Background In light of the recent trend toward earlier dialysis initiation and its association with mortality among patients with end-stage renal disease, we hypothesized that frailty is associated with higher estimated glomerular filtration rate (eGFR) at dialysis start and may confound the relation between earlier dialysis initiation and mortality. Methods We examined frailty among participants of the Comprehensive Dialysis Study (CDS), a special study of the US Renal Data System, which enrolled incident patients from September 1, 2005, through June 1, 2007. Patients were followed for vital status through September 30, 2009, and for time to first hospitalization through December 31, 2008. We used multivariate logistic regression to model the association of frailty with eGFR at dialysis start and proportional hazards regression to assess the outcomes of death or hospitalization. Results Among 1576 CDS participants included, the prevalence of frailty was 73%. In multivariate analysis, higher eGFR at dialysis initiation was associated with higher odds of frailty (odds ratio [OR], 1.44 [95% CI, 1.23–1.68] per 5 mL/min/1.73 m2; P<.001). Frailty was independently associated with mortality (hazard ratio [HR], 1.57 [95% CI, 1.25–1.97]; P<.001) and time to first hospitalization (HR, 1.26 [95% CI, 1.09–1.45]; P<.001). While higher eGFR at dialysis initiation was associated with mortality (HR, 1.12 [95% CI, 1.02–1.23] per 5 mL/min/1.73 m2; P=.02), the association was no longer statistically significant after frailty was accounted for (HR, 1.08 [95% CI, 0.98–1.19] per 5 mL/min/1.73 m2; P=.11). Conclusions Frailty is extremely common among patients starting dialysis in the United States and is associated with higher eGFR at dialysis initiation. Recognition of signs and symptoms of frailty by clinicians may prompt earlier initiation of dialysis and may explain, at least in part, the well-described association between eGFR at dialysis initiation and mortality.

The objectives of this review were (1) to review recent literature on the rates, risk factors, and outcomes of infections in patients who had chronic kidney disease (CKD) and did or did not require renal replacement therapy; (2) to review literature on the efficacy and use of selected vaccines for patients with CKD; and (3) to outline a research framework for examining key issues regarding infections in patients with CKD. Infection-related hospitalizations contribute substantially to excess morbidity and mortality in patients with ESRD, and infection is the second leading cause of death in this population. Patients who have CKD and do not require renal replacement therapy seem to be at higher risk for infection compared with patients without CKD; however, data about patients who have CKD and do not require dialysis therapy are very limited. Numerous factors potentially predispose patients with CKD to infection: advanced age, presence of coexisting illnesses, vaccine hyporesponsiveness, immunosuppressive therapy, uremia, dialysis access, and the dialysis procedure. Targeted vaccination seems to have variable efficacy in the setting of CKD and is generally underused in this population. In conclusion, infection is a primary issue when caring for patients who receive maintenance dialysis. Very limited data exist about the rates, risk factors, and outcomes of infection in patients who have CKD and do not require dialysis. Future research is needed to delineate accurately the epidemiology of infections in these populations and to develop effective preventive strategies across the spectrum of CKD severity.

Background Trimethylamine-N-oxide (TMAO) is a product of metabolism of phosphatidylcholine (lecithin) and carnitine by the intestinal microbiome. Elevated serum concentrations of TMAO have been linked to adverse cardiovascular outcomes in the general population. We examined correlates of serum TMAO and the relations among serum TMAO concentrations, all-cause mortality and cardiovascular mortality and hospitalizations in a nationally derived cohort of patients new to hemodialysis (HD). Methods We quantified serum TMAO by liquid chromatography and online tandem mass spectrometry and assessed nutritional and cardiovascular risk factors in 235 patients receiving hemodialysis and measured TMAO in pooled serum from healthy controls. We analyzed time to death and time to cardiovascular death or hospitalization using Cox proportional hazards regression. Results Serum TMAO concentrations (median 43, (25th – 75th percentile 28–67 µM/L) were elevated compared to persons with normal or near normal kidney function (1.41 ± 0.49 µM/L). TMAO was directly correlated with serum albumin (Spearman rank correlation 0.24, 95% CI 0.12, 0.35; P < 0.001), prealbumin (0.19, 95% CI 0.07, 0.31; P =0.003), and creatinine (0.21, 95% CI 0.08, 0.33; P =0.002), and inversely correlated with log CRP (−0.18, 95% CI −0.30, – 0.06; P =0.005). Higher serum concentrations of TMAO were not significantly associated with time to death (0.84, CI 0.65, 1.09 P=0.19) or time to cardiovascular hospitalization or cardiovascular death (0.88, CI 0.57, 1.35 P =0.55). Conclusions Serum TMAO concentrations were markedly elevated and correlated directly with biochemical markers of nutritional status and inversely with markers of inflammation in patients receiving hemodialysis. There was no significant association between serum TMAO concentrations and all-cause mortality or cardiovascular death or hospitalizations. In patients receiving dialysis – in contrast to the general population – adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status.

