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Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA., (Copyright © 2011 by the American Society of Nephrology)

Background: The safety and efficacy of different types of β-blocker therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD., Methods and Results: We performed a post hoc analysis of pooled individual patient data (n=4217) from 2 multinational, double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study). Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death. Non-dialysis-dependent CKD was defined by estimated glomerular filtration rate ≤60 mL/min/1.73 m(2), using the abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort, 50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93; P=0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P=0.011), HF mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P=0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P=0.0009), and the composite of cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P<0.001) but was without significant effect on sudden cardiac death (HR, 0.76; 95% CI, 0.56 to 1.05; P=0.098). There was no significant interaction between treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate <45 mL/min/1.73 m(2) (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo., Conclusions: This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy is similarly efficacious in HF patients with more advanced kidney disease requires further study.

Background: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)>or=60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics., Study Design: Test of diagnostic accuracy., Setting & Participants: Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index., Index Tests: eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine., Reference Test: Measured GFR using urinary or plasma clearance of exogenous filtration markers., Results: Mean measured GFR was 68+/-36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR>or=90 mL/min/1.73 m2., Limitations: Limited number of elderly people and racial and ethnic minorities with measured GFR., Conclusions: The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR>or=60 mL/min/1.73 m2 can be reported using the CKD-EPI equation., (Copyright (c) 2010 National Kidney Foundation, Inc. All rights reserved.)

Background and Objectives: Dyslipidemia confers a paradoxical survival advantage in patients with kidney failure. Data are limited in the earlier stages of chronic kidney disease (CKD)., Design, Setting, Participants, and Measurements: This was a cohort study in 840 subjects with stage 3 to 4 CKD enrolled in the Modification of Diet in Renal Disease study. Cox models were used to examine the relationship of total cholesterol (TC), non-HDL-cholesterol (NHDL-C), triglycerides (TG), and HDL-cholesterol (HDL-C) with all-cause and cardiovascular disease (CVD) mortality and progression to kidney failure., Results: During a mean follow-up of 10 years, there were 208 deaths, 128 deaths from CVD, and 554 subjects reached kidney failure. There was no association between tertiles of any of the lipid variables and mortality; the lowest HDL-C tertile (1.44, 1.18 to 1.78) had increased risk of kidney failure but covariate adjustment abolished this association. In analyses with lipids as continuous variables, there was a significant association with all-cause mortality for TC (hazard ratio [HR] per 10-mg/dl increase, 95% confidence intervals [CI] = 1.03, 1.0 to 1.06) that disappeared with covariate adjustment; there was no association of TG, HDL-C, and NHDL-C as continuous variables with all-cause or CVD mortality. There was a significant inverse association between HDL-C and kidney failure (HR = 0.93, CI = 0.87 to 0.99) in an unadjusted Cox model that was attenuated after adjustment for covariates (HR = 0.98 CI = 0.91 to 1.06)., Conclusions: In this cohort, with predominantly nondiabetic CKD patients, hyperlipidemia is not an independent predictor of long-term outcomes.

Background: The long-term effect of a very low-protein diet on the progression of kidney disease is unknown. We examined the effect of a very low-protein diet on the development of kidney failure and death during long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study., Study Design: Long-term follow-up of study B of the MDRD Study (1989-1993)., Setting & Participants: The MDRD Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 255 trial participants with predominantly stage 4 nondiabetic chronic kidney disease., Intervention: A low-protein diet (0.58 g/kg/d) versus a very low-protein diet (0.28 g/kg/d) supplemented with a mixture of essential keto acids and amino acids (0.28 g/kg/d)., Outcomes: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality until December 31, 2000., Results: Kidney failure developed in 227 (89%) participants, 79 (30.9%) died, and 244 (95.7%) reached the composite outcome of either kidney failure or death. Median duration of follow-up until kidney failure, death, or administrative censoring was 3.2 years, and median time to death was 10.6 years. In the low-protein group, 117 (90.7%) participants developed kidney failure, 30 (23.3%) died, and 124 (96.1%) reached the composite outcome. In the very low-protein group, 110 (87.3%) participants developed kidney failure, 49 (38.9%) died, and 120 (95.2%) reached the composite outcome. After adjustment for a priori-specified covariates, hazard ratios were 0.83 (95% confidence interval, 0.62 to 1.12) for kidney failure, 1.92 (95% confidence interval, 1.15 to 3.20) for death, and 0.89 (95% confidence interval, 0.67 to 1.18) for the composite outcome in the very low-protein diet group compared with the low-protein diet group., Limitations: Lack of dietary protein measurements during follow-up., Conclusion: In long-term follow-up of the MDRD Study, assignment to a very low-protein diet did not delay progression to kidney failure, but appeared to increase the risk of death.

