Cell and Transport Physiology Localization and Regulation of the Epithelial Ca2+Channel TRPV6 in the Kidney Mix or Match: Why Have Two Distinct Epithelial Calcium Channels?
Understanding mechanisms of calciumexcretion is central to many areas of nephrology, includinghypertension, stone formation, diuretic use, and others. Expressioncloning of the epithelial calcium channels has been an excitingadvance. Both "renal" (TRPV5, ECaC1,) and "intestinal" (TRPV6,CaT1, ECaC2) isoforms have been described and are differentgene products. Rene Bindels’ group has made major contributionsto this area and recently showed that co-expression of bothisoforms results in functional homotetramers and heterotetramerswith distinct Ca2+ transport kinetic profiles. In this issue,they describe apical expression of the "intestinal" isoformin the distal convoluted tubule, connecting segment, and corticaland medullary collecting tubule of the mouse. It is surprisingto find the "intestinal" isoform expressed along the entirelength of the aldosterone-responsive distal tubule, with thepossibility of heterotetrameric expression of different functionalchannels. Separate isoforms are important if each has a differentregulatory program; in this instance, however, both TRPV5 andTRPV6 are regulated by 1,25-dihydroxyvitamin D3. There may wellbe important but subtle differences in the functional and regulatoryfeatures of these heterotetrameric channels that provide segment-specificregulation of renal Ca2+ absorption. Page 2731
Cell Biology Urea Restrains Aldosterone-Induced Development of PNA-Binding on Embryonic Renal Collecting Duct Epithelia Does Urea Regulate Cell Differentiation in the Collecting Duct?
The renal collecting duct is composedof several different cell types, including principal cells,-intercalated cells, -intercalated cells, and inner medullarycollecting duct cells. However, little is known about how thedifferentiation of these cells is regulated and how their distributionalong the collecting duct is determined. Using an innovativecell culture system, Schumacher et al. found that the differentiationof embryonic collecting duct cells into cells that were labeledwith peanut agglutinin (PNA), a marker of ß-intercalatedcells, could be inhibited by the addition of urea. The effectof urea was specific, since the addition of NaCl or mannitoldid not affect PNA labeling. Moreover, the number of PNA-positivecells in the kidney is higher in the cortex than in the medulla,whereas the concentration of urea is higher in the medulla.Although the effects of urea need to be confirmed in vivo andthe PNA-positive cells need to be identified, this study suggestsan entirely new role of urea in regulating cell differentiationin the renal collecting duct. Page 2758
Hemodynamics and Vascular Regulation Role of Oxidative Stress in Endothelial Dysfunction and Enhanced Responses to AngII of Afferent Arterioles from Rabbits Infused with AngII Angiotensin II and Reactive Oxygen Species: An Unholy Alliance.
Angiotensin II (AngII) plays a keyrole in the genesis of renal damage and of some forms of hypertension.AngII-mediated vasoconstriction of preglomerular vessels isa particularly important aspect of its renal actions. One importantfeature of low-dose AngII is that the action is amplified astime goes by. The classical signaling pathways of the AT1 receptor-mediatedresponses have been well characterized in the past. The workof Wang et al. shows that the mechanisms underlying the slowpressor response of AngII are complex, but they involve oldacquaintances that are well known from studies on endothelialcell toxicity: oxidative stress and reactive oxygen species.The cell wall permeant superoxide dismutase mimetic tempol abrogatedthis reactive oxygen species (ROS)-mediated effect. This findingis not only mechanistically interesting, adding another layerof complexity to the action of AngII; it may also provide arationale for novel strategies of intervention. Page 2783
Immunology and Pathology The Fine Specificity and Cytokine Profile of T-Helper Cells Responsive to the 3 Chain of Type IV Collagen in Goodpasture’s Disease What Do T Cells Recognize in Goodpature’s Disease?
Cairns et al. report on the peptidespecificity and cytokine profile of peripheral blood lymphocytesfrom patients with Goodpasture’s disease. They testedthe response of peripheral blood lymphocytes to a panel of syntheticpeptides spanning the sequence of the 3 chain of type IV collagen.The authors report a few interesting findings. First, the affinityof the peptide to HLA-DR15 (strongly correlated with disease)was also strongly correlated with the ability of the peptideto elicit proliferation. Second, some peptides elicited a Th1response, and resolution of disease was accompanied by secretionof IL-10. Third, naturally processed peptides rarely induceda T-cell response. A major question remains. What is the exactrole of T-cell responses to the specific type IV collagen peptidesin the pathogenesis of disease? Page 2801
Pathophysiology of Renal Disease and Progression Reversal of Glomerulosclerosis after High-Dose Enalapril Treatment in Subtotally Nephrectomized Rats Progress on Progression.
