OBJECTIVES: To assess whether chronic kidney disease (CKD) is independently associated with incident physical‐function limitation.
DESIGN: Prospective cohort study.
SETTING: Two sites: Pittsburgh, ...Pennsylvania, and Memphis, Tennessee.
PARTICIPANTS: Two thousand one hundred thirty‐five men and women aged 70 to 79 without functional limitation at baseline from the Health, Aging and Body Composition Study.
MEASUREMENTS: Functional limitation was defined as difficulty in walking one‐quarter of a mile or climbing 10 steps on two consecutive reports 6 months apart (in the same function). Kidney function was measured using serum cystatin C. Estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula (<60 versus ≥60 mL/min per 1.73 m2), was a secondary predictor. Muscle strength, lean body mass according to dual energy x‐ray absorptiometry, comorbidity, medication use, and inflammatory markers were evaluated as covariates.
RESULTS: Persons in the highest (≥1.13 mg/L) quartile of cystatin C experienced a significantly higher risk of developing functional limitation than those in the lowest (<0.86 mg/L) quartile (hazard ratio (HR)=1.70, 95% confidence interval (CI)=1.40–2.07). The association between the fourth cystatin C quartile and functional limitation remained after adjustment for demographics, lean body mass, comorbidity, muscle strength, and gait speed (HR=1.41, 95% CI=1.13–1.75), although the association was attenuated after adjustment for markers of inflammation (HR=1.15, 95% CI=0.90–1.46). Similar results were found for eGFR less than 60 mL/min per 1.73 m2, although the association with functional limitation remained after adjustment for inflammatory markers (HR=1.30, 95% CI=1.08–1.56).
CONCLUSION: CKD is associated with the development of functional impairment independent of comorbidity, body composition, and tests of strength and physical performance. The mechanism may be related to a heightened inflammatory state in CKD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background Infection is a common cause of hospitalization in adults receiving hemodialysis. Limited data are available about downstream events resulting from or following these hospitalizations. ...Study Design Retrospective cohort study using the US Renal Data System. Setting & Participants Medicare beneficiaries initiating in-center hemodialysis therapy in 2005 to 2008. Factors Demographics, dual Medicare/Medicaid eligibility, body mass index, comorbid conditions, initial vascular access type, nephrology care prior to dialysis therapy initiation, residence in a care facility, tobacco use, biochemical measures, and type of infection. Outcomes 30-day hospital readmission or death following first infection-related hospitalization. Results 60,270 Medicare beneficiaries had at least one hospitalization for infection. Of those who survived the initial hospitalization, 15,113 (27%) were readmitted and survived the 30 days following hospital discharge, 1,624 (3%) were readmitted to the hospital and then died within 30 days of discharge, and 2,425 (4%) died without hospital readmission. Complications related to dialysis access, sepsis, and heart failure accounted for 12%, 9%, and 7% of hospital readmissions, respectively. Factors associated with higher odds of 30-day readmission or death without readmission included non-Hispanic ethnicity, lower serum albumin level, inability to ambulate or transfer, limited nephrology care prior to dialysis therapy, and specific types of infection. In comparison, older age, select comorbid conditions, and institutionalization had stronger associations with death without readmission than with readmission. Limitations Findings limited to Medicare beneficiaries receiving in-center hemodialysis. Conclusions Hospitalizations for infection among patients receiving in-center hemodialysis are associated with exceptionally high rates of 30-day hospital readmission and death without readmission.
