Showing papers in "Journal of The American Society of Nephrology in 2002"

A Role for Uric Acid in the Progression of Renal Disease

Abstract: . Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 ± 2.5 versus 17.5 ± 3.4%; P versus 1.52 ± 0.47; P in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhihbitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.

A Conditionally Immortalized Human Podocyte Cell Line Demonstrating Nephrin and Podocin Expression

Abstract: Recent molecular insights have established the podocyte as a key component of the glomerular filtration barrier, and hence an important common pathway in proteinuric diseases. A conditionally immortalized human podocyte cell line has been developed by transfection with the temperature-sensitive SV40-T gene. These cells proliferate at the "permissive" temperature (33 degrees C). After transfer to the "nonpermissive" temperature (37 degrees C), they entered growth arrest and expressed markers of differentiated in vivo podocytes, including the novel podocyte proteins, nephrin, podocin, CD2AP, and synaptopodin, and known molecules of the slit diaphragm ZO-1, alpha-, beta-, and gamma-catenin and P-cadherin. The differentiation was accompanied by a growth arrest and the upregulation of cyclin-dependent kinase inhibitors, p27 and p57, as well as cyclin D(1), whereas cyclin A was downregulated. These data are consistent with cell cycle protein expression during podocyte maturation in vivo. In conclusion, the development of this cell line provides a new tool in the study of podocyte biology, which will enable accurate assessment of the behavior of these complex cells in health and disease.

Effects of Increased Peritoneal Clearances on Mortality Rates in Peritoneal Dialysis: ADEMEX, a Prospective, Randomized, Controlled Trial

Abstract: Small-solute clearance targets for peritoneal dialysis (PD) have been based on the tacit assumption that peritoneal and renal clearances are equivalent and therefore additive. Although several studies have established that patient survival is directly correlated with renal clearances, there have been no randomized, controlled, interventional trials examining the effects of increases in peritoneal small-solute clearances on patient survival. A prospective, randomized, controlled, clinical trial was performed to study the effects of increased peritoneal small-solute clearances on clinical outcomes among patients with end-stage renal disease who were being treated with PD. A total of 965 subjects were randomly assigned to the intervention or control group (in a 1:1 ratio). Subjects in the control group continued to receive their preexisting PD prescriptions, which consisted of four daily exchanges with 2 L of standard PD solution. The subjects in the intervention group were treated with a modified prescription, to achieve a peritoneal creatinine clearance (pCrCl) of 60 L/wk per 1.73 m(2). The primary endpoint was death. The minimal follow-up period was 2 yr. The study groups were similar with respect to demographic characteristics, causes of renal disease, prevalence of coexisting conditions, residual renal function, peritoneal clearances before intervention, hematocrit values, and multiple indicators of nutritional status. In the control group, peritoneal creatinine clearance (pCrCl) and peritoneal urea clearance (Kt/V) values remained constant for the duration of the study. In the intervention group, pCrCl and peritoneal Kt/V values predictably increased and remained separated from the values for the control group for the entire duration of the study (P < 0.01). Patient survival was similar for the control and intervention groups in an intent-to-treat analysis, with a relative risk of death (intervention/control) of 1.00 [95% confidence interval (CI), 0.80 to 1.24]. Overall, the control group exhibited a 1-yr survival of 85.5% (CI, 82.2 to 88.7%) and a 2-yr survival of 68.3% (CI, 64.2 to 72.9%). Similarly, the intervention group exhibited a 1-yr survival of 83.9% (CI, 80.6 to 87.2%) and a 2-yr survival of 69.3% (CI, 65.1 to 73.6%). An as-treated analysis revealed similar results (overall relative risk = 0.93; CI, 0.71 to 1.22; P = 0.6121). Mortality rates for the two groups remained similar even after adjustment for factors known to be associated with survival for patients undergoing PD (e.g., age, diabetes mellitus, serum albumin levels, normalized protein equivalent of total nitrogen appearance, and anuria). This study provides evidence that increases in peritoneal small-solute clearances within the range studied have a neutral effect on patient survival, even when the groups are stratified according to a variety of factors (age, diabetes mellitus, serum albumin levels, normalized protein equivalent of total nitrogen appearance, and anuria) known to affect survival. No clear survival advantage was obtained with increases in peritoneal small-solute clearances within the range achieved in this study.

