2008 JASN IMPACT FACTOR 7.505	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Articles

This Month’s Highlights

Cell and Transport Physiology
Human Podocytes Possess a Stretch-Sensitive, Ca^2+-Activated K⁺ Channel: Potential Implications for the Control of Glomerular Filtration

Podocyte Physiology on the Rise.
The glomerular epithelial cells (podocytes) define the most critical barrier in the formation of the glomerular filtrate. The slit diaphragms between these cells are complex arrays of newly characterized proteins, mutations of which have recently been linked to a number of proteinuric kidney diseases. The focus of the paper by Morton et al. in the current issue is on the characterization of a K⁺ channel in the podocytes that may be involved in podocyte response to physiologic stimuli, including changes in glomerular capillary pressure, hormonal agonists and even stretch- and swelling-induced membrane deformation. Increased intracellular Ca⁺⁺ also activates these K⁺ channels, providing a common pathway for understanding the response of podocytes to hormonal agonists. Better definition of podocyte physiology may provide new insights into the regulation of glomerular filtration, and perhaps open up new therapeutic vistas in the treatment of proteinuric renal diseases. Page 2981

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 pulsatile stretch on the glomerular capillary bed where it clearly alters the biology of glomerular cells and their response to injury. However, mechanical stretch is also well known to alter vascular smooth muscle behavior and induce both proliferation and apoptosis, or death. In this study, Massfelder et al. expose vascular smooth muscle cells from both resistance and compliance vessels to stretch and examine the role of the poly protein PTHrP in the cellular response. They find that PTHrP gene expression is increased and that PTHrP facilitates proliferation by counteracting the inhibitory effects of stretch on proliferation, thus potentially contributing to the cellular hyperplasia that characterizes restenosis or vascular access failure. The observation is another piece of the puzzle we need to assemble in order to effectively deal with the negative consequences of stretch on renal arterioles, glomerular capillaries and vessels modified for vascular access. Page 3016

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 and pancreas but are embryonic lethal. Mice with heterozygous mutations of Pkd1 survive to adulthood but rarely develop kidney cysts. Greg Germino’s laboratory has produced the first conditional knockout of Pkd1 that accurately reproduces the phenotype of humans with ADPKD. Using homologous recombination, they inserted loxP sites into the introns flanking exons 2-4 of the Pkd1 gene. Cre/loxP recombination results in deletion of the exons and generates a null allele. The conditional Pkd1 knockout mice were crossed with MMTV-Cre mice that express Cre at low levels in multiple tissues including the kidney. The resulting progeny developed cysts in the kidneys and livers during adulthood, similar to humans with ADPKD. Mice with a conditionally inactivated Pkd1 gene represent a major step forward in PKD mouse models and should be useful in the study of the pathogenesis of ADPKD. Page 3035

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 complexities of molecular manipulations and elegant in its simplicity. Obviously, renal stones are a major clinical problem for thousands of patients who populate all renal clinics and offices. We have made major strides in understanding the metabolic parameters which increase the risk of stone formation, but remarkably little attention has been paid to understanding why most people that exhibit these abnormalities do not have stones and only a few do. This study uses calcium oxalate crystals as a surrogate for stones and monolayers of the readily available MDCK distal nephron cell line to model the renal epithelium to examine what makes crystals bind to cells as a nidus for stone formation. The results are not surprising – most things looked at that irritate or injure the cells like uric acid, ischemia and cell migration to repair injury facilitated crystal adherence, while PGE₂ and maneuvers that alter cell surface sialoglycoproteins reduced it. This is an excellent example of the application of simple laboratory technology to examine a common and poorly understood clinical problem. The paper certainly does not provide all the answers, but it poses the question in a simple experimental context that can easily be expanded and built upon to look deeper. Page 3052

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 diabetic glomerulosclerosis after isolated pancreas transplantation, there has been much recent interest in the surprising ability of glomerulosclerosis to regress after different interventions in several models of renal damage. Undoubtedly podocyte loss will introduce an element of irreversibility, however. The details of how the glomerulus readjusts its architecture, particularly the capillary network, had remained obscure. It was unknown whether capillaries change their length, their number, their geometry, or whether they underwent branching. The glomerulus, according to Malpighi (1628-1694) an "organum mirabile", again surprised the investigators by adopting the simplest solution – removal or addition of capillaries of unchanged length and geometry as documented by Adamczak in this issue. He gave subtotally nephrectomized rats extremely high doses of ACE inhibitors which were presumably necessary to interfere with local RAS and then showed that changes in glomerular and tuft volume and capillary numbers occur surprisingly rapidly (but one has to keep in mind the difference of life span between humans and rats). Unresolved remains the question: which signals tell the glomerulus to modify its microvascular architecture. Page 3063

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 peritoneal dialysis has been the subject of much debate. Rosengren et al. have used, in a rat model, an innovative technique to measure colloid interstitial pressure in peritoneum, muscle and skin. They have demonstrated the intra-peritoneal hydrostatic pressure generated by infusion of peritoneal fluid causes edema in the tissues surrounding the peritoneum. This decreased colloid oncotic pressure becomes the driving force for re-absorption of fluid from the peritoneum during the latter part of the dwell. Subsequently, this fluid is removed by the lymphatic system. Knowledge of this mechanism of fluid removal will add to the information required to predict fluid kinetics with computer derived treatment strategies. Page 3111

