Vandana Menon

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Uric Acid and Long-term Outcomes in CKD

BACKGROUND Hyperuricemia is prevalent in patients with chronic kidney disease (CKD); however, data are limited about the relationship of uric acid levels with long-term outcomes in this patient population. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N = 840) conducted from 1989 to 1993 to examine the effects of strict blood pressure control and dietary protein restriction on progression of stages 3 to 4 CKD. This analysis included 838 patients. PREDICTOR Uric acid level. OUTCOMES & MEASUREMENTS The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular disease (CVD) mortality, and kidney failure. RESULTS Mean age was 52 +/- 12 (SD) years, glomerular filtration rate was 33 +/- 12 mL/min/1.73 m(2), and uric acid level was 7.63 +/- 1.66 mg/dL. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) died of CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.07 to 2.32), a trend toward CVD mortality (HR, 1.47; 95% CI, 0.90 to 2.39), and no association with kidney failure (HR, 1.20; 95% CI, 0.95 to 1.51) compared with the lowest tertile. In continuous analyses, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30) and 16% increased risk of CVD mortality (HR, 1.16; 95% CI, 1.01 to 1.33), but was not associated with kidney failure (HR, 1.02; 95% CI, 0.97 to 1.07). LIMITATIONS Primary analyses were based on a single measurement of uric acid. Results are generalizable primarily to relatively young white patients with predominantly nondiabetic CKD. CONCLUSIONS In patients with stages 3 to 4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality, but not kidney failure.

Adiponectin and Mortality in Patients with Chronic Kidney Disease

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular filtration rate (GFR) rate was 33 +/- 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean +/- SD adiponectin was 12.8 +/- 8.0 mug/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-mug/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Cystatin C as a risk factor for outcomes in chronic kidney disease.

