Differences in Phosphate and Parathyroid Hormone Concentrations over the Day among Patients on Hemodialysis.

BACKGROUND: Elevated serum phosphate and parathyroid hormone (PTH) concentrations are associated with cardiovascular events, bone disease, and mortality in patients on maintenance hemodialysis. Although circadian changes are known in people with CKD, it is unknown whether differences occur in these parameters over the course of a day in people receiving hemodialysis. METHODS: We used clinical data from Fresenius Medical Care US dialysis clinics to determine how the time of day when measurements were collected (hemodialysis treatment start time) may be associated with serum phosphate and PTH concentrations. We used harmonic regression to assess these associations while accounting for demographic data and treatment parameters. RESULTS: A total of 96,319 patients receiving maintenance hemodialysis were included in this analysis. Patients had a mean age of 64±14 years, 43% were women, and dialysis start times ranged from 3:00 am to 7:59 pm. The mean serum phosphate concentration was 5.2±1.5 mg/dl, and the median PTH was 351 pg/ml (interquartile range [IQR], 214-547). In fully adjusted models, serum phosphate had a nadir at 11:00 am of 4.97 (IQR, 4.94-5.01) mg/dl and a peak at 7:00 pm of 5.56 (IQR, 5.50-5.62) mg/dl. Serum PTH had a nadir at 9:00 am of 385 (IQR, 375-395) pg/ml and a peak at 7:00 pm of 530 (IQR, 516-547) pg/ml. CONCLUSIONS: Among patients receiving maintenance hemodialysis, concentrations of PTH and phosphate before a dialysis session vary with the time of day that these values are measured. Consideration of whether these values were obtained at peak or nadir times of the day may be important in treatment decisions.

Kidney Health Initiative ESKD Data Standards Project.

The end-stage kidney disease (ESKD) Data Standards Project was launched by the Kidney Health Initiative (KHI) with the goal of standardizing dialysis-related measurements for research use. KHI is a public-private partnership between the American Society of Nephrology, US Food and Drug Administration, and organizations with an interest in kidney disease. KHI promotes safe and effective patient-centered therapies for people with kidney disease. In 2018, KHI established a workgroup with expertise in nephrology, nursing, quality management, ESKD data, organizational management, and clinical research. The workgroup identified 5 topic areas and 8 specific measures for the development of standards on the basis of the existing ESKD Measurement Specification Manual published by the Centers for Medicare & Medicaid Services. The topic areas were ultrafiltration rate, vascular access, dialysis small solute clearance (3 data standards), hospitalization (2 data standards), and mortality. The research standards were approved by the workgroup, reviewed by external reviewers, and opened to public comment. The data standards attempt to achieve balance between brevity and completeness in the face of knowledge gaps. The ESKD Data Standards are publicly available on the KHI website (https://khi.asn-online.org/projects/project.aspx?ID=78).

Mineral bone disease in autosomal dominant polycystic kidney disease.

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 µm3/µm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

Clinical Course of SARS-CoV-2 Infection in Adults with ESKD Receiving Outpatient Hemodialysis.

Background: Patients with ESKD on maintenance dialysis receive dialysis in common spaces with other patients and have a higher risk of severe SARS-CoV-2 infections. They may have persistently or intermittently positive SARS-CoV-2 RT-PCR tests after infection. We describe the clinical course of SARS-CoV-2 infection and the serologic response in a convenience sample of patients with ESKD to understand the duration of infectivity. Methods: From August to November 2020, we enrolled patients on maintenance dialysis with SARS-CoV-2 infections from outpatient dialysis facilities in Atlanta, Georgia. We followed participants for approximately 42 days. We assessed COVID-19 symptoms and collected specimens. Oropharyngeal (OP), anterior nasal (AN), and saliva (SA) specimens were tested for the presence of SARS-CoV-2 RNA, using RT-PCR, and sent for viral culture. Serology, including neutralizing antibodies, was measured in blood specimens. Results: Fifteen participants, with a median age of 58 (range, 37‒77) years, were enrolled. Median duration of RT-PCR positivity from diagnosis was 18 days (interquartile range [IQR], 8‒24 days). Ten participants had at least one, for a total of 41, positive RT-PCR specimens ≥10 days after symptoms onset. Of these 41 specimens, 21 underwent viral culture; one (5%) was positive 14 days after symptom onset. Thirteen participants developed SARS-CoV-2-specific antibodies, 11 of which included neutralizing antibodies. RT-PCRs remained positive after seroconversion in eight participants and after detection of neutralizing antibodies in four participants; however, all of these samples were culture negative. Conclusions: Patients with ESKD on maintenance dialysis remained persistently and intermittently SARS-CoV-2-RT-PCR positive. However, of the 15 participants, only one had infectious virus, on day 14 after symptom onset. Most participants mounted an antibody response, including neutralizing antibodies. Participants continued having RT-PCR-positive results in the presence of SARS-CoV-2-specific antibodies, but without replication-competent virus detected.