Using a rat renal ablation modelof injury, Adamczak et al. add to a growing body of evidencethat what had been regarded in older literature as "irreversible"progressive fibrosing or sclerosing renal injury may indeedbe at least partially reversible. Indices measuring glomerular,tubulointerstitial, and vascular fibrosis were all improvedby angiotensin-converting enzyme (ACE) inhibitor therapy, alreadyin widespread use for treatment of kidney disease, when comparedwith appropriate control animals. This is a much-desired goalof this therapy, but achievement has been difficult to provein animal models or document in humans. Left unresolved is whetherthe beneficial effect was the result of blockade of the renin-angiotensinsystem or lowering of blood pressure. Page 2833 (see also editorialon Fogo, pp. 2990)
CLINICAL SCIENCE
Clinical Nephrology Hemodialysis and Peritoneal Dialysis: A Comparison of Adjusted Mortality Rates by the Duration of Dialysis: An Analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2 Selecting a Treatment Modality, Still No Clear Evidence.
The evidence supporting a clinician’srecommendation of hemodialysis (HD) or peritoneal dialysis (PD)remains less than satisfactory. Clinical trials have not addressedthis issue, and studies of comparative survival are hamperedby marked differences in the mortality risk factors and modalityswitching. Termorshuizen et al. address these issues in themulticenter Netherlands Cooperative Study on the Adequacy ofDialysis (NECOSAD). The authors observed statistically nonsignificantsurvival advantage between PD and HD patients during the first2 yr of treatment. Beyond 2 yr, there was a marked and significantsurvival advantage among patients treated with HD, and age anddiabetes influenced this pattern of risk. The authors raisethe hypothesis that sequential PD then HD may provide superiorsurvival when compared with either modality alone, a suggestionthat warrants further study. Page 2851
Human Genetics Molecular Analysis of the SFLT2 Gene in Patients with Renal Glucosuria Renal Glucosuria Caused by Mutations of SGLT2.
An important function of the renalproximal tubule is the reabsorption of filtered glucose, sono significant glucose appears in the urine in the absence ofhyperglycemia. The reabsorption of glucose in the proximal tubuleis a sodium-dependent process that is mediated by one or moresodium-glucose cotransporters. At least five distinct sodium-glucosecotransporters have been identified in the kidney. However,it remains controversial which ones are importantly involvedin glucose reabsorption. Santer et al. identified 23 familieswith renal glucosuria, a rare genetic trait manifesting as isolatedglucosuria in the absence of Fanconi syndrome or diabetes. In21 of the 23 families, they identified mutations of the SGLT2gene, which is believed to encode a low-affinity sodium-glucosecotransporter. Individuals carrying two SGLT2 mutations hadsevere glucosuria, whereas many heterozygous carriers had mildglucosuria. These studies demonstrate that SGLT2 plays an importantrole in glucose reabsorption in humans. Page 2873
Epidemiology and Outcomes Racial Differences in the Progression from Chronic Renal Insufficiency to End-Stage Renal Disease In the United States Prevalence of CKD but not Risk of ESRD Are Comparable among Blacks and Whites.
African Americans and other minoritygroups have an excess risk of end-stage renal disease (ESRD),and it is often assumed that higher rates of chronic kidneydisease (CKD) account for the disproportionate rates of ESRD.The report by Hsu et al. in this issue of JASN challenges thisassumption. They estimate the 5-yr risk of developing ESRD withdata from the Third National Health and Nutrition ExaminationSurvey (NHANES III) and the United States Renal Data System.They found comparable rates of CKD among whites and AfricanAmericans; however, during a 5-yr follow-up period, AfricanAmericans had nearly 5-fold greater risk of developing ESRD.Tarver-Carr et al. (J Am Soc Nephrol 13: 2363–2370, 2002)used NHANES II data to show that education, poverty, maritalstatus, smoking, alcohol use, physical inactivity, obesity,the presence of diabetes and hypertension, elevated serum cholesteroland systolic BP, and a history of cardiovascular disease accountfor 44% of this excess risk. Which, if any, of these factorsare associated with rates of differential rates of progressionremains to be studied. Page 2902
Risk Factors for Chronic Kidney Disease: A Prospective Study of 23,534 Men and Women in Washington County, Maryland Lower BP Treatment Goals for CKD Beneficial.