Morphologic Changes in the Peritoneal Membrane of Patients with Renal Disease

Abstract: This study examined the morphologic features of the parietal peritoneal membranes of 130 patients undergoing peritoneal dialysis (PD) and compared them with the features of the peritoneal membranes of normal individuals, uremic predialysis patients, and patients undergoing hemodialysis. The median thickness of the submesothelial compact collagenous zone was 50 µm for normal subjects, 140 µm for uremic patients, 150 µm for patients undergoing hemodialysis, and 270 µm for patients undergoing PD (P 97 mo, 700 µm (n = 19)]. Vascular changes included progressive subendothelial hyalinization, with luminal narrowing or obliteration. These changes were absent in samples from normal subjects but were present in 28% of samples from uremic patients and 56% of biopsies from patients undergoing PD. In the PD group, the prevalence of vasculopathy increased significantly with therapy duration (P = 0.0001). The density of blood vessels per unit length of peritoneum was significantly higher for patients with membrane failure and was correlated with the degree of fibrosis (P = 0.01). For the first time, a comprehensive cross-sectional analysis of the morphologic changes in the peritoneal membranes of patients undergoing PD is provided. The infrequency of fibrosis in the absence of vasculopathy suggests that vasculopathy may predispose patients to the development of fibrosis. This study provides a sufficiently large cohort of samples to allow structure-function relationships to be established, as well as providing a repository of tissue for further studies.

The Polycystic Kidney Disease Proteins, Polycystin-1, Polycystin-2, Polaris, and Cystin, Are Co-Localized in Renal Cilia

Abstract: Recent evidence has suggested an association between structural and/or functional defects in the primary apical cilium of vertebrate epithelia and polycystic kidney disease (PKD). In Caenorhabditis elegans, the protein orthologues of the PKD-related proteins, polycystin-1 (LOV-1), polycystin-2 (PKD2), and polaris (OSM-5), co-localize in the cilia of male-specific sensory neurons, and defects in these proteins cause abnormalities of cilia structure and/or function. This study sought to determine whether the mammalian polycystins are expressed in primary cilia of renal epithelia and whether these proteins co-localize with polaris and cystin, the newly described, cilia-associated protein that is disrupted in the cpk mouse. To begin to address this issue, the expression of the protein products encoded by the PKD1, PKD2, Tg737, and cpk genes were examined in mouse cortical collecting duct (mCCD) cells using an immunofluorescence-based approach with a series of previously well-characterized antibodies. The mCCD cells were grown on cell culture inserts to optimize cell polarization and cilia formation. The data demonstrate co-localization in cilia of polycystin-1 and polycystin-2, which are the principal proteins involved in autosomal dominant polycystic kidney disease, with polaris and cystin, which are proteins that are disrupted in the Tg737(orpk)and cpk mouse models of autosomal recessive polycystic kidney disease, respectively. These data add to a growing body of evidence that suggests that primary cilium plays a key role in normal physiologic functions of renal epithelia and that defects in ciliary function contribute to the pathogenesis of PKD.

Renal Insufficiency and Subsequent Death Resulting from Cardiovascular Disease in the United States

Abstract: . Several epidemiologic studies reported that persons with renal insufficiency might have increased cardiovascular disease-related mortality rates in select populations. The association between renal insufficiency and increased cardiovascular disease-related and all-cause mortality rates during 16 yr of follow-up monitoring was examined among participants who were 30 to 74 yr of age at the baseline examinations in 1976 to 1980, with urinary protein dipstick measurements ( n = 8786) or serum creatinine levels of ≤3.0 mg/dl ( n = 6354), from the Second National Health and Nutrition Examination Survey Mortality Study. GFR were estimated by adjusting serum creatinine levels for age, race, and gender, using the Modification of Diet in Renal Disease formula. Cardiovascular disease-related mortality rates were 6.2, 17.9, and 37.2 deaths/1000 person-yr among subjects with urinary protein levels of P trend = 0.02). The corresponding relative hazards for all-cause-related death were 1.64 (1.23 to 2.18) and 2.00 (1.13 to 3.55; P trend

