Na Transport in Autosomal Recessive Polycystic Kidney Disease (ARPKD) Cyst Lining Epithelial Cells Cyst Epithelial Cells in ARPKD Reabsorb Sodium.
In autosomal dominant polycystickidney disease (ADPKD), the cells lining the cysts have beenshown to secrete fluid, which may contribute to cyst formation.However, it was not known whether similar transport abnormalitieswere present in autosomal recessive PKD (ARPKD). Rohatgi etal. cultured cyst epithelial cells from ARPKD kidneys and found,unexpectedly, that they reabsorbed sodium at higher rates thannormal collecting duct cells. The Na/K-ATPase, which is normallylocated in the basolateral membrane, was found in the apicalmembrane, and the expression of the epithelial Na channel (ENaC)was increased. This study has several important implications.First, in contrast to ADPKD, fluid secretion is not importantfor cyst formation in ARPKD. Second, abnormalities in epithelialcell polarity are present in ARPKD as well as in ADPKD. Third,enhanced sodium reabsorption may contribute to the developmentof hypertension in ARPKD.
Hormones, Growth Factors, Cell Signaling, Cell Biology and Structure
N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Inhibits TGF-–Mediated Plasminogen Activator Inhibitor-1 Expression via Inhibition of Smad Pathway in Human Mesangial Cells Another Benefit of ACE Inhibition: It’s More than Meets the Nucleus!
N-acetyl-seryl-aspartyl-lysyl-proline(Ac-SDKP) is a normal plasma protein that inhibits proliferationof hematopoietic stem cells. Ac-SDKP is exclusively hydrolyzedby ACE, and plasma Ac-SDKP levels increase substantially inpatients taking ACE inhibitor drugs. Why is this of interestto nephrologists? Ac-SDKP has impressive anti-fibrotic effectsboth in vitro and in vivo. The study by Kanasaki et al. shedsnew insights into why this is so. It demonstrates that Ac-SDKPblocks the key intracellular signaling pathways involved inTGF- signaling. In particular, it demonstrates that Ac-SDKPinduced the translocation of Smad7 from the nucleus to the cytoplasm.Smad7 triggers a TGF-–negative feedback loop by competitivelybinding to and blocking the TGF- type I receptor. To demonstratethat this effect was biologically significant, TGF-–treatedhuman mesangial cells were shown to express less plasminogenactivator inhibitor-1 and procollagen I mRNA when Ac-SDKP wasadded to the culture media. These observations provide anotherexplanation for the renoprotective and anti-fibrotic actionsof ACE inhibitor drugs and add further evidence to a rapidlyexpanding body of literature that identifies TGF- intracellularsignaling as a promising therapeutic target.
Immunology and Pathology
Renal mRNA Levels as Prognostic Tools in Kidney Disease Molecular Tools and the Renal Biopsy — Can We Predict Progression?
Eikmans et al. provide a report onprogress toward a long-established goal of many in the nephrologycommunity to use molecular analysis of renal biopsies to predictthe future, especially with regard to resolution or scarringoutcomes of renal injury. This study focuses on TGF- and severalcomponents of the extracellular matrix and finds, using real-timePCR of mRNA obtained from renal biopsies, that there is limitedpredictive value of tubulointerstitial TGF- mRNA for short-term(1 mo) worsening of renal function and long-term (1 yr) favorableoutcomes. Glomerular fibronectin mRNA was also moderately correlatedwith changes in GFR over a 12-mo period. The predictive valuesof these findings are not strong; considering the labor andexpense of this type of analysis, these studies do not yet providea compelling benefit/cost ratio to introduce such studies intoroutine clinical practice in the near future. Nevertheless,the promise of such analyses continues to enchant nephropathologists,and the present study helps define some methodology and oneapproach to data analysis that may bring us closer to the prize.
Pathophysiology of Renal Disease
Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors Calcimimetics — Beyond Bone Disease.
Efforts to elucidate the signal mechanismsby which parathyroid cells (contraintuitively) suppress hormonesecretion when ambient Ca++ concentration increases led to thediscovery of a calcium-sensing protein, which continuously monitorsCa++ concentration in the extracellular fluid. Clarificationof its molecular function led to the ingenious development ofsmall molecules that modulate calcium-sensing through allostericinteraction. They either inhibit (calcimimetics) or stimulate(calciolytics) PTH secretion by fooling the parathyroid cell.The development of calcimimetics raised great hopes for providinga tool to lower PTH secretion in order to prevent parathyroidhyperplasia and to ameliorate or prevent renal bone disease.The study by Ogata et al. shows that the potential of calcimimeticsmay extend far beyond. In the subtotally nephrectomized rat,the authors were able to demonstrate that calcimimetics attenuatedprogression of renal failure (evaluated by albuminuria and glomerulosclerosis),lowered BP, reversed dyslipidemia, and partially abrogated pathologyof cardiac structure. Similar effects were seen with parathyroidectomy,pointing to PTH excess as the culprit. However, given the ubiquitouspresence of calcium sensors in various target organs, includingthe kidneys, the possibility must be examined whether some ofthe effects are also due to intrinsic (beneficial) effects ofcalcimimetics independent of PTH.