Background: Greater body mass index (BMI) is associated with worse survival in the general population, but appears to confer a survival advantage in patients with kidney failure treated by hemodialysis. Data are limited on the relationship of BMI with mortality in patients in the earlier stages of chronic kidney disease (CKD)., Study Design: Cohort study., Setting & Participants: The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 1,759 subjects., Predictor: BMI., Outcomes & Measurements: Cox models were used to evaluate the relationship of quartiles of BMI with all-cause and cardiovascular disease (CVD) mortality., Results: Mean GFR and BMI were 39 +/- 21 (SD) mL/min/1.73 m(2) and 27.1 +/- 4.7 kg/m(2), respectively. During a mean follow-up of 10 years, there were 453 deaths (26%), including 272 deaths (16%) from CVD. In unadjusted Cox models, quartiles 3 (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.11 to 1.90) and 4 (HR, 1.58; 95% CI, 1.21 to 2.06) were associated with increased risk of all-cause mortality compared with quartile 1. Adjustment for demographic, CVD, and kidney disease risk factors and randomization status attenuated this relationship for quartiles 3 (HR, 0.81; 95% CI, 0.60 to 1.09) and 4 (HR, 0.83; 95% CI, 0.61 to 1.20). In unadjusted Cox models, quartiles 3 (HR, 1.66; 95% CI, 1.17 to 2.36) and 4 (HR, 1.63; 95% CI, 1.15 to 2.33) were associated with increased risk of CVD mortality. Multivariable adjustment attenuated this relationship for quartiles 3 (HR, 0.92; 95% CI, 0.63 to 1.36) and 4 (HR, 0.85; 95% CI, 0.57 to 1.27)., Limitations: Primary analyses were based on single measurement of BMI. Because the MDRD Study cohort included relatively young white subjects with predominantly nondiabetic CKD, results may not be generalizable to all patients with CKD., Conclusions: In this cohort of subjects with predominantly nondiabetic CKD, BMI does not appear to be an independent predictor of all-cause or CVD mortality.

Background: No study has compared cystatin C level, serum creatinine concentration, and estimated glomerular filtration rate (GFR) as risk factors for outcomes in chronic kidney disease (CKD), and none has compared measured GFR with CKD in any population., Objective: To compare cystatin C level with serum creatinine concentration and iothalamate GFR as risk factors for death and kidney failure., Design: Observational study using serum cystatin C assayed from baseline samples of the Modification of Diet in Renal Disease Study (1989-1993)., Setting: 15 clinical centers in the United States that participated in the Modification of Diet in Renal Disease Study., Participants: 825 trial participants with stage 3 or 4 nondiabetic CKD who had measurements of serum cystatin C., Measurements: All-cause mortality, cardiovascular (CVD) mortality, and kidney failure until December 2000., Results: Mean cystatin C level, creatinine concentration, and GFR were 2.2 mg/L (SD, 0.7), 212.16 micromol/L (SD, 88.4) (2.4 mg/dL [SD, 1.0]), and 33 mL/min per 1.73 m2 (SD, 12), respectively. Median follow-up was 10 years. Twenty-five percent of patients (n = 203) died of any cause, 15% (n = 123) died of CVD, and 66% (n = 548) reached kidney failure. In multivariate-adjusted models, 1-SD decreases in 1/creatinine, GFR, and 1/cystatin C were associated with increased risks for all-cause mortality of 1.27 (95% CI, 1.06 to 1.49), 1.27 (CI, 1.08 to 1.49), and 1.41 (CI, 1.18 to 1.67), respectively. For CVD mortality, the increased risks were 1.32 (CI, 1.05 to 1.64), 1.28 (CI, 1.04 to 1.59), and 1.64 (CI, 1.28 to 2.08), respectively. For kidney failure, the increased risks were 2.81 (CI, 2.48 to 3.18), 2.41 (CI, 2.15 to 2.70), and 2.36 (CI, 2.10 to 2.66), respectively., Limitation: The Modification of Diet in Renal Disease Study cohort may not be representative of all patients with nondiabetic CKD because participants were more likely to reach kidney failure than death in follow-up., Conclusion: The association of cystatin C level with all-cause and CVD mortality was as strong as or perhaps stronger than that of iothalamate GFR with these outcomes in stage 3 or 4 CKD.