The recent JNC-7 guidelines (JAMA289: 2560–2572, 2003) recommend that hypertension in individualswith chronic kidney disease be treated to a BP of less than130/80 mm Hg. These recommendations revise the current targetof 130/85 mm Hg and explicitly incorporate CKD. Haroun et al.examine the 20-yr risk of end-stage renal disease (ESRD) orrenal death associated with increased BP. They found a gradedincrease in chronic kidney disease (CKD) risk above a BP of140/80 mm Hg and evidence for additional protection below thatlevel. These findings are in accord with a meta-analysis bythe ACE Inhibition in Progressive Renal Disease (AIPRD) Studygroup (Ann Intern Med 139: 244–252, 2003) and are consistentwith the JNC-7 recommendations. However, the AIPRD group notedincreased risk below a SBP of 110 mm Hg, and the risk-to-benefitof lower BP goals in CKD patients needs to be established throughadditional clinical trials and observational studies. Untilthese studies are forthcoming, JNC-7 treatment goals providea sound basis for clinical decision-making. Page 2934
Dialysis Comparison of Arteriovenous Grafts in the Thigh and Upper Extremities in Hemodialysis Patients Thigh AV Grafts are Successful in Selected HD Patients.
The reluctance to place an arteriovenous(AV) graft in the thigh is based on anecdotal experience andretrospective studies. In this issue, Miller et al. report theresults of a 3.5-yr prospective study in a single center. Althoughthe technical failure rate was twice as high as for upper extremitygrafts (12.7 versus 5.8%), the clinical results were comparablefor intervention-free survival, thrombosis-free survival, andtime to permanent failure. The total intervention rate was similarat 2.15 versus 1.70 per year for thigh and upper extremity grafts,respectively. Those receiving thigh grafts had been on hemodialysislonger and were less likely to have diabetes. The former reflectsthigh grafts being placed in those who had failed upper extremitygrafts; the latter reflects the exclusion of those with significantperipheral vascular disease. Access loss due to infection tendedto be greater for thigh than upper extremity grafts (11.1 versus5.2%), but there was no clinically apparent morbidity relatedto ischemic disease in the leg with the thigh graft. Thigh graftsshould be considered a viable option for hemodialysis patientswho have exhausted options for a permanent vascular access inthe upper extremities. However, this is a single-center studyin which all grafts were placed by a single surgeon. Generalizationto other centres must be cautious. Page 2942
Transplantation A Nomogram for Predicting the Likelihood of Delayed Graft Function in Adult Cadaveric Renal Transplant Recipients Predicting DGF in Renal Transplant Recipients.
Delayed graft function (DGF) ofrenal allografts remains a significant clinical problem in kidneytransplant recipients. DGF complicates the clinical managementof renal transplant recipients in the early posttransplant periodand may be a risk factor for development of chronic allograftnephropathy and graft loss. Irish et al. used recipient anddonor factors to develop a novel nomogram to predict the occurrenceof DGF. This nomogram should have important implications fromthe standpoint of predicting DGF and potentially interveningtherapeutically to prevent and/or minimize the impact of DGF.The latter will require further clinical studies to prove theutility of the nomogram in renal transplant recipients. Page2967
-intercalated cells, 
-intercalated cells, and inner medullary collecting duct cells. However, little is known about how the differentiation of these cells is regulated and how their distribution along the collecting duct is determined. Using an innovative cell culture system, Schumacher et al. found that the differentiation of embryonic collecting duct cells into cells that were labeled with peanut agglutinin (PNA), a marker of ß-intercalated cells, could be inhibited by the addition of urea. The effect of urea was specific, since the addition of NaCl or mannitol did not affect PNA labeling. Moreover, the number of PNA-positive cells in the kidney is higher in the cortex than in the medulla, whereas the concentration of urea is higher in the medulla. Although the effects of urea need to be confirmed in vivo and the PNA-positive cells need to be identified, this study suggests an entirely new role of urea in regulating cell differentiation in the renal collecting duct. Page 2758 
