Showing papers in "Journal of The American Society of Nephrology in 2004"

Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis

Abstract: Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited

Abstract: The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Minimal Changes of Serum Creatinine Predict Prognosis in Patients after Cardiothoracic Surgery: A Prospective Cohort Study

Abstract: Acute renal failure increases risk of death after cardiac surgery. However, it is not known whether more subtle changes in renal function might have an impact on outcome. Thus, the association between small serum creatinine changes after surgery and mortality, independent of other established perioperative risk indicators, was analyzed. In a prospective cohort study in 4118 patients who underwent cardiac and thoracic aortic surgery, the effect of changes in serum creatinine within 48 h postoperatively on 30-d mortality was analyzed. Cox regression was used to correct for various established demographic preoperative risk indicators, intraoperative parameters, and postoperative complications. In the 2441 patients in whom serum creatinine decreased, early mortality was 2.6% in contrast to 8.9% in patients with increased postoperative serum creatinine values. Patients with large decreases (DeltaCrea or =0.5 mg/dl. For all groups, increases in mortality remained significant in multivariate analyses, including postoperative renal replacement therapy. After cardiac and thoracic aortic surgery, 30-d mortality was lowest in patients with a slight postoperative decrease in serum creatinine. Any even minimal increase or profound decrease of serum creatinine was associated with a substantial decrease in survival.

Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies

Abstract: Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.

Epithelial to Mesenchymal Transition in Renal Fibrogenesis: Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention

Abstract: Mature tubular epithelial cells in adult kidney can undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is fundamentally linked to the pathogenesis of renal interstitial fibrosis. Emerging evidence indicates that a large proportion of interstitial fibroblasts are actually originated from tubular epithelial cells via EMT in diseased kidney. Moreover, selective blockade of EMT in a mouse genetic model dramatically reduces fibrotic lesions after obstructive injury, underscoring a definite importance of EMT in renal fibrogenesis. Tubular EMT is proposed as an orchestrated, highly regulated process that consists of four key steps: (1) loss of epithelial cell adhesion; (2) de novo alpha-smooth muscle actin expression and actin reorganization; (3) disruption of tubular basement membrane; and (4) enhanced cell migration and invasion. Of the many factors that regulate EMT in different ways, transforming growth factor-beta1 is the most potent inducer that is capable of initiating and completing the entire EMT course, whereas hepatocyte growth factor and bone morphogenetic protein-7 act as EMT inhibitors both in vitro and in vivo. Multiple intracellular signaling pathways have been implicated in mediating EMT, in which Smad/integrin-linked kinase may play a central role. This article attempts to provide a comprehensive review of recent advances on understanding the pathologic significance, molecular mechanism, and therapeutic intervention of EMT in the setting of chronic renal fibrosis.

A Clinical Score to Predict Acute Renal Failure after Cardiac Surgery

Abstract: The risk of mortality associated with acute renal failure (ARF) after open-heart surgery continues to be distressingly high. Accurate prediction of ARF provides an opportunity to develop strategies for early diagnosis and treatment. The aim of this study was to develop a clinical score to predict postoperative ARF by incorporating the effect of all of its major risk factors. A total of 33,217 patients underwent open-heart surgery at the Cleveland Clinic Foundation (1993 to 2002). The primary outcome was ARF that required dialysis. The scoring model was developed in a randomly selected test set (n = 15,838) and was validated on the remaining patients. Its predictive accuracy was compared by area under the receiver operating characteristic curve. The score ranges between 0 and 17 points. The ARF frequency at each score level in the validation set fell within the 95% confidence intervals (CI) of the corresponding frequency in the test set. Four risk categories of increasing severity (scores 0 to 2, 3 to 5, 6 to 8, and 9 to 13) were formed arbitrarily. The frequency of ARF across these categories in the test set ranged between 0.5 and 22.1%. The score was also valid in predicting ARF across all risk categories. The area under the receiver operating characteristic curve for the score in the test set was 0.81 (95% CI 0.78 to 0.83) and was similar to that in the validation set (0.82; 95% CI 0.80 to 0.85; P = 0.39). In conclusion, a score is valid and accurate in predicting ARF after open-heart surgery; along with increasing its clinical utility, the score can help in planning future clinical trials of ARF.