Adiponectin, Metabolic Risk Factors, and Cardiovascular Events among Patients with End-Stage Renal Disease

Abstract: Adiponectin (ADPN), which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. Among human subjects, plasma ADPN concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma ADPN levels were investigated and the predictive power of ADPN levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 +/- 13 mo. Plasma ADPN levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 +/- 7.7 microg/ml) than among healthy subjects (6.3 +/- 2.0 microg/ml), were independent of age, and were higher (P = 0.03) among women (15.2 +/- 7.9 microg/ml) than among men (14.0 +/- 7.4 microg/ml). For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 +/- 7.3 microg/ml) than among event-free patients (15.8 +/- 7.8 microg/ml). There was a 3% risk reduction for each 1 microg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

TGF-β signaling in renal disease

Abstract: . Since discovery over a decade ago of a role for the cytokine TGF-s as key mediator of glomerular and tubulointerstitial pathobiology in chronic kidney diseases, studies of TGF-s signaling in the kidney have focused on the molecular biology of fibrogenesis. In recent years, glomerular and tubular epithelial cell apoptosis and cellular transdifferentiation have been proposed as putative primary pathomechanisms that may underlie progression of renal disease. This review describes evidence in support of nonlinear models and functional roles of TGF-s signaling in mediating apoptosis and epithelial-to-mesenchymal transdifferentiation (EMT) in chronic progressive renal disease. Emphasis is placed on cell context-dependent models of TGF-s signaling providing a conceptual framework to consolidate seemingly distinct pathomechanisms of progression of glomerular and tubulointerstitial disease.E-mail: bottinge@aecom.yu.edu

Podocyte biology and response to injury.

Abstract: The visceral glomerular epithelial cell, also called podocyte, is a terminally differentiated cell that lines the outer aspect of the glomerular basement membrane (GBM). It therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked

Traditional Cardiovascular Disease Risk Factors in Dialysis Patients Compared with the General Population: The CHOICE Study

Abstract: Although atherosclerotic cardiovascular disease (ASCVD) risk in end-stage renal disease (ESRD) is 5 to 30 times that of the general population, few data exist comparing ASCVD risk factors among new dialysis patients to the general population. This cross-sectional study of 1041 dialysis patients describes the prevalence of ASCVD risk factors at the beginning of ESRD compared with estimates of ASCVD risk factors in the adult US population derived from the Third National Health and Nutrition Examination (NHANES III). CHOICE Study participants had a high prevalence of diabetes (54%), hypertension (96%), left ventricular hypertrophy by electrocardiogram (EKG) criteria (22%), low physical activity (80%), hypertriglyceridemia (36%), and low HDL cholesterol (33%). CHOICE participants were more likely to be older, black, and male than NHANES III participants. After adjustment for age, race, gender, and ASCVD (defined as myocardial infarction, revascularization procedure, stroke, carotid endarterectomy, and amputation in CHOICE; and as myocardial infarction and stroke in NHANES III), the prevalence of diabetes, hypertension, left ventricular hypertrophy by EKG, low physical activity, low HDL cholesterol, and hypertriglyceridemia were still more common in CHOICE participants. Smoking, obesity, hypercholesterolemia, and high LDL cholesterol, however, were less common in CHOICE than NHANES III participants. The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants (13%) than in the NHANES III participants (6%). In summary, many ASCVD risk factors are more prevalent in ESRD than in the general population and may explain some, but probably not all, of the increased ASCVD risk in ESRD.

Maintenance Dialysis Population Dynamics: Current Trends and Long-Term Implications

Abstract: Despite a general recognition that treatment of end-stage renal disease (ESRD) has become a large-scale undertaking, the size of the treated population and the associated costs are not well quantified. This report combines data available from a variety of sources and places the current (midyear 2001) estimated global maintenance dialysis population at just over 1.1 million patients. The size of this population has been expanding at a rate of 7% per year. Total therapy cost per patient per year in the United States is approximately 66,000 dollars. Assuming that this figure is a reasonable global average, the annual worldwide cost of maintenance ESRD therapy in the year 2001, excluding renal transplantation, will be between 70 and 75 billion US dollars. If current trends in ESRD prevalence continue, as seems probable, the ESRD population will exceed 2 million patients by the year 2010. The care of this group represents a major societal commitment: the aggregate cost of treating ESRD during the coming decade will exceed 1 trillion dollars, a thought-provoking sum by any economic metric.

Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys.

Abstract: Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date The characteristics and functional significance of the HIF response in vivo are largely unknown High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (01% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia) These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1 HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation

Genetics and Pathogenesis of Polycystic Kidney Disease

Abstract: Eberhard Ritz Polycystic kidney disease (PKD), a common genetic cause of chronic renal failure in children and adults, is characterized by the accumulation of fluid-filled cysts in the kidney and other organs. The renal cysts originate from the epithelia of the nephrons and renal collecting system

The MRP4/ABCC4 Gene Encodes a Novel Apical Organic Anion Transporter in Human Kidney Proximal Tubules: Putative Efflux Pump for Urinary cAMP and cGMP

Abstract: The cyclic nucleotides cAMP and cGMP play key roles in cellular signaling and the extracellular regulation of fluid balance. In the kidney, cAMP is excreted across the apical proximal tubular membrane into urine, where it reduces phosphate reabsorption through a dipyridamole-sensitive mechanism that is not fully understood. It has long been known that this cAMP efflux pathway is dependent on ATP and is inhibited by probenecid. However, its identity and whether cGMP shares the same transporter have not been established. Here the expression, localization, and functional properties of human multidrug resistance protein 4 (MRP4) are reported. MRP4 is localized to the proximal tubule apical membrane of human kidney, and membrane vesicles from Sf9 cells expressing human MRP4 exhibit ATP-dependent transport of [(3)H]cAMP and [(3)H]cGMP. Both probenecid and dipyridamole are potent MRP4 inhibitors. ATP-dependent [(3)H]methotrexate and [(3)H]estradiol-17beta-D-glucuronide transport by MRP4 and interactions with the anionic conjugates S-(2,4-dinitrophenyl)-glutathione, N-acetyl-(2,4-dinitrophenyl)-cysteine, alpha-naphthyl-beta-D-glucuronide, and p-nitrophenyl-beta-D-glucuronide are also demonstrated. In kidneys of rats deficient in the apical anionic conjugate efflux pump Mrp2, Mrp4 expression is maintained at the same level. It is concluded that MRP4 is a novel apical organic anion transporter and the putative efflux pump for cAMP and cGMP in human kidney proximal tubules.

Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney

Abstract: Renal excretion of organic anions and cations is mediated by the organic ion transporter family (SLC22A). In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney. The expression level of hOAT3 mRNA was the highest among the organic ion transporter family, followed by that of hOAT1 mRNA. The hOCT2 mRNA level was the highest in the human OCT family, and the level of hOCTN2 mRNA was higher than that of hOCTN1. hOCT1 mRNA showed the lowest level of expression in organic ion transporter family. hOAT1, hOAT3, and hOCT2 proteins were detected in crude membranes from the kidney of all patients by Western blot analyses, whereas hOCT1 protein could not be detected. Immunohistochemical analyses showed that both hOAT1 and hOAT3 were localized to the basolateral membrane of the proximal tubules in the cortex, and hOCT2 was localized to the basolateral membrane of the proximal tubules in both the cortex and medullary ray. Immunohistochemical analyses of serial sections indicated that hOAT1, hOAT3, and hOCT2 were coexpressed in a portion of the proximal tubules. These results suggest that hOAT1, hOAT3, and hOCT2 play predominant roles in the transport of organic ions across the basolateral membrane of human proximal tubules.

Acute Humoral Rejection in Kidney Transplantation: II. Morphology, Immunopathology, and Pathologic Classification

Abstract: The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

Henoch-Schönlein Purpura in Adults: Outcome and Prognostic Factors

Abstract: Henoch-Schonlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] <50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl <30 ml/min), and 14% moderate renal insufficiency (CrCl <50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.