Background: The relationship between total homocysteine (tHcy) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4., Methods and Results: The Modification of Diet in Renal Disease Study was a randomized, controlled trial of 840 patients. Serum tHcy was measured in frozen samples collected at baseline (n=804). Survival status and cause of death were obtained from the National Death Index. To evaluate its association with all-cause and cardiovascular disease (CVD) mortality, tHcy was evaluated both as tertiles (<14.7, 14.7 to 19.5, > or =19.6 micromol/L) and as a continuous variable (per 10/micromol/L). Participants had a mean age of 52+/-12 years and glomerular filtration rate (GFR) of 33+/-12 mL/min per 1.73 m2; 60% were male, and 85% were white. During a median follow-up of 10 years, 195 (24%) died from any cause, and 118 (15%) from CVD. The level of GFR was lower and proteinuria higher in the highest tHcy tertile. There was no association between the highest tertile of tHcy and all-cause (hazard ratio [HR]; 95% confidence interval [CI[, 1.32, 0.94 to 1.85) or CVD (HR; 95% CI, 1.50, 0.96 to 2.34) mortality in univariate analyses; this association was further attenuated by adjustment for GFR (HR; 95% CI all-cause, 1.04, 0.72 to 1.51; CVD, 1.20, 0.73 to 1.95). There was no association between tHcy as a continuous variable and all-cause (0.98, 0.83 to 1.16) or CVD (1.04, 0.85 to 1.27) mortality., Conclusions: Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study. Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function.

In the general population, hyperglycemia in the absence of diabetes may be associated with increased risk for mortality. Hyperglycemia is prevalent in chronic kidney disease; however, the relationship between glycosylated hemoglobin (HbA(1c)) as a marker of chronic hyperglycemia and outcomes has not been studied in nondiabetic chronic kidney disease. HbA(1c) was measured at baseline in the randomized cohort of the Modification of Diet in Renal Disease Study (n = 840). Participants with diabetes (n = 43), fasting glucose levels >126 mg/dl (n = 20), or missing HbA(1c) levels (n = 9) were excluded. Survival status until December 2000 was obtained from the National Death Index. Death was classified as cardiovascular (CVD) when the primary cause was International Classification of Disease, Ninth Revision codes 390 to 459. Cox models were performed to assess the relationship of HbA(1c) with all-cause and CVD mortality. Mean (SD) age was 52 (12) years, and mean (SD) GFR was 32 (12) ml/min per 1.73 m(2). Eighty-six percent of participants were white, and 61% were male. Mean (SD) HbA(1c) was 5.6% (0.5). A total of 169 (22%) patients died, 96 (13%) from CVD. After adjustment for randomization assignments and demographic, CVD, and kidney disease factors, HbA(1c) was a predictor of all-cause mortality (hazard ratio per 1% increase 1.73; 95% confidence interval 1.24 to 2.41; P = 0.001). There was a trend toward statistical significance in the relationship between HbA(1c) and CVD mortality (hazard ratio per 1% increase 1.53; 95% confidence interval 0.96 to 2.43; P = 0.07). HbA(1c) is associated with increased mortality in nondiabetic kidney disease. Hyperglycemia may be a potential therapeutic target and HbA(1c) may be important as a risk stratification tool in this high-risk population.