Abstract Background Frailty is common in the elderly and in persons with chronic diseases. Few studies have examined the association of frailty with chronic kidney disease. Methods We used data from ...the Third National Health and Nutrition Examination Survey to estimate the prevalence of frailty among persons with chronic kidney disease. We created a definition of frailty based on established validated criteria, modified to accommodate available data. We used logistic regression to determine whether and to what degree stages of chronic kidney disease were associated with frailty. We also examined factors that might mediate the association between frailty and chronic kidney disease. Results The overall prevalence of frailty was 2.8%. However, among persons with moderate to severe chronic kidney disease (estimated glomerular filtration rate < 45 mL/min/1.73 m2 ), 20.9% were frail. The odds of frailty were significantly increased among all stages of chronic kidney disease, even after adjustment for the residual effects of age, sex, race, and prevalent chronic diseases. The odds of frailty associated with chronic kidney disease were only marginally attenuated with additional adjustment for sarcopenia, anemia, acidosis, inflammation, vitamin D deficiency, hypertension, and cardiovascular disease. Frailty and chronic kidney disease were independently associated with mortality. Conclusion Frailty is significantly associated with all stages of chronic kidney disease and particularly with moderate to severe chronic kidney disease. Potential mechanisms underlying the chronic kidney disease and frailty connection remain elusive.
Background Impaired kidney function has been associated with increased risk for death, myocardial infarction, stroke, and heart failure in high-risk populations. We evaluated whether impaired kidney ...function predicted risk of fatal cardiovascular disease independent of prevalent and incident cardiovascular events. Methods The Health, Aging, and Body Composition study is a cohort of well-functioning, elderly participants aged 70 to 79 years at entry. We measured serum cystatin C and creatinine from baseline plasma samples of 3044 participants and followed them over 6 years, examining the associations among kidney function, cardiovascular death, and incident cardiovascular events. Cystatin C was categorized as low (<0.84 mg/L), medium (0.84-1.18 mg/L), or high (≥1.19 mg/L); serum creatinine (cutoff value of ≥1.3 in women and ≥1.5 in men) and estimated glomerular filtration rate (eGFR; greater and less than 60 mL/min per 1.73 m2 ) were dichotomized. Results During follow-up, 242 cardiovascular deaths occurred, of which 69 were in participants without prior cardiovascular events; 294 incident cardiovascular events occurred including 135 myocardial infarctions and 163 strokes. Higher cystatin C concentrations were significantly associated with cardiovascular death (adjusted hazard ratio HR 1.70, 95% confidence interval CI 1.05-2.76 for the medium cystatin C group; and HR 2.24, 95% CI 1.30-3.86 for the high cystatin C group, relative to the low cystatin C group). The point estimate was of greater magnitude in the analysis that excluded prevalent cardiovascular disease (adjusted HR 2.68, 95% CI 0.94-7.70 for the medium cystatin C group; and HR 4.91, 95% CI, 1.55-15.54 for the high cystatin C group). Elevated creatinine levels (adjusted HR 1.54, 95% CI 1.02-2.33, and HR 2.28, 95% CI 1.10-4.73 among participants without a history of cardiovascular disease) were also associated with cardiovascular death. No significant association was found between low eGFR and cardiovascular death. In addition, cystatin C, low eGFR, or elevated creatinine levels were not associated with other cardiovascular events. Conclusion Impaired kidney function is a strong predictor of cardiovascular death, particularly among participants without prior history of cardiovascular disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2–related factor 2 (Nrf2) activator, slows progression to end-stage ...renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention. Methods and Results We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to <30 mL min−1 1.73 m−2 ) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl– and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events. Conclusions Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background A well-accepted definition of frailty includes measurements of physical performance, which may limit its clinical utility. Study Design In a cross-sectional study, we compared prevalence ...and patient characteristics based on a frailty definition that uses self-reported function to the classic performance-based definition and developed a modified self-report−based definition. Setting & Participants Prevalent adult patients receiving hemodialysis in 14 centers around San Francisco and Atlanta in 2009-2011. Index Tests Self-report−based frailty definition in which a score lower than 75 on the Physical Function scale of the 36-Item Short Form Health Survey (SF-36) was substituted for gait speed and grip strength in the classic definition; modified self-report definition with optimized Physical Function score cutoff points derived in a development (one-half) cohort and validated in the other half. Reference Test Performance-based frailty defined as 3 of the following: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. Results 387 (53%) patients were frail based on self-reported function, of whom 209 (29% of the cohort) met the performance-based definition. Only 23 (3%) met the performance-based definition of frailty only. The self-report definition had 90% sensitivity, 64% specificity, 54% positive predictive value, 93% negative predictive value, and 72.5% overall accuracy. Intracellular water per kilogram of body weight and serum albumin, prealbumin, and creatinine levels were highest among nonfrail individuals, intermediate among those who were frail by self-report, and lowest among those who also were frail by performance. Age, percentage of body fat, and C-reactive protein level followed an opposite pattern. The modified self-report definition had better accuracy (84%; 95% CI, 79%-89%) and superior specificity (88%) and positive predictive value (67%). Limitations Our study did not address prediction of outcomes. Conclusions Patients who meet the self-report–based but not the performance-based definition of frailty may represent an intermediate phenotype. A modified self-report definition can improve the accuracy of a questionnaire-based method of defining frailty.