Anemia and Renal Insufficiency Are Independent Risk Factors for Death among Patients with Congestive Heart Failure Admitted to Community Hospitals: A Population-Based Study

Abstract: The purpose of this retrospective cohort study was to examine the associations among chronic kidney disease, anemia, and risk of death among patients with heart failure. Retrospective cohort study. Patients with a principal diagnosis of heart failure (ICD9 codes 402.01, 402.11, 402.91, 404.01, 404.11, 404.91, and 428.xx) were included. Chronic kidney disease (CKD) was defined as a serum creatinine >1.4 mg/dl for women and >1.5 mg/dl for men. There were 665 eligible patients in the sample with a mean (SD) age of 75.7 (10.9) yr; 60% were women, 71% were white, and 38% had CKD. On admission, a hematocrit > or =40% was found for 30.3% of the patients; 22.9% had a hematocrit between 36% and 40%, 33.2% between 30% and 35%, and 13.6% had a hematocrit of or =40%; 33.8% (RR, 1.08; 95% CI. 0.79 to 1.47) for hematocrit 36 to 39%; 36.7% (RR, 1.17; 95% CI, 0.89 to 1.54) for hematocrit between 30 and 35%; and 50.0% (RR, 1.60; 95% CI, 1.19 to 2.16) for those with a hematocrit <30% (chi(2) for trend was 7.37; P = 0.007). Both hematocrit and serum creatinine were independently associated with increased risk of death during follow-up after controlling for other patient risk factors. In conclusion, CKD and anemia are frequent among older patients with heart failure and are independent predictors of subsequent risk of death.

Inflammation, Malnutrition, and Cardiac Disease as Predictors of Mortality in Hemodialysis Patients

Abstract: Various studies suggest a strong association between nutrition and clinical outcome in hemodialysis (HD) patients. Several morbidity factors that per se increase the risk of a poor outcome, such as cardiovascular disease (CVD) and inflammation, may also cause malnutrition. Among laboratory parameters used to assess nutritional status, serum albumin appears to be a particularly strong predictor of morbidity and mortality. This study assessed the importance of nutritional status and inflammation and other comorbidity factors as predictors of mortality in HD patients. Nutritional status was evaluated in 128 HD patients by subjective global nutritional assessment (SGNA) and by measuring several anthropometric markers (actual body weight, percentage of actual body weight to desirable body weight, midarm muscle circumferences, triceps skinfold thickness), and serum albumin, plasma insulin such as insulin growth factor-1 and as a marker of inflammation, serum C-reactive protein (s-CRP) levels. The mortality during the next 36 mo was analyzed in relation to age, gender, CVD, SGNA, serum albumin, CRP, and several other factors by Kaplan-Meier analysis multivariate. Cox proportional hazard analysis was used to identify independent predictors of mortality. After 36 mo, 58 patients were still on HD treatment, 57 patients (45%) had died while receiving treatment, and 13 had received a kidney transplant. The main cause of death was CVD (58%), followed by infection (18%); malnutrition/cachexia was a rare direct cause of death (5%). Kaplan-Meier analysis showed that age, female gender, CVD, diabetes, SGNA, all anthropometric parameters, serum albumin, plasma insulinlike growth factor-1, and s-CRP were significant predictors of mortality. Analysis by the Cox model showed that age, gender, CVD, nutritional status (SGNA), and CRP were independent predictors of mortality at 36 mo. A low albumin level was not an independent predictor, although it was strongly associated with a reduced survival rate in the Kaplan-Meier analysis. Inflammation, malnutrition, and CVD appeared to contribute to increased mortality in a stepwise manner. The mortality at 36 mo was 0% when none of these complications was present, whereas the mortality was 75% in those patients with all three risk factors present at baseline. It is concluded that in addition to malnutrition and comorbidities (CVD, diabetes mellitus), inflammation (elevated s-CRP) is a significant independent risk factor for mortality in HD patients. Inflammation, malnutrition, and CVD appear to be interrelated, each additionally contributing to the high mortality in these patients.

