Cystatin C and Creatinine Concentrations Are Uninformative Biomarkers of Sarcopenia: A Cross-Sectional NHANES Study.

OBJECTIVES: Differences in creatinine and cystatin C-based estimates of glomerular filtration rate (eGFRDiff = eGFRCr - eGFRCysC) may reflect differences in muscle mass. We sought to determine if eGFRDiff (1) reflects lean mass, (2) identifies sarcopenic individuals beyond estimates based on age, body mass index (BMI), and sex; and (3) demonstrates associations differently in those with and without chronic kidney disease (CKD). DESIGN AND METHODS: This cross-sectional study included 3,754 participants, ages 20-85 years, with creatinine and cystatin C concentration levels, and dual-energy X-ray absorptiometry scans from National Health and Nutrition Examination Survey data (1999-2006). Dual-energy X-ray absorptiometry-derived appendicular lean mass index (ALMI) estimated muscle mass. Non-race-based CKD Epidemiology Collaboration equations estimated glomerular filtration rate using eGFRCr, eGFRCysC, and both biomarkers (eGFRCysC&Cr). CKD was defined as eGFRCysC&Cr <60 mL/minute/1.73 m2. ALMI sex-specific T-scores (compared with young adult) < -2.0 defined sarcopenia. In estimating ALMI, we compared the coefficient of determination (R2) values from: 1) eGFRDiff, 2) clinical characteristics (age, BMI, and sex), and 3) clinical characteristics plus eGFRDiff. Using logistic regression, we evaluated each model's C-statistic to diagnose sarcopenia. RESULTS: eGFRDiff was negatively and weakly associated with ALMI (No CKD: R2 = 0.006, p-value 0.002; CKD: R2 = 0.001, P value .9). Clinical characteristics explained most of the variation in ALMI (No CKD: R2 = 0.851, CKD: R2 = 0.828), and provided strong discrimination of sarcopenia (No CKD C-statistic: 0.950; CKD C-statistic: 0.943). Adding eGFRDiff improved the R2 by 0.025, and the C-statistic by 0.003. Tests for interaction between eGFRDiff and CKD were not significant (all P values > .05). CONCLUSIONS: Although eGFRDiff has statistically significant associations with ALMI and sarcopenia in univariate analyses, multivariate analyses demonstrate that eGFRDiff does not capture more information beyond routine clinical characteristics (age, BMI, and sex).

Association between cause of kidney failure and fracture incidence in a national US dialysis population cohort study.

Background: Whether fracture rates, overall and by fracture site, vary by cause of kidney failure in patients receiving dialysis is unknown. Methods: Using the US Renal Data System, we compared fracture rates across seven causes of kidney failure in patients who started dialysis between 1997 and 2014. We computed unadjusted and multivariable adjusted proportional sub-distribution hazard models, with fracture events (overall, and by site) as the outcome and immunoglobulin A nephropathy as the reference group. Kidney transplantation and death were competing events. Results: Among 491 496 individuals, with a median follow-up of 2.0 (25%, 75% range 0.9-3.9) years, 62 954 (12.8%) experienced at least one fracture. Patients with diabetic nephropathy, vasculitis or autosomal polycystic kidney disease (ADPKD) had the highest (50, 46 and 40 per 1000 person-years, respectively), and patient with lupus nephritis had the lowest (20 per 1000 person-years) fracture rates. After multivariable adjustment, diabetic nephropathy [hazard ratio (HR) 1.43, 95% confidence interval 1.33-1.53], ADPKD (HR 1.37, 1.26-1.48), vasculitis (HR 1.22, 1.09-1.34), membranous nephropathy (HR 1.16, 1.02-1.30) and focal segmental glomerulosclerosis (FSGS) (HR 1.13, 1.02-1.24) were associated with a significantly higher, and lupus nephritis with a significantly lower (HR 0.85, 0.71-0.98) fracture hazard. The hazards for upper extremity and lower leg fractures were significantly higher in diabetic nephropathy, ADPKD, FSGS and membranous nephropathy, while the hazard for vertebral fracture was significantly higher in vasculitis. Our findings were limited by the lack of data on medication use and whether fractures were traumatic or non-traumatic, among other factors. Conclusions: Fracture risk, overall and by fracture site, varies by cause of end-stage kidney disease. Future work to determine underlying pathogenic mechanisms contributing to differential risks might inform more tailored treatment strategies. Our study was limited by lack of data regarding numerous potential confounders or mediators including medications and measures or bone biomarkers.