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).
We quantified serum TMAO by liquid chromatography and online tandem mass spectrometry and assessed nutritional and cardiovascular risk factors in 235 patients receiving HD 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.
Serum TMAO concentrations of patients undergoing HD (median, 43 μM/L; 25th-75th percentile, 28-67 μM/L) were elevated compared with those 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 <.001), prealbumin (Spearman rank correlation, 0.19; 95% CI, 0.07-0.31; P = .003), and creatinine (Spearman rank correlation, 0.21; 95% CI, 0.08-0.33; P = .002) and inversely correlated with log C-reactive protein (Spearman rank correlation, -0.18; 95% CI, -0.30 to -0.06; P = .005). Higher serum concentrations of TMAO were not significantly associated with time to death (Spearman rank correlation, 0.84; CI, 0.65-1.09; P = .19) or time to cardiovascular hospitalization or cardiovascular death (Spearman rank correlation, 0.88; CI, 0.57-1.35; P = .55).
Serum TMAO concentrations were markedly elevated and correlated directly with biochemical markers of nutritional status and inversely with markers of inflammation in patients receiving HD. There was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations. In patients receiving dialysis-in contrast with the general population-adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status.
Background Infection is an important cause of hospitalization and death in patients receiving dialysis. Few studies have examined the full range of infections experienced by dialysis patients. The ...purpose of this study is to examine types, rates, and risk factors for infection in older persons starting dialysis therapy. Study Design Retrospective observational cohort study. Setting & Participants The cohort was assembled from the US Renal Data System and included patients aged 65-100 years who initiated dialysis therapy between January 1, 2000, and December 31, 2002. Exclusions included prior kidney transplant, unknown dialysis modality, or death, loss to follow-up, or transplant during the first 90 days of dialysis therapy. Patients were followed up until death, transplant, or study end on December 31, 2004. Predictors Baseline demographics, comorbid conditions, and serum albumin and hemoglobin levels. Outcomes & Measurements Infection-related hospitalizations were ascertained using discharge International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) codes. Hospitalization rates were calculated for each type of infection. The Wei-Lin-Weissfeld model was used to examine risk factors for up to 4 infection-related events. Results 119,858 patients were included, 7,401 of whom were on peritoneal dialysis therapy. During a median follow-up of 1.9 years, infection-related diagnoses were observed in approximately 35% of all hospitalizations. Approximately 50% of patients had at least 1 infection-related hospitalization. Rates (per 100 person-years) of pulmonary, soft-tissue, and genitourinary infections ranged from 8.3-10.3 in patients on peritoneal dialysis therapy and 10.2-15.3 in patients on hemodialysis therapy. Risk factors for infection included older age, female sex, diabetes, heart failure, pulmonary disease, and low serum albumin level. Limitations Use of ICD-9-CM codes, reliance on Medicare claims to capture hospitalizations, use of the Medical Evidence Form to ascertain comorbid conditions, and absence of data for dialysis access. Conclusion Infection-related hospitalization is frequent in older patients on dialysis therapy. A broad range of infections, many unrelated to dialysis access, result in hospitalization in this population.
