Cell and Transport Physiology
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 syndrome is thought to originate with vascular underfilling and stimulation of pressure and volume sensors (afferent limb) followed by increased renal salt and water retention (efferent limb). Studies in the 1970s by Levinsky’s group demonstrated that sodium retention in nephrotic rats occurs primarily in the collecting duct. Brenner’s lab showed that sodium retention also occurs in the proximal tubule, 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 shifts the sodium/hydrogen exchanger–3 (NHE3) from a subapical association with megalin to the apical membrane. Megalin is an albumin receptor; therefore, a reasonable hypothesis is that the displacement of NHE3 is a result of the increased load of albumin presented to and resorbed by the proximal tubule. An interesting feature of the study is that sodium retention preceded the proteinuria, suggesting that vascular underfill from hypoalbuminemia cannot 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 renal function predict the risk of cardiovascular disease remains controversial. de Leeuw et al. examine this issue among patients with isolated systolic hypertension. They report that impaired renal function and proteinuria, but not elevated serum uric acid, are associated with increased risk of cardiovascular mortality and morbidity. Further, these associations were stronger among women and nondiabetic patients. This study extends observations that impaired renal function is a marker for cardiovascular outcomes among patients with preexisting cardiovascular disease. Whether the same is true among individuals without clinical cardiovascular disease and mild degrees of impaired renal function remains uncertain. Of particular interest in this study was the observation that impaired GFR and proteinuria were both independently associated with increased risk of cardiovascular outcomes. This raises the possibility that changes in GFR and glomerular permselectivity may be markers for different aspects of 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 decades since ANCA antibodies were first associated with renal vasculitis like microscopic polyangiitis and Wegener granulomatosus, the issue of whether these antibodies are pathogenic or clinically useful in monitoring disease activity remains unresolved (see the editorial by Falk on pages 1977–1979 in the July issue of JASN). If ANCA are pathogenic, the mechanism probably involves binding 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 to this issue and measure membrane-localized PR3 rather than ANCA in patients with Wegener in remission and in controls. They also report that increased membrane localization of PR3 is associated with increased risk of relapse in quiescent patients, although there is significant overlap. The findings do not confirm a pathogenic role for anti-PR3 antibody in these patients, but they do provide another piece of evidence that the PR3–anti-PR3 system is in some way a part of the disease process. And so the search for the definitive experiment and answer awaits future studies.⇑
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 autosomal recessive disorder characterized by metabolic alkalosis, hypokalemia, hypercalciuria, and secondary hyperaldosteronism. Bartter syndrome is genetically heterogeneous and can arise from mutations in the Na-K-Cl cotransporter (NKCC2), the renal potassium channel (ROMK), the renal chloride channel (CLC-Kb), or the chloride channel ß-subunit (barttin). The extracellular calcium-sensing receptor (CaSR), which regulates PTH secretion in the parathyroid glands, is also highly expressed in the thick ascending limb of the loop of Henle and has been thought to inhibit sodium reabsorption in this nephron segment. Vargas-Poussou et al. identified a child with an activating mutation of CaSR who presented with metabolic alkalosis, hypokalemia, renal salt wasting, and increased urinary calcium excretion. This patient provides proof-of-principle that activation of the CaSR inhibits sodium reabsorption in the thick ascending limb of the loop of Henle, leading to the physiologic 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 circulating antidiuretic hormone, can be inherited as an X-linked or autosomal trait. X-linked NDI is caused by mutations of the V2 vasopressin receptor. Autosomal recessive and autosomal dominant NDI are caused by mutations of the gene encoding the aquaporin-2 water channel. Marr et al.identified several new missense and frameshift mutations of the aquaporin-2 gene in five families with autosomal recessive NDI. When expressed in Xenopus oocytes, the mutant water channels were poorly transported to the plasma membrane and were instead retained in the endoplasmic reticulum. Some mutant 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 autosomal recessive NDI arises because mutant aquaporin-2 is not transported to the plasma membrane correctly. If this is the case, then chemical chaperones that restore normal aquaporin-2 trafficking may 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 indicated for prevention of PTFE graft failure. Maintenance of vascular access patency is a vexing problem for hemodialysis patients with PTFE grafts, and there is considerable interest in developing interventions that will extend graft life. Crowther et al. report a randomized multicenter controlled trial of the effect of low-dose warfarin on the risk of PTFE graft failure. They found that an INR between 1.4 and 1.9 did not reduce the time to graft thrombosis in the intervention group. The study was particularly well designed; double-blinding was accomplished with sham-monitoring and placebo dose adjustment among controls. The study was terminated early because the initial dosing of warfarin was associated with a higher-than-expected failure rate and because a mid-study protocol change to allow higher warfarin doses resulted in unacceptable bleeding rates, particularly among patients who were also receiving aspirin. In view of the lack of improved graft survival and the significant increased risk of clinically significant bleeding associated with low-dose warfarin in this study, use of anticoagulation to maintain PTFE graft patency should not be part of the routine management 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 pressure among hemodialysis patients is well known and led to the hypothesis that 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 highest in winter and lowest in summer. The lower blood pressures in the summer were associated with higher outdoor temperature and less intradialytic fluid gain. Predialysis blood urea nitrogen levels were highest in March, and this coincided with peak protein catabolic rates as well as higher energy and protein intakes recorded in dietary diaries. These observations must be accounted for in longitudinal studies that use these variables, either as 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 whether peritoneal dialysis (PD) or hemodialysis is the optimal initial dialysis therapy. Ideally randomized clinical trials would examine the differences in survival, quality of life, and cost-benefit associated with the two treatments. In their absence, observational studies like the one by Winkelmayer et al. in this issue of JASN must provide evidence to resolve this issue. The authors examined the association between treatment modality and risk of death among older adult dialysis patients. They report that PD was associated with a 24% higher mortality during the first year of treatment, particularly among diabetic patients. The report has several important features. First an inception cohort was used to avoid survivor bias. Second, a propensity score was used to control for a large number of covariates with a single, summary score. Finally, the propensity score conserved enough information to allow use of an indicator variable for each of the 56 dialysis facilities represented in their analysis to control for center effects. Clinicians should incorporate this information in their discussions with patients of the risks and benefits associated with initial treatment options for renal replacement 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 reported in JASN a threefold to fourfold increased lifetime risk of ESRD among African Americans compared with white patients, with lifetime risks of ESRD for African Americans of the same magnitude as breast and prostate cancer. The report in this issue of JASN by Tarver-Carr et al. uses the NHANES II Mortality Study to examine explanatory risk factors that might account for this remarkable excess in risk. They found that differences in poverty, education, marital status, smoking status, BMI, alcohol use, physical activity, diabetes, hypertension, CVD, systolic blood pressure, and cholesterol accounted for 43.8% of this excess risk among African Americans. Further, most of the excess risk among African Americans was observed among adults aged 30 to 59 yr, and these factors accounted for only 27% of the additional risk in this age group, compared with 56% among individuals aged 60+ yr. These observations raise the questions as to what factors might account for the remaining excess risk for ESRD among African Americans and why this risk is disproportionately distributed among younger African Americans.⇑
- © 2002 American Society of Nephrology
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