelson P
Differences between the data from free flow and intubated flow in women with urinary incontinence. What do they mean?
Neurourol Urodyn. 2007 Oct 10;
AIMS: To assess the effects of a urethral catheter on the urodynamic data extracted from uroflow in women, and to interpret the differences from free uroflow using the VBN(R) mathematical micturition model. METHODS: Urodynamic data of 217 consecutive (June 2002 to December 2004) women with urinary incontinence and without neurological disease or more than grade 2 prolapse were reviewed. Inclusion criteria were to perform one free flow (FF) and one intubated flow (IF) (voided volumes of at least 100 ml and continuous flow curves). Voiding parameters: volumes, maximum flow rate, detrusor pressure and flow time, were analyzed as some characteristic ratios. The VBN(R) model was used to make simulations of various pathophysiological hypotheses. RESULTS: Significant increased residual volume and flow time, decreased maximum flow rate were observed during IF. Twenty five patients had a residual volume only during IF; in that group, both decrease of Q(max) and increase of flow time were significant. Simulations showed that the geometrical effect of the catheter was not the only cause and allowed to propose the occurrence of a compression-like effect of the urethra and of a fading of the detrusor excitation after Q(max) to explain the results. CONCLUSION: Significant differences were found between the data from a FF and an IF in women with urinary incontinence. These findings bring to the fore the impact of the transurethral catheter and underline the necessity to obtain at least one FF and one IF during a urodynamic session. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Podnar S
Clinical and neurophysiologic testing of the penilo-cavernosus reflex.
Neurourol Urodyn. 2007 Oct 9;
AIMS: Both clinical and neurophysiologic testing of the penilo-cavernosus reflex is used in clinical practice. The aim of the present study was to determine the as yet unestablished potential contribution of sacral reflex testing to the diagnostic evaluation of patients with suspected neuropathic sacral lesions. METHODS: Fifty-three men with clinical, electrodiagnostic, and radiologic signs of chronic cauda equina or conus medullaris lesions were studied. Clinical examination, including assessment of anal sphincter tone and perianal sensation, and both clinical and neurophysiologic testing of the penilo-cavernosus reflex, were performed. The sacral reflex was elicited on a single (normal latency: <39.4 msec) and double (<36.0 msec) electrical, and on mechanical stimulation (<35.5 msec). Responses were recorded by a concentric needle electrode inserted consecutively into the left and right bulbocavernosus muscles. The response from the more abnormal side was further analyzed. RESULTS: Clinical testing of the penilo-cavernosus reflex was abnormal in 81% of patients with normal anal squeeze, in 78% with normal perianal sensation, and in 50-67% with bilaterally normal neurophysiologic findings on three different stimulation techniques. Neurophysiologic testing of the reflex was abnormal in 69-94% of patients with normal anal squeeze, in 56-67% with normal perianal sensation, and in 44-67% of patients with a clinically normal reflex. CONCLUSIONS: The study supported the clinical utility of both clinical and neurophysiologic measurement of the penilo-cavernosus reflex. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

De Wachter S, Van Meel TD, Wyndaele JJ
Can a faked cystometry deceive patients in their perception of filling sensations? A study on the reliability of spontaneously reported cystometric filling sensations in patients with non-neurogenic lower urinary tract dysfunction.
Neurourol Urodyn. 2007 Oct 9;
AIMS: To evaluate the reliability of spontaneously reported bladder sensations during real and faked cystometry in patients with non-neurogenic lower urinary tract dysfunction. METHODS: Fifty-nine patients with non-neurogenic lower urinary tract dysfunction were submitted to a real and faked filling cystometry and were asked to describe all bladder-related sensations they experienced during the investigations. All patients were told that the bladder had to be filled twice, but during the faked cystometry, no water was infused in the bladder. RESULTS: During the real cystometry, the normal pattern of filling sensation was reported by 88%. During the faked cystometry, none of the patients reported the normal pattern of filling sensations. Five patients reported first sensation of filling, one first desire to void (FDV). None of the patients reported a strong desire to void (SDV) during the faked cystometry. CONCLUSIONS: Asking patients with a non-neurogenic lower urinary tract dysfunction to report on the bladder filling sensations during cystometry is a valid method for sensory evaluation. A minority of patients may report some sensation of bladder filling even without actual bladder filling. Memory and habituation may play a role in the perception of bladder sensation and one should be aware of this. However, reporting some sensation during faked cystometry not necessarily means the evaluation of the perception of bladder filling is unreliable. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Appell RA, Sand PK
Nocturia: Etiology, diagnosis, and treatment.
