Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease Effects of PKD2 Mutations on the Severity of Polycystic Kidney Disease.
Autosomal dominant polycystic kidneydisease (ADPKD), the most common renal genetic disorder, iscaused by mutations of PKD1 or PKD2. Mutations of PKD2 accountfor 15% of cases and produce a disease that is later in onsetbut otherwise phenotypically identical to the disease causedby mutations of PKD1. In this issue, Magistroni et al. reportthe largest genotype-phenotype correlation that has been performedfor PKD2. They studied 461 affected individuals from 71 familieswith PKD2 mutations. Their major findings were that 40% of individualshad chronic renal failure or end-stage renal disease (ESRD),mean age of onset of ESRD was 72 years, and female patientsdeveloped ESRD 8 years later than male patients. Unlike a previousstudy, the location of the mutation in the gene did not affectdisease severity. However, splice site mutations produced amilder disease compared with other types of mutations. The considerablevariability in disease among individuals with the same mutationindicates that disease severity is heavily influenced by additionalgenetic and/or environmental factors.
Hematopoietic Stem Cells Contribute to the Regeneration of Renal Tubules after Renal Ischemia-Reperfusion Injury in Mice Beyond Dopamine and Lasix? Hematopoietic Stem Cells Repopulate Necrotic Tubules with New Tubular Cells.
Despite its frequency as a clinicalproblem requiring nephrology consultation, the incidence andoutcome of acute renal failure (ARF) from ischemic acute tubularnecrosis (ATN) have remained constant for decades. This is notfor lack of research on the topic; indeed, major advances havebeen made in understanding the roles of various hemodynamicprocesses, apoptosis, oxidant injury, growth factors, etc. inregulating tubular cell death and regeneration. None of thesehave yet led to successful clinical interventions. In this issue,Lin et al. report an entirely new approach to ATN. Using sophisticatedmolecular genetics and marking technology, they harvested malehematopoietic stem cells and infused them into female recipientswith unilateral ATN. The results are dramatic. Illustrationsshow the donor stem cells later lining the walls of necroticproximal tubules and also acquiring and expressing markers ofhealthy proximal tubular cells. The article does not reportfunctional data to document improved tubular or kidney function,but the fact that the stem cells repopulated injured tubulesand became tubular cells is enough for now. This article isan exciting illustration of the potential applications for stemcell therapy in renal diseases. Stay tuned — there willbe a lot more to come in this area.
Pathophysiology of Renal Disease
Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant -Actinin-4 A New Mouse Model of Inherited FSGS.
Focal and segmental glomerulosclerosis(FSGS) is a major cause of renal failure that is increasingin frequency. Most cases are sporadic and of unknown etiology,but inherited forms of FSGS have also been described. -Actinin-4is a cytoskeletal protein that is mutated in humans with a rareautosomal dominant form of FSGS. Michaud et al. expressed amutant form of -actinin-4 in transgenic mice using a podocyte-specificpromoter from the nephrin gene. Mutant transgenic mice exhibitedproteinuria, elevated blood pressure, and renal histologic findingsof FSGS. Moreover, the expression of nephrin, a component ofthe glomerular slit diaphragm, was markedly reduced. These studiesconfirm that mutations of -actinin-4 cause FSGS and indicatethat the actin cytoskeleton is required to maintain the integrityof the slit diaphragm complex. -Actinin-4 transgenic mice representthe first mouse model of inherited human FSGS and should beuseful for further exploration of the pathogenesis and treatmentof familial as well as sporadic forms of the disease.
Mineral Metabolism and Bone Disease
Menopause and Postmenopausal Hormone Use and Risk of Incident Kidney Stones Bones, Stones, and Hormones: Another Insight into the Factors that Regulate Stone Formation in Women.
It has been recognized for some timethat women are at decreased risk of kidney stones. The protectiveeffect of gender is associated with lower urinary calcium excretion,and it has been suggested that estrogen may contribute to thisprotection against kidney stone formation. Mattix-Kramer etal. examined the protective role of estrogen in the prospectiveNurses’ Health cohort study of over 121,000 women. Theyreport a higher risk among women experiencing surgical, butnot age-related, menopause and that these associations persistafter accounting for hormone replacement therapy. These observationssuggest either that the rapidity of increased calcium loss frombone after surgical menopause increases the risk of kidney stonescompared with women experiencing age-related menopause or thatother non-estrogen effects of surgical menopause are responsiblefor the differences in risk. These factors might include lossof androgen production from the removed ovaries, increased excretionof stone-promoting factors, or changes in urine inhibitory activitytoward crystal aggregation.
Clinical Nephrology
Broadening the Spectrum of Diseases Related to Podocin Mutations Frequent Occurrence of Podocin Mutations in Children with Nephrotic Syndrome.