The Inflammatory Syndrome: The Role of Adipose Tissue Cytokines in Metabolic Disorders Linked to Obesity

Abstract: The metabolic effects of obesity have made this highly prevalent disease one of the most common risk factors for diabetes, hypertension, and atherosclerosis, the leading causes of end-stage renal failure. However, obesity per se, as defined by body mass index, is less predictive of the development of these diseases than is the presence of a constellation of obesity-related abnormalities now known as the metabolic syndrome. Recognition of this syndrome, which can readily be identified in clinical settings using defined threshold values for waist circumference, BP, fasting glucose, and dyslipidemia, allows for earlier intervention in these high-risk patients. Systemic insulin resistance has been implicated as one possible factor that links visceral obesity to adverse metabolic consequences; however, the mechanism whereby adipose tissue causes alterations in insulin sensitivity remains unclear. Infection and inflammation are commonly associated with insulin resistance, and visceral obesity is associated with a chronic, low-grade inflammatory state, suggesting that inflammation may be a potential mechanism whereby obesity leads to insulin resistance. Moreover, adipose tissue is now recognized as an immune organ that secretes numerous immunomodulatory factors and seems to be a significant source of inflammatory signals known to cause insulin resistance. Therefore, inflammation within white adipose tissue may be a crucial step contributing to the emergence of many of the pathologic features that characterize the metabolic syndrome and result in diabetes and atherosclerosis. This review describes the role of proinflammatory cytokines and hormones released by adipose tissue in generating the chronic inflammatory profile associated with visceral obesity.

Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.

Abstract: Patients with ESRD have a high circulating calcium (Ca) phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vas- cular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesi- cles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhib- itor fetuin-A and calcified minimally. Importantly, MV re- leased under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pre- treatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.

Chronic Kidney Disease Awareness, Prevalence, and Trends among U.S. Adults, 1999 to 2000

Abstract: The incidence of kidney failure treatment in the United States increased 57% from 1991 to 2000. Chronic kidney disease (CKD) prevalence was 11% among U.S. adults surveyed in 1988 to 1994. The objective of this study was to estimate awareness of CKD in the U.S. population during 1999 to 2000 and to determine whether the prevalence of CKD in the United States increased compared with 1988 to 1994. Analysis was conducted of nationally representative samples of noninstitutionalized adults, aged 20 yr and older, in two National Health and Nutrition Examination Surveys conducted in 1988 to 1994 (n = 15,488) and 1999 to 2000 (n = 4101) for prevalence +/- SE. Awareness of CKD is self-reported. Kidney function (GFR), kidney damage (microalbuminuria or greater), and stages of CKD (GFR and albuminuria) were estimated from calibrated serum creatinine, spot urine albumin to creatinine ratio (ACR), age, gender, and race. GFR was estimated using the simplified Modification of Diet in Renal Disease Study equation. Self-reported awareness of weak or failing kidneys in 1999 to 2000 was strongly associated with decreased kidney function and albuminuria but was low even in the presence of both conditions. Only 24.3 +/- 6.4% of patients at GFR 15 to 59 ml/min per 1.73 m(2) and albuminuria were aware of CKD compared with 1.1 +/- 0.3% at GFR of 90 ml/min per 1.73 m(2) or greater and no microalbuminuria. At moderately decreased kidney function (GFR 30 to 59 ml/min per 1.73 m(2)), awareness was much lower among women than men (2.9 +/- 1.6 versus 17.9 +/- 5.9%; P = 0.008). The prevalence of moderately or severely decreased kidney function (GFR 15 to 59 ml/min per 1.73 m(2)) remained stable over the past decade (4.4 +/- 0.3% in 1988 to 1994 and 3.8 +/- 0.4% in 1999 to 2000; P = 0.23). At the same time, the prevalence of albuminuria (ACR >/= 30 mg/g) in single spot urine increased from 8.2 +/- 0.4% to 10.1 +/- 0.7% (P = 0.01). Overall CKD prevalence was similar in both surveys (9% using ACR > 30 mg/g for persistent microalbuminuria; 11% in 1988 to 1994 and 12% in 1999 to 2000 using gender-specific ACR cutoffs). Despite a high prevalence, CKD awareness in the U.S. population is low. In contrast to the dramatic increase in treated kidney failure, overall CKD prevalence in the U.S. population has been relatively stable.