Neurourol Urodyn. 2007 Oct 9;
Voiding at night, or nocturia, is a common reason for interrupted sleep in the adult population. The condition affects both men and women, with an incidence that increases dramatically with age. Nocturia has a negative impact on quality of life, affecting both morbidity and mortality. Effective diagnosis of the condition is dependent on a clear understanding of its underlying etiology. In general, the causes of nocturia fall into three categories: diurnal polyuria, nocturnal polyuria, and low bladder capacity. In some individuals, however, nocturnal polyuria and low bladder capacity may both contribute to the overall symptomatology of nocturia. Addressing any underlying conditions that contribute to nocturia is the first step in treating the condition. Lifestyle and behavioral changes may provide benefit in some individuals, but for many, the only option is pharmacotherapy. Antimuscarinic agents are first-line therapies for overactive bladder and are often used in the management of nocturia. Pharmacological and physicochemical differences between available antimuscarinic agents, however, translate into different safety and tolerability profiles, which may make some agents more suitable for use in certain populations, including the elderly. Careful selection of the most appropriate antimuscarinic medication is therefore central in optimizing treatment outcomes. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Arrighi N, Bodei S, Peroni A, Mirabella G, Zani D, Simeone C, Cunico SC, Spano P, Sigala S
Detection of muscarinic receptor subtypes in human urinary bladder mucosa: Age and gender-dependent modifications.
Neurourol Urodyn. 2007 Oct 9;
AIMS: Muscarinic receptor subtypes expressed in the human urinary bladder mucosa were characterized, investigating whether there were gender-dependent differences and if aging could induce changes in their expression. METHODS: The study was carried out on 34 subjects, 22 men and 12 women, divided in four groups, based on gender and age. Gene expression was evaluated by quantitative RT-PCR. The Western blot was performed using the 4-12% NuPAGE Bis-Tris Gel System. RESULTS: The molecular expression of each subtype of the M(1) receptor family was observed and it was not influenced either by gender or age. M(2) receptor family transcripts revealed that both M(2) and M(4) were detected and that the M(2) transcripts were modified by both gender and age. Indeed, M(2) mRNA was lower in old rather than adult men (P < 0.05), but higher in rather old than adult women (P < 0.05). Further, adult men expressed more M(2) mRNA than adult women (P < 0.05), while the opposite was detected in old age (P < 0.05). The Western blot followed by quantification confirmed that the mRNAs were translated into proteins, and that the M(2) subtype showed similar modifications found at molecular level. DISCUSSION: The selective modification of M(2) receptors observed at the urinary bladder mucosa levels indicates that this anatomical structure could play an active role in the pathophysiology of micturition and supports evidence suggesting an effect of antimuscarinic drugs at this level. Whether these results may influence the age-dependent development of micturition disorders remains to be determined. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Yokoyama T, Kumon H, Nagai A
Correlation of urinary nerve growth factor level with pathogenesis of overactive bladder.
