The relative importance of sarcopenia and its individual components as independent predictors of mortality in the dialysis population has not been determined. We estimated whole-body muscle mass using pre-dialysis bioimpedance spectroscopy measurements in 645 ACTIVE/ADIPOSE-enrolled prevalent hemodialysis patients from San Francisco and Atlanta. Low muscle mass was defined as two standard deviations below sex-specific means for young adults from NHANES and indexed to height², body weight, body surface area, or body mass index. We evaluated the association of sarcopenia (low muscle mass) by four indexing methods, weak hand grip strength, and slow gait speed with mortality. Seventy-eight deaths were observed during a mean follow-up of 1.9 years. Sarcopenia was not significantly associated with mortality after adjusting for covariates. No muscle mass criteria were associated with death, regardless of indexing metrics. In contrast, having weak grip strength or slow walking speed was associated with mortality in the adjusted model. Only gait slowness significantly improved the predictive accuracy for death with an increase in C-statistic from 0.63 to 0.68. However, both gait slowness and hand grip weakness significantly improved the net reclassification index compared to models without performance measures (50.5% for slowness and 33.7% for weakness), whereas models with muscle size did not. Neither sarcopenia nor low muscle mass by itself was a better predictor of mortality than functional limitation alone in patients receiving hemodialysis. Thus, physical performance measures, including slow gait speed and weak hand grip strength, were associated with mortality even after adjustment for muscle size and other confounders.

Objective

Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin.

Design/setting

We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships.

Subjects

Participants were aged ≥18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months.

Main outcome measures

Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy.

Results

Mean age was 56 ± 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m² per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF-23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to -0.02).

Conclusion

We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients.

Background

Latinx individuals are disproportionally burdened by kidney diseases compared to non-Latinx White individuals and are underrepresented in kidney-related research. We aimed to describe stakeholder perspectives on Latinx patient engagement in kidney-related research.

Methods

We conducted a thematic analysis of two online moderated discussions and an interactive online survey with open-text responses involving participants (i.e. stakeholders), with personal and/or professional experiences with Latinx patients with kidney diseases and their families/caregivers.

Results

Among the eight stakeholders (Female:75%; Latinx ethnicity:88%), there were three physicians, one nurse, one patient with kidney disease who received a kidney transplant, one policy maker, one Doctor of Philosophy, and one executive director of a non-profit health organization. We identified five themes. The majority of themes and their respective subthemes (in parentheses) reflected barriers to engagement: Lack of personal relevance (unable to relate to research staff and marketing resources, and unclear benefit of research to self, family, and community); fear and vulnerability (immigration concerns, stigma with seeking care, skepticism of Western medicine); logistical and financial barriers (limited opportunities to enroll in clinical trials, out-of-pocket costs, transportation issues); and distrust and asymmetry of power (related to limited English proficiency or health literacy, and provider bias). The last theme centered on stimulating interest and establishing trust in the research process.

Conclusions

To overcome barriers to engagement in kidney-related research and establish trust among potential Latinx research participants, stakeholders recommended employing cultural responsiveness and community-based strategies. These strategies can help identify local health priorities, enhance research recruitment and retention strategies, and establish partnerships that continue to elevate research endeavors aiming to enhance the health of Latinx individuals with kidney diseases.

Background

Despite the high prevalence of frailty among patients receiving hemodialysis, few preventable or treatable contributing causes have been identified. Hypogonadism is also common in this population and low serum testosterone concentrations share several clinical phenotypes with frailty. We hypothesized that low serum testosterone concentrations would be associated with frailty and several of its individual components.

Methods

We used data from 440 men from A Cohort Study To Investigate the Value of Exercise in ESRD/Analysis Designed to Investigate the Paradox of Obesity and Survival in ESRD, a longitudinal study that recruited participants from 14 dialysis centers in Atlanta, GA and the San Francisco, CA Bay Area from 2009 to 2011. We assessed frailty using the Fried Frailty Phenotype. We examined the association between free testosterone (as a continuous and dichotomous variable) and frailty, individual frailty components, sarcopenia, lower extremity function and muscle mass estimation by creatinine and body impedance spectroscopy over 12 months using generalized estimating equations.