Mesenchymal Stem Cells Are Renotropic, Helping to Repair the Kidney and Improve Function in Acute Renal Failure

Abstract: Injury to a target organ can be sensed by bone marrow stem cells that migrate to the site of damage, undergo differentiation, and promote structural and functional repair. This remarkable stem cell capacity prompted an investigation of the potential of mesenchymal and hematopoietic stem cells to cure acute renal failure. The model of renal injury induced in mice by the anticancer agent cisplatin was chosen. Injection of mesenchymal stem cells of male bone marrow origin remarkably protected cisplatin-treated syngeneic female mice from renal function impairment and severe tubular injury. Y chromosome-containing cells localized in the context of the tubular epithelial lining and displayed binding sites for Lens culinaris lectin, indicating that mesenchymal stem cells engraft the damaged kidney and differentiate into tubular epithelial cells, thereby restoring renal structure and function. Mesenchymal stem cells markedly accelerated tubular proliferation in response to cisplatin-induced damage, as revealed by higher numbers of Ki-67-positive cells within the tubuli with respect to cisplatin-treated mice that were given saline. Hematopoietic stem cells failed to exert beneficial effects. These results offer a strong case for exploring the possibility that mesenchymal stem cells by virtue of their renotropic property and tubular regenerative potential may have a role in the treatment of acute renal failure in humans.

Endothelial dysfunction : Mechanisms of hypertension: Cells, hormones, and the kidney

Abstract: Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties. It is associated with most forms of cardiovascular disease, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyper-polarizing factor. Upregulation of adhesion molecules, generation of chemokines such as macrophage chemoattractant peptide-1, and production of plasminogen activator inhibitor-1 participate in the inflammatory response and contribute to a prothrombic state. Vasoactive peptides such as angiotensin II and endothelin-1; the accumulation of asymmetric dimethyl-arginine, an endogenous nitric oxide inhibitor; hypercholesterolemia; hyperhomocysteinemia; altered insulin signaling; and hyperglycemia can contribute to these different mechanisms. Detachment and apoptosis of endothelial cells (anoikis) are associated phenomena. Endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Reductions in circulating endothelial progenitor cells that participate in regeneration of the endothelium participate in endothelial pathophysiology. The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events. Correction of endothelial dysfunction may be associated with reduced cardiovascular risk. Circulating endothelial progenitor cells may represent a potential therapeutic approach for endothelial dysfunction.

Arterial Calcifications and Bone Histomorphometry in End-Stage Renal Disease

Abstract: Arterial calcification (AC) is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex, including disturbances of mineral metabolism and active expression of various mineral-regulating proteins. An inverse relationship between AC and bone density has been documented in uremic patients. In the study presented here, which included 58 patients with ESRD on hemodialysis (HD), bone-histomorphometry characteristics were compared with the AC scores (0 to 4) determined according to the number of arterial sites with calcifications. Patients with AC scores of 0 (no calcifications), or 1 or 2 (mild calcifications) had similar serum parathyroid hormone levels and bone histomorphometry, with larger osteoclast resorption, higher osteoclast numbers, and larger osteoblastic and double tertracycline-labeled surfaces. In contrast, patients with high AC scores (3 and 4) were characterized by lower serum parathyroid hormone, low osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces, and high percentages of aluminum-stained surfaces. According to multivariate analysis, AC score was positively associated with age (P < 0.0001), daily dose of calcium-containing phosphate binders (P = 0.009), and bone aluminum-stained surfaces (P = 0.037), and an inverse correlation was observed with osteoblastic surfaces (P = 0.001). A high AC score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. These findings suggest that therapeutic interventions associated with excessive lowering of parathyroid activity (parathyroidectomy, excessive calcium or aluminum load) favor lower bone turnover and adynamic bone disease, which could influence the development and progression of AC.