Epidemiology of Anemia Associated with Chronic Renal Insufficiency among Adults in the United States: Results from the Third National Health and Nutrition Examination Survey

Abstract: Anemia associated with chronic renal insufficiency (CRI) may have substantial clinical and public health importance, but little is known about its epidemiology. This study aims to quantify the relationship between reduced renal function and hemoglobin level, to assess the iron status of subjects with CRI, and to estimate the burden of anemia associated with CRI. The Third National Health and Nutrition Examination Survey (NHANES III) (1988 to 1994) data on 15,971 adults aged >18 yr with measurements of serum creatinine, hemoglobin, and iron profile were analyzed. General linear models were used to determine the relationship between hemoglobin level and Cockcroft-Gault creatinine clearance (CrCl) and to estimate the likelihood of anemia at different levels of renal function in different demographic subgroups. Sample weights were used to produce weighted regression parameters and population estimates. A statistically significant decrease in hemoglobin was apparent among men starting at CrCl 80 ml/min, the decrease in hemoglobin for subjects with CrCl 20 to 30 ml/min was 1.0 g/dl in women and 1.4 g/dl in men. A substantial number of subjects with CRI might not have sufficient iron stores to support erythropoiesis as judged by the NKF-K/DOQI transferrin saturation or serum ferritin targets. Among those with CrCl 20 to 30 ml/min, 46% of women and 19% of men had transferrin saturation <20%, and 47% of women and 44% of men had serum ferritin <100 ng/ml. Results estimate that 13.5 million US adults had CrCl < or =50 ml/min. The overall burden of CRI associated anemia, defined as hemoglobin <11 g/dl, was 800,000 adults. The public health burden of anemia associated with CRI may be substantial, given the large number of people with CRI; and that even a modest reduction in renal function is associated with decreased hemoglobin level.

Role of the Microvascular Endothelium in Progressive Renal Disease

Abstract: The role of the vascular endothelium in progressive renal disease is not well understood. This review presents evidence that progressive renal disease is characterized by a progressive loss of the microvasculature. The loss of the microvasculature correlates directly with the development of glomerular and tubulointerstitial scarring. The mechanism is mediated in part by a reduction in the endothelial proliferative response, and this impairment in capillary repair is mediated by alteration in the local expression of both angiogenic (vascular endothelial growth factor) and antiangiogenic (thrombospondin 1) factors in the kidney. The alteration in balance of angiogenic growth factors is mediated by both macrophage-associated cytokines (interleukin-1beta) and vasoactive mediators. Finally, there is intriguing evidence that stimulation of angiogenesis and/or capillary repair may stabilize renal function and slow progression and that this benefit occurs independently of effects on BP or proteinuria. Therefore, angiogenic agents may represent a novel therapeutic approach for slowing the progression of renal disease.

Differential Expression Patterns of Claudins, Tight Junction Membrane Proteins, in Mouse Nephron Segments

Abstract: As the first step in understanding the physiologic functions of claudins (tight junction integral membrane proteins) in nephrons, the expression of claudin-1 to -16 in mouse kidneys was examined by Northern blotting Among these claudins, only claudin-6, -9, -13, and -14 were not detectable Claudin-5 and -15 were detected only in endothelial cells Polyclonal antibodies specific for claudin-7 and -12 were not available Therefore, the distributions of claudin-1, -2, -3, -4, -8, -10, -11, and -16 in nephron segments were examined with immunofluorescence microscopy For identification of individual segments, antibodies specific for segment markers were used Immunofluorescence microscopic analyses of serial frozen sections of mouse kidneys with polyclonal antibodies for claudins and segment markers revealed that claudins demonstrated very complicated, segment-specific, expression patterns in nephrons, ie, claudin-1 and -2 in Bowman's capsule, claudin-2, -10, and -11 in the proximal tubule, claudin-2 in the thin descending limb of Henle, claudin-3, -4, and -8 in the thin ascending limb of Henle, claudin-3, -10, -11, and -16 in the thick ascending limb of Henle, claudin-3 and -8 in the distal tubule, and claudin-3, -4, and -8 in the collecting duct These segment-specific expression patterns of claudins are discussed, with special reference to the physiologic functions of tight junctions in nephrons