Neurourol Urodyn. 2007 Oct 8;
AIMS: The origin of overactive bladder (OAB), which is a leading cause of lower urinary tract symptoms, remains unknown. Nerve growth factor (NGF) is one of the neurotrophic factors which are needed for the maintenance of sensory neurons. It is known that too much expression of NGF may induce bladder hyperactivity. In this study, we explored the correlation of the level of urinary NGF with various pathogenic OAB such as idiopathic, neurogenic OAB, and bladder outlet obstruction (BOO). METHODS: The study group included 51 OAB patients. Thirteen patients (7 females and 6 males) had idiopathic detrusor overactivity (DO) without BOO, 6 female idiopathic OAB without DO (sensory urgency), 16 patients with BOO due to BPH, and 16 patients with neurogenic DO (10 due to spinal cord injury (SCI), 6 due to cerebrovascular disease (CVD)). Thirty-two patients who had normal cystometric findings (23 females and 9 males) without OAB symptoms were used as controls. Urinary NGF levels were measured by enzyme-linked immunosorbent assay technique (ELISA) and the results were normalized based on creatinine (Cr) concentration. RESULTS: The urinary NGF levels in patients with neurogenic DO due to SCI, BOO, and sensory urgency were significantly higher compared with those of normal cystometric finding patients. However, the levels of urinary NGF were not statistically significant between patients with idiopathic DO without BOO, neurogenic DO due to CVD and patients with normal cystometric findings. CONCLUSIONS: These data suggest that urinary NGF levels could serve as a basis for adjunct diagnosis of OAB. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Mascarenhas F, Cocuzza M, Gomes CM, Leão N
Trigonal injection of botulinum toxin-A does not cause vesicoureteral reflux in neurogenic patients.
Neurourol Urodyn. 2007 Oct 3;
AIMS: We evaluated the effect of botulinum toxin type A (BTX-A) injections in the trigone on the antireflux mechanism and evaluated its short-term efficacy. MATERIALS AND METHODS: Between April and December 2006, 21 patients (10 men and 11 women) were prospectively evaluated. All were incontinent due to refractory NDO and underwent detrusor injection of 300 units of BTX-A, including 50 units into the trigone. Baseline and postoperative evaluation after eight weeks included cystogram, urinary tract ultrasound and urodynamics. RESULTS: At baseline, 20 patients had no vesicoureteral (VUR) and one had grade II unilateral VUR. Postoperative evaluation revealed no cases of de novo VUR and the patient with preinjection VUR had complete resolution of the reflux. Ultrasound showed 5 (23.8%) patients with hydronephrosis before BTX-A injection and only one (4.8%) at the followup evaluation (p=0.066). After treatment, 9 (42.8%) patients became dry, 11 (52.4%) were improved and one (4.8%) had no improvement. Improved patients received antimuscarinic treatment and 8 (38.1%) became dry, with a final total continence rate of 80.1%. Cystometric capacity increased from 271+/-92 to 390+/-189 ml (p=0.002), reflex volume varied from 241+/-96 to 323+/-201 ml (p=0.020) and maximum detrusor pressure reduced from 66+/-39 to 38+/-37 cm H(2)O (p<0.001). CONCLUSIONS: Our results confirm the safety of trigone injections of BTX-A in terms of development of VUR and upper urinary tract damage. Whether they are beneficial for patients with NDO or other causes of voiding dysfunction will need further studies. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Zalm PJ, Stiggelbout AM, Aardoom I, Deckers S, Greve IG, Nijeholt GA, Pelger RC
Development and validation of the pelvic floor inventories Leiden (PelFIs).
Neurourol Urodyn. 2007 Sep 25;
AIMS: To evaluate the validity and reliability in Dutch of the Pelvic Floor Inventories Leiden (PelFIs) for men and women, an administered questionnaire, developed to create a condition-specific pelvic floor questionnaire addressing all symptoms of micturition, defecation and sexual dysfunction related to pelvic floor dysfunction. METHODS: The PelFIs is an 83-item instrument for women and 76-item instrument for men measuring the degree of pelvic floor dysfunction, containing nine different domains. Questions have been selected which, from a clinical point of view, should configure a domain. The PelFIs was administered to healthy volunteers (N = 120), and to patients (N = 100). Reliability of the PelFIs was assessed by internal consistency and test-retest reliability. Construct validity was established comparing healthy volunteers and patients by intercorrelating the domains. RESULTS: A total of 220 questionnaires were completed; by 147 women and 73 men. Some domains in the men's questionnaire had a low alpha (alpha) although the overall alpha was good. The overall of the domains for men ranged from 0.53 to 0.90. The internal consistency for the total scale of men's questionnaire was 0.84. The overall of the domains in women ranged from 0.60 to 0.85. The internal consistency of the women's questionnaire was 0.88 for the total scale. Intraclass correlation ranged from 0.65 to 0.88. Differences between healthy volunteers and patients were statistically significant for all domains. CONCLUSION: The PelFIs is a new, practical and conceptually clear questionnaire, which focus on micturition, defecation and/or sexual dysfunction related to pelvic floor dysfunction. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Chapple C
Editorial.