Vascular Calcification Mechanisms

Abstract: Vascular calcification is highly correlated with cardiovascular disease mortality, especially in patients with ESRD or diabetes. In addition to the devastating effects of inappropriate biomineralization seen in cardiac valvulopathies, calciphylaxis, and idiopathic arterial calcification, vascular calcification is now recognized as a marker of atherosclerotic plaque burden as well as a major contributor to loss of arterial compliance and increased pulse pressure seen with age, diabetes, and renal insufficiency. In recent years, several mechanisms to explain vascular calcification have been identified including (1) loss of inhibition, (2) induction of bone formation, (3) circulating nucleational complexes, and (4) cell death. Alterations in calcium (Ca) and phosphorus (P) balance as seen in patients with ESRD promotes vascular calcification via multiple mechanisms and may explain the alarmingly high levels of cardiovascular disease deaths in these patients. Strategies to control Ca and P levels in patients with ESRD have met with early success in preventing progression of vascular calcification. Whether or not vascular calcification can be reversed is not yet known, but exciting new studies suggest that this may be possible in the future.

Amelioration of Ischemic Acute Renal Injury by Neutrophil Gelatinase-Associated Lipocalin

Abstract: Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGAL-treated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.

Lymphatic Neoangiogenesis in Human Kidney Transplants Is Associated with Immunologically Active Lymphocytic Infiltrates

Abstract: . Renal transplant rejection is caused by a lymphocyte-rich inflammatory infiltrate that attacks cortical tubules and endothelial cells. Immunosuppressive therapy reduces the number of infiltrating cells; however, their exit routes are not known. Here a >50-fold increase of lymphatic vessel density over normal kidneys in grafts with nodular mononuclear infiltrates is demonstrated by immunohistochemistry on human renal transplant biopsie susing antibodies to the lymphatic endothelial marker protein podoplanin. Nodular infiltrates are constantly associated with newly formed, Ki-67–expressing lymphatic vessels and contain the entire repertoire of T and B lymphocytes to provide specific cellular and humoral alloantigenic immune responses, including Ki-67 + CD4 + and CD8 + T lymphocytes, S100 + dendritic cells, and Ki-67 + CD20 + B lymphocytes and λ- and κ-chain-expressing plasmacytoid cells. Numerous chemokine receptor CCR7 + cells within the nodular infiltrates seemed to be attracted by secondary lymphatic chemokine (SLC/CCL21) that is produced and released by lymphatic endothelial cells in a complex with podoplanin. From these results, it is speculated that lymphatic neoangiogenesis not only contributes to the export of the rejection infiltrate but also is involved in the maintenance of a potentially detrimental alloreactive immune response in renal transplants and provides a novel therapeutic target.

Immediate Postoperative Renal Function Deterioration in Cardiac Surgical Patients Predicts In-Hospital Mortality and Long-Term Survival

