Sex Differences in Cardiovascular Outcomes in CKD: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: Cardiovascular events are less common in women than men in general populations; however, studies in chronic kidney disease (CKD) are less conclusive. We evaluated sex-related differences in cardiovascular events and death in adults with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,778 women and 2,161 men enrolled in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURE: Sex (women vs men). OUTCOME: Atherosclerotic composite outcome (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: During a median follow-up period of 9.6 years, we observed 698 atherosclerotic events (women, 264; men, 434), 762 heart failure events (women, 331; men, 431), 435 cardiovascular deaths (women, 163; men, 274), and 1,158 deaths from any cause (women, 449; men, 709). In analyses adjusted for sociodemographic, clinical, and metabolic parameters, women had a lower risk of atherosclerotic events (HR, 0.71 [95% CI, 0.57-0.88]), heart failure (HR, 0.76 [95% CI, 0.62-0.93]), cardiovascular death (HR, 0.55 [95% CI, 0.42-0.72]), and death from any cause (HR, 0.58 [95% CI, 0.49-0.69]) compared with men. These associations remained statistically significant after adjusting for cardiac and inflammation biomarkers. LIMITATIONS: Assessment of sex hormones, which may play a role in cardiovascular risk, was not included. CONCLUSIONS: In a large, diverse cohort of adults with CKD, compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and mortality from any cause. These differences were not explained by measured cardiovascular risk factors.

Protein carbamylation and chronic kidney disease progression in the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established. METHODS: We conducted two nested case-control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study. RESULTS: At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9-32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0-11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN. CONCLUSIONS: Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation's association with mortality was smaller in this limited sample size.

Healthy lifestyle and risk of kidney disease progression, atherosclerotic events, and death in CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and cardiovascular events among adults with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: 4 lifestyle factors (regular physical activity, body mass index [BMI] of 20-<25kg/m(2), nonsmoking, and "healthy diet"), individually and in combination. OUTCOMES: CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. MEASUREMENTS: Multivariable-adjusted Cox proportional hazards. RESULTS: During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI≥25kg/m(2) and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 [95% CI, 0.58-0.97] and 0.61 [95% CI, 0.45-0.82] for BMIs of 25 to <30 and ≥30kg/m(2), respectively, versus 20 to <25kg/m(2); HR for nonsmoking of 0.68 [95% CI, 0.55-0.84] compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 [95% CI, 0.46-0.96] for BMI of 25-<30 vs 20-<25kg/m(2) and 0.55 [95% CI, 0.40-0.75] vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 [95% CI, 0.52-0.79] vs inactive), BMI≥30kg/m(2) (HR, 0.64 [95% CI, 0.43-0.96] vs 20-<25kg/m(2)), and nonsmoking (HR, 0.45 [95% CI, 0.34-0.60] vs current smoker). BMI<20kg/m(2) was associated with increased all-cause mortality risk (HR, 2.11 [95% CI, 1.13-3.93] vs 20-<25kg/m(2)). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). LIMITATIONS: Lifestyle factors were measured only once. CONCLUSIONS: Regular physical activity, nonsmoking, and BMI≥25kg/m(2) were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.

Are nutritional status indicators associated with mortality in the Hemodialysis (HEMO) Study?

BACKGROUND: The purpose of this study was to determine if indicators of nutritional status were associated with subsequent mortality in hemodialysis patients. METHODS: Twelve selected nutrition indicators were measured prior to randomization in the Mortality and Morbidity in Hemodialysis (HEMO) Study. Relative risks (RR) of mortality were assessed at <6 months and >6 months of follow-up using Cox regression after controlling for case mix, comorbidity, and treatment assignment (high vs. standard Kt/V and high vs. low membrane flux). RESULTS: Low values of most nutritional status indicators were associated with increased RR of mortality. RRs were greatest over the short term (<6 months) and diminished with increasing follow-up (>6 months). Increases in body mass index (BMI) at lower levels (e.g., < or =25 kg/m(2)) and increases in serum albumin at any level were associated with reduced short-term RR, even after adjusting for case mix, treatment assignment, and for the joint effects of equilibrated normalized protein catabolic rate, total cholesterol, and serum creatinine. For >6 months' follow-up, increases in values among those with lower levels of BMI and serum albumin (< or =3.635 g/dL) and increases in all serum creatinine levels were associated with lower RR. CONCLUSION: Nutrition indicators are associated with subsequent mortality in a time-dependent manner, with greatest effects at <6 months of follow-up. The RR for these indicators may also vary within different ranges of values.

Association of nutritional markers with physical and mental health status in prevalent hemodialysis patients from the HEMO study.