Dialysis
Sustained-Release Diltiazem Reduces Myocardial Ischemic Episodes in End-Stage Renal Disease: A Double-Blind, Randomized, Crossover, Placebo-Controlled Trial Evidence-Based Therapy for Ischemic Heart Disease in Dialysis Patients.
One of the hallmarks of evidence-basedmedicine is the steady accumulation of therapeutic informationderived from well-designed clinical trials like that reportedby Cice et al. in this issue of JASN. The authors address thecalcium channel blocker dose that results in the greatest degreeof suppression of silent myocardial ischemia in hemodialysispatients. They conducted a randomized, double-blind, crossover,placebo-controlled trial that compared the burden of symptomaticand silent ischemic heart disease episodes among patients treatedwith various doses of a calcium channel blocker. They reportthat a higher dose of the calcium channel blocker was necessaryfor reduction of silent ischemia compared with that necessaryfor the reduction of symptomatic episodes of ischemic heartdisease. Increased doses of Diltiazem necessary for the controlof silent ischemia were well tolerated. Further, additionalreduction in symptomatic episodes was observed at the higherdoses associated with reduction in silent ischemia. It remainsto be demonstrated that reduction in ischemic burden reducesCVD mortality among hemodialysis patients. Physicians treatingsymptomatic ischemia should consider these results when titratingdoses of calcium channel blockers to clinically optimal levels.
Epidemiology and Outcomes
Octogenarians Reaching End-Stage Renal Disease: Cohort Study of Decision-Making and Clinical Outcomes Rational Decision-Making for Elderly Patients Facing Dialysis.
The US hemodialysis population over75 yr of age increased 12.5% annually between 1995 and 1999.The rate of increase during the same period for individualsbetween 65 and 74 yr of age was 8.2% per year, while increasesof 5.0% and 0.3% per year were noted for individuals aged 45to 64 yr and 20 to 44 yr, respectively. These age-specific increasesdo not fully reflect the impact of the aging of the US populationon the ESRD population. The proportion of the US ESRD populationaged 75 yr and older increased from 15.9% in 1990 to 23.1% in1999, an increase of 68%. Clinicians caring for the elderlyneed information about the outcome of ESRD care like that reportedby Joly et al. in this issue of JASN. They conducted a retrospectivecohort study of incident elderly ESRD patients to examine factorsassociated with selection for renal replacement therapy andsubsequent survival among those placed on dialysis. They foundthat being diabetic and having a late referral to a nephrologistand poor social support were associated with the likelihoodof starting dialysis. Survival during the first year was associatedwith nutritional status, functional status, and late referral.The median survival of elderly patients electing to start renalreplacement therapy (29 mo) was threefold that of individualswho declined dialysis. Although we need to know much more aboutthe pre-ESRD care of this growing population, this report maymitigate pessimism with respect to the utility of dialysis forelderly patients and may help encourage early referral to thecare of a nephrologist of this segment of the pre-ESRD population.
Transplantation
The Impact of Repeated Subclinical Acute Rejection on the Progression of Chronic Allograft Nephropathy Is Chronic Allograft Nephropathy an Immunologic Process?
Shishido et al. show that the progressionof histopathology to chronic allograft nephropathy in transplantedkidneys and renal functional deterioration over time are correlatedwith the presence of subclinical acute inflammation as detectedin sequential protocol biopsies. This is the largest study inchildren in which sequential protocol biopsies have been obtained.It adds to a body of literature in which the deleterious effectsof subclinical rejection on allograft function and pathology,detectable only by a program of protocol biopsies, has beenclearly demonstrated. This article adds to the impetus for implementationof protocol biopsy regimens in the management of renal transplants.The authors further reinforce the emerging concept that persistentchronic (albeit subclinical) active inflammation contributessignificantly to the evolution of chronic allograft nephropathy.
–Mediated Plasminogen Activator Inhibitor-1 Expression via Inhibition of Smad Pathway in Human Mesangial Cells