Preemptive Kidney Transplantation: The Advantage and the Advantaged

Abstract: It remains unclear whether preemptive transplantation is beneficial, and if so, who benefits. A total of 38,836 first, kidney-only transplants between 1995 and 1998 were retrospectively studied. A surprising 39% of preemptive transplants were from cadaver donors, and the proportions of cadaver donor transplants that were preemptive changed little, from 7.3% in 1995 to 7.7% in 1998. Preemptive transplants using cadaver donors were more likely among recipients aged 0 to 17 yr versus 18 to 29 yr (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.94 to 3.17), white versus black (OR, 2.33; 95% CI, 2.03 to 2.68), able to work versus unable to work (OR, 1.42; 95% CI, 1.26 to 1.61), covered by private insurance versus Medicare (OR, 4.77; 95% CI, 4.26 to 5.32), or recipients with a college degree versus no college degree (OR, 1.34; 95% CI, 1.17 to 1.54). Preemptive transplants were less likely for Hispanics versus non-Hispanics (OR, 0.57; 95% CI, 0.50 to 0.67), patients with type 2 versus type 1 diabetes (OR, 0.76; 95% CI, 0.61 to 0.96), and for 2 to 5 HLA mismatches compared with 0 HLA mismatches (OR range, 0.77 to 0.82). In adjusted Cox proportional hazards analysis, the relative risk of graft failure for preemptive transplantation was 0.75 (0.67 to 0.84) among 25,758 cadaver donor transplants and 0.73 (0.64 to 0.83) among 13,078 living donor transplants, compared with patients who received a transplant after already being on dialysis. Preemptive transplantation was associated with a reduced risk of death: 0.84 (0.72 to 0.99) for cadaver donor transplants and 0.69 (0.56 to 0.85) for living donor transplants. Thus, preemptive transplantation, which is associated with improved patient and graft survival, is less common among racial minorities, those who have less education, and those who must rely on Medicare for primary payment. Alterations in the payment system, emphasis on early referral, and changes in cadaver kidney allocation could increase the number of patients who benefit from preemptive transplantation.

Capillary Deposition of Complement Split Product C4d in Renal Allografts is Associated with Basement Membrane Injury in Peritubular and Glomerular Capillaries: A Contribution of Humoral Immunity to Chronic Allograft Rejection

Abstract: Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.

Atherosclerotic Renal Artery Stenosis: Epidemiology, Cardiovascular Outcomes, and Clinical Prediction Rules

Abstract: Atherosclerotic renal artery stenosis is the most common primary disease of the renal arteries, and it is associated with two major clinical syndromes, ischemic renal disease and hypertension. The prevalence of this disease in the population is undefined because there is no simple and reliable test that can be applied on a large scale. Renal artery involvement in patients with coronary heart disease and/or heart failure is frequent, and it may influence cardiovascular outcomes and survival in these patients. Suspecting renal arterial stenosis in patients with recurrent episodes of pulmonary edema is justified by observations showing that about one third of elderly patients with heart failure display atherosclerotic renal disease. Whether interventions aimed at restoring arterial patency may reduce the high mortality in patients with heart failure is still unclear because, to date, no prospective study has been carried out in these patients. Increased awareness of the need for cost containment has renewed the interest in clinical cues for suspecting renovascular hypertension. In this regard, the DRASTIC study constitutes an important attempt at validating clinical prediction rules. In this study, a clinical rule was derived that predicted renal artery stenosis as efficiently as renal scintigraphy (sensitivity: clinical rule, 65% versus scintigraphy, 72%; specificity: 87% versus 92%). When tested in a systematic and quantitative manner, clinical findings can perform as accurately as more complex tests in the detection of renal artery stenosis.

Vascular Endothelial Growth Factor Gene Polymorphisms Are Associated with Acute Renal Allograft Rejection