Context Does cystatin C, glomerular filtration rate (GFR), or creatinine better predict mortality? Contribution This study examined long-term outcomes of 825 adults with nondiabetic chronic kidney disease who had participated in 2 trials of protein restriction in the early 1990s. Higher cystatin C and creatinine levels and lower GFR at baseline were all associated with an increased risk for kidney failure and for all-cause and cardiovascular mortality. Associations between cystatin C and cardiovascular mortality seemed slightly stronger than those between GFR or creatinine and cardiovascular mortality. Implication Cystatin C levels seem to be at least as strongly associated with mortality as either GFR or creatinine concentration in adults with nondiabetic chronic kidney disease. The Editors Mild to moderate reductions in kidney function are associated with a marked increase in the risk for cardiovascular disease (CVD) (14). Assessing the degree of kidney function is now recognized as an important component of risk stratification for CVD morbidity and mortality. Cystatin C is a novel measure of kidney function (5, 6) that seems to be less sensitive than creatinine to factors other than glomerular filtration rate (GFR), particularly muscle mass (7). Thus, the serum cystatin C level may be a better marker of kidney function than the serum creatinine concentration, especially in elderly persons and in the setting of mild kidney dysfunction (8, 9). Cystatin C is easily measured in serum, making it a practical alternative to measured GFR, which is too cumbersome for clinical practice. Studies in elderly persons suggest that the cystatin C level has a stronger association with CVD events than do creatinine concentration and GFR estimated from serum creatinine (1012). No study has compared cystatin C and serum creatinine as risk factors for outcomes in persons with established chronic kidney disease (CKD). Furthermore, no study has compared outcomes on the basis of cystatin C level versus measured GFR, the gold standard for measurement of kidney function. We examined the associations of cystatin C level, creatinine concentration, and measured GFR with all-cause and CVD mortality and kidney failure in patients with CKD stages 3 to 4. Methods Study Sample The Modification of Diet in Renal Disease (MDRD) Study, conducted from 1989 to 1993, was a randomized, controlled trial of the effect of dietary protein restriction and blood pressure control on the progression of kidney disease (13). In brief, 840 patients with predominantly nondiabetic kidney disease and reduced GFR were included in the MDRD Study. Key inclusion criteria were age 18 to 70 years and a serum creatinine concentration of 106.08 to 618.81 mol/L (1.2 to 7.0 mg/dL) in women and 123.76 to 618.81 mol/L (1.4 to 7.0 mg/dL) in men. Glomerular filtration rate was measured at screening and again after a 3-month baseline period, during which patients were instructed about the study procedures, dietary protein intake, and control of blood pressure. We use the term screening GFR to refer to the first baseline GFR for screening and the term 3-month baseline GFR to refer to the GFR measured at the end of the 3-month baseline period. The range of screening GFR (10 to 65 mL/min per 1.73 m2) was less restrictive than the range for 3-month baseline GFR (13 to 55 mL/min per 1.73 m2). Patients were eligible for study A if their 3-month baseline GFR was 25 to 55 mL/min per 1.73 m2 and for study B if it was 13 to 24 mL/min per 1.73 m2. Patients in studies A and B were combined for the current analyses. Because the measured GFR ranged from 13 to 55 mL/min per 1.73 m2, with 6% of the cohort having a GFR less than 15 mL/min per 1.73 m2, the study sample consists predominantly of patients with stage 3 or 4 CKD, as defined by the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (14). Baseline Measurement of Kidney Function Glomerular filtration rate was measured by using iothalamate clearance (15). After subcutaneous injection of 125I-iothalamate, investigators collected 4 consecutive urine and 5 serum samples after an equilibration period of 1 hour. Measurements of serum and urine radioactivity were performed at the central MDRD Study laboratory. Glomerular filtration rate was calculated as the time-weighted averages of urine excretion rates and the serum concentration of the marker over the collection periods and was adjusted for body surface area. Estimated GFR was calculated from baseline serum creatinine concentration by using the 4-variable MDRD Study equation: 186.3(serum creatinine concentration1.154)(age0.203)1.212 (if black)0.742 (if female) (16). Serum creatinine was measured at baseline at the Cleveland Clinic Foundation, Cleveland, Ohio, by using the kinetic alkaline picrate assay on a Beckman Astra CX3 (Beckman, Fullerton, California). Cystatin C was measured in frozen samples collected at baseline from 825 participants of the MDRD Study. Samples were assayed for cystatin C by using a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring, Deerfield, Illinois). Measurement of a quality control specimen was included in each analytic run. Calculation of the SD and the coefficient of variation demonstrated an interrun precision for the assay of 5.6% (mean cystatin C level, 1.62 mg/L [SD, 0.09]; n= 14). Outcomes We assessed 4 outcomes: all-cause mortality, CVD mortality, kidney failure (the need for renal replacement therapy with dialysis or transplantation), and a composite outcome of kidney failure and all-cause mortality. We ascertained survival status and cause of death from the National Death Index and ascribed deaths to CVD if the primary cause of death was International Classification of Diseases, Ninth Revision, codes 390 to 459 or if kidney disease was listed as the primary cause of death and CVD was the secondary cause. We defined survival time as the time from randomization to death or end of follow-up (31 December 2000). We obtained kidney failure outcomes from the U.S. Renal Data System. The institutional review boards of The Cleveland Clinic, Cleveland, Ohio, and TuftsNew England Medical Center, Boston, Massachusetts, approved the data collection procedures. Statistical Analysis We compared baseline characteristics of the study sample across quartiles of serum cystatin C values and calculated P values for linear trend. We also compared baseline characteristics across quartiles of estimated GFR (Appendix Table). Because serum cystatin C and creatinine vary as the inverse of GFR, we used the inverse of serum cystatin C (1/cystatin C) and creatinine (1/creatinine) to facilitate direct comparison with GFR. Pearson correlations were used to examine univariate associations among the 3 measures of kidney function. We calculated incidence rates for all-cause mortality, CVD mortality, and kidney failure by quartiles of each baseline measure of kidney function: 1/creatinine, GFR, estimated GFR, and 1/cystatin C. Appendix Table. Baseline Characteristics, by Quartile of Estimated Glomerular Filtration Rate* We compared the association of the baseline measures of kidney function with outcomes by using unadjusted and adjusted Cox proportional hazards models. Covariates specified a priori in the adjusted models were age, race, sex, smoking, history of diabetes and CVD, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and log-transformed proteinuria. Models for kidney failure and the composite outcome were adjusted for cause of kidney disease in addition to the previously listed covariates. The models for the mortality outcomes included patients with kidney failure and were censored only at death or the end of follow-up. The models for kidney failure and the composite outcome were censored at kidney failure, death, or the end of follow-up. We repeated the adjusted Cox models for each of the 4 outcomes after additional adjustment for log-transformed C-reactive protein (CRP) level. We entered the measures of kidney function as continuous variables (1/creatinine, GFR, and 1/cystatin) and calculated the hazard ratios and 95% CIs per 1-SD change in each measure to allow a standardized comparison across measures with the same scale. We tested for nonlinearity by examining the functional form of the relationship of all-cause mortality risk and CVD mortality risk versus each marker of kidney function as a continuous variable while controlling for the covariates by fitting a cubic smoothing spline. We tested proportional hazards assumptions by using log(log) survival plots and plots of Schoenfeld residuals versus survival time. We used S-Plus, version 6.2 (Insightful Corp., Seattle, Washington), and SPSS, version 14.0 (SPSS, Chicago, Illinois), to perform the statistical analyses. Additional Analyses We repeated the adjusted Cox models for each outcome by using 2 additional measures of kidney function. First, we used estimated GFR because measuring GFR is impractical in clinical practice and research settings and, hence, GFR estimated from the serum creatinine concentration is often used as a surrogate measure. Second, to reduce variability in GFR measurements, we used the average of 2 baseline iothalamate GFR measurements performed 3 months apart. Sensitivity Analyses Transformation of cystatin C and serum creatinine values may make the expressions of their effects relative to SDs less comparable than if no transformation had been performed. To address this issue, we repeated the unadjusted Cox models with hazard ratios comparing the 80th to the 20th percentile of decreasing kidney function. Because entry criteria into the MDRD Study were based on GFR values, the range of GFR, but not of cystatin C or creatinine, is artificially restricted by study design. To address this limitation, we performed 2 sets of sensitivity analyses. First, because study entry was based o

Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease

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.

Effect of a Very Low-Protein Diet on Outcomes: Long-term Follow-up of the Modification of Diet in Renal Disease (MDRD) Study

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.

Asymmetric Dimethylarginine and Mortality in Stages 3 to 4 Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, reduces bioavailability of nitric oxide and induces endothelial dysfunction. This dimethylated amino acid accumulates in chronic kidney disease and may be involved in the pathophysiology of cardiovascular disease (CVD) in this population. DESIGN, SETTINGS, PARTICIPANTS, & METHODS The Modification of Diet in Renal Disease Study was a randomized, controlled trial conducted between 1989 and 1993. We measured ADMA in frozen samples collected at baseline (n = 820) and obtained survival status, up to December 31, 2000, from the National Death Index. We examined the relationship of ADMA with prevalent CVD and performed multivariable Cox models to examine the relationship of ADMA with all-cause and CVD mortality. RESULTS Mean (SD) age was 52 (12) yr, GFR was 32 +/- 12 ml/min per 1.73 m(2), and ADMA was 0.70 +/- 0.25 micromol/L. A 1-SD increase in ADMA was associated with a 31% increased odds of prevalent CVD in an adjusted logistic regression model. During the 10-yr follow-up period, 202 (25%) participants died of any cause, 122 (15%) from CVD, and 545 (66%) reached kidney failure. In multivariable Cox models, a 1-SD increase in ADMA was associated with a 9% increased risk for all-cause and 19% increased risk for CVD mortality. CONCLUSIONS In this cohort of patients with predominantly nondiabetic, stages 3 to 4 chronic kidney disease, there was a strong association of ADMA with prevalent CVD and a modest association with all-cause and CVD mortality.