Conversion from Intravenous Vitamin D Analogs to Oral Calcitriol in Patients Receiving Maintenance Hemodialysis.

BACKGROUND AND OBJECTIVES: In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D3) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation. RESULTS: A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%; P=0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences. CONCLUSIONS: Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.

Mortality and Hospitalizations among Sickle Cell Disease Patients with End-Stage Kidney Disease Initiating Dialysis.

BACKGROUND: Sickle cell disease (SCD) is the most common inherited hematological disorder and a well-described risk factor for end-stage kidney disease (ESKD). Mortality and hospitalizations among patients with SCD who develop ESKD remain understudied. Furthermore, prior studies focused only on SCD patients where ESKD was caused by SCD. We aimed to describe mortality and hospitalization risk in all SCD patients initiating dialysis and explore risk factors for mortality and hospitalization. METHODS: We performed a national observational cohort study of African American ESKD patients initiating dialysis (2000-2014) in facilities affiliated with a large dialysis provider. SCD was identified by diagnosis codes and matched to a reference population (non-SCD) by age, sex, dialysis initiation year, and geographic region of care. Sensitivity analyses were conducted by restricting to patients where SCD was recorded as the cause of ESKD. RESULTS: We identified 504 SCD patients (mean age: 47 ± 14 years; 48% females) and 1,425 reference patients (mean age: 46 ± 14 years; 49% females). The median follow-up was 2.4 (IQR 1.0-4.5) years. Compared to the reference, SCD was associated with higher mortality risk (hazard ratio 1.66; 95% confidence interval [CI]: 1.36-2.03) and higher hospitalization rates (incidence rate ratio 2.12; 95% CI: 1.88-2.38) in multivariable analyses. Exploratory multivariable mortality risk models showed the largest mortality risk attenuation with the addition of time-varying hemoglobin and high-dose erythropoietin, but the association of SCD with mortality remained significant. Sensitivity analyses (restricted to ESKD caused by SCD) also showed significant associations between SCD and mortality and hospitalizations, but with larger effect estimates. High-dose erythropoietin was associated with the highest risk for mortality and hospitalization in SCD. CONCLUSIONS: Among ESKD patients, SCD is associated with a higher risk for mortality and hospitalization, particularly in patients where SCD is identified as the cause of ESKD.

Development and content validity of a hemodialysis symptom patient-reported outcome measure.

PURPOSE: To describe the process and preliminary qualitative development of a new symptom-based patient-reported outcome measure (PROM) intended to assess hemodialysis treatment-related physical symptoms. METHODS: Experienced interviewers conducted concept elicitation and cognitive debriefing interviews with individuals receiving in-center hemodialysis in the United States. Concept elicitation interviews involved eliciting spontaneous reports of symptom experiences and probing to further explore and confirm concepts. We used patient-reported concepts to generate a preliminary symptom PROM. We conducted 3 rounds of cognitive debriefing interviews to evaluate symptom relevance, item interpretability, and draft item structure. We iteratively refined the measure based on cognitive interview findings. RESULTS: Forty-two adults receiving in-center hemodialysis participated in the concept elicitation interviews. A total of 12 symptoms were reported by > 10% of interviewees. We developed a 13-item initial draft instrument for testing in 3 rounds of cognitive interviews with an additional 52 hemodialysis patients. Participant responses and feedback during cognitive interviews led to changes in symptom descriptions, division of the single item "nausea/vomiting" into 2 distinct items, removal of daily activity interference items, addition of instructions, and clarification about the recall period, among other changes. CONCLUSIONS: Symptom Monitoring on Renal Replacement Therapy-Hemodialysis (SMaRRT-HD™) is a 14-item PROM intended for use in hemodialysis patents. SMaRRT-HD™ uses a single treatment recall period and a 5-point Likert scale to assess symptom severity. Qualitative interview data provide evidence of its content validity. SMaRRT-HD™ is undergoing additional testing to assess measurement properties and inform measure scoring.

Performance Characteristics of Profiling Methods and the Impact of Inadequate Case-mix Adjustment.