Abstract: . Acute rejection is a major cause of reduced survival of renal allografts. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is expressed widely by renal tissue and T cells. VEGF influences adhesion and migration of leukocytes across the endothelium. This study investigates whether genetically determined variation in VEGF expression influences the development of renal allograft rejection. VEGF promoter polymorphisms were examined by using sequence-specific primer–PCR in 173 renal transplant recipients. Acute rejection occurred in 38.7%; median time to first rejection episode was 14 d. VEGF in vitro expression was investigated in stimulated leukocytes from 30 controls. The − 1154*G and − 2578*C alleles were associated with higher VEGF production. VEGF −1154 GG and GA genotypes were significantly associated with acute rejection risk at 3 mo ( P = 0.004, odds ration [OR] = 6.8, 95% CI = 1.8 to 25 and P = 0.035, OR = 4.1, 95% CI = 1.1 to 15, respectively). Furthermore, VEGF −2578 CC and CA genotypes were associated with increased rejection risk ( P = 0.005, OR = 4.1, 95% CI = 1.5 to 11.3 and P = 0.035, OR = 2.7, 95% CI = 1.1 to 7, respectively). These polymorphisms demonstrate linkage disequilibrium ( P = 0.001). These data indicate that the − 1154*G and − 2578*C containing genotypes, encoding higher VEGF production, are strongly associated with acute rejection and may be useful markers of rejection risk.

Clinical Course of Polyoma Virus Nephropathy in 67 Renal Transplant Patients

Abstract: Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.

Predictive Performance of Renal Function Equations for Patients with Chronic Kidney Disease and Normal Serum Creatinine Levels

Abstract: Accurate renal function measurements are important for the diagnosis and treatment of kidney disease, proper medication dosing, interpretation of possible uremic symptoms, and decision-making regarding when to initiate renal replacement therapy. Because the use of highly accurate filtration markers to measure renal function has traditionally been limited by cumbersome and costly techniques and the involvement of radioactivity (among other factors), renal function is typically estimated by using specially derived prediction equations. These formulae usually use serum creatinine levels, i.e., a marker of filtration that is insensitive to mild/moderate decreases in GFR. Although attempts have been made to validate certain renal function prediction equations among patients with chronic kidney disease (CKD) with abnormal serum creatinine levels, this is the first study to specifically evaluate the predictive performance of these equations for patients with CKD and serum creatinine levels in the normal range. The results of eight prediction equations for 109 patients with CKD and serum creatinine levels of < or =1.5 mg/dl were compared with standard iohexol GFR values. The most accurate results were obtained with the Cockroft-Gault and Bjornsson equations. The most precise formulae were the Modification of Diet in Renal Disease Study equations, although they were highly biased. Even the most accurate results exhibited levels of error that made them suboptimal for clinical treatment of these patients. These results suggest that measurement of GFR with endogenous or exogenous filtration markers might be the most prudent strategy for the assessment of renal function in the CKD population with normal serum creatinine levels. Further studies are needed to confirm the generalizability of these findings for this patient subgroup.

Renal tubular acidosis: the clinical entity

Abstract: The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3−), the excretion of hydrogen ion (H+), or both. This condition was first described in 1935 ([1][1]), confirmed as a renal tubular disorder in 1946 ([2][2]), and designated “

Marked Increase of Asymmetric Dimethylarginine in Patients with Incipient Primary Chronic Renal Disease

Abstract: In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 +/- 0.9 micromol/L) than in control subjects (n = 16; age 45 +/- 10 yr; serum creatinine 1.0 +/- 0.1 mg/dl; ADMA 1.4 +/- 0.7 micromol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 +/- 9 yr; serum creatinine 1.1 +/- 0.1 mg/dl; GFR 120 +/- 14 ml x min(-1) x 1.73 m2; ADMA 4.0 +/- 0.7 micromol/L), in patients with moderate renal failure (n = 15; 47 +/- 7 yr; 1.8 +/- 0.3 mg/dl; 65 +/- 10 ml x min(-1) x 1.73 m2; 3.8 +/- 0.6 micromol/L) and in patients with advanced renal failure (n = 13; 46 +/- 9 yr; 4.2 +/- 0.9 mg/dl; 25 +/- 4 ml x min(-1) x 1.73 m2; 4.7 +/- 1.2 micromol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 +/- 0.8 micromol/L) and in hypertensive (n = 27; 4.2 +/- 0.9 micromol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 +/- 2.9 micromol/L) and in patients with normal GFR (11.0 +/- 2.9 micromol/L), but were significantly higher in patients with moderate renal failure (17.7 +/- 4.1 micromol/L) and particularly in patients with advanced renal failure (28.2 +/- 10.6 micromol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.