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of >60 ml/min per 1.73 m(2); 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m(2); 42 normotensive subjects with ADPKD and eGFR of >60 ml/min per 1.73 m(2); and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F(2α (8-epi-PGF2α)) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. RESULTS The hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of >60, and hypertensive ADPKD with eGFR of >60. The normotensive ADPKD eGFR >60, hypertensive ADPKD eGFR >60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF(2α) and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. CONCLUSIONS Inflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.

Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis

BackgroundIncreasing rates of resistant and multidrug-resistant (MDR) P. aeruginosa in hospitalized patients constitute a major public health threat. We present a systematic review of the clinical and economic impact of this resistant pathogen.MethodsStudies indexed in MEDLINE and Cochrane databases between January 2000-February 2013, and reported all-cause mortality, length of stay, hospital costs, readmission, or recurrence in at least 20 hospitalized patients with laboratory confirmed resistant P. aeruginosa infection were included. We accepted individual study definitions of MDR, and assessed study methodological quality.ResultsThe most common definition of MDR was resistance to more than one agent in three or more categories of antibiotics. Twenty-three studies (7,881 patients with susceptible P. aeruginosa, 1,653 with resistant P. aeruginosa, 559 with MDR P. aeruginosa, 387 non-infected patients without P. aeruginosa) were analyzed. A random effects model meta-analysis was feasible for the endpoint of all-cause in-hospital mortality. All-cause mortality was 34% (95% confidence interval (CI) 27% – 41%) in patients with any resistant P. aeruginosa compared to 22% (95% CI 14% – 29%) with susceptible P. aeruginosa. The meta-analysis demonstrated a > 2-fold increased risk of mortality with MDR P. aeruginosa (relative risk (RR) 2.34, 95% CI 1.53 – 3.57) and a 24% increased risk with resistant P. aeruginosa (RR 1.24, 95% CI 1.11 – 1.38), compared to susceptible P. aeruginosa. An adjusted meta-analysis of data from seven studies demonstrated a statistically non-significant increased risk of mortality in patients with any resistant P. aeruginosa (adjusted RR 1.24, 95% CI 0.98 – 1.57). All three studies that reported infection-related mortality found a statistically significantly increased risk in patients with MDR P. aeruginosa compared to those with susceptible P. aeruginosa. Across studies, hospital length of stay (LOS) was higher in patients with resistant and MDR P. aeruginosa infections, compared to susceptible P. aeruginosa and control patients. Limitations included heterogeneity in MDR definition, restriction to nosocomial infections, and potential confounding in analyses.ConclusionsHospitalized patients with resistant and MDR P. aeruginosa infections appear to have increased all-cause mortality and LOS. The negative clinical and economic impact of these pathogens warrants in-depth evaluation of optimal infection prevention and stewardship strategies.

Filtration Markers May Have Prognostic Value Independent of Glomerular Filtration Rate

Serum levels of creatinine, cystatin C, or β trace protein allow estimation of GFR, but whether these markers contribute additional prognostic information beyond that reflected in GFR is unknown. Here, we analyzed data from the Modification of Diet in Renal Disease study, which provided baseline levels of these markers for 816 participants with a median follow-up of 16.6 years. We examined associations between the reciprocals of these filtration markers and (125)I iothalamate GFR, expressed per SD, with kidney failure and mortality. In univariate analysis, lower GFR and higher levels of each filtration marker associated with a higher risk for all outcomes. After adjustment for GFR in a Cox proportional hazards model, higher creatinine associated with a higher risk for kidney failure but a lower risk for all-cause mortality. Higher cystatin C and β trace protein associated with a higher risk for both kidney failure and all-cause mortality. In models including either cystatin C or β trace protein, the association of GFR with all-cause mortality was no longer significant after the addition of the filtration marker, suggesting the possibility of multicollinearity. In summary, after adjustment for GFR, levels of creatinine, cystatin C, and β trace protein, each remained directly associated with kidney failure but differed with respect to their associations with mortality. These differences may be a result of non-GFR-related associations of filtration markers, residual confounding by GFR, or collinearity between the filtration markers and GFR. β trace protein and cystatin C seem to provide more consistent prognostic information than creatinine.