Neurourol Urodyn. 2007;26(6): [Abstract]

Wyndaele JJ, De Wachter S
The sensory bladder (1): An update on the different sensations described in the lower urinary tract and the physiological mechanisms behind them.
Neurourol Urodyn. 2007 Sep 19;
AIMS: To give an update of the actual information on sensory function in the lower urinary tract (LUT). METHODS: We give an up-to-date review of the most modern and reasonable approach to the topic of physiological mechanisms involved in LUT sensory function and different sensations described in the LUT. RESULTS: Although the sensory function of the LUT is a main player in the function of continence and micturition, it has been dealt with rather superficially for many decades. More recently the interest in this function grows and does so rapidly, both in basic as in clinical research. Sensation depends on neurophysiologic mechanisms in several different nerves, receptors, and transmitters. This knowledge creates a better understanding of sensory symptoms. Different stimuli can elicit sensations in the LUT such as bladder filling, micturition, noxious stimuli, external stimuli. CONCLUSION: Sensation is the prerequisite of conscious bladder control and deserves full attention in the management of LUT dysfunction. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]


Abstracts of the 37th Annual Meeting of the International Continence Society, Rotterdam, The Netherlands, 20-24 August 2007.
Neurourol Urodyn. 2007;26(5): [Abstract]

Latthe PM, Foon R, Toozs-Hobson P
Prophylactic antibiotics in urodynamics: A systematic review of effectiveness and safety.
Neurourol Urodyn. 2007 Sep 11;
AIMS: To assess the effectiveness and safety of administering prophylactic antibiotics in reducing the risk of urinary tract infection (UTI) after urodynamic studies (UDS). METHODS: The CENTRAL, MEDLINE, EMBASE, CINAHI, LILIACS (up to January 2007), TRIP database, The National Library for Health, the citation lists of review articles, conference abstracts (2004-2006) and hand search of reference lists to identify relevant reviews and articles. Randomised controlled trials (RCTs) comparing effectiveness of prophylactic antibiotics with placebo or nothing in reducing bacteriologically proven UTI after invasive cystometry were included. Two reviewers extracted data independently and the results were expressed as peto odds ratio with 95% confidence intervals using fixed effects model in ReV Man 4.2.8 software. RESULTS: Eight RCTs with 995 patients were included. The majority of the patients were female. The studies were methodologically poor. The primary outcome in all but one study was newly acquired infection defined as colony count >10(5)/ml in urine tested post UDS. On meta-analysis, there was 40% reduction in the risk of significant bacteriuria with administration of prophylactic antibiotics (Peto odds ratio 0.39; 95% confidence interval 0.24-0.61). The antibiotics used differed in dose, type and duration. One minor skin rash and one major anaphylactic reaction requiring steroid injection therapy was reported in the treatment group. One would need to give prophylactic antibiotics to 13 individuals undergoing UDS to prevent one significant bacteriuria of unknown clinical significance. CONCLUSION: The use of prophylactic antibiotics in urodynamics reduces the risk of significant bacteriuria. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Lin YH, Liu G, Daneshgari F
A mouse model of simulated birth trauma induced stress urinary incontinence.