Podocin is an integral membrane proteinthat is located in the foot processes of glomerular epithelialcells. Mutations of the podocin gene (NPHS2) have been identifiedin humans with familial and sporadic forms of steroid-resistantnephrotic syndrome. Caridi et al. screened for podocin mutationsin 135 children presenting with sporadic steroid-resistant orsteroid-sensitive nephrotic syndrome. Overall, homozygous podocinmutations were identified in 12% of children with steroid-resistantnephrotic syndrome. Single podocin mutations were identifiedin eight patients, five of whom presented with drug-sensitivedisease. Although the possibility that the second mutation wasnot detected cannot be excluded, these results raise the possibilitythat heterozygous podocin mutations may also predispose to nephroticsyndrome, perhaps in conjunction with mutations of other glomerularproteins, such as nephrin. This study verifies that podocinmutations are a common cause of sporadic nephrotic syndrome,and it expands the spectrum of patients to include those withsteroid-sensitive disease.
Dialysis
Determinants of Survival among HIV-Infected Chronic Dialysis Patients Survival of HIV-Infected Chronic Dialysis Patients.
The dramatic improvement in survivalof HIV-infected patients with use of highly active antiretroviraltherapy (HAART) has not occurred among HIV-infected patientsinitiating dialysis. The median survival of all HIV-infectedpatients in San Francisco with an opportunistic infection increasedfrom 16 months in 1995 to 81 months in 1996. Among 115 patientswith HIV initiating dialysis at the San Francisco General Hospital,there was an increase in median survival from 9.4 to 16.1 monthsbetween the pre-HAART and the HARRT era. Factors associatedwith improved survival were higher CD4 counts (hazard ratio[HR], 0.86 per 50 cells/mm3 increase) and higher serum albumin(HR, 0.53 per 1 g/dl increase) at initiation. The poorer survivalmay be partly explained by a higher proportion of African-Americanpatients, injection drug use, and hepatitis C co-infection.However, only 33% of patients initiating dialysis during theHAART era were receiving this therapy. Factors associated withunder-utilization of HARRT therapy in this population shouldbe targeted for correction.
Epidemiology and Outcomes
Cardiovascular Risk Factors Are Differently Associated with Urinary Albumin Excretion in Men and Women Can the Increased Risk of Cardiovascular Disease in Men Be Explained by Differences in Urinary Albumin Excretion between Men and Women?
The discrepancy in risk of atheroscleroticcardiovascular disease between men and women cannot be fullyexplained by gender-specific differences in prevalence of traditionalrisk factors. Urinary albumin excretion (UAE) is a new cardiovascularrisk factor. In this issue of JASN, Verhave et al. report thatUAE is associated with the level of several cardiovascular riskfactors and is higher among men compared with women. They furthernoted that the UAE was greater among men at each risk factorlevel and that this interaction persisted after controllingfor the joint effects of relevant risk factors. These observationssuggest that male patients may be more susceptible to endothelialinjury if UAE is a marker of impaired endothelial function.Other interpretations of these observations include the possibilitythat gender-related differences in renal injury may accountfor the increased UAE seen in men and may also contribute toincreased risk of CVD through mechanisms, such as increasedsystemic oxidative stress, that do not involve endothelial function.It is also possible that the increased UAE noted by Verhaveet al. may also reflect gender differences in the existing burdenof preclinical atherosclerosis, which is linked in well-definedmechanisms to increased risk of glomerulotubular injury. Theseobservations contribute to the growing need to better definethe nexus between proteinuria and other cardiovascular riskfactors in the pathogenesis of atherosclerotic cardiovasculardisease and progressive renal injury.
Transplantation
Normal Human Kidney HLA-DR–Expressing Renal Microvascular Endothelial Cells: Characterization, Isolation, and Regulation of MHC Class II Expression Another Role for Statins in the Kidney: Regulation of HLA-DR Antigen Expression and Possibly T Cell–Mediated Inflammation.
HLA-DR initiates CD4 T cell responsesby presenting bound antigen to specific T cell receptors inthe presence of co-stimulatory molecules. In normal human kidney,HLA-DR is abundantly expressed on renal microvascular endothelialcells (RMEC) of peritubular and glomerular capillaries. It istherefore available to circulating T cells and may impart asurveillance capacity for initiation of inflammatory responses,including transplant rejection. Using multi-laser flow cytometryto identify cells in a standard renal biopsy, Muczynski et al.show that normal RMEC obtained from renal biopsies express HLA-DRbut lack the co-stimulatory molecules required to prime naïveT cells (CD80 and CD86). However, they do express the co-stimulatorymolecules that enhance sensitized T cell activation (CD40 andCD58). Thus RMEC HLA-DR may facilitate anergy in naïveT cells but intensify primed T cell responses. They also showthat RMEC HLA-DR expression, which in vitro requires normalphysiologic concentrations of -interferon, is under the controlof a statin-sensitive transcription factor. HLA-DR expressionand associated T cell responses may therefore be amenable toregulation with statins.
-Actinin-4
-interferon, is under the control of a statin-sensitive transcription factor. HLA-DR expression and associated T cell responses may therefore be amenable to regulation with statins. 