Profiling or evaluation of health care providers involves the application of statistical models to compare each provider's performance with respect to a patient outcome, such as unplanned 30-day hospital readmission, adjusted for patient case-mix characteristics. The nationally adopted method is based on random effects (RE) hierarchical logistic regression models. Although RE models are sensible for modeling hierarchical data, novel high dimensional fixed effects (FE) models have been proposed which may be well-suited for the objective of identifying sub-standard performance. However, there are limited comparative studies. Thus, we examine their relative performance, including the impact of inadequate case-mix adjustment.

Frailty Among Patients Receiving Hemodialysis: Evolution of Components and Associations With Mortality.

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.

Using Technology to Inform and Deliver Precise Personalized Care to Patients With End-Stage Kidney Disease.

Consistent with the increase of precision medicine, the care of patients with end-stage kidney disease (ESKD) requiring maintenance dialysis therapy should evolve to become more personalized. Precise and personalized care is nuanced and informed by a number of factors including an individual's needs and preferences, disease progression, and response to and tolerance of treatments. Technology can support the delivery of more precise and personalized care through multiple mechanisms, including more accurate and real-time assessments of key care elements, enhanced treatment monitoring, and remote monitoring of home dialysis therapies. Data from health care and non-health care sources and advanced analytical methods such as machine learning can be used to create novel insights, and large volumes of data can be integrated to support clinical decisions. Health care models continue to evolve and the opportunities and need for novel care approaches supported by technology and health informatics continue to expand as the delivery and organization of health care changes. Ultimately, precise personalized care for ESKD, including dialysis therapy, will become more feasible as the biological, social, and environmental determinants of health are more broadly understood and as advances in science, engineering, and information management create the means to provide truly precise care for ESKD.

Time-dynamic profiling with application to hospital readmission among patients on dialysis.

Standard profiling analysis aims to evaluate medical providers, such as hospitals, nursing homes, or dialysis facilities, with respect to a patient outcome. The outcome, for instance, may be mortality, medical complications, or 30-day (unplanned) hospital readmission. Profiling analysis involves regression modeling of a patient outcome, adjusting for patient health status at baseline, and comparing each provider's outcome rate (e.g., 30-day readmission rate) to a normative standard (e.g., national "average"). Profiling methods exist mostly for non time-varying patient outcomes. However, for patients on dialysis, a unique population which requires continuous medical care, methodologies to monitor patient outcomes continuously over time are particularly relevant. Thus, we introduce a novel time-dynamic profiling (TDP) approach to assess the time-varying 30-day readmission rate. TDP is used to estimate, for the first time, the risk-standardized time-dynamic 30-day hospital readmission rate, throughout the time period that patients are on dialysis. We develop the framework for TDP by introducing the standardized dynamic readmission ratio as a function of time and a multilevel varying coefficient model with facility-specific time-varying effects. We propose estimation and inference procedures tailored to the problem of TDP and to overcome the challenge of high-dimensional parameters when examining thousands of dialysis facilities.

Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis.

BACKGROUND: In hemodialysis (HD) patients, higher lipid levels are associated with lower mortality. Lipid-lowering therapy does not reduce all-cause mortality or cardiovascular (CV) mortality. Lipoproteins play a role in the innate immune system. Our objective was to determine whether protection from infection might counterbalance adverse CV outcomes associated with lipoproteins. METHODS: We examined associations between serum apolipoprotein (Apo) A1, B, C2, C3, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol and triglyceride levels and infectious mortality or hospitalization, CV mortality or hospitalization, and all-cause mortality in 433 prevalent HD patients. Cox models with time-varying apolipoprotein concentrations collected every 6 months for up to 2 years were used for analyses. RESULTS: Median follow-up time for all-cause mortality was 2.7 years (25th-75th percentile range: 2.2-3.4 years). One hundred seventy-nine (41%) patients had an infection-related event. In multivariable models, higher Apo B and LDL were associated with lower risks of infection-related outcomes (hazard ratio Apo B 0.92 [95% confidence interval 0.86-0.99 per 10 mg/dL, P = .03]; hazard ratio LDL 0.93 [95% confidence interval 0.87-1.00 per 10 mg/dL, P = .05]). Sixty-three (15%) participants had a CV-related event. No significant associations were observed between lipoproteins and CV outcomes. Eighty-seven (20%) participants died. Higher Apo A1, Apo B, and Apo C3 were associated with lower risks of all-cause mortality. There was no interaction between the use of lipid-lowering medication and any of the outcomes. CONCLUSION: Associations of lipoproteins with lower risk of serious infection accompanied by no significant association with CV events may help to explain the paradoxical association between lipids and survival and lack of benefit of lipid-lowering therapies in HD.