Abstract: Postoperative renal function deterioration is a serious complication after cardiac surgery with cardiopulmonary bypass and is associated with increased in-hospital mortality. However, the long-term prognosis of patients with postoperative renal deterioration is not fully determined yet. Therefore, both in-hospital mortality and long-term survival were studied in patients with postoperative renal function deterioration. Included were 843 patients who underwent cardiac surgery with cardiopulmonary bypass in 1991. Postoperative renal function deterioration (increase in serum creatinine in the first postoperative week of at least 25%) occurred in 145 (17.2%) patients. In these patients, in-hospital mortality was 14.5%, versus 1.1% in patients without renal function deterioration (P < 0.001). Multivariate analysis significantly associated in-hospital mortality with postoperative renal function deterioration, re-exploration, postoperative cerebral stroke, duration of operation, age, and diabetes. In patients who were discharged alive, during long-term follow-up (100 mo), mortality was significantly increased in the patients with renal function deterioration (n = 124) as compared with those without renal function deterioration (hazard ratio 1.83; 95% confidence interval 1.38 to 3.20). Also after adjustment for other independently associated factors, the risk for mortality in patients with postoperative renal function deterioration remained elevated (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32). The elevated risk for long-term mortality was independent of whether renal function had recovered at discharge from hospital. It is concluded that postoperative renal function deterioration in cardiac surgical patients not only results in increased in-hospital mortality but also adversely affects long-term survival.

Dietary Factors and the Risk of Incident Kidney Stones in Men: New Insights after 14 Years of Follow-up

Abstract: Diet plays an important role in the pathogenesis of kidney stones. Because the metabolism of many dietary factors, such as calcium, may change with age, the relation between diet and kidney stones may be different in older adults. Uncertainty also remains about the association between many dietary factors, such as vitamin C, magnesium, and animal protein, and the risk of kidney stone formation. To examine the association between dietary factors and the risk of incident, symptomatic kidney stones in men and to determine whether these associations vary with age, a prospective cohort study was conducted of 45,619 men without a history of nephrolithiasis. Self-administered food frequency questionnaires were used to assess diet every 4 yr. A total of 1473 incident symptomatic kidney stones were documented during 477,700 person-years of follow-up. For men aged <60 yr, the multivariate relative risk (RR) for stone formation in the highest quintile of dietary calcium as compared with the lowest quintile was 0.69 (95% confidence interval [CI], 0.56 to 0.87; P = 0.01 for trend). By contrast, there was no association between dietary calcium and stone formation in men aged 60 yr or older. The multivariate RR for men who consumed 1000 mg or greater of vitamin C per day compared with those who consumed less than the recommended dietary allowance of 90 mg/d was 1.41 (95% CI, 1.11 to 1.80; P = 0.01 for trend). Other dietary factors showed the following multivariate RR among men in the highest quintile of intake compared with those in the lowest: magnesium, 0.71 (95% CI, 0.56 to 0.89; P = 0.01 for trend); potassium, 0.54 (95% CI, 0.42 to 0.68; P < 0.001 for trend); and fluid, 0.71 (95% CI, 0.59 to 0.85; P < 0.001 for trend). Animal protein was associated with risk only in men with a body mass index <25 kg/m(2) (RR, 1.38; 95% CI, 1.05 to 1.81; P = 0.03 for trend). Sodium, phosphorus, sucrose, phytate, vitamin B(6), vitamin D, and supplemental calcium were not independently associated with risk. In conclusion, the association between calcium intake and kidney stone formation varies with age. Magnesium intake decreases and total vitamin C intake seems to increase the risk of symptomatic nephrolithiasis. Because age and body size affect the relation between diet and kidney stones, dietary recommendations for stone prevention should be tailored to the individual patient.