Results

The mean age was 56.1 ± 14.2 years and 27% were white. A 50% lower concentration of free testosterone was associated with 1.40-fold higher odds of being frail [95% confidence interval (CI) 1.05-1.53] and 1.40-fold higher odds of becoming frail over 12 months (95% CI 1.07-1.73). This association was mainly due to an association with two components of frailty: grip strength and gait speed. In addition, 50% lower free testosterone concentration was associated with a 1.55-fold higher odds of having sarcopenia (95% CI 1.09-2.02) and 1.72-fold higher odds for developing sarcopenia (95% CI 1.13-2.33) as well as with lower muscle mass and a decrease in muscle mass over 12 months as estimated by serum creatinine and by bioelectrical impedance spectroscopy.

Conclusion

Serum free testosterone concentration was associated with frailty, physical function, sarcopenia and muscle mass as well as with changes in these outcomes over 12 months. Testosterone replacement may be a feasible therapeutic target toward prevention of frailty, although clinical trials are needed to test this possibility.

Background

Use of serum creatinine to estimate GFR may lead to underestimation of the association between self-reported frailty and kidney function. Our objectives were to evaluate the association of measured GFR (mGFR) with self-reported frailty among patients with CKD and to determine whether self-reported frailty was associated with death after adjusting for mGFR.

Methods

Participants in the Modification of Diet in Renal Disease study (1989-1993) had GFR measured using iothalamate clearance (mGFR), and GFR was estimated based on the CKD-EPI creatinine (eGFRcr) and cystatin C (eGFRcys) equations. We defined self-reported frailty as three or more of: exhaustion, poor physical function, low physical activity, and low body weight. Death was ascertained through 2007 using the National Death Index and the United States Renal Data System.

Results

Eight hundred twelve MDRD participants (97 %) had complete data on self-reported frailty (16 % prevalence, N = 130) and mGFR (mean (SD) 33.1 ± 11.7 ml/min/1.73 m(2)). Higher GFR was associated with lower odds of self-reported frailty based on mGFR, (OR 0.71, 95 % CI 0.60-0.86 per 10 ml/min/1.73 m(2)), eGFRcr (OR 0.80, 95 % CI 0.67-0.94 per 10 ml/min/1.73 m(2)), and eGFRcys (OR 0.75, 95 % CI 0.62-0.90 per 10 ml/min/1.73 m(2)). Median follow-up was 17 (IQR 11-18) years, with 371 deaths. Self-reported frailty was associated with a higher risk of death (HR 1.71, 95 % CI 1.26-2.30), which was attenuated to a similar degree when mGFR (HR 1.48, 95 % CI 1.08-2.00), eGFRcr (HR 1.57, 95 % CI 1.15-2.10), or eGFRcys (HR 1.51, 95 % CI 1.10-2.10) was included as an indicator of kidney function.

Conclusions

We found an inverse association between kidney function and self-reported frailty that was similar for mGFR, eGFR and eGFRcys. In this relatively healthy cohort of clinical trial participants with CKD, using serum creatinine to estimate GFR did not substantially alter the association of GFR with self-reported frailty or of self-reported frailty with death.

Background

A randomized trial of a pedometer-based intervention with weekly activity goals led to increased walking among dialysis patients. However, the association of participant-expressed motivations and barriers to participation and performance in such an intervention has not been determined.

Methods

Thirty dialysis patients were randomized to a 12-week pedometer-based intervention with weekly step goals. Participants were asked about motivations and barriers to the increasing activity via weekly semi-scripted telephone interviews. We examined the association of these motivations and barriers with achieving weekly goals, reaching overall targets and increasing steps through multivariable linear and logistic regression analyses adjusted for age, sex, body mass index, dialysis modality and baseline steps.

Results

The most common motivations were desire to maintain/improve functional ability (30%) and activity (30%). The most common barriers were health-related (33%). Motivation to maintain/improve functional ability was associated with achieving weekly goals 17.9% more often [95% confidence interval (CI) 1.7-34.2] and with a greater increase in steps (1524 steps; 95% CI 61-2989) than those lacking this motivation. Experiencing a health-related barrier was not associated with the decreased achievement of weekly goals but was associated with lower odds of reaching overall targets (odds ratio = 0.06; 95% CI 0.01-0.53) and a smaller increase in steps (-1640 steps, 95% CI -3244 to -36). No patients who reported weather/environmental barriers or safety concerns reached overall targets.

Conclusions

Participants who express a desire to maintain/improve functional ability may be particularly suited for activity interventions. Health-related setbacks should be met with revised goals. Reporting environmental or safety concerns may merit lowering overall targets.

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.

Background

Understanding how components of frailty change over time and how they can be modeled as time-dependent predictors of mortality could lead to better risk prediction in the dialysis population.

Methods

We measured frailty at baseline, 12 months, and 24 months among 727 patients receiving hemodialysis in Northern California and Atlanta. We examined the likelihood of meeting frailty components (weight loss, exhaustion, low physical activity, weak grip strength, and slow gait speed) as a function of time in logistic regression analysis and association of frailty components with mortality in time-updated multivariable Cox models.

Results

Physical activity and gait speed declined, exhaustion and grip strength did not change, and the odds of meeting the weight loss criterion declined with time. All five components were associated with higher mortality in multivariable analyses, but gait speed was the strongest individual predictor. All frailty components except physical inactivity were independently associated with mortality when all five components were included in the same model. The number of frailty components met was associated with mortality in a gradient that ranged from a hazard ratio of 2.73 for one component to 10.07 for five components met; the model including all five components was the best model based on Akaike information criterion.

Conclusions

Measurement of all frailty components was necessary for optimal mortality prediction, and the number of components met was strongly associated with mortality in this cohort.

Background

Earlier qualification for the kidney transplant waitlist expedites transplant and is therefore associated with improved outcomes. U.S. Organ Procurement and Transplantation Network policies state that "measured or calculated creatinine clearance or glomerular filtration rate less than or equal to 20 mL/min" triggers waitlist time accrual. The choice of qualification method is somewhat arbitrary, and the policy implies that decline in renal function is monotonic.

Methods

(1) We used survival analysis to quantify temporal differences in waitlist qualification by applying 3 kidney-function-estimating equations (Cockcroft-Gault, Modification of Diet in Renal Disease study, Chronic Kidney Disease Epidemiology Collaboration) to serial creatinine measurements from 3 patient cohorts: 1 of waitlisted patients at a major U.S. academic center and 2 national, multicenter cohorts of chronic kidney disease patients (African American Study of Kidney Disease and Hypertension, Modification of Diet in Renal Disease). (2) Survival analysis assessed whether requiring patients to demonstrate persistently reduced renal function on 2 occasions at least 90 days apart would meaningfully change qualification order.

Results

On average, time to waitlist qualification would be delayed on the order of 1 to 2 years by using calculated creatinine clearance (per the Cockcroft-Gault equation). Compared with current policy, requiring demonstration of persistently reduced renal function delayed qualification by 0.6 to 2.1 years and caused 40% to 50% of patients to switch the order in which they qualify by 6 months or more.

Conclusions

The kidney transplantation policies should be revised, such that timing of waitlist qualification is more standardized. We suggest that mention of using calculated creatinine clearance be dropped from the Organ Procurement and Transplantation Network policy wording and the units to quantify kidney function be changed to mL/min per 1.73 m². Some consideration should be given to whether requiring persistently reduced renal function would better identify patients most likely to benefit from earlier waitlist qualification.

Background

Although frailty has been linked to higher risk of falls and fracture in the general population, only few studies have examined the extent to which frailty is associated with these outcomes among patients with end-stage renal disease, who are at particularly high risk for these events.

Methods

A total of 1,646 patients who were beginning maintenance hemodialysis in 297 dialysis units throughout the United States from September 2005 to June 2007 were enrolled in the Comprehensive Dialysis Study, and 1,053 Medicare beneficiaries were included in this study. Self-reported frailty was defined by the patients endorsing 2 or more of the following: poor physical functioning, exhaustion or low physical activity. Falls and fractures requiring medical attention were identified through Medicare claims data. We examined the association between frailty and the time to first fall or fracture using the Fine-Gray modification of Cox proportional hazards regression, adjusted for demographics, Quételet's body mass index, diabetes mellitus, heart failure and atherosclerosis.

Results

Seventy-seven percent of patients were frail by self-report. The median length of follow-up was 2.5 (1.0-3.9) years. Crude rates of first medically urgent falls or fractures were 66 and 126 per 1,000 person-years in non-frail and self-reported frail participants, respectively. After accounting for demographic factors, comorbidities and the competing risk of death, self-reported frailty was associated with a higher risk of falls or fractures requiring medical attention (hazards ratio 1.60, 95% CI 1.16-2.20).

Conclusion

Participants reporting frailty experienced nearly twice the risk of medically urgent falls or fractures compared to those who did not report frailty.