Group-Based Exercise in CKD Stage 3b to 4: A Randomized Clinical Trial.

RATIONALE & OBJECTIVE: We aimed to test interventions to improve physical activity in persons with advanced chronic kidney disease not yet receiving dialysis. STUDY DESIGN: Randomized controlled trial with parallel-group design. SETTING & PARTICIPANTS: We embedded a pragmatic referral to exercise programming in high-volume kidney clinics servicing diverse populations in San Jose, CA, and Atlanta, GA. We recruited 56 participants with estimated glomerular filtration rates < 45 mL/min/1.73 m2. INTERVENTIONS: We randomly assigned participants to a mobile health (mHealth) group-wearable activity trackers and fitness professional counseling, or an Exercise is Medicine intervention framework (EIM) group-mHealth components plus twice-weekly small-group directed exercise sessions customized to persons with kidney disease. We performed assessments at baseline, 8 weeks at the end of active intervention, and 16 weeks after passive follow-up and used multilevel mixed models to assess between-group differences. OUTCOMES: Activity tracker total daily step count. RESULTS: Of 56 participants, 86% belonged to a racial/ethnic minority group; randomly assigned groups were well balanced on baseline step count. In intention-to-treat analyses, the EIM and mHealth groups both experienced declines in daily step counts, but there was an attenuated reduction in light intensity physical activity (standard error 0.2 [5.8] vs -8.5 [5.4] min/d; P = 0.08) in the EIM compared with the mHealth group at 8 weeks. In as-treated analyses, total daily step count, distance covered, and light and moderate-vigorous activity minutes per day improved in the EIM group and declined in the mHealth group at 8 weeks (standard error +335 [506] vs -884 [340] steps per day; P = 0.05; P < 0.05 for secondary measures), but group differences faded at 16 weeks. There were no differences in quality-of-life and mental health measures during the study. LIMITATIONS: Small sample size, limited duration of study, assessment of intermediate outcomes (steps per day). CONCLUSIONS: A clinic-integrated referral to small-group exercise sessions is feasible, safe, and moderately effective in improving physical activity in an underserved population with high comorbid conditions. FUNDING: Normon S Coplon Applied Pragmatic Clinical Research program. TRIAL REGISTRATION: NCT03311763.

Perceptions of physical activity and technology enabled exercise interventions among people with advanced chronic kidney disease: a qualitative study.

BACKGROUND: Exercise improves health outcomes and quality of life in persons with chronic kidney disease (CKD). The numbers of persons with advanced CKD meeting physical activity guidelines however is low. We undertook a qualitative study of men and women aged 36-74 from various race/ethnic populations with advanced CKD not requiring dialysis to describe their experiences and opinions around prior physical activity, motivating factors for and barriers to exercise, and perceptions of exercise-promoting technology and group-based programming designed to improve physical activity levels. METHODS: Nineteen persons with advanced CKD not requiring dialysis were interviewed at two high volume nephrology clinics enriched with racial/ethnic minority patients (Emory University and Santa Clara Valley Medical Center). We used thematic analysis to identify dominant themes (n = 4) and subthemes (n = 19) around exercise experience, barriers, motivators, views, and preferences. RESULTS: Four dominant themes and 19 subthemes were identified. The most common motivators to exercise included physical and mental health benefits, appearance, improvement in energy levels, and potential social interaction in group-based programs. Common barriers included health concerns, particularly complications related to other co-morbidities, as well as time and transportation constraints. Participants were skeptical of exercise programs solely reliant on technology. CONCLUSIONS: The use of group-based exercise programs may motivate persons with CKD to increase exercise levels, while programs entirely based on technology may be less effective.

Changes in Body Composition, Muscle Strength, and Fat Distribution Following Kidney Transplantation.

