Cell and Transport Physiology Human Podocytes Possess a Stretch-Sensitive, Ca2+-Activated K+ Channel: Potential Implications for the Control of Glomerular Filtration
Podocyte Physiology on the Rise.
The glomerular epithelial cells (podocytes) define the mostcritical barrier in the formation of the glomerular filtrate.The slit diaphragms between these cells are complex arrays ofnewly characterized proteins, mutations of which have recentlybeen linked to a number of proteinuric kidney diseases. Thefocus of the paper by Morton et al. in the current issue ison the characterization of a K+ channel in the podocytes thatmay be involved in podocyte response to physiologic stimuli,including changes in glomerular capillary pressure, hormonalagonists and even stretch- and swelling-induced membrane deformation.Increased intracellular Ca++ also activates these K+ channels,providing a common pathway for understanding the response ofpodocytes to hormonal agonists. Better definition of podocytephysiology may provide new insights into the regulation of glomerularfiltration, and perhaps open up new therapeutic vistas in thetreatment of proteinuric renal diseases. Page2981
Cell Biology Role of Parathyroid Hormone-Related Protein in the Regulation of Stretch-Induced Renal Vascular Smooth Muscle Cell Proliferation
PTHrP: Another player in the vascular stenosis picture?
Although pulsatile vascular flow is central to circulatory hemodynamics,in the kidney most attention has focused on the effects of pulsatilestretch on the glomerular capillary bed where it clearly altersthe biology of glomerular cells and their response to injury.However, mechanical stretch is also well known to alter vascularsmooth muscle behavior and induce both proliferation and apoptosis,or death. In this study, Massfelder et al. expose vascular smoothmuscle cells from both resistance and compliance vessels tostretch and examine the role of the poly protein PTHrP in thecellular response. They find that PTHrP gene expression is increasedand that PTHrP facilitates proliferation by counteracting theinhibitory effects of stretch on proliferation, thus potentiallycontributing to the cellular hyperplasia that characterizesrestenosis or vascular access failure. The observation is anotherpiece of the puzzle we need to assemble in order to effectivelydeal with the negative consequences of stretch on renal arterioles,glomerular capillaries and vessels modified for vascular access.Page3016
Genetics and Development A Functional Floxed Allele of Pkd1 that can be Conditionally Inactivated In Vivo
Conditional Pkd1 Knockout Mouse.
Homozygous Pkd1 knockout mice develop cysts in the kidneys andpancreas but are embryonic lethal. Mice with heterozygous mutationsof Pkd1 survive to adulthood but rarely develop kidney cysts.Greg Germino’s laboratory has produced the first conditionalknockout of Pkd1 that accurately reproduces the phenotype ofhumans with ADPKD. Using homologous recombination, they insertedloxP sites into the introns flanking exons 2-4 of the Pkd1 gene.Cre/loxP recombination results in deletion of the exons andgenerates a null allele. The conditional Pkd1 knockout micewere crossed with MMTV-Cre mice that express Cre at low levelsin multiple tissues including the kidney. The resulting progenydeveloped cysts in the kidneys and livers during adulthood,similar to humans with ADPKD. Mice with a conditionally inactivatedPkd1 gene represent a major step forward in PKD mouse modelsand should be useful in the study of the pathogenesis of ADPKD.Page3035
Mineral Metabolism and Bone Disease Modulation of Proliferating Renal Epithelial Cell Affinity for Calcium Oxalate Monohydrate Crystals
Why do some people get calcium stones while others with the same metabolic abnormalities don’t?
You will enjoy reading this study, free as it is of the complexitiesof molecular manipulations and elegant in its simplicity. Obviously,renal stones are a major clinical problem for thousands of patientswho populate all renal clinics and offices. We have made majorstrides in understanding the metabolic parameters which increasethe risk of stone formation, but remarkably little attentionhas been paid to understanding why most people that exhibitthese abnormalities do not have stones and only a few do. Thisstudy uses calcium oxalate crystals as a surrogate for stonesand monolayers of the readily available MDCK distal nephroncell line to model the renal epithelium to examine what makescrystals bind to cells as a nidus for stone formation. The resultsare not surprising – most things looked at that irritateor injure the cells like uric acid, ischemia and cell migrationto repair injury facilitated crystal adherence, while PGE2 andmaneuvers that alter cell surface sialoglycoproteins reducedit. This is an excellent example of the application of simplelaboratory technology to examine a common and poorly understoodclinical problem. The paper certainly does not provide all theanswers, but it poses the question in a simple experimentalcontext that can easily be expanded and built upon to look deeper.Page3052
Pathophysiology of Renal Disease and Progression Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular Microvasculature
Regression of Glomerulosclerosis: Simple but Elegant Adjustment of Capillary Architecture.
