Cell Biology Reduction of Perlecan Synthesis and Induction of TGF-1 in Human Peritoneal Mesothelial Cells Due to High Dialysate Glucose Concentration: Implication in Peritoneal Dialysis Peritoneal Membrane Failure: Perlecan Limits Leakiness.
Although membrane failure is themajor factor that limits the utility of peritoneal dialysisas a mode of therapy for end-stage renal disease (ESRD), themechanisms causing peritoneal membrane failure in patients onperitoneal dialysis are not well known. Altering the peritonealmembrane anionic barrier increases the transperitoneal passageof proteins. Perlecan is a ubiquitous protein that significantlycontributes to the negative charge of basement membranes. Yunget al. have shown that high glucose reduced perlecan levelsin cultured mesothelial cells, and reduced expression was alsonoted in patients on long-term peritoneal dialysis. These effectsare mediated through increased TGF-. These important insightsinto novel mechanisms of peritoneal membrane failure may eventuallycontribute to designing potential therapies. Page1178
Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202 Inhibiting the Cell Cycle Improves Renal Function.
Two years ago, the Nobel prizefor medicine went to investigators studying the cell cycle.We are now reaping the therapeutic benefits of these earlierstudies. The histological hallmark of HIV-associated nephropathyis collapsing FSGS, which is characterized by podocyte proliferation.Previous studies have shown that this is due to activation ofthe cell cycle. Nelson and colleagues have now performed thenext experiment. They administered a small molecule cell cycleinhibitor (Roscovitine) to mice with experimental HIV-associatednephropathy. Amazingly, inhibition of the cell cycle significantlyreduced the histologic and clinical severity of the renal lesion,with minimal side effects noted. This study provides a rationalefor extending the observations to clinical studies. Page1212
Genetics and Development Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family Partial Nephrogenic Diabetes Insipidus due to Mutation of Aquaporin-2.
Inherited nephrogenic diabetesinsipidus (NDI) can arise from mutations in the vasopressin2 receptor or the aquaporin-2 water channel. Boccalandro etal. studied a Mexican family in which polyuria and polydipsiaappeared soon after birth. They found that affected family memberswere homozygous for a missense mutation (valine-168 to methionine)of aquaporin-2. Although the mutation has been described previously,they were the first to functionally characterize the mutantprotein. Using the Xenopus oocyte expression system, they foundthat unlike many aquaporin-2 mutants that are retained in theendoplasmic reticulum, some of the V168M mutant protein waspresent on the cell surface where it could mediate water transport.Consistent with this observation, affected family members showedsome improvement in urine osmolality after administration ofddAVP, indicating that they had partial NDI. These studies representthe first description of inherited NDI due to aquaporin-2 mutationsin individuals of Mexican ancestry. The high prevalence of themutation in the small town from which the family originatessuggests a possible founder effect. Page1223
Hemodynamics and Vascular Regulation Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage An Enzyme Inhibitor that Separates the Good from the Bad and the Ugly?
The links among angiotensin II,oxidative stress, kinins, and the effects of hypertension onthe renal microvasculature have been elusive. There has evenbeen some debate about the proximate effects of hypertensionon renal vascular injury. Other groups have highlighted theproinflammatory and even immunogenic responses, especially toangiotensin II in "hypertensive nephrosclerosis." The studiespresented by Zhao et al. in this issue of JASN focus on a specificinflammatory pathway that regulates renal vascular tone. Theepoxyeicosatrienoic acids (EET) have antihypertensive and antiinflammatoryeffects, especially on the afferent arterioles, in angiotensinII–induced hypertension in the rat. Soluble epoxidasehydrolases (SEH) metabolize EET into inactive dihydroxyeicosatrienoicacids. Zhao et al. used a novel inhibitor of SEH to slow thebreakdown of EET and demonstrated protection of the renal microvasculatureand renal structural elements with reduced albuminuria in angiotensinII–induced hypertension in the rat. It will be very interestingto see if SHE inhibitors have similar protective effects onthe cardiovascular system and/or in other models of hypertensionand intrarenal angiotensin II excess like diabetes. Page1244
Pathophysiology of Renal Disease and Progression Hematopoietic Stem Cell Mobilization–Associated Granulocytosis Severely Worsens Acute Renal Failure Can We Treat ATN with Stem Cells? Maybe, But There Are Some Problems to Work out First.