RATIONALE & OBJECTIVE: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania. EXPOSURE: Kidney transplantation. OUTCOME: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALMFMI) is an established index of relative sarcopenia. ANALYTICAL APPROACH: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls. RESULTS: At transplantation, ALMI, ALMIFMI, muscle strength, and muscle density z scores were lower versus controls (all P≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P<0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMIFMI deficits (mean z score of-0.31 at 24 months; P=0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P=0.02). Muscle strength relative to ALMI also improved (P=0.04) but remained low compared with controls (P=0.01). Exercise increased in the early months after transplantation (P<0.05) but remained lower than controls (P = 0.02). LIMITATIONS: Lack of muscle biopsies precluded assessment of muscle histology and metabolism. CONCLUSIONS: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia.

Validation of a description of sarcopenic obesity defined as excess adiposity and low lean mass relative to adiposity.

BACKGROUND: This study aims to assess the construct validity of a body composition-defined definition of sarcopenic obesity based on low appendicular lean mass relative to fat mass (ALMIFMI ) and high fat mass index (FMI) and to compare with an alternative definition using appendicular lean mass index (ALMI) and percent body fat (%BF). METHODS: This is a secondary analysis of two cohort studies: the National Health and Examination Survey (NHANES) and the Health, Aging, and Body Composition study (Health ABC). Sarcopenic obesity was defined as low ALMIFMI combined with high FMI and was compared with a widely used definition based on ALMI and %BF cut-points. Body composition Z-scores, self-reported disability, physical functioning, and incident disability were compared across body composition categories using linear and logistic regression and Cox proportional hazards models. RESULTS: Among 14, 850 participants from NHANES, patients with sarcopenic obesity defined by low ALMIFMI and high FMI (ALMIFMI -FMI) had above-average FMI Z-scores [mean (standard deviation): 1.00 (0.72)]. In contrast, those with sarcopenic obesity based on low ALMI and high %BF (ALMI-%BF) had below-average FMI Z-scores. A similar pattern was observed for 2846 participants from Health ABC. Participants with sarcopenic obesity based on ALMIFMI -FMI had a greater number of disabilities, worse physical function, and a greater risk of incident disability compared with those defined based on ALMI-%BF. CONCLUSIONS: Body composition-defined measures of sarcopenic obesity defined as excess adiposity and lower-than-expected ALMI relative to FMI are associated with functional deficits and incident disability and overcome the limitations of using %BF in estimating obesity in this context.

Effects of Weight History on the Association Between Directly Measured Adiposity and Mortality in Older Adults.

BACKGROUND: It is controversial whether an altered relationship between adiposity and mortality occurs with aging. We evaluated associations between adiposity and mortality in younger and older participants before and after considering historical weight loss. METHODS: This study used whole-body dual-energy x-ray absorptiometry data from the National Health and Nutrition Examination Survey in adults at least 20 years of age. Fat mass index (FMI), determined by dual-energy x-ray absorptiometry, was converted to age-, sex-, and race-specific Z-Scores. Percent change in weight from the maximum reported weight was determined and categorized. Cox proportional hazards models assessed associations between quintile of FMI Z-Score and mortality. Sequential models adjusted for percent weight change since the maximum weight. RESULTS: Participants with lower FMI were more likely to have lost weight from their maximum, particularly among older participants with lower FMI. Substantially greater risk of mortality was observed for the highest quintile of FMI Z-Score compared to the second quintile among younger individuals [HR 2.50 (1.69, 3.72) p < .001]. In contrast, a more modest association was observed among older individuals in the highest quintile [HR 1.23 (0.99, 1.52) p = .06] (p for interaction <.001). In both the younger and older participants, the risks of greater FMI Z-Score were magnified when adjusting for percent weight change since maximum reported weight. CONCLUSIONS: Older people with low fat mass report greater historical weight loss, potentially explaining substantially altered relationships between fat mass and mortality in older individuals. As a result, epidemiologic studies performed in older populations will likely underestimate the causal risks of excess adiposity.

A multi-imaging modality study of bone density, bone structure and the muscle - bone unit in end-stage renal disease.