Background: Abnormalities of mineral metabolism are prevalent in patients with kidney failure and are associated with increased risk for cardiovascular events. There are limited data investigating relationships of phosphorus and calcium-phosphorus product with outcomes in patients with chronic kidney disease (CKD) stages 3 to 4., Methods: Serum phosphorus and calcium were measured at baseline in 840 participants from the randomized cohort of the Modification of Diet in Renal Disease Study. Survival status until December 31, 2000, was obtained from the National Death Index. Cox models were performed to assess the relationship of serum phosphorus level and calcium-phosphorus product with all-cause and cardiovascular disease (CVD) mortality., Results: Mean serum phosphorus level was 3.8 +/- 0.7 mg/dL (1.23 +/- 0.23 mmol/L), calcium-phosphorus product was 34.7 +/- 6.3 mg2/dL2, and glomerular filtration rate (GFR) was 33 +/- 12 mL/min/1.73 m2 (0.55 +/- 0.20 mL/s/1.73 m2). All-cause and CVD mortality rates were 25% and 15%. Serum phosphorus level was not related to all-cause mortality in multivariable models (P = 0.46). In unadjusted analysis, serum phosphorus level was associated with (hazard ratio [HR] per 1 mg/dL increase, 1.34; 95% confidence interval [CI], 1.05 to 1.71; P = 0.02) increased risk for CVD mortality, but this association was partly attenuated and not statistically significant after adjustment for GFR and other confounders (HR, 1.27; 95% CI, 0.94 to 1.73; P = 0.12). Calcium-phosphorus product was not associated with all-cause mortality in unadjusted (P = 0.23) or multivariate analysis (P = 0.35). Calcium-phosphorus product was related to CVD mortality in unadjusted (HR per 10 mg2/dL2 increase, 1.30; 95% CI, 1.01 to 1.69; P = 0.04) analysis, but this association was not statistically significant after adjustment for GFR and other confounders (HR, 1.22; 95% CI, 0.89 to 1.66; P = 0.23)., Conclusion: In the Modification of Diet in Renal Disease Study cohort, serum phosphorus level and calcium-phosphorus product were not statistically associated with all-cause or CVD mortality after adjustment for GFR; however larger studies with additional statistical power are needed to evaluate these relationships, especially in the context of current practice patterns in patients with CKD.

Background: It is unclear whether lipoprotein(a) (Lp[a]) levels in patients with chronic kidney disease (CKD) are elevated as a result of reduced glomerular filtration rate (GFR) or other factors associated with CKD. The goal of this study is to describe the association of Lp(a) level with GFR in the context of apoprotein(a) (apo[a]) isoform size, race, and other kidney disease-related factors, such as proteinuria, serum albumin level, C-reactive protein (CRP) level, and serum lipid levels., Methods: Lp(a) and apo(a) isoforms were measured in serum samples obtained at baseline from 804 participants in the Modification of Diet in Renal Disease study (GFR range, 13 to 55 mL/min/1.73 m2). The cross-sectional association between Lp(a) level and GFR, apo(a) isoform size, race, and other variables was analyzed in univariate and multivariate linear regression., Results: Median Lp(a) level was greater in blacks than whites (97.5 versus 28.1 nmol/L; P < 0.001). Those with a low-molecular-weight apo(a) isoform size had greater Lp(a) levels than those with a high-molecular-weight apo(a) isoform size (57.5 versus 21.3 nmol/L; P < 0.001). Lp(a) level was not associated with GFR. Low-molecular-weight apo(a), black race, and greater levels of proteinuria, CRP, and triglycerides were independently associated with greater Lp(a) levels., Conclusion: In this population with CKD stages 3 to 4, GFR was not associated with Lp(a) level, whereas other factors related to CKD, such as proteinuria, CRP level, and triglyceride level, as well as genetic factors such as apo(a) isoform size and race, were associated with Lp(a) level.

Background: C-Reactive protein (CRP) level is elevated in kidney failure and may be related to malnutrition and cardiovascular disease (CVD). Data are limited regarding relationships between CRP levels and glomerular filtration rate (GFR), nutritional indices, and CVD in patients with earlier stages of kidney disease., Methods: CRP was assayed from samples from the Modification of Diet in Renal Disease (MDRD) Study (n = 801). CRP distributions were compared between the MDRD Study and National Health and Nutrition Examination Survey (NHANES; 1999 to 2000). Associations between CRP level and GFR, nutritional indices, serum albumin levels, and CVD risk factors were examined in the MDRD Study., Results: Geometric means of CRP, adjusted for age and sex, were similar in NHANES (0.23 mg/dL) and the MDRD Study (0.22 mg/dL). In the MDRD Study, CRP level was related directly to measures of body fat and CVD risk factors, inversely with serum albumin level and energy intake, and unrelated to GFR. In multivariable analysis adjusting for other determinants of serum albumin level, high CRP level (>0.6 mg/dL) was associated with a 0.07-g/dL (0.7-g/L; 95% confidence interval [CI], 0.03 to 0.12) lower mean serum albumin level. After adjusting for traditional CVD risk factors, the odds of CVD were 1.73 (95% CI, 1.07 to 2.78) times greater in subjects with a high CRP level., Conclusion: GFR level does not appear to influence CRP level in the earlier stages of chronic kidney disease. CRP levels are independently associated with serum albumin level and CVD prevalence. Inflammation may be involved in the pathophysiological state of malnutrition and CVD in the earlier stages of predominantly nondiabetic kidney disease.