OBJECTIVE: To determine associations of potentially modifiable nutritional factors with physical and mental health status after adjusting for sociodemographic and comorbid conditions. DESIGN: Cross-sectional multivariable analysis. SETTING: Fifteen dialysis centers across the United States participating in the Reduction of Morbidity and Mortality Among Hemodialysis Patients (HEMO) study. PATIENTS: Enrollment of 1,545 prevalent hemodialysis subjects in the HEMO study. INDEPENDENT (PREDICTOR) VARIABLES: The following nutritional markers were assessed in this analysis: serum albumin, energy intake, protein catabolic rate, serum creatinine, midarm muscle circumference, calf circumference, and smoking status. Smoking status, although not a nutritional factor per se, was also included because it is a modifiable lifestyle factor. MAIN OUTCOME MEASURES: Physical and mental health status were assessed using the medical staff-assessed Karnofsky Index and the patient self-assessed Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: After adjusting for sociodemographic factors and comorbid conditions, serum albumin, serum creatinine, and calf circumference were independently associated with Karnofsky Index scores. Similarly, serum creatinine and calf circumference were also independently associated with the Physical Component Summary (PCS) score of the SF-36. Of the nutritional variables selected, no variables were significantly associated with the Mental Component Summary (MCS) score of the SF-36. CONCLUSIONS: Markers of poor nutrition were associated with decreased physical functioning scores, independent of case mix. Measures that improve nutrition may therefore have wide-reaching effects to improve not only morbidity and mortality but also health-related quality of life for patients with end-stage renal disease.

Nutritional status affects quality of life in Hemodialysis (HEMO) Study patients at baseline.

OBJECTIVE: To evaluate associations between frequently used indicators for assessing nutritional status and health-related quality of life in hemodialysis patients after controlling for demographics, comorbidity, and dialysis dose. DESIGN: Survey of 1,387 hemodialysis patients enrolled at baseline in the Hemodialysis (HEMO) Study. Nutritional status indicators included dietary energy intake, equilibrated normalized protein catabolic rate (enPCR), serum creatinine (SCr), serum albumin (SAlb), body mass index (BMI), calf circumference, and appetite. Health-related quality of life was measured by the Medical Outcomes Study Short Form-36 (MOS-SF-36) summary measures: the Physical Component Scale (PCS) and Mental Component Scale (MCS). SETTING: Fifteen clinical sites throughout the United States providing in-center hemodialysis. RESULTS: The mean PCS score was 36.1 +/- 10 SD, lower than normative data in healthy populations. PCS scores were lower among women, whites, and those with diabetes, severe comorbidities, and poor appetites. Appetite, dietary energy intake, SAlb, and SCr were strongly associated with PCS scores even after controlling for demographics and comorbidity. The sum of the parameter estimates for the effects of nutritional status on PCS was large, 7 points or more depending on the individual's nutritional status indicators. The mean MCS score was 49.7 +/- 10.1 SD, similar to scores in healthy populations, but lower among those with severe comorbidities, poor appetites, advanced age, and more years on dialysis. Appetite, age, and years on dialysis were significantly associated with MCS after controlling for other demographics and comorbidity. Dialysis dose did not significantly alter these relationships. CONCLUSION: Easy-to-use indicators for assessing nutritional status (appetite, energy intake, SAlb, and SCr) together are strongly associated with health-related quality of life, even after controlling for comorbidities and dose of dialysis in hemodialysis patients, providing an additional reason for maximizing patients' nutritional status and health.

Nutritional status assessed from anthropometric measures in the HEMO study.

OBJECTIVE: Anthropometric methods are screening techniques for assessing nutritional stores of fat and lean tissues among persons with renal disease. This report presents cross-sectional baseline data on anthropometric indicators of nutritional status from a group of hemodialysis patients in a multicenter clinical trial, the Hemodialysis (HEMO) Study. DESIGN: The HEMO Study is a prospective, multicenter, randomized, 2 x 2 factorial clinical trial to evaluate the efficacy of the delivered dose of dialysis, defined by Kt/V, and membrane flux in reducing morbidity and mortality in (maintenance) hemodialysis patients. Standardized measures of weight, stature, body mass index (BMI), arm and calf circumference, and triceps and subscapular skinfolds were taken immediately after dialysis. The analytic methods consisted of univariate statistics, including means, standard deviations, and selected percentiles presented as tables of descriptive statistics. Study findings were compared with corresponding national reference data from the Second National Health and Nutrition Examination Survey (NHANES II). PATIENTS: Eligible patients between 18 and 80 years of age on chronic hemodialysis for at least 3 months, receiving hemodialysis 3 times per week and with a residual renal clearance of < 1.5 mL/min were examined. Patients also had to be able to attain an eKt/V of > or = 1.45 in 4.5 hours or an anthropometric volume < 45 to 50 L thus excluding persons with body weights over about 85 kg. The study sample consisted of the first 1,000 randomized patients, 464 men and 536 women; 642 blacks, 318 whites; and 40 of other racial backgrounds out of 1,847 randomized. RESULTS: Differences in nutritional status by sex, race, duration of dialysis, and comorbid disease were found among these patients enrolled in the HEMO Study. In comparison with NHANES II, these hemodialysis patients were, on average, lighter with less adipose and muscle tissue than healthy persons of the same ages. These findings can be indicators of persons with chronic disease. Those with diabetes were overweight based on their BMI values. CONCLUSION: These HEMO Study data provide a clinical reference for the use of these anthropometric indicators in assessing the nutritional status of contemporary hemodialysis patients weighing < 85 kg.