Regulation of the Proximal Tubular Sodium/Proton Exchanger NHE3 in Rats with Puromycin Aminonucleoside (PAN)–Induced Nephrotic Syndrome Why Do Patients with Nephrotic Syndrome Retain Fluid?
Anasarca in the nephrotic syndromeis thought to originate with vascular underfilling and stimulationof pressure and volume sensors (afferent limb) followed by increasedrenal salt and water retention (efferent limb). Studies in the1970s by Levinsky’s group demonstrated that sodium retentionin nephrotic rats occurs primarily in the collecting duct. Brenner’slab showed that sodium retention also occurs in the proximaltubule, albeit to a lesser extent, in rats with puromycin aminonucleoside(PAN)–induced nephrotic syndrome. In this issue of JASN,Besse-Eschmann et al. report that PAN nephrosis in rats shiftsthe sodium/hydrogen exchanger–3 (NHE3) from a subapicalassociation with megalin to the apical membrane. Megalin isan albumin receptor; therefore, a reasonable hypothesis is thatthe displacement of NHE3 is a result of the increased load ofalbumin presented to and resorbed by the proximal tubule. Aninteresting feature of the study is that sodium retention precededthe proteinuria, suggesting that vascular underfill from hypoalbuminemiacannot entirely explain the edema of the nephrotic syndrome.
Hemodynamics, Hypertension and Vascular Regulation
Prognostic Significance of Renal Function in Elderly Patients with Isolated Systolic Hypertension: Results from the Syst-Eur Trial Another Chapter in the Story of Why Mild Renal Disease Increases Risk of Cardiovascular Mortality and Morbidity.
The degree to which markers of renalfunction predict the risk of cardiovascular disease remainscontroversial. de Leeuw et al. examine this issue among patientswith isolated systolic hypertension. They report that impairedrenal function and proteinuria, but not elevated serum uricacid, are associated with increased risk of cardiovascular mortalityand morbidity. Further, these associations were stronger amongwomen and nondiabetic patients. This study extends observationsthat impaired renal function is a marker for cardiovascularoutcomes among patients with preexisting cardiovascular disease.Whether the same is true among individuals without clinicalcardiovascular disease and mild degrees of impaired renal functionremains uncertain. Of particular interest in this study wasthe observation that impaired GFR and proteinuria were bothindependently associated with increased risk of cardiovascularoutcomes. This raises the possibility that changes in GFR andglomerular permselectivity may be markers for different aspectsof cardiovascular disease risk.
Immunology and Pathology
Neutrophil Membrane Expression of Proteinase 3 (PR3) Is Related to Relapse in PR3-ANCA–Associated Vasculitis Another Chapter in the "Is ANCA Pathogenic?" Story.
Although it has been over two decadessince ANCA antibodies were first associated with renal vasculitislike microscopic polyangiitis and Wegener granulomatosus, theissue of whether these antibodies are pathogenic or clinicallyuseful in monitoring disease activity remains unresolved (seethe editorial by Falk on pages 1977–1979 in the July issueof JASN). If ANCA are pathogenic, the mechanism probably involvesbinding to PR3 and MPO translocated to the neutrophil surface,facilitating activation and localization of neutrophils in vessels.In this issue of JASN, Rarok et al. take another approach tothis issue and measure membrane-localized PR3 rather than ANCAin patients with Wegener in remission and in controls. Theyalso report that increased membrane localization of PR3 is associatedwith increased risk of relapse in quiescent patients, althoughthere is significant overlap. The findings do not confirm apathogenic role for anti-PR3 antibody in these patients, butthey do provide another piece of evidence that the PR3–anti-PR3system is in some way a part of the disease process. And sothe search for the definitive experiment and answer awaits futurestudies.
Pathophysiology of Renal Disease
Functional Characterization of a Calcium-Sensing Receptor Mutation in Severe Autosomal Dominant Hypocalcemia with a Bartter-Like Syndrome A New Molecular Basis for Bartter Syndrome.
Bartter syndrome is an autosomalrecessive disorder characterized by metabolic alkalosis, hypokalemia,hypercalciuria, and secondary hyperaldosteronism. Bartter syndromeis genetically heterogeneous and can arise from mutations inthe Na-K-Cl cotransporter (NKCC2), the renal potassium channel(ROMK), the renal chloride channel (CLC-Kb), or the chloridechannel ß-subunit (barttin). The extracellular calcium-sensingreceptor (CaSR), which regulates PTH secretion in the parathyroidglands, is also highly expressed in the thick ascending limbof the loop of Henle and has been thought to inhibit sodiumreabsorption in this nephron segment. Vargas-Poussou et al.identified a child with an activating mutation of CaSR who presentedwith metabolic alkalosis, hypokalemia, renal salt wasting, andincreased urinary calcium excretion. This patient provides proof-of-principlethat activation of the CaSR inhibits sodium reabsorption inthe thick ascending limb of the loop of Henle, leading to thephysiologic manifestations of Bartter syndrome.
Cell-Biologic and Functional Analyses of Five New Aquaporin-2 Missense Mutations that Cause Recessive Nephrogenic Diabetes Insipidus What Goes Wrong in Autosomal Recessive Nephrogenic Diabetes Insipidus that Makes Aquaporin Not Work?