Vascular Access and All-Cause Mortality: A Propensity Score Analysis

Abstract: The native arteriovenous fistula (AVF) is the preferred vascular access because of its longevity and its lower rates of infection and intervention. Recent studies suggest that the AVF may offer a survival advantage. Because these data were derived from observational studies, they are prone to potential bias. The use of propensity scores offers an additional method to reduce bias resulting from nonrandomized treatment assignment. Adult (age 18 yr or more) patients who commenced hemodialysis in Australia and New Zealand on April 1, 1999, until March 31, 2002, were studied by using the Australian and New Zealand Dialysis and Transplant Association (ANZDATA) Registry. Cox regression was used to determine the effect of access type on total mortality. Propensity scores were calculated and used both as a controlling variable in the multivariable model and to construct matched cohorts. The catheter analysis was stratified by dialysis duration at entry to ANZDATA to satisfy the proportional-hazard assumption. There were 612 deaths in 3749 patients (median follow-up, 1.07 yr). After adjustment for confounding factors and propensity scores, catheter use was predictive of mortality. Patients with arteriovenous grafts (AVG) also had a significantly increased risk of death. Effect estimates were also consistent in the smaller propensity score-matched cohorts. Both AVG and catheter use in incident hemodialysis patients are associated with significant excess of total mortality. Reducing catheter use and increasing the proportion of patients commencing hemodialysis with a mature AVF remain important clinical objectives.

Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator.

Abstract: The critical role of hyperglycemia in the genesis of diabetic nephropathy has been established by cell culture studies, experimental animal models, and clinical trials. Certain cytokines and growth factors have been identified as likely mediators of the effects of high ambient glucose on the kidney, but prominent among these is TGF-beta, a prototypical hypertrophic and fibrogenic cytokine. Overexpression of TGF-beta has been demonstrated in the glomerular and tubulointerstitial compartments of experimental diabetic animals. The TGF-beta receptor signaling system is also triggered, as evidenced by upregulation of the TGF-beta type II receptor and activation of the downstream Smad signaling pathway. Treatment of diabetic mice with neutralizing anti-TGF-beta antibodies prevents the development of renal hypertrophy, mesangial matrix expansion, and the decline in renal function. Antibody therapy also reverses the established lesions of diabetic glomerulopathy. These studies argue strongly in support of the hypothesis that overactivity of the TGF-beta system in the kidney is a crucial mediator of diabetic renal hypertrophy and mesangial matrix expansion.

Corticosteroid Effectiveness in IgA Nephropathy: Long-Term Results of a Randomized, Controlled Trial

Abstract: Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histologic scores can influence steroid response. A secondary analysis of a multicenter, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted. Ten-year renal survival was significantly better in the steroid than in the control group (97% versus 53%; log rank test P = 0.0003). In the 72 patients who did not reach the end point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 h at baseline, 1.1 g/24 h after 6 mo, and 0.6 g/24 h after a median of 7 yr). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr. Steroids were effective in every histologic class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histologic score, a reduction in proteinuria after 6 mo, and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome. Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.

Erythropoietin Protects the Kidney against the Injury and Dysfunction Caused by Ischemia-Reperfusion

Abstract: Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.

Timing of Complications in Percutaneous Renal Biopsy

Abstract: Percutaneous renal biopsy (PRB) is a safe and effective tool in the diagnosis and management of renal disease; however, the optimal timing of observation after biopsy is not clearly established. With the use of real-time ultrasound guidance, PRB of native kidneys was performed in 750 adult patients at an academic institution by an attending nephrologist or fellow between June 1983 and June 2002. All patients were observed for 23 to 24 h after biopsy for the presence, severity, and timing of complications. Biopsy-related complications occurred in 98 (13%) patients; minor complications occurred in 50 (6.6%) patients, and major complications occurred in 48 (6.4%) patients. One (0.1%) patient died as a result of the biopsy. Multivariate analysis using logistic regression found only serum creatinine at baseline predictive of a complication. Patients with a serum creatinine > or = 5.0 mg/dl were 2.3 times as likely to have a complication (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.1; P or = 33% of complications.

Evaluation of Intravenous Immunoglobulin as an Agent to Lower Allosensitization and Improve Transplantation in Highly Sensitized Adult Patients with End-Stage Renal Disease: Report of the NIH IG02 Trial

Abstract: Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] > or =50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean +/- SEM serum creatinine of 1.68 +/- 0.28 for IVIG versus 1.28 +/- 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.

Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

Abstract: Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.

Rapamycin Markedly Slows Disease Progression in a Rat Model of Polycystic Kidney Disease

Abstract: Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.