Two recent papers in JASN havegenerated considerable excitement by showing that in ischemicacute renal failure (ATN) necrotic renal tubular cells can bereplaced by hematopoietic stem cells and that these new cellsmay accelerate recovery from ATN. A logical extension of thesefindings would be to see if a noninvasive method of mobilizingendogenous stem cells from the marrow would also have a beneficialeffect in ATN. Tregel et al. performed this experiment and foundthat ATN was considerably worse rather than better. This wasapparently due to nephrotoxic effects of the neutrophils thatwere also mobilized, along with other marrow cells, and overcamethe beneficial effects of the stem cells. This is still a verypromising area of research, but there clearly are a few bugsto work out before it moves to the bedside. Page1261
Basic Dialysis Endotoxin-Induced Chemokine Expression in Murine Peritoneal Mesothelial Cells: The Role of Toll-Like Receptor 4 Specific Peritoneal Membrane Receptors Taking Their Toll.
Among the causes of eventual reductionin peritoneal clearance in patients on chronic peritoneal dialysisis bacterial peritonitis. Peritonitis, which continues to plaguepatients on peritoneal dialysis, is characterized by chemokineand cytokine activation and leukocyte infiltration. These processeslead eventually to peritoneal dysfunction, and in many patientsto scarring of the peritoneum. The host’s toll-like receptors(TLR) recognize bacterial components and are therefore criticalin the early defense against infection. Kato et al. have shownthat TLR-4 increased in response to an infectious stimulus.They showed that the typical chemokine response that accompaniesthis injury was absent in mutant mice with a TLR-4 mutation.TLR are getting considerable press in the scientific literaturethese days for their role in a variety of disease processes.This study provides novel insights into the role they play inthe peritoneal membrane’s response to infection, and itmay contribute to designing ways to modify that response topreserve peritoneal function. Page1289
CLINICAL SCIENCE
Clinical Nephrology Cost of Medical Care for Chronic Kidney Disease and Comorbidity Among Enrollees in a Large HMO Population How Much Does CKD Increase Individual Health Care Costs? A Lot!
The per-patient annual cost oftreating end-stage renal disease (ESRD) is estimated by theUnited States Renal Data System (USRDS) as $45,000/year andvaries between $17,000/year for transplant recipients and $54,000/yearfor hemodialysis patients. The report by Smith et al. in thisissue of JASN extends these observations to patients acrossthe spectrum of chronic kidney disease. They examined the directhealth care costs and resource use of 14,000 patients with chronickidney disease (CKD) compared with 28,000 patients without CKDin a large managed-care organization. The estimated annual healthcare costs incurred by patients with CKD was stable over increasingstages of CKD and ranged between 1.6 and 2.5 times that of non-CKDpatients. Interestingly, costs tended to decline with increasingsurvival among individuals with the most severe CKD and werehigher among patients with moderate CKD compared with individualswith either mild or severe CKD. While similar analyses are neededin other comprehensive health care systems like Medicaid andMedicare, these results emphasize the economic burden of missedopportunities to identify early CKD and to successfully implementtherapies aimed at delaying or preventing its progression. Page1300
Epidemiology and Outcomes Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease: A Pooled Analysis of Community-Based Studies It’s Not Just ESRD. CKD Also Significantly Increases the Risk of Cardiovascular Disease.
An increased risk of cardiovasculardisease mortality among end-stage renal disease (ESRD) patientshas been recognized for some time, and recent analyses of UnitedStates Renal Data System (USRDS) data show that age-, sex-,and race-specific risk of death are substantially greater amongdialysis patients compared with the general population. Therole of chronic kidney disease (CKD) as a risk factor for cardiovasculardisease in non-ESRD patients is less clear, and a report fromthe Framingham study found no independent association afteraccounting for other risk factors. The report by Sarnak andhis colleagues in this issue of JASN combines patient-leveldata from four cohort studies, including both the FraminghamHeart Study and Framingham Offspring Study, to further examinethis issue. They report that CKD defined by a Modification ofDiet in Renal Disease (MDRD)–estimated GFR between 15and 60 ml/min per 1.73 m2 is associated with a 19% increasedrisk of a composite outcome of myocardial infarction, fatalcoronary heart disease, stroke, and death. Importantly, theynoted a significant interaction between kidney function andrace, with African Americans with CKD experiencing a 76% riskof cardiovascular disease in contrast to a 13% increase amongwhites when compared with individuals from their respectiverace groups without CKD. It is interesting to speculate thatthe same mechanisms that contribute to the apparent more rapidprogression of CKD to ESRD among African Americans may alsocontribute to the increased severity of cardiovascular diseaseamong African Americans with CKD. Page1307
Drawbacks of the Use of Indirect Estimates of Renal Function to Evaluate the Effect of Risk Factors on Renal Function More Issues with Measuring GFR Accurately.
It is now accepted that the serumcreatinine is an imprecise means of identifying individualswith chronic kidney disease (CKD), and current guidelines recommendthat clinicians use an estimation of either GFR or creatinineclearance to identify individuals with an estimated GFR of lessthan 60 ml/min per m2 as having CKD. The report by Verhave etal. in this issue of JASN underscores the need for further developmentof these estimating equations before they can be used for analyticalpurposes, as opposed to screening for CKD. The authors showthat, when compared to one another and to measured creatinineclearance, the Cockcroft-Gault and Modification of Diet in RenalDisease (MDRD) estimating equations vary differently over valuesof patient characteristics included in the Cockcroft-Gault andMDRD formula, including gender, age, and weight. In contrast,the variation across ranges of characteristics not includedin the estimating formula, such as blood pressure and cholesterol,are more comparable to those observed for measured creatinineclearance. The authors suggest that this result likely reflectsa type of statistical collinearity where the variables usedto estimate the outcome are so highly correlated that theirindependent influences on the response variable cannot be reliablyestimated. Current efforts underway to provide a more accurateand validated revision of the current generation of GFR estimatingequations should deal with the issues raised by Verhave et al.Page1316
Differential Risk of Hypertensive Disorders of Pregnancy among Hispanic Women Gestational Hypertension and Preeclampsia among Hispanic Women.
Increased risk of preeclampsiahas been reported for African-American women compared with whitewomen. The report by Wolf et al. shows that similar increasedrisks for preeclampsia exist among Hispanic women compared withwhite women. Unexpectedly for those who consider gestationalhypertension and preeclampsia as a continuum, this increasedrisk among Hispanic women was not observed for gestational hypertension,and the factors associated with the two conditions differed,suggesting that differences in the pathogenesis of the two conditionsmight exist as well. On the basis of their findings, the authorssuggest that the onset of hypertension in pregnant Hispanicwomen most likely represents incipient preeclampsia. This suggestionshould be tested in other observational data and the implicationsfor management of hypertension during pregnancy in prospectivetrials established. Page1330
Clinical Transplantation Pharmacoepidemiology of Anemia in Kidney Transplant Recipients ACEI and Anemia Following Transplant.
The contribution and clinicalrelevance of angiotensin-converting enzyme inhibitor (ACEI)and angiotensin receptor blocker (ARB) use in the occurrenceof erythropoietin resistance and anemia among patients withchronic kidney disease remains uncertain. The article by Winklemayeret al. in this issue of JASN provides additional support foran association between blockade of the renin-angiotensin system(RAS) and anemia among posttransplant patients by demonstratinga dose-dependent association between ACEI and the degree ofposttransplant anemia. These observations raise questions withrespect to the cost-effective management of cardiovascular riskand protection of renal function in posttransplant patients.These issues can only be fully resolved with evidence that allowsus to balance the beneficial effects of ACEI/ARB use and correctionof anemia against the effectiveness and increased costs of erythropoietindosing necessitated by RAS blockade. Page1347
1 in Human Peritoneal Mesothelial Cells Due to High Dialysate Glucose Concentration: Implication in Peritoneal Dialysis