Background: Pathological similarities between atherosclerosis and glomerulosclerosis suggest that risk factors for the two processes may be similar. Elevated total homocysteine (tHcy) levels and low B vitamin levels are risk factors for atherosclerosis, but have not been evaluated sufficiently as risk factors for the progression of kidney disease., Methods: Frozen samples from the Modification of Diet in Renal Disease Study were assayed for serum tHcy, cysteine, pyridoxal 5-phosphate (PLP), folate, and vitamin B12 levels in 804 participants. These factors were evaluated in both continuous and categorical analyses as risk factors for glomerular filtration rate (GFR) decline by using univariate and multivariable analyses., Results: At baseline, mean tHcy levels in study A (GFR, 25 to 55 mL/min/1.73 m2) and study B (GFR, 13 to 24 mL/min/1.73 m2) were 16.9 micromol/L (median, 15.6 micromol/L) and 23.0 micromol/L (median, 20.5 micromol/L), respectively. Mean follow-up was 2.2 years. Mean GFR declines were -4.35 and -3.65 mL/min/y in studies A and B, respectively. There was no significant association between change in GFR with baseline level of tHcy in univariate (-0.26 mL/min/y per 1-SD unit increase in tHcy level; 95% confidence interval [CI], -0.67 to 0.15) or multivariable (-0.18 mL/min/y per 1-SD unit increase in tHcy level; 95% CI, -0.53 to 0.17) analysis in study A or univariate (0.07 mL/min/y per 1-SD unit increase in tHcy level; 95% CI, -0.36 to 0.51) or multivariable (0.24 mL/min/y per 1-SD unit increase in tHcy level; 95% CI, -0.16 to 0.64) analysis in study B. Similarly, higher cysteine levels and lower B vitamin levels were not associated with faster rates of GFR decline in multivariable analysis in either study., Conclusion: Higher tHcy or cysteine levels and lower folate, PLP, and vitamin B12 levels are not independent risk factors for progression of nondiabetic kidney disease., (Copyright 2002 by the National Kidney Foundation, Inc.)

Background: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs.Methods: We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis.Results: Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%-41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery.Conclusions: CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes. [ABSTRACT FROM AUTHOR]

Background: Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population.Methods: In the EPPIC trials, patients were randomly assigned 1:1 to treatment with AST-120 or placebo. The primary endpoint was a composite of dialysis initiation, kidney transplantation, or doubling of serum creatinine. The EPPIC trial pooled population was evaluated with the same statistical methods used for analysis of the primary and secondary efficacy endpoints. The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]).Results: An analysis of the placebo population suggested baseline urinary protein to urinary creatinine ratio (UP/UCr) ≥1.0 and hematuria were independent risk factors for event occurrence and eGFR lowering. Analysis of the high risk patients revealed a difference in the primary endpoint occurrence between treatment groups, if angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers were administered (hazard ratio 0.74, 95% confidence interval 0.56-0.96). Also, the eGFR changes from baseline in the AST-120 group were smaller than that in the placebo group (P = 0.035).Conclusions: CKD progression may have an association with baseline UP/UCr and hematuria. Treatment with AST-120 may delay the time to the primary endpoint in patients with progressive CKD receiving standard therapy, thus warranting further investigation. [ABSTRACT FROM AUTHOR]