BACKGROUNDAmong older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.OBJECTIVETo compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.DesignThe CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.PARTICIPANTS1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.MAIN MEASURESThe outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.KEY RESULTSDuring 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.CONCLUSIONSOlder adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

Studies of frailty among patients on hemodialysis have relied on definitions that substitute self-reported functioning for measures of physical performance and omit weight loss or substitute alternate criteria. We examined the association between body composition and a definition of frailty that includes measured physical performance and weight loss in a cross-sectional analysis of 638 adult patients receiving maintenance hemodialysis at 14 centers. Frailty was defined as having three of following characteristics: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. We performed logistic regression with body mass index (BMI) and bioelectrical impedance spectroscopy (BIS)-derived estimates of intracellular water (ICW), fat mass, and extracellular water (ECW) as the main predictors, and age, sex, race, and comorbidity as covariates. Overall, 30% of participants were frail. Older age (odds ratio [OR], 1.31 per 10 years; 95% confidence interval [95% CI], 1.14 to 1.50), diabetes (OR, 1.65; 95% CI, 1.13 to 2.40), higher fat mass (OR, 1.18; 95% CI, 1.02 to 1.37), and higher ECW (OR, 1.33; 95% CI, 1.20 to 1.47) associated with higher odds of frailty. Higher ICW associated with lower odds of frailty (OR, 0.80 per kg; 95% CI, 0.73 to 0.87). The addition of BMI data did not change the area under the receiver operating characteristics curve (AUC; AUC=0.66 versus 0.66; P=0.71), but the addition of BIS data did change the AUC (AUC=0.72; P,0.001). Thus, individual components of body composition but not BMI associate strongly with frailty in this cohort of patients receiving hemodialysis.

Physical inactivity contributes to the frailty and the decline in function that develops over time among patients with end-stage renal disease. We assessed physical activity among 1547 ambulatory patients new to dialysis in the United States Renal Data System Comprehensive Dialysis Study. We used a self-reporting Human Activity Profile that included Maximal and Adjusted Activity Scores and compared results to established norms by age and gender. Physical activity was found to be extremely low with scores for all age and gender categories below the 5th percentile of healthy individuals and 95% of patients had scores consonant with low fitness. Older age, female gender, diabetes, atherosclerotic disease, and a low level of education were associated with lower activity scores assessed by univariate and multivariable linear regression analysis. Higher serum albumin, creatinine, and lower body mass index, but not hemoglobin levels, were associated with greater physical activity. By multivariable analysis, patients on hemodialysis using a catheter reported lower levels of physical activity compared to those on peritoneal dialysis, hemodialysis using an arteriovenous fistula, or with a graft. Lower Maximal and Adjusted Activity Scores were associated with poor physical function and mental health. Hence, physical activity is distressingly low among patients new to dialysis. Thus, strategies to enhance activity in these patients should be explored.

SummaryBackground and objectives Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants.Design, setting, participants, & measurements CHS enrolled community-dwelling adults age $65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR cys ). Secondary analyses examined eGFR using serum creatinine (eGFR SCr ). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity.Results The mean age was 75 years and the median eGFR cys was 73 ml/min per 1.73 m 2 . Among participants with an eGFR cys ,45 ml/min per 1.73 m 2 , 24% had prevalent frailty. In multivariable analysis and compared with eGFR cys $90 ml/min per 1.73 m 2 , eGFR cys categories of 45-59 (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR cys categories of 60-75 (incidence rate ratio [IRR], 1.72; 95% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95% CI, 0.90 to 2.60) was not. Lower levels of eGFR SCr were not associated with higher risk of prevalent or incident frailty.Conclusions In community-dwelling elders, lower eGFR cys was associated with a higher risk of prevalent and incident frailty whereas lower eGFR SCr was not. These findings highlight the importance of considering non-GFR determinants of kidney function.

BACKGROUND Physical activity promotes diverse metabolic benefits that may moderate the long-term risk of progressive kidney dysfunction. OBJECTIVE To test the hypothesis that greater physical activity is associated with a lower risk of rapid kidney function decline among a general population of older adults. DESIGN Prospective cohort study of community-dwelling older men and women. SETTING Community-based sample in 4 U.S. sites recruited from Medicare eligibility files. PARTICIPANTS A total of 5888 men and women aged 65 years or older participating in the Cardiovascular Health Study. Participants who did not complete at least two measurements of kidney function, those who were unable to complete basic household chores, and those with missing physical activity data were excluded, leaving 4011 participants for analysis. MAIN EXPOSURE MEASURE Physical activity score calculated by summation of leisure-time activity (ordinal score of 1–5 for quintiles of 105, 480, 1012.5, and 2089 kilocalories per week) and walking pace (ordinal score of 1–3 for categories of less than 2, 2–3, and greater than 3 miles per hour). MAIN OUTCOME MEASURE Rapid kidney function decline, defined by the loss of >3.0 mL/min per 1.73 m2 per year in the estimated glomerular filtration rate, calculated using longitudinal serum measurements of cystatin C. RESULTS There were 958 participants (23.9%) with a rapid decline in kidney function, (4.1 events per 100 person-years). The estimated risk of rapid kidney function decline was 16% in the highest physical activity group and 30% in the lowest physical activity group. After full adjustment for demographics, clinical, and subclinical disease characteristics, the two highest physical activity groups were associated with a 28% lower (95% CI: 21% to 41% lower) risk of rapid kidney function decline, compared to the two lowest physical activity groups. Greater kilocalories of leisure time physical activity, walking pace, and exercise intensity were each also associated with a lower incidence of rapid kidney function decline. CONCLUSION Greater physical activity is associated with a lower risk of rapid kidney function decline among older adults.