Following the documentation of delayed regression of diabeticglomerulosclerosis after isolated pancreas transplantation,there has been much recent interest in the surprising abilityof glomerulosclerosis to regress after different interventionsin several models of renal damage. Undoubtedly podocyte losswill introduce an element of irreversibility, however. The detailsof how the glomerulus readjusts its architecture, particularlythe capillary network, had remained obscure. It was unknownwhether capillaries change their length, their number, theirgeometry, or whether they underwent branching. The glomerulus,according to Malpighi (1628-1694) an "organum mirabile", againsurprised the investigators by adopting the simplest solution– removal or addition of capillaries of unchanged lengthand geometry as documented by Adamczak in this issue. He gavesubtotally nephrectomized rats extremely high doses of ACE inhibitorswhich were presumably necessary to interfere with local RASand then showed that changes in glomerular and tuft volume andcapillary numbers occur surprisingly rapidly (but one has tokeep in mind the difference of life span between humans andrats). Unresolved remains the question: which signals tell theglomerulus to modify its microvascular architecture. Page3063
Basic Dialysis Acute Peritoneal Dialysis in Rats Results in a Marked Reduction of Interstitial Colloid Osmotic Pressure
Why is Fluid Reabsorbed During PD?
The mechanism by which fluid is re-absorbed during peritonealdialysis has been the subject of much debate. Rosengren et al.have used, in a rat model, an innovative technique to measurecolloid interstitial pressure in peritoneum, muscle and skin.They have demonstrated the intra-peritoneal hydrostatic pressuregenerated by infusion of peritoneal fluid causes edema in thetissues surrounding the peritoneum. This decreased colloid oncoticpressure becomes the driving force for re-absorption of fluidfrom the peritoneum during the latter part of the dwell. Subsequently,this fluid is removed by the lymphatic system. Knowledge ofthis mechanism of fluid removal will add to the informationrequired to predict fluid kinetics with computer derived treatmentstrategies. Page3111
CLINICAL SCIENCE
Epidemiology and Outcomes Hemoglobin Targets for the Anemia of Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials
Correction of Anemia: Higher is Not Better.
There continues to be considerable discussion with respect tothe optimal hemoglobin target for patients with CKD. This reflectsthe importance of anemia correction in improving the qualityof like of CKD patients and the association between hemoglobinlevel and risk of cardiovascular disease and progression ofkidney disease. The major concern about normalization of hemoglobin,interestingly, is not cost-benefit considerations, but the possibilitythat higher hemoglobin levels may confer increased risk of mortality,perhaps from increased rates of CVD. Until additional well-designedclinical trials are conducted to specifically examine therapeuticthresholds for hemoglobin in relevant CKD populations, cliniciansmust rely on earlier studies for evidence to support hemoglobintargets for CKD patients. The meta-analysis by Strippoli etal. in this issue of JASN nicely summarizes the existing clinicaltrial data. They identified 19 trials with over 2638 patientswhere either treatment with erythropoietin was compared to noerythropoietin treatment or the efficacy of different erythropoietindoses was compared. Among patients with cardiovascular diseasehigher attained hemoglobin was associated with increased riskof death. These results emphasize the importance of evidence-basedclinical decision making and underscore the need for additionclinical trials, some in progress, that address the optimalmanagement of anemia among patients with cardiovascular andkidney disease. These findings should remind clinicians thatthere is little evidence for anemia treatment that results inhemoglobin levels in excess of currently recommended targets.Page3154
A Comparison of Iothalamate-GFR and Serum Creatinine-Based Outcomes: Acceleration in the Rate of GFR Decline in the African-American Study of Kidney Disease and Hypertension (AASK)
GFR Declines Faster Than You Think.