Introduction: End-stage renal disease (ESRD) is associated with perturbations in thyroid hormone concentrations and an increased prevalence of hypothyroidism. Few studies have examined the effects of hemodialysis dose or frequency on endogenous thyroid function. Methods: Within the Frequent Hemodialysis Network (FHN) trials, we examined the prevalence of hypothyroidism in patients with ESRD. Among those with endogenous thyroid function (without overt hyper/hypothyroidism or thyroid hormone supplementation), we examined the association of thyroid hormone concentration with multiple parameters of self-reported health status, and physical and cognitive performance, and the effects of hemodialysis frequency on serum thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3) levels. Conventional thrice-weekly hemodialysis was compared to in-center (6 d/wk) hemodialysis (Daily Trial) and Nocturnal (6 nights/wk) home hemodialysis (Nocturnal Trial) over 12 months. Findings: Among 226 FHN Trial participants, the prevalence of hypothyroidism was 11% based on thyroid hormone treatment and/or serum TSH ≥8 mIU/mL. Among the remaining 195 participants (147 Daily, 48 Nocturnal) with endogenous thyroid function, TSH concentrations were modestly (directly) correlated with age (r = 0.16, P = 0.03) but not dialysis vintage. Circulating thyroid hormone levels were not associated with parameters of health status or physical and cognitive performance. Furthermore, frequent in-center and nocturnal hemodialysis did not significantly change (baseline to month 12) TSH, FT4, or FT3 concentrations in patients with endogenous thyroid function. Discussion: Among patients receiving hemodialysis without overt hyper/hypothyroidism or thyroid hormone treatment, thyroid indices were not associated with multiple measures of health status and were not significantly altered with increased dialysis frequency. [ABSTRACT FROM AUTHOR]

The article presents a study seeking to determine whether the drug clopidogrel reduces early failure of hemodialysis fistulas among patients treated with hemodialysis. The design, setting, and participants of the double-blind, placebo controlled trial involving 877 patients with end-stage renal disease or advanced chronic kidney disease are detailed. The main outcomes measured were fistula thrombosis and failure of the fistula to become suitable for dialysis. Researchers conclude that clopidogrel was capable of reducing the frequency of early thrombosis of arteriovenous fistulas, but it failed to increase the proportion of fistulas that became suitable for dialysis.

Cystatin C is being considered as a replacement for serum creatinine in the estimation of the glomerular filtration rate (GFR); however, its plasma levels might be affected by factors other than the GFR, such as protein intake. We performed a post hoc analysis of the data in the Modification of Diet in Renal Disease study, in which we compared serum creatinine and cystatin C levels in 741 patients with available estimates of protein intake at baseline prior to their randomization to diets containing various amounts of protein, and at 2 years of follow-up in 426 of these patients in whom a cystatin C measurement was available. The 503 patients in study A (GFR 25-55 ml/min per 1.73 m2) had been assigned a low (0.58 g/kg per day) or a usual (1.3 g/kg per day) protein intake, and the 238 participants in study B (GFR 13-24 ml/min per 1.73 m2) were assigned a very low (0.28 g/kg per day) or the low protein intake. In either study group, lowering the dietary protein intake reduced the change in creatinine, but did not have a significant change in cystatin C. Thus, in patients with moderate-to-severe chronic kidney disease, serum cystatin C unlike serum creatinine was not affected by dietary protein intake independent of changes in GFR. Hence, cystatin C may allow more accurate estimates of GFR than creatinine for patients with reduced protein intake. Further study of other non-GFR determinants of cystatin C is needed before the widespread adoption. [ABSTRACT FROM AUTHOR]

A higher body mass index is associated with better outcomes in hemodialysis patients; however, this index does not differentiate between fat and muscle mass. In order to clarify this, we examined the relationship between measures of fat and muscle mass and mortality in 1709 patients from the Hemodialysis Study. Triceps skin-fold thickness was used to assess body fat and mid-arm muscle circumference was used to assess muscle mass. Cox regression was used to evaluate the relationship between measures of body composition with all-cause mortality after adjustments for demographic, cardiovascular, dialysis, and nutrition-related risk factors. During a median follow-up of 2.5 years, there were 802 deaths. In adjusted models with continuous covariates, higher triceps skin-fold thickness and higher body mass index were significantly associated with decreased hazards of mortality, while higher mid-arm muscle circumference showed a trend toward decreased mortality. In adjusted models, lower quartiles of triceps skin-fold thickness, mid-arm muscle circumference, and body mass index were all significantly associated with higher all-cause mortality. These studies show that body composition in end-stage renal disease bears a complex relationship to all-cause mortality. [ABSTRACT FROM AUTHOR]