Congenital nephrogenic diabetes insipidus(NDI), in which the collecting duct is unresponsive to circulatingantidiuretic hormone, can be inherited as an X-linked or autosomaltrait. X-linked NDI is caused by mutations of the V2 vasopressinreceptor. Autosomal recessive and autosomal dominant NDI arecaused by mutations of the gene encoding the aquaporin-2 waterchannel. Marr et al.identified several new missense and frameshiftmutations of the aquaporin-2 gene in five families with autosomalrecessive NDI. When expressed in Xenopus oocytes, the mutantwater channels were poorly transported to the plasma membraneand were instead retained in the endoplasmic reticulum. Somemutant channels also had intrinsic defects in water permeability.Although these results need to be confirmed in principal cells,they suggest that the defect in urinary concentration in autosomalrecessive NDI arises because mutant aquaporin-2 is not transportedto the plasma membrane correctly. If this is the case, thenchemical chaperones that restore normal aquaporin-2 traffickingmay be a useful therapy.
Clinical Nephrology
Low-Intensity Warfarin Is Ineffective for the Prevention of PTFE Graft Failure in Patients on Hemodialysis: A Randomized Controlled Trial Low-Dose Warfarin Probably Doesn’t Work in PTFE Grafts and May Be Dangerous.
Low-dose warfin is not indicatedfor prevention of PTFE graft failure. Maintenance of vascularaccess patency is a vexing problem for hemodialysis patientswith PTFE grafts, and there is considerable interest in developinginterventions that will extend graft life. Crowther et al. reporta randomized multicenter controlled trial of the effect of low-dosewarfarin on the risk of PTFE graft failure. They found thatan INR between 1.4 and 1.9 did not reduce the time to graftthrombosis in the intervention group. The study was particularlywell designed; double-blinding was accomplished with sham-monitoringand placebo dose adjustment among controls. The study was terminatedearly because the initial dosing of warfarin was associatedwith a higher-than-expected failure rate and because a mid-studyprotocol change to allow higher warfarin doses resulted in unacceptablebleeding rates, particularly among patients who were also receivingaspirin. In view of the lack of improved graft survival andthe significant increased risk of clinically significant bleedingassociated with low-dose warfarin in this study, use of anticoagulationto maintain PTFE graft patency should not be part of the routinemanagement of hemodialysis patients.
Dialysis
Seasonal Variations in Clinical and Laboratory Variables in Chronic Hemodialysis Patients Summertime—And Dialysis Patients Do Better.
Seasonal variation in blood pressureamong hemodialysis patients is well known and led to the hypothesisthat other variables might be affected by seasonal characteristics.Data were obtained from 1445 patients enrolled in the HEMO study.Among 21 variables, 13 showed a significant seasonal variation.Predialysis systolic and diastolic blood pressures were highestin winter and lowest in summer. The lower blood pressures inthe summer were associated with higher outdoor temperature andless intradialytic fluid gain. Predialysis blood urea nitrogenlevels were highest in March, and this coincided with peak proteincatabolic rates as well as higher energy and protein intakesrecorded in dietary diaries. These observations must be accountedfor in longitudinal studies that use these variables, eitheras independent variables or as surrogate outcome variables.
Epidemiology and Outcomes
Comparing Mortality of Patients on Hemodialysis versus Peritoneal Dialysis: A Propensity Score Approach Is Peritoneal Dialysis Dangerous for Diabetic Patients during the First Year?
There is continuing debate over whetherperitoneal dialysis (PD) or hemodialysis is the optimal initialdialysis therapy. Ideally randomized clinical trials would examinethe differences in survival, quality of life, and cost-benefitassociated with the two treatments. In their absence, observationalstudies like the one by Winkelmayer et al. in this issue ofJASN must provide evidence to resolve this issue. The authorsexamined the association between treatment modality and riskof death among older adult dialysis patients. They report thatPD was associated with a 24% higher mortality during the firstyear of treatment, particularly among diabetic patients. Thereport has several important features. First an inception cohortwas used to avoid survivor bias. Second, a propensity scorewas used to control for a large number of covariates with asingle, summary score. Finally, the propensity score conservedenough information to allow use of an indicator variable foreach of the 56 dialysis facilities represented in their analysisto control for center effects. Clinicians should incorporatethis information in their discussions with patients of the risksand benefits associated with initial treatment options for renalreplacement therapy.
Excess Risk of Chronic Kidney Disease among African-American versus White Subjects in the United States: A Population-Based Study of Potential Explanatory Factors If African Americans Are at Increased Risk of ESRD, Why Is That So?
Kiberd and Clase recently reportedin JASN a threefold to fourfold increased lifetime risk of ESRDamong African Americans compared with white patients, with lifetimerisks of ESRD for African Americans of the same magnitude asbreast and prostate cancer. The report in this issue of JASNby Tarver-Carr et al. uses the NHANES II Mortality Study toexamine explanatory risk factors that might account for thisremarkable excess in risk. They found that differences in poverty,education, marital status, smoking status, BMI, alcohol use,physical activity, diabetes, hypertension, CVD, systolic bloodpressure, and cholesterol accounted for 43.8% of this excessrisk among African Americans. Further, most of the excess riskamong African Americans was observed among adults aged 30 to59 yr, and these factors accounted for only 27% of the additionalrisk in this age group, compared with 56% among individualsaged 60+ yr. These observations raise the questions as to whatfactors might account for the remaining excess risk for ESRDamong African Americans and why this risk is disproportionatelydistributed among younger African Americans.
