Mutations in the Human Na-K-2Cl Cotransporter (NKCC2) Identified in Bartter Syndrome Type I Consistently Result in Nonfunctional Transporters Abnormalities of the Na-K-Cl Cotransporter in Bartter Syndrome.
Bartter syndrome, an inherited disorderof renal NaCl reabsorption, can be caused by mutations of theNa-K-Cl cotransporter (NKCC2), potassium channel (ROMK), chloridechannel (ClC-Kb), or Barttin. Mutations of NKCC2 produce a severeneonatal form of Bartter syndrome with polyuria, polyhydramnios,hypokalemic metabolic alkalosis, and hypercalciuria. To determinethe effects NKCC2 mutations on the function of the protein,Starremans et al. expressed cRNAs encoding wild-type or mutantNKCC2 in Xenopus oocytes. Surprisingly, they found that injectionof identical amounts of cRNA produced significantly lower amountsof mutant protein compared with wild-type. The small amountof mutant protein that was produced was appropriately localizedin the plasma membrane but was functionally inactive. In Gitelmansyndrome, by contrast, the mutant Na-Cl cotransporter (NCC)is often retained in the endoplasmic reticulum. These studiesrepresent the first functional characterization of NKCC2 mutationsin Bartter syndrome. Although the results need to be confirmedin mammalian cells, they suggest that mutations of the NKCC2gene cause reduced expression and loss of function of the Na-K-Clcotransporter without affecting trafficking to the plasma membrane.
Hemodynamics, Hypertension and Vascular Regulation
Lead-Induced Downregulation of Soluble Guanylate Cyclase in Isolated Rat Aortic Segments Mediated by Reactive Oxygen Species and Cyclooxygenase-2 Lead — Yet Another Culprit Causing Endothelial Cell Dysfunction by Interfering with Nitric Oxide Bioavailability and Action.
Historically, lead poisoning wasan important public health problem causing hypertension, gout,and renal failure. This hazard has been virtually eliminatedin most (but not all) Western countries. Nevertheless, interestin the complex mechanisms of lead has continued. Recent studieshave shown that lead must be added to the growing list of culpritsof which action is mediated by interfering with endothelialcell-dependent, NO-mediated vasodilatation. It had been shownthat lead decreases the bioavailability of NO by increasingreactive oxygen species, which scavenge and inactivate NO. Thepresent study adds to the complexity by documenting that, independentof the NO-generating system, lead in vitro causes concentration-dependentreduction in the expression of the 1 subunit of the heterotrimericsoluble guanylate cyclase, i.e., the effector arm of NO. Thiswas associated with increased generation of superoxide anionsvia NADH oxidase or other pathways and by upregulation of cyclooxygenase-2.Vitamin C partially abrogated to downregulation of soluble guanylatecyclase, and this was also found after administration of a proteinkinase A inhibitor or a cyclooxygenase-2 inhibitor. The authorsprovide evidence that vitamin C reduced expression of Cox-2and superoxide anion generation, while the Cox-2 inhibitor failedto affect superoxide anion production, presumably acting viamodifying the availability of cAMP. The findings shed furtherlight on the longstanding puzzle of how lead causes hypertensionand renal dysfunction. In retrospect, they justify determinedefforts to eliminate environmental exposure to lead.
Immunology and Pathology Plasminogen Activator Inhibitor-1 Is a Significant Determinant of Renal Injury in Experimental Crescentic Glomerulonephritis Another Approach to Preventing Crescents in RPGN.
Crescent formation is a consequence,in large part, of intraglomerular coagulation and fibrin deposition.While some forms of anticoagulant therapy can inhibit crescentformation experimentally, systemic anticoagulation in humanshas often been accompanied by unacceptable risks of bleeding.In this issue, Kitching et al. show that plasminogen activatorinhibitor 1 (PAI-1), another more recently recognized componentof the coagulation system, is as critical to crescent formationas fibrin. PAI-1 inhibits fibrin breakdown and thereby enhancescrescent formation; mice with intact PAI-1 might therefore beexpected to suffer more severe crescentic glomerulonephritis,whereas mice lacking this inhibitor would break down fibrinmore rapidly and have less severe disease. The authors of thisstudy use genetically manipulated mice to show exactly that.The documentation of a major role for PAI-1 in crescentic glomerulonephritisobviously offers another promising therapeutic target in treatingrapidly progressive, crescentic glomerulonephritis. Developinginhibitors of PAI -1 could prove more useful and significantlyless toxic than general anticoagulation to a level that preventsfibrin deposition.