Homocysteine in chronic kidney disease: Effect of low protein diet and repletion with B vitamins.Background.Data are limited on the determinants of homocysteine (tHcy) and its relationship with nutritional indices, and dietary protein intake, in the earlier stages of chronic kidney disease (CKD).Methods.Levels of tHcy were assayed at baseline (N= 804) and 1 year postrandomization (N= 678) in the Modification of Diet in Renal Disease (MDRD) Study[study A, glomerular filtration rate (GFR) 25 to 55 mL/min/1.73 m2 and study B GFR 13 to 24 mL/min/1.73 m2]. Participants were randomly assigned to different blood pressure targets and protein diets and all subjects received a multivitamin supplement containing 1 mg of folic acid, 10 mg pyridoxal 5′-phosphate (PLP) and 6μg of vitamin B12. Multivariable analyses were used to evaluate determinants of tHcy at baseline and 1 year.Results.The prevalence of hyperhomocysteinemia (tHcy>15μmol/L) at baseline was 56% in study A and 85% in study B. Baseline tHcy was negatively correlated with measures of body fat and dietary protein intake. Folate, vitamin B12, and GFR were the major determinants of tHcy levels. Of the patients with hyperhomocysteinemia at baseline, 49% and 24% reduced their tHcy levels at 1 year to≤15μmol/L in study A and study B, respectively. There was no association between dietary protein intake and odds of developing hyperhomocysteinemia at 1 year in study A (P= 0.94) or study B (P= 0.10).Conclusion.Hyperhomocysteinemia is partly amenable to correction by vitamin supplementation in CKD stages 3 and 4. There is insufficient evidence to suggest that low tHcy is associated with poor nutritional status in the MDRD Study cohort. B vitamins and GFR, but not dietary protein, are the major determinants of tHcy in this patient population. [ABSTRACT FROM AUTHOR]

Background: Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. However, the course and determinants of renal failure in this type of diabetes have not been clearly defined. Methods: We studied glomerular function at intervals of 6 to 12 months for 4 years in 194 Pima Indians selected to represent different stages in the development and progression of diabetic renal disease. Initially, 31 subjects had normal glucose tolerance, 29 had impaired glucose tolerance, 30 had newly diagnosed diabetes, and 104 had had diabetes for five years or more; of these 104, 20 had normal albumin excretion, 50 had microalbuminuria, and 34 had macroalbuminuria. The glomerular filtration rate, renal plasma flow, urinary albumin excretion, and blood pressure were measured at each examination. Results: Initially, the mean (±SE) glomerular filtration rate was 143±7 ml per minute in subjects with newly diagnosed diabetes, 155±7 ml per minute in those with microalbuminuria, and 124±7 ml per minute in those with macroalbuminuria; these values were 16 percent, 26 percent, and 1 percent higher, respectively, than in the subjects with normal glucose tolerance (123±4 ml per minute). During four years of follow-up, the glomerular filtration rate increased by 18 percent in the subjects who initially had newly diagnosed diabetes (P = 0.008); the rate declined by 3 percent in those with microalbuminuria at base line (P = 0.29) and by 35 percent in those with macroalbuminuria (P<0.001). Higher base-line blood pressure predicted increasing urinary albumin excretion (P = 0.006), and higher base-line urinary albumin excretion predicted a decline in the glomerular filtration rate (P<0.001). The initial glomerular filtration rate did not predict worsening albuminuria. Conclusions: The glomerular filtration rate is elevated at the onset of NIDDM and remains so while normal albumin excretion or microalbuminuria persists. It declines progressively after the development of macroalbuminuria. (N Engl J Med 1996;335:1636-42.) [ABSTRACT FROM AUTHOR]

Background: Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases. Methods: In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients. Results: The mean follow-up was 2.2 years. In study 1, the projected mean decline in the glomerular filtration rate at three years did not differ significantly between the diet groups or between the blood-pressure groups. As compared with the usual-protein group and the usual-blood-pressure group, the low-protein group and the low-blood-pressure group had a more rapid decline in the glomerular filtration rate during the first four months after randomization and a slower decline thereafter. In study 2, the very-low-protein group had a marginally slower decline in the glomerular filtration rate than did the low-protein group (P = 0.07). There was no delay in the time to the occurrence of end-stage renal disease or death. In both studies, patients in the low-blood-pressure group who had more pronounced proteinuria at base line had a significantly slower rate of decline in the glomerular filtration rate. Conclusions: Among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease. (N Engl J Med 1994;330:877-84.) [ABSTRACT FROM AUTHOR]