Neurourol Urodyn. 2007 Sep 11;
AIMS: To facilitate future applications of transgenic or knockout technologies in studies of simulated birth trauma induced stress urinary incontinence (SUI), we aimed to create a mouse model of SUI and explore the possible pathogenesis of this condition. METHODS: Thirty female C57BL/6 mice were randomly distributed into five groups. Four groups underwent vaginal distention (VD) for 1 hr, using a modified 6-Fr. Foley catheter with a balloon dilated to 0.3, 0.2, or 0.1 ml or sham distention. Four days after VD, all mice underwent leak-point pressure (LPP) measurement via an implanted suprapubic tube (SPT). The normal control group only had SPT placement and LPP measurement. After sacrifice, the urethras of the mice were harvested for routine histological examination and nerve staining. RESULTS: LPPs were significantly lower in groups after VD with 0.3- or 0.2-ml balloon than in control and sham distention groups (10.29 +/- 6.70, 14.65 +/- 6.51, 37.78 +/- 5.10, and 30.30 +/- 5.30 cm H(2)O, respectively). There were no significant differences in LPP between control and sham groups. Histology showed no significant differences in urethral striated muscle among the five groups. The density of immunoreactive neurofilaments in the urethra decreased after VD with 0.3- or 0.2-ml balloon. CONCLUSION: As a model of birth trauma, VD can induce SUI in female mice, the severity of which is related to intravaginal balloon size. Partial urethral denervation plays a plausible role in the pathogenesis of SUI. This novel mouse model could be used for further mechanistic studies of female SUI. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Everaerts W, Gevaert T, Nilius B, De Ridder D
On the origin of bladder sensing: Tr(i)ps in urology.
Neurourol Urodyn. 2007 Sep 11;
The mammalian TRP family consists of 28 channels that can be subdivided into 6 different classes: TRPV (vanilloid), TRPC (canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. Currently, a lot of scientific research is devoted to these channels and their role in sensing mechanisms throughout the body. In urology, there's a growing conviction that disturbances in afferent (sensory) mechanisms are highly important in the pathogenesis of functional problems. Therefore, the TRP family forms an interesting new target to focus on. In this review we attempt to summarize the existing knowledge about TRP channels in the urogenital tract. So far, TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 (the vanilloid receptor) has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels in the (patho)physiology of the urogenital tract. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]

Smith PP, Hurtado E, Smith CP, Boone TB, Somogyi GT
Comparison of cystometric methods in female rats.
Neurourol Urodyn. 2007 Sep 11;
AIMS: Rat cystometry is a common model used to investigate urinary storage and voiding function. The effect of cystometric instrumentation in rat studies might be a source of deviation from normal physiologic responses. We hypothesized that transurethral catheterization would produce obstruction-related changes, and that suprapubic catheterization would limit volume-related functions as well as disrupt normal urothelial sensory function. We investigated the influence of transurethral and suprapubic catheterization on storage and voiding in the rat model. METHODS: Three groups of female SD rats 250-300 g under urethane anesthesia were studied. Cystometric and pseudoaffective responses to physiologic voiding with and without suprapubic catheter placement, and cystometry via suprapubic and transurethral catheterization were studied. RESULTS: In free-voiding animals, per-void volume was 1.8 +/- 0.2 ml with an average flow rate of 0.18 ml/sec, and intercontraction interval (ICI) 60 min. Suprapubic catheterization decreased the ICI and per-void volume consistent with capacity reduction. Suprapubic cystometry did not significantly alter parameters compared to voiding except for a shortened ICI. Bladder pressures and somatic responses were increased, and urine flow impaired by transurethral cystometry. Terazosin did not significantly improve voiding parameters. CONCLUSIONS: Other than volume-related parameter changes probably related to surgical compromise of bladder capacity, suprapubic catheterization does not alter the cystometric and physiologic responses to voiding when compared to normal, uninstrumented voiding. Transurethral cystometry appears to be obstructive and may activate nociceptive reflexes. For this reason, whenever possible, urodynamic testing using the rat model should employ suprapubic catheterization. Neurourol. Urodynam. (c) 2007 Wiley-Liss, Inc. [Abstract]