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 to the optimal hemoglobin target for patients with CKD. This reflects the importance of anemia correction in improving the quality of like of CKD patients and the association between hemoglobin level and risk of cardiovascular disease and progression of kidney disease. The major concern about normalization of hemoglobin, interestingly, is not cost-benefit considerations, but the possibility that higher hemoglobin levels may confer increased risk of mortality, perhaps from increased rates of CVD. Until additional well-designed clinical trials are conducted to specifically examine therapeutic thresholds for hemoglobin in relevant CKD populations, clinicians must rely on earlier studies for evidence to support hemoglobin targets for CKD patients. The meta-analysis by Strippoli et al. in this issue of JASN nicely summarizes the existing clinical trial data. They identified 19 trials with over 2638 patients where either treatment with erythropoietin was compared to no erythropoietin treatment or the efficacy of different erythropoietin doses was compared. Among patients with cardiovascular disease higher attained hemoglobin was associated with increased risk of death. These results emphasize the importance of evidence-based clinical decision making and underscore the need for addition clinical trials, some in progress, that address the optimal management of anemia among patients with cardiovascular and kidney disease. These findings should remind clinicians that there is little evidence for anemia treatment that results in hemoglobin levels in excess of currently recommended targets. Page 3154

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 at a steady rate of loss of GFR that can be captured by plots of the reciprocal of the serum creatinine or measures of GFR. Changes in the slope of progressive loss are assumed to reflect factors external to the intrinsic mechanisms of injury. This assumption is central to observational studies that examine the association between changes in GFR and risk factors for CKD. The report in this issue of JASN on estimates of GFR slopes over time from the African-American Study of Kidney Disease and Hypertension (AASK) trial calls this assumption into question. When they compared mean changes in iothalamate GFR and MDRD estimates of GFR that found that the rate of GFR decline increased during follow-up. The authors note that the acceleration in GFR decline needs to be confirmed in other large databases and, if seen in other populations, the mechanism responsible for the increased rate of decline as CKD advances need to be identified. For the clinician, these observations underscore the need for close supervision and timely management of preparation for renal replacement therapy of patients in Stage 4 and 5 CKD. Page 3175

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 increased risk of cardiovascular disease and, among individuals with coronary artery disease, heart failure and stroke, the prevalence of impaired kidney function is substantially greater then that reported for comparable populations without CVD. The mechanisms for the association between atherosclerotic cardiovascular disease and chronic kidney disease are poorly understood. The standard Framingham risk factors for CVD, including male gender, hypertension, diabetes mellitus, cigarette smoking, and hypercholesterolemia, are also associated with increased risk of progression of chronic kidney disease, but the predict less than half of the variations in risk of CVD in the general population and account for only a small portion of the variability in the rate of progression of CKD. The report by Fried et al. in this issue of JASN provides evidence that risk factors associated with inflammation and thrombosis, both of which independently increase the risk of atherosclerotic heart disease, are also associated with increased risk of progression of CKD. The increasing overlap between risk factors for injury to the heart and kidney suggest that, in addition to aggressive blood pressure control, blockade of the rennin-angiotensin-aldosterone system, lipid lowering therapy and smoking cessation, novel targets for common reno- and cardio-protective intervention may exist. Page 3184

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 significant clinical problem in the treatment of chronic dialysis patients. Even after correcting for known causes, such as iron deficiency and hyperparathyroidism, a significant number of dialysis patients show hyporesponsiveness to EPO. Jun Wada and colleagues have previously shown that circulating hematopoietic stem cells isolated from EPO-resistant patients have a reduced ability to differentiate into erythroid progenitors. In this issue, they elucidate the possible mechanism. EPO acts by binding to a cell surface receptor that then activates the Jak/STAT intracellular signaling pathway. Wada et al. found that stem cells from EPO-resistant patients contained high levels of SHP-1, an endogenous inhibitor of Jak/STAT signaling. Moreover, inhibition of SHP-1 with antisense oligos increased the activity of the Jak/STAT signaling pathway and partially restored erythroid differentiation. SHP-1 may represent a novel therapeutic target for treatment of EPO-resistance in dialysis patients. Page 3215

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 utility of urinary proteome analysis in transplant recipients with stable graft function and healthy volunteers compared to patients with biopsy-proven acute renal allograft rejection and correlate this with clinical, morphologic and laboratory data. They then used four complementary bioinformatic classification techniques to analyze the data generated. They were able to correctly classify transplant and normal urine with an accuracy of 100% and with a positive predictive value of 91.6% for acute rejection compared with stable transplants. Urinary proteomic analysis may provide a powerful tool for immunological monitoring especially when combined with other assays including peripheral and intragraft monitoring of alloimmune responses. A major question remains to be addressed: whether such assays will have predictive value to help in predicting outcome and thus modifying therapy to improve it. Page 3240

Related Articles

Human Podocytes Possess a Stretch-Sensitive, Ca²⁺-Activated K⁺ Channel: Potential Implications for the Control of Glomerular Filtration

Michael J. Morton, Katie Hutchinson, Peter W. Mathieson, Ian R. Witherden, Moin A. Saleem, and Malcolm Hunter
J. Am. Soc. Nephrol. 2004 15: 2981-2987. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Articles