End stage renal disease (ESRD) is associated with sarcopenia and skeletal fragility. The objectives of this cross-sectional study were to (1) characterize body composition, bone mineral density (BMD) and bone structure in hemodialysis patients compared with controls, (2) assess whether DXA areal BMD (aBMD) correlates with peripheral quantitative CT (pQCT) measures of volumetric BMD (vBMD), cortical dimensions and MRI measures of trabecular microarchitecture, and (3) determine the magnitude of bone deficits in ESRD after adjustment for muscle mass. Thirty ESRD participants, ages 25 to 64 years, were compared with 403 controls for DXA and pQCT outcomes and 104 controls for MRI outcomes; results were expressed as race- and sex- specific Z-scores relative to age. DXA appendicular lean mass index (ALMI kg/m2) and total hip, femoral neck, ultradistal and 1/3rd radius aBMD were significantly lower in ESRD, vs. controls (all p < 0.01). pQCT trabecular vBMD (p < 0.01), cortical vBMD (p < 0.001) and cortical thickness (due to a greater endosteal circumference, p < 0.02) and MRI measures of trabecular number, trabecular thickness, and whole bone stiffness were lower (all p < 0.01) in ESRD, vs. controls. ALMI was positively associated with total hip, femoral neck, ultradistal radius and 1/3rd radius aBMD and with tibia cortical thickness (R = 0.46 to 0.64). Adjustment for ALMI significantly attenuated bone deficits at these sites: e.g. mean femoral neck aBMD was 0.79 SD lower in ESRD, compared with controls and this was attenuated to 0.33 with adjustment for ALMI. In multivariate models within the dialysis participants, pQCT trabecular vBMD and cortical area Z-scores were significant and independently (all p < 0.02) associated with DXA femoral neck, total hip, and ultradistal radius aBMD Z-scores. Cortical vBMD (p = 0.01) and cortical area (p < 0.001) Z-scores were significantly and independently associated with 1/3rd radius areal aBMD Z-scores (R2 = 0.62). These data demonstrate that DXA aBMD captures deficits in trabecular and cortical vBMD and cortical area. The strong associations with ALMI, as an index of skeletal muscle, highlight the importance of considering the role of sarcopenia in skeletal fragility in patients with ESRD.

Relative sarcopenia and mortality and the modifying effects of chronic kidney disease and adiposity.

BACKGROUND: Conventional definitions of sarcopenia based on lean mass may fail to capture low lean mass relative to higher fat mass, that is, relative sarcopenia. The objective of this study is to determine the associations of sarcopenia and relative sarcopenia with mortality independent of co-morbidities, and whether chronic kidney disease (CKD) and adiposity alter these associations. METHODS: Dual energy X-ray absorptiometry-derived appendicular lean mass index (ALMI, kg/m2 ) and fat mass index (FMI, kg/m2 ) were assessed in 14 850 National Health and Nutrition Examination Survey participants from 1999 to 2006 and were linked to death certificate data in the National Death Index with follow-up through 2011. Sarcopenia was defined using sex-specific and race/ethnicity-specific standard deviation scores compared with young adults (T-scores) as an ALMI T-score < -2 and relative sarcopenia as fat-adjusted ALMI (ALMIFMI ) T-score < -2. Glomerular filtration rate (GFR) was estimated using creatinine-based (eGFRCr ) and cystatin C-based (eGFRCys ) regression equations. RESULTS: Three (3.0) per cent of National Health and Nutrition Examination Survey participants met criteria for sarcopenia and 8.7% met criteria for relative sarcopenia. Sarcopenia and relative sarcopenia were independently associated with mortality (HR sarcopenia 2.20, 95% CI 1.69 to 2.86; HR relative sarcopenia 1.60, 95% CI 1.31 to 1.96). The corresponding population attributable risks were 5.2% (95% CI 3.4% to 6.4%) and 8.4% (95% CI 4.8% to 11.2%), respectively. Relative sarcopenia remained significantly associated with mortality (HR 1.32, 95% CI 1.08 to 1.61) when limited to the subset who did not meet the criteria for sarcopenia. The risk of mortality associated with relative sarcopenia was attenuated among persons with higher FMI (P for interaction <0.01) and was not affected by CKD status for either sarcopenia or relative sarcopenia. CONCLUSIONS: Sarcopenia and relative sarcopenia are significantly associated with mortality regardless of CKD status. Relative sarcopenia is nearly three-fold more prevalent amplifying its associated mortality risk at the population level. The association between relative sarcopenia and mortality is attenuated in persons with higher FMI.

Chronic Kidney Disease and the Adiposity Paradox: Valid or Confounded?

OBJECTIVE: Obesity, defined by body mass index (BMI), is associated with lower mortality risk in patients with chronic kidney disease (CKD). BMI and % body fat (%BF) are confounded by muscle mass, while DXA derived fat mass index (FMI) overcomes this limitation. We compared the associations between obesity and mortality in persons with CKD using multiple estimates of adiposity, and determined whether muscle mass, inflammation and weight loss modify these associations. METHODS: Obesity was defined using BMI and DXA-derived FMI and %BF cut-offs in 2,852 NHANES participants with CKD from 1999-2006 and linked to the National Death Index with follow up through 2011. Cox proportional hazards models assessed associations between mortality and measures of obesity. RESULTS: Obesity based on FMI and continuous variables, FMI, BMI and %BF were associated with lower mortality. The protective association of obesity was less pronounced among participants with higher muscle mass and was no longer significant after adjustment for prior weight loss. Inflammation did not modify these associations. CONCLUSIONS: We observed lower mortality associated with higher fat mass, particularly among persons with lower muscle mass. The prevalence of >10% weight loss was half as common among obese compared to non-obese participants and confounded these associations.

Physical activity promotion for patients transitioning to dialysis using the "Exercise is Medicine" framework: a multi-center randomized pragmatic trial (EIM-CKD trial) protocol.

BACKGROUND: Patients on dialysis are physically inactive, with most reporting activity levels below the fifth percentile of healthy age-matched groups. Several small studies have reported efficacy of diverse exercise interventions among persons with CKD and those on dialysis. However, no single intervention has been widely adopted in real-world practice, despite a clear need in this vulnerable population with high rates of mortality, frailty, and skilled nursing hospitalizations. METHODS/DESIGN: We describe a pragmatic clinical trial for an exercise intervention among patients transitioning to dialysis. We will use an existing framework - Exercise is Medicine (EIM) - developed by the American College of Sports Medicine. After undertaking formative qualitative research to tailor the EIM framework to the advanced CKD population (eGFR < 30 ml/min/1.73m2), we will randomize 96 patients from two regions-Atlanta and Bay Area-in two intervention arms with incremental levels of clinical-community integration: physical activity assessment during Nephrology clinical visit, brief counseling at pre-dialysis education, and physical activity wearable (group 1) versus group 1 intervention components plus a referral to a free, EIM practitioner-led group exercise program over 16 weeks (group 2; 8 week core intervention; 8-week follow up). We will assess efficacy by comparing between group differences in minutes/week of objectively measured moderate intensity physical activity. To evaluate implementation, we will use questionnaires for assessing barriers to referral, participation and retention along the path of the intervention. Further we will have a plan for dissemination of the intervention by partnering with relevant stakeholders. DISCUSSION: The overall goal is to inform the development of a practical, cost-conscious intervention "package" that addresses barriers and challenges to physical activity commonly faced by patients with advanced CKD and can be disseminated amongst interested practices. TRIAL REGISTRATION: ClinicalTrials.gov identifier (Dated:10/17/2017): NCT03311763 .

A Qualitative Assessment of Mismatch Between Dialysis Modality Selection and Initiation.

At our institution, we have noted that end-stage renal disease patients choosing a home dialysis modality after education often initiate renal replacement therapy with in-center hemodialysis (HD) instead. We interviewed 24 such patients (23 choosing peritoneal dialysis [PD], one choosing home HD) to determine reasons for this mismatch. The most common reasons cited for not starting home dialysis were: lack of confidence/concerns about complications, lack of space or home-related issues, a feeling of insufficient education, and perceived medical or social contraindications. We propose several potential strategies to help patients start with their preferred modality.

Association of Acute Interstitial Nephritis with Carnivora, a Venus Flytrap Extract, in a 30-Year-Old Man with Hodgkin's Lymphoma.

Acute interstitial nephritis (AIN) is a common cause of acute kidney injury and has been associated with a variety of medications. This is the case of 30-year-old man with Hodgkin's lymphoma who on routine labs before chemotherapy was found to have acute nonoliguric renal failure. A kidney biopsy was performed and confirmed the diagnosis of acute interstitial nephritis. The patient had taken several medications including a higher dose of Carnivora, a Venus flytrap extract, composed of numerous amino acids. The medication was discontinued and kidney function improved towards the patient's baseline indicating that this may be the possible cause of his AIN. Proximal tubular cell uptake of amino acids increasing transcription of nuclear factor-kappaB is a proposed mechanism of AIN from this compound.