Background Few data are available regarding the long-term mortality rate for patients receiving nocturnal home hemodialysis. Study Design Posttrial observational study. Setting & Participants ...Frequent Hemodialysis Network (FHN) Nocturnal Trial participants who consented to extended follow-up. Intervention The FHN Nocturnal Trial randomly assigned 87 individuals to 6-times-weekly home nocturnal hemodialysis or 3-times-weekly hemodialysis for 1 year. Patients were enrolled starting in March 2006 and follow-up was completed by May 2010. After the 1-year trial concluded, FHN Nocturnal participants were free to modify their hemodialysis prescription. Outcomes & Measurements We obtained dates of death and kidney transplantation through July 2011 using linkage to the US Renal Data System and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment. Results Median follow-up for the trial and posttrial observational period was 3.7 years. In the nocturnal arm, there were 2 deaths during the 12-month trial period and an additional 12 deaths during the extended follow-up. In the conventional arm, the numbers of deaths were 1 and 4, respectively. In the nocturnal dialysis group, the overall mortality HR was 3.88 (95% CI, 1.27-11.79; P = 0.01). Using as-treated analysis with a 12-month running treatment average, the HR for mortality was 3.06 (95% CI, 1.11-8.43; P = 0.03). Six-month running treatment data analysis showed an HR of 1.12 (95% CI, 0.44-3.22; P = 0.7). Limitations These results should be interpreted cautiously due to a surprisingly low (0.03 deaths/patient-year) mortality rate for individuals randomly assigned to conventional home hemodialysis, low statistical power for the mortality comparison due to the small sample size, and the high rate of hemodialysis prescription changes. Conclusions Patients randomly assigned to nocturnal hemodialysis had a higher mortality rate than those randomly assigned to conventional dialysis. The implications of this result require further investigation.
Background Iron deficiency anemia and serum phosphate levels > 4.0 mg/dL are relatively common in chronic kidney disease stages 3 to 5 and are associated with higher risks of progressive loss of ...kidney function, cardiovascular events, and mortality. Study Design Double-blind, placebo-controlled, randomized trial. Setting & Participants 149 patients with estimated glomerular filtration rates < 60 mL/min/1.73 m2 , iron deficiency anemia (hemoglobin, 9.0-12.0 g/dL; transferrin saturation TSAT ≤ 30%, serum ferritin ≤ 300 ng/mL), and serum phosphate levels ≥ 4.0 to 6.0 mg/dL. Use of intravenous iron or erythropoiesis-stimulating agents was prohibited. Intervention Randomization to treatment for 12 weeks with ferric citrate coordination complex (ferric citrate) or placebo. Outcomes & Measurements Coprimary end points were change in TSAT and serum phosphate level from baseline to end of study. Secondary outcomes included change from baseline to end of treatment in values for ferritin, hemoglobin, intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and estimated glomerular filtration rate. Results Ferric citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32% ± 14% and reduced serum phosphate levels from 4.5 ± 0.6 to 3.9 ± 0.6 mg/dL, while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect on serum phosphate level (4.7 ± 0.6 to 4.4 ± 0.8 mg/dL; between-group P < 0.001 for each). Ferric citrate increased hemoglobin levels (from 10.5 ± 0.8 to 11.0 ± 1.0 g/dL; P < 0.001 vs placebo), reduced urinary phosphate excretion 39% ( P < 0.001 vs placebo), and reduced serum intact FGF-23 levels from a median of 159 (IQR, 102-289) to 105 (IQR, 65-187) pg/mL ( P = 0.02 vs placebo). The incidence and severity of adverse effects were similar between treatment arms. Limitations The study is limited by relatively small sample size and short duration and by having biochemical rather than clinical outcomes. Conclusions Short-term use of ferric citrate repletes iron stores, increases hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5.
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