It is often assumed that the progression of CKD proceeds ata steady rate of loss of GFR that can be captured by plots ofthe reciprocal of the serum creatinine or measures of GFR. Changesin the slope of progressive loss are assumed to reflect factorsexternal to the intrinsic mechanisms of injury. This assumptionis central to observational studies that examine the associationbetween changes in GFR and risk factors for CKD. The reportin this issue of JASN on estimates of GFR slopes over time fromthe African-American Study of Kidney Disease and Hypertension(AASK) trial calls this assumption into question. When theycompared mean changes in iothalamate GFR and MDRD estimatesof GFR that found that the rate of GFR decline increased duringfollow-up. The authors note that the acceleration in GFR declineneeds to be confirmed in other large databases and, if seenin other populations, the mechanism responsible for the increasedrate of decline as CKD advances need to be identified. For theclinician, these observations underscore the need for closesupervision and timely management of preparation for renal replacementtherapy of patients in Stage 4 and 5 CKD. Page3175
Inflammatory and Prothrombotic Markers and the Progression of Renal Disease in Elderly Individuals
The CVD/CKD connection: Inflammation increases the risk of progression as well as the risk of CVD.
In patients with chronic kidney disease (CKD) are at increasedrisk of cardiovascular disease and, among individuals with coronaryartery disease, heart failure and stroke, the prevalence ofimpaired kidney function is substantially greater then thatreported for comparable populations without CVD. The mechanismsfor the association between atherosclerotic cardiovascular diseaseand chronic kidney disease are poorly understood. The standardFramingham risk factors for CVD, including male gender, hypertension,diabetes mellitus, cigarette smoking, and hypercholesterolemia,are also associated with increased risk of progression of chronickidney disease, but the predict less than half of the variationsin risk of CVD in the general population and account for onlya small portion of the variability in the rate of progressionof CKD. The report by Fried et al. in this issue of JASN providesevidence that risk factors associated with inflammation andthrombosis, both of which independently increase the risk ofatherosclerotic heart disease, are also associated with increasedrisk of progression of CKD. The increasing overlap between riskfactors for injury to the heart and kidney suggest that, inaddition to aggressive blood pressure control, blockade of therennin-angiotensin-aldosterone system, lipid lowering therapyand smoking cessation, novel targets for common reno- and cardio-protectiveintervention may exist. Page3184
Clinical Dialysis The Critical Role of SHP-1 in the rHuEPO Hyporesponsive Anemia in Chronic Hemodialysis Patients
Mechanism of EPO Resistance.
Resistance to recombinant erythropoietin (EPO) remains a significantclinical problem in the treatment of chronic dialysis patients.Even after correcting for known causes, such as iron deficiencyand hyperparathyroidism, a significant number of dialysis patientsshow hyporesponsiveness to EPO. Jun Wada and colleagues havepreviously shown that circulating hematopoietic stem cells isolatedfrom EPO-resistant patients have a reduced ability to differentiateinto erythroid progenitors. In this issue, they elucidate thepossible mechanism. EPO acts by binding to a cell surface receptorthat then activates the Jak/STAT intracellular signaling pathway.Wada et al. found that stem cells from EPO-resistant patientscontained high levels of SHP-1, an endogenous inhibitor of Jak/STATsignaling. Moreover, inhibition of SHP-1 with antisense oligosincreased the activity of the Jak/STAT signaling pathway andpartially restored erythroid differentiation. SHP-1 may representa novel therapeutic target for treatment of EPO-resistance indialysis patients. Page3215
Clinical Transplantation Bioinformatic Analysis of the Urine Proteome of Acute Allograft Rejection
Can We Diagnose Transplant Rejection From the Urine? Proteomics Comes to the Bedside.
In this study, O’Riordan et al. report on the utilityof urinary proteome analysis in transplant recipients with stablegraft function and healthy volunteers compared to patients withbiopsy-proven acute renal allograft rejection and correlatethis with clinical, morphologic and laboratory data. They thenused four complementary bioinformatic classification techniquesto analyze the data generated. They were able to correctly classifytransplant and normal urine with an accuracy of 100% and witha positive predictive value of 91.6% for acute rejection comparedwith stable transplants. Urinary proteomic analysis may providea powerful tool for immunological monitoring especially whencombined with other assays including peripheral and intragraftmonitoring of alloimmune responses. A major question remainsto be addressed: whether such assays will have predictive valueto help in predicting outcome and thus modifying therapy toimprove it. Page3240