Molecular Medicine, Genetics and Development A Gene Locus for Steroid-Resistant Nephrotic Syndrome with Deafness Maps to Chromosome 14q24.2 Mapping of a New Syndrome of Steroid-Resistant Nephrotic Syndrome and Deafness.
Several genes that cause inheritedforms of nephrotic syndrome in humans have been identified.Mutations of nephrin cause congenital nephrotic syndrome ofthe Finnish type, mutations of podocin cause steroid-resistantnephrotic syndrome, and mutations of -actinin-4 cause autosomaldominant nephrotic syndrome. In this issue, Ruf et al. identifya locus on chromosome 14 for a rare association of autosomalrecessive steroid-resistant nephrotic syndrome and deafness.Using homozygosity mapping in a highly inbred Palestinian family,they localized the gene locus through a genome-wide scan andthen further refined the gene interval to a segment of approximately7 Mb containing approximately 50 candidate genes. This studyis potentially of great interest because it pinpoints the existenceof a gene involved in a new entity associating steroid-resistantnephrotic syndrome and deafness. Cloning of the gene promisesto shed novel insights into the molecular pathogenesis of nephroticsyndrome, the structure of the glomerular slit diaphragm, andsensorineural deafness.
Pathophysiology of Renal Disease BMP-7 Is an Efficacious Treatment of Vascular Calcification in a Murine Model of Atherosclerosis and Chronic Renal Failure Vascular Calcification — An Active Process Susceptible to Modulation by Circulating Factors?
Evidence has recently accumulatedthat vascular calcification in uremia is more than the passiveconsequence of supersaturation after transgression of a criticalCa x P solubility product. It appears instead to be, at leastin part, an active process, as indicated by the fact that vascularsmooth muscle cells transdifferentiate to acquire an osteoblast-likephenotype. This line of thought is reinforced by the presentobservation that bone morphogenetic protein-7 (BMP-7), an importantmorphogen in renal development that is locally expressed inthe adult kidney and is presumably present at low concentrationsin the circulation, diminishes calcium deposits in the intimaand media of uremic LDL-R-/- mice on a high-fat diet. In parallel,the expression of osteocalcin, an osteoblastic marker, was decreased.One can hypothesize that BMP-7 maintains VSMC differentiationand precludes transdifferentiation into an osteoblast-like phenotype.Although indirect effects, e.g., via influencing ions or calcium-regulatinghormones, have not yet been thoroughly excluded, the findingsmay point to the fascinating perspective that vascular calcificationin uremia as an active process may be modulated by circulatingfactors.
Clinical Nephrology The Contribution of Increased Diabetes Prevalence and Improved Myocardial Infarction and Stroke Survival to the Increase in Treated End-Stage Renal Disease What Is Causing the Epidemic of ESRD? Some Answers and Surprises.
The reasons for the continuing increasein the incidence of ESRD are poorly understood. In this issueof JASN, Muntner et al. assess three possible contributionsto the epidemic increase in ESRD: increase in the US population,prevalence of diabetes, and decreased mortality due to cardiovasculardisease. They estimate that 41% of the increased incidence inESRD observed in the US population between 1978 and 1991 couldbe attributed to these factors and that two thirds of the explainedincrease was due to the increased prevalence of diabetes. Theseestimates suggest that other factors may be influencing theincreased risk of ESRD observed in the US population and underscorethe need for continued investigation of causes for the currentepidemic. Muntner et al. also report that the estimated rateof ESRD among Americans with diabetes was 2567 cases per millionpersons; among individuals surviving a myocardial infarctionor stroke, the estimated rate was 1463 cases per million persons.This contrasts to an estimated ESRD rate of 153 cases per millionpersons among individuals without diabetes mellitus or a historyof stroke or myocardial infarction. These estimates provideadditional support for the growing interest in identifying explanatoryfactors for the joint occurrence of cardiovascular disease andchronic kidney disease.
Dialysis Ankle-Brachial Blood Pressure Index Predicts All-Cause and Cardiovascular Mortality in Hemodialysis Patients Can We Predict the Risk of Cardiovascular Disease and Death in Dialysis Patients with Just a Blood Pressure Cuff?