Heterozygous and Homozygous Factor H Deficiencies Associated with Hemolytic Uremic Syndrome or Membranoproliferative Glomerulonephritis: Report and Genetic Analysis of 16 Cases

Abstract: Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. HUS onset occurred from birth to midadulthood, and disease progression was variable. Four children with homozygous or heterozygous FH deficiency and HUS underwent renal transplantation, which was successful in three but failed as a result of recurrence of HUS in one patient. All but one patient exhibited alternative pathway-mediated complement consumption, with no detectable FH antigenic levels or with 50% immunochemical or functional FH levels in the case of complete or partial deficiency, respectively. The molecular mechanisms of the deficiency were documented in all cases by exon-specific sequencing analysis. These mechanisms included nucleotide substitutions, insertion, or deletion located in SCR 2, 7, 11, 13, 15, and 20, leading to an amino acid substitution or to a stop codon. This report emphasizes the variability in the clinical progression of kidney diseases associated with FH deficiencies. Genetic analysis reveals the molecular abnormalities associated with FH deficiencies to be polymorphous.

Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease

Abstract: Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innate and adaptive immune responses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.

Prospective Study of Tnf Blockade with Infliximab in Anti-Neutrophil Cytoplasmic Antibody-Associated Systemic Vasculitis

Abstract: . Tumor necrosis factor α (TNFα) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNFα blockade is a potential therapy for these disorders. Methods: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] ≥ 10; n = 16); study II examined persistent disease (BVAS ≥ 4; n = 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. Results: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] = 10.5 to 14.0) at entry to 0.3 (CI = 0.2 to 0.9) at wk 14 ( P P = 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI = 15.0 to 32.5) at entry to 8.8 (CI = 5.9 to 11.7) at wk 14 ( P = 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. Conclusion: TNFα blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.

Calcium, Phosphate, and Parathyroid Hormone Levels in Combination and as a Function of Dialysis Duration Predict Mortality: Evidence for the Complexity of the Association between Mineral Metabolism and Outcomes

Abstract: Current literature suggests associations between abnormal mineral metabolism (MM) to cardiovascular disease in dialysis populations, with conflicting results. MM physiology is complex; therefore, it was hypothesized that constellations of MM parameters, reflecting this complexity, would be predictive of mortality and that this effect would be modified by dialysis duration (DD). Prevalent dialysis patients in British Columbia, Canada, who had measurements of calcium (Ca), phosphate (Pi), and parathyroid hormone (iPTH) between January and March 2000 were followed prospectively until December 2002. Statistical analysis included Cox proportional hazard models with Ca, Pi, and iPTH alone and in combination as explanatory variables; analyses were stratified by DD. The 515 patients included in this analysis represent British Columbia and Canadian dialysis populations: 69% were on hemodialysis, mean age was 60 +/- 17 yr, 40% were female, and 34% had diabetes. Mean Ca and Pi values were 2.32 +/- 0.22 mmol/L and 1.68 +/- 0.59 mmol/L, respectively, and median iPTH was 15.8 pmol/L (25th to 75th percentile: 6.9 to 37.3 pmol/L). Serum Pi, after adjusting for demographic, dialysis type and adequacy, hemoglobin, and albumin, independently predicted mortality (risk ratio [RR], 1.56 per 1 mmol/L; 95% confidence interval [CI], 1.15 to 2.12; P = 0.004). When combinations of parameters were modeled (overall P = 0.003), the combinations of high serum Pi and Ca with high iPTH (RR, 3.71; 95% CI, 1.53 to 9.03; P = 0.004) and low iPTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < 0.001) had highest risks for mortality as compared with the combination of high iPTH with normal serum Ca and Pi that had the lowest mortality and was used as index category. These effects varied across different strata of DD. This analysis demonstrates the importance of examining combinations of MM parameters as opposed to single variables alone and the effect of DD. In so doing, the complex interaction of time and MM can begin to be understand. Further exploration is required.

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

Abstract: Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (CUA). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and CUA/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These CUA/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo.