N-Glycosylation at Two Sites Critically Alters Thiazide Binding and Activity of the Rat Old Drugs Bring New Insights into How NaCl Transporters Work.
Transport proteins have been knownfor some time to be glycosylated on extra-cytoplasmic loops.Standard computer models readily predict the location of thesugar additions on asparagines residues, and enzymatic strippingof those sugars shifts the molecular weight of the protein.Nevertheless, it has been generally difficult to demonstratethat the sugars have any important role in transporter function.If anything, glycosylation prevention has been associated withreduced substrate affinity. In this issue, Hoover et al. reportan unusual example in the case of the rat thiazide-sensitiveNaCl co-transporter, in which lack of glycosylation appearsto reduce surface expression while simultaneously increasingthe affinity of the transporter for its substrate. The datasuggest that, for some transporters, glycosylation might beimportant in maintaining the transporter in an active form inthe membrane, perhaps by improving its stability or preventingit from proteolysis, as has been observed for misfolded proteinsinside the lumen of the endoplasmic reticulum. Whether thereare natural double (compound) mutations in the co-transporterthat prevent both asparagine residues from undergoing glycosylation,thus presenting clinically as a Gitelman syndrome, remains tobe seen.
Hemodynamics, Hypertension and Vascular Regulation
The Apolipoprotein E Knockout Mice: A Model Documenting Accelerated Atherogenesis in Uremia Modeling the Cardiovascular Disease of Uremia.
This study demonstrates that the mildrenal insufficiency caused by subtotal nephrectomy can acceleratethe development of vascular lesions in the apolipoprotein Eknockout mouse, a well-recognized animal model of atherosclerosis.Mice undergoing subtotal nephrectomy develop more extensivevascular disease than those subject to unilateral nephrectomy,while both of these groups and animals receiving a sham operationhad more extensive aortic changes than controls of similar geneticbackground undergoing the same procedures. This may become auseful model for the investigation of atherosclerosis associatedwith uremia. Some important caveats to bear in mind includethe difficulty in separating out the effects of renal failureper se versus the accompanying lipid changes that were presentin animals undergoing surgery and the relatively undevelopedstate of the atherosclerotic plaques (e.g., the lack of intimalsmooth muscle cell involvement) at a time point as late as 20weeks after birth. Nonetheless, these findings do support theattractive but still unproved hypothesis that uremia directlyaggravates atherosclerotic disease.
Immunology and Pathology
Bacterial CpG-DNA Aggravates Immune Complex Glomerulonephritis: Role of TLR9-Mediated Expression of Chemokines and Chemokine Receptor Linking Bacterial and Viral Infections to Glomerulonephritis.
This article makes a novel and potentiallyvery important observation that unmethylated CpG dinucleotidemotifs, a feature of many prokaryotes (e.g., bacteria and viruses)used as part of mammalian innate immunity recognized by sometoll-like receptors, lead to a series of activation events,including release of numerous inflammatory cytokines and inductionof a Th1-type immune response. The authors hypothesize thatCpG-DNA might prove immunostimulatory with aggravation of immunecomplex glomerulonephritis. Using the murine model of horseapoferritin–induced glomerulonephritis, the authors foundthat CpG indeed exacerbated glomerulonephritis. Two separatepathogenetic effects may underlie this finding: (1) a T cellskewing toward a Th1 cytokine profile and (2) induction withinthe glomerulus of chemokine expression, resulting in the attractionof mononuclear leukocytes expressing the toll-like receptor9. In aggregate, these studies show that bacterial CpG-DNA aggravatesimmune complex glomerulonephritis in this mouse model and illuminatesone mechanism by which infections may exacerbate existing glomerulonephritisin humans. This is a novel finding and worthy of follow-up inother experimental models of glomerulonephritis.
Molecular Medicine, Genetics and Development
Alternatively Used Promoters and Distinct Elements Direct Tissue-Specific Expression of Nephrin A Novel Isoform of Nephrin Expressed Only in the Brain.
The ancients believed that the kidneyexisted to provide man with thought. Perhaps they were right!Nephrin is a major component of the slit diaphragms, which arelocated between the podocyte foot processes and contribute tothe glomerular filtration barrier. Mutations of the nephringene are responsible for congenital nephrotic syndrome of theFinnish type. The nephrin gene shows a highly restricted patternof expression in the kidney, pancreatic islets, and centralnervous system. Beltcheva et al. have sought to understand themechanisms responsible for the tissue-specific expression ofnephrin. Various fragments of the nephrin promoter were linkedto a beta-galactosidase reporter gene and tested for expressionin transgenic mice. These studies led unexpectedly to the discoveryof a new exon of the nephrin gene that encodes a different amino-terminusof the protein. The alternative form of nephrin is expressedonly in the brain, including the choroid plexus. Although itsfunction in the brain is not understood, the authors speculatethat nephrin could be involved in transport through the blood-brainbarrier. In addition, the region of the nephrin promoter from2 kb to 4 kb upstream to the transcription start site was foundto be important for expression in podocytes.
Clinical Nephrology
Mortality Differences by Dialysis Modality among Incident ESRD Patients with and without Coronary Artery Disease Hemo Versus PD? For Patients with Coronary Disease, Hemo May Be Preferable.
Selecting a means of renal replacementtherapy is one of the most important decisions facing patientswith advanced chronic kidney disease. Patients rely on theirphysicians for information about the respective risks and benefitsof each modality when making their decision, and the physicianrelies on evidence available from clinical research to satisfythis need. Unfortunately, hard evidence in the form of randomizedcomparisons of peritoneal dialysis and hemodialysis is unavailable,and clinicians seeking information about the comparative benefitsand risk of these treatments must rely on observational studiesof the two modalities, like that reported by Ganesh et al. inthis issue of JASN. The authors report complex interactionsamong diabetic ESRD, prevalent coronary artery disease, durationand persistence of initial therapy, treatment modality, andsurvival among incident ESRD patients that warrant close attentionby clinicians concerned with helping patients make an informedtreatment choice. Among their findings is their observationthat, contrary to expectation, incident patients with coronaryartery disease did not fare as well on peritoneal dialysis ason hemodialysis. This result alone underscores the need forwell-designed trials that provide well-controlled comparisonsof the two modalities
Prognostic Value of Myocardial Perfusion Studies in Patients with End-Stage Renal Disease Assessed for Kidney or Pancreas Transplantation: A Meta-Analysis Patients with Negative Scans and Echos Can Probably Be Spared Angiography in the Pretransplant Evaluation.
Clinicians are frequently requiredto select and use tools to assign a diagnostic probability thata patient has prevalent cardiovascular disease. This informationis then used to assess risk and to subsequently guide therapeuticdecision-making. The clinician must consider the degree of diagnosticcertitude that is needed to accurately assign risk of CVD. Canone rely on noninvasive diagnostic testing to detect prevalentCVD, or is it necessary to proceed to angiography? The articleby Rabbat et al. addresses this issue with a meta-analysis ofthe prognostic utility of nuclear scintigraphy and echocardiographyfor the detection of high-risk asymptomatic individuals beingevaluated for kidney or pancreas transplantation. The authorsreport that a positive noninvasive test is associated with increasedrisk of both death and myocardial infarction and may indicatethe need for additional diagnostic evaluation. In contrast,a negative noninvasive test is associated with a low risk ofsubsequent CVD events and, in the absence of conflicting clinicalinformation, can identify patients who might not benefit frominvasive testing
Dialysis
Bioartificial Kidney Ameliorates Gram-Negative Bacteria-Induced Septic Shock in Uremic Animals To Combat Septicemia in ARF — Are Tubular Epithelial Cells the Answer?
Treatment of acute renal failure withthe systemic inflammatory response syndrome and multiorgan failurecontinues to be unsatisfactory. The field is littered with theskeletons of plausible hypotheses that have been refuted laterby study results. Fissell et al. tested the hypothesis thatfailure of the metabolic and immunoregulatory functions of proximaltubular cells in ARF contributes to the poor outcome of SIRS.Binephrectomized uremic dogs were given intraperitoneal injectionsof E. coli and treated then with continuous venovenous hemofiltrationwithout or with a hollowfiber device in series coated with porcinerenal proximal tubule cells. The device provided survival advantageand led to higher IL-10 concentrations. The results of thissmall pilot study are encouraging, but all good studies raisemore questions than answers. Is the effect specific for proximaltubular cells (or would hepatocytes do the same job)? Are therespecies differences? Which is the crucial metabolite produced?Is IL-10 only a surrogate marker? Would stem or progenitor cell–derivedcultures provide the same benefit? This study, though not thedefinite answer, undoubtedly opens a new perspective in an areaof nephrology that is in dire need for innovative approaches.
Epidemiology and Outcomes
Electrocardiographic Left Ventricular Hypertrophy in Renal Transplant Recipients: Prognostic Value and Impact of Blood Pressure and Anemia More Evidence that LVH Pretransplant Is Bad and Some Insights into Why.
Cardiovascular disease has emergedas an important cause of morbidity and mortality after transplantation,and recognition and management of CVD among these patients isan increasingly important concern. Rigatto et al. report theassociation between left ventricular hypertrophy defined byECG and subsequent risk of death among 473 renal transplantrecipients who survived at least 1 year posttransplant. Theyfound that LVH was present at baseline in 13.7% of the subjectsand that it was associated with a 90% increased risk of mortalityand over a twofold increase risk of heart failure during follow-up.Finally, they report that anemia and hypertension at baselinewere risk factors for subsequent increase in LVH. This studyextends previous observations that pretransplant LVH is associatedwith increased posttransplant mortality and provides additionalinsight into the course of LVH during the posttransplant period.Finally, it provides additional evidence for an associationbetween anemia, hypertension, and risk of progressive LVH. Theauthors note that appropriate clinical trials must be conductedto determine if modification of these risk factors results inimproved outcomes of care.
A Propensity Analysis of Late Versus Early Nephrologist Referral and Mortality on Dialysis We Keep Saying This, But Is Anyone Listening? Referral to a Nephrologist More Than 3 Months before Dialysis Reduces Mortality by 36%.
Good care matters. There is an epidemicof ESRD occurring in the United States and throughout the world.The limited nephrology manpower available in the United Statesmakes it likely that specialists other than nephrologists willprovide much of the care during the progression of chronic kidneydisease. This raises a key issue of when the nephrologist shouldbecome responsible for pre-ESRD care. There is growing evidencethat nephrology care during the year preceding the beginningof ESRD treatment is associated with decreased morbidity andmortality following the onset of renal replacement therapy.The report by Winkelmayer et al. in this issue of JASN usesa propensity analysis to examine the possibility that the benefitof early nephrology care is due to better access to health servicesrather than specific renal-related care. The authors reporta 36% increase in mortality among individuals with similar propensityscores who were seen by a nephrologist for the first time lessthan 90 days before beginning renal replacement therapy. Theauthors conclude that, while late referral to a nephrologistis an independent risk factor for early death after the onsetof ESRD, further research is needed to identify interventionsto prevent this increased risk. This research should includestudies to determine the optimal timing of nephrology referraland the best organization of nephrology resources that resultin optimal survival after the onset of ESRD treatment.
Transplantation
Donor Tissue Characteristics Influence Cadaver Kidney Transplant Function and Graft Survival but Not Rejection Donor Tissue and Renal Transplant Outcome: A New Look.
We all continue to seek better waysto reduce rejection and prolong survival of renal allografts.In this article, the authors present an analysis of outcomesof 440 cadaver transplants at their center from 220 donors between1990 and 2000. They analyzed the outcomes of pairs of donorkidneys in order to determine the relative influence of donorfactors (tissue quality, donor age, perfusion injury, etc.)on graft outcome. The data show that kidney transplant functionis strongly linked to donor-related factors. In contrast, allograftrejection affects survival and function but is not primarilydetermined by donor tissue; graft survival reflects both factors.Therefore, allograft rejection appears to be primarily determinedby the recipient alloimmune response and immunosuppression andnot be donor tissue factors. An important issue in this articleis the fact that all transplants occurred in a single centerso that center effect and immunosuppression protocols did notaffect outcome. What is the clinical relevance of these observations?How can transplant nephrologists and surgeons use this informationprospectively to determine whether to use donor organs or toadjust immunosuppression? The answer requires further prospectivestudies, especially in the area if adjusting immunosuppressionto avoid or minimize nephrotoxic drugs, especially in conditionsof donor tissue of less than optimal quality!
Dialysis, Kidney Transplantation, or Pancreas Transplantation for Patients with Diabetes Mellitus and Renal Failure: A Decision Analysis of Treatment Options We Don’t Know All the Answers, but We Do Know Some of Them.
Complex decisions. Clinicians arefrequently required to combine diverse information into therapeuticrecommendations that patients can weigh against their own expectationsand values before making an informed choice. This process isfrequently informal, relying on the clinician’s memoryand acquaintance with the relevant literature. Informal decision-makingis fraught with pitfalls that result from faulty memory, lackof accurate information about diagnostic and prognostic probabilities,and qualitative methods of weighing and combining information.Decision analysis is a formal process that seeks to overcomemany of these problems by explicitly defining the structureof the decision-making and using quantitative methods to comparevarious treatment strategies. The article by Knoll and Nicholin this issue of JASN applies decision analysis to an importantissue for patients with ESRD secondary to type I diabetes mellitus:"Which kind of transplantation is best: cadavaric kidney transplant,living related transplant, simultaneous kidney/pancreas transplant,or kidney followed by pancreas transplant?" As one might expect,the characteristics of the patient and the availability of aliving related donor influence the answer. Of interest, amongpatients with minimal metabolic complications from their diabetesand with a living donor, kidney transplantation alone was foundto be the best strategy. Clinicians can use information derivedfrom formal decision analyses in combination with patient preferencesand the outcome performance of local transplant programs tohelp patients arrive at informed decisions about difficult therapeuticchoices.