Ono et al. examine the associationbetween the ankle-brachial blood pressure index (ABPI) and mortalityin a cohort of 1010 Japanese hemodialysis patients. This reportextends observations that ABPI is a risk factor for all-causeand cardiovascular mortality in the general population to ahemodialysis population. Decreased ABPI was present in 16.5%of patients at baseline and was associated with increase inrisk of all-cause and cardiovascular disease mortality. Therelationship was graded, persisted after accounting for otherrisk factors, and was independent of a previous history of cardiovasculardisease. If these observations are supported in other populations,then low ABPI may prove useful in identifying a high-risk hemodialysispopulation that might be studied in clinical trials to determinethe benefit of intensive interventions to modify the risk ofsubsequent cardiovascular disease and death.
Change in Allograft Function among Long-Term Kidney Transplant Recipients Long-Term Transplant Patients Are a Major Component of the Chronic Kidney Disease Population.
Although transplantation rates havenot increased substantially during the last decade, the populationof individuals who are alive with a transplanted kidney at anyone time has nearly doubled from 56,000 individuals in 1991to 104,000 in 2000, 27% of all patients reported in 2000 bythe USRDS. This constitutes a substantial population of individualswith CKD. Gill et al. analyze renal transplant registry datato describe the pattern of posttransplant renal function innearly 41,000 patients transplanted between 1987 and 1996. During5 years of follow-up, variable patterns of renal function werenoted, with 50% of these patients either maintaining or improvingestimated GFR. The factors identified as independently associatedwith increased rate of loss of GFR included younger age, malegender, black race, primary cause of ESRD other than polycystickidney disease, older donor age and cadaveric source, and HLAmismatch. The rate of loss in GFR was greater during the laterposttransplant period and was associated with higher posttransplantGFR. Although the rate of loss of renal function overall wasmodest at 1.66 ml/min per year, there are some patients whohave substantially higher rates of decline. Additional researchshould include studies to identify modifiable risk factors forthe higher rates of loss of renal function and for the accelerationof loss with time.
Transplantation
Regulatory CD25+ T Cells in Human Kidney Transplant Recipients Are Regulatory T Cells the Major Factor in Governing the Immune Response to Allografts?
Salama et al. provide for the firsttime evidence that regulatory T cells (CD5+) are functionalin human kidney transplant recipients. Using an ELISPOT assaysystem, these cells have been identified in the peripheral bloodof approximately 50% of kidney transplant recipients who arehyporesponsive to donor HLA-DR allopeptides (indirect allorecognitionpathway). Therefore, regulation is an important mechanism resultingin donor-specific hyporesponsiveness in some kidney transplantrecipients. Interestingly, an accompanying article by Game etal. shows that regulation is not operative in the case of hyporesponsivenessto donor cells (direct allorecognition pathway), suggestingthat T cell anergy and/or apoptosis may mediate such hyporesponsiveness.Regulatory cells therefore function to suppress the indirectbut not the direct alloimmune response in human transplant recipients.These results are important for development of novel assaysto monitor transplant recipients undergoing new strategies targetedat minimizing immunosuppression or inducing tolerance and forunderstanding the mechanisms of regulation in humans with autoimmunediseases and cancer.
1 subunit of the heterotrimeric soluble guanylate cyclase, i.e., the effector arm of NO. This was associated with increased generation of superoxide anions via NADH oxidase or other pathways and by upregulation of cyclooxygenase-2. Vitamin C partially abrogated to downregulation of soluble guanylate cyclase, and this was also found after administration of a protein kinase A inhibitor or a cyclooxygenase-2 inhibitor. The authors provide evidence that vitamin C reduced expression of Cox-2 and superoxide anion generation, while the Cox-2 inhibitor failed to affect superoxide anion production, presumably acting via modifying the availability of cAMP. The findings shed further light on the longstanding puzzle of how lead causes hypertension and renal dysfunction. In retrospect, they justify determined efforts to eliminate environmental exposure to lead. 
-actinin-4 cause autosomal dominant nephrotic syndrome. In this issue, Ruf et al. identify a locus on chromosome 14 for a rare association of autosomal recessive steroid-resistant nephrotic syndrome and deafness. Using homozygosity mapping in a highly inbred Palestinian family, they localized the gene locus through a genome-wide scan and then further refined the gene interval to a segment of approximately 7 Mb containing approximately 50 candidate genes. This study is potentially of great interest because it pinpoints the existence of a gene involved in a new entity associating steroid-resistant nephrotic syndrome and deafness. Cloning of the gene promises to shed novel insights into the molecular pathogenesis of nephrotic syndrome, the structure of the glomerular slit diaphragm, and sensorineural deafness. 