Associations of Body Mass Index and Body Fat With Markers of Inflammation and Nutrition Among Patients Receiving Hemodialysis.

BACKGROUND: Understanding the extent to which visceral and subcutaneous body fat are associated with markers of nutrition and inflammation in patients on dialysis therapy could shed light on the obesity paradox and the biology of subcutaneous fat. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 609 adults receiving hemodialysis who participated in the ACTIVE/ADIPOSE Study. PREDICTORS: Body mass index (BMI), waist circumference, and bioelectrical impedance spectroscopy-derived estimates of percent body fat. OUTCOMES: C-Reactive protein (CRP), interleukin 6 (IL-6), prealbumin, albumin, leptin, and adiponectin concentrations. MEASUREMENTS: We performed linear regression analyses to examine the extent to which proxies of visceral and subcutaneous fat were associated with inflammation, nutrition, and adiposity-related hormones. RESULTS: BMI was directly associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.30 [95% CI, 0.22-0.38] per 10kg/m2; for ln[IL-6 in pg/mL]: 0.10 [95% CI, 0.02-0.18] per 10kg/m2), but was not associated with markers of nutrition. BMI was also inversely associated with adiponectin and directly associated with leptin. With waist circumference and percent body fat (as a proxy of visceral and subcutaneous fat, respectively) modeled together, waist circumference was associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.21 [95% CI, 0.09-0.34] per 10cm; for ln[IL-6 in pg/mL]: 0.18 [95% CI, 0.07-0.29] per 10cm), whereas percent body fat was not associated with CRP (standardized estimate for ln[CRP in mg/L]: 0.03 [95% CI, -0.10 to 0.15] per 1%) and was inversely associated with IL-6 (standardized estimate for ln[IL-6 in pg/mL]: -0.15 [95% CI, -0.27 to -0.02] per 1%). In addition, waist circumference was inversely associated with prealbumin and albumin (standardized estimates of -0.12 [95% CI, -0.23 to -0.02] mg/dL per 10cm and -0.17 [95% CI, -0.28 to -0.06] g/dL per 10cm, respectively), and percent body fat was directly associated with prealbumin and albumin (0.20 [95% CI, 0.07-0.32] mg/dL and 0.15 [95% CI, 0.02-0.28] g/dL per 1%, respectively). Higher waist circumference was associated indirectly with adiponectin and directly with leptin concentrations. LIMITATIONS: Although the observed associations implicate visceral fat as the cause of inflammation, it cannot be determined in this cross-sectional study. CONCLUSIONS: Proxies of visceral and subcutaneous fat appear to have opposing associations with biomarkers of inflammation and nutrition. Subcutaneous fat may be an indicator of nutritional status, and visceral fat, an indicator of inflammation.

Factors Associated with Frailty and Its Trajectory among Patients on Hemodialysis.

BACKGROUND AND OBJECTIVES: Frailty is common among patients on hemodialysis and associated with adverse outcomes. However, little is known about changes in frailty over time and the factors associated with those changes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To address these questions, we examined 762 participants in the A Cohort to Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD cohort study, among whom frailty was assessed at baseline and 12 and 24 months. We used ordinal generalized estimating equations analyses and modeled frailty (on a scale from zero to five possible components) and death during follow-up. RESULTS: The mean frailty score at baseline was 1.9, and the distribution of frailty scores was similar at each evaluation. However, most participants' scores changed, with patients improving almost as often as worsening (overall change, 0.2 points per year; 95% confidence interval, 0.1 to 0.3). Hispanic ethnicity (0.6 points per year; 95% confidence interval, 0.0 to 1.1) and diabetes (0.7 points per year; 95% confidence interval, 0.3 to 1.0) were associated with higher frailty scores and higher serum albumin concentration with lower frailty scores (-1.1 points per g/dl; 95% confidence interval, -1.5 to -0.7). In addition, patients whose serum albumin increased over time were less likely to become frail, with each 1-g/dl increase in albumin associated with a 0.4-point reduction in frailty score (95% confidence interval, -0.80 to -0.05). To examine the underpinnings of the association between serum albumin and frailty, we included serum IL-6, normalized protein catabolic rate, and patient self-report of hospitalization within the last year in a second model. Higher IL-6 and hospitalization were statistically significantly associated with worse frailty at any point and worsening frailty over time, whereas normalized protein catabolic rate was not independently associated with frailty. CONCLUSIONS: There was substantial year to year variability in frailty scores, with approximately equal numbers of patients improving and worsening. Markers of inflammation and hospitalization were independently associated with worsening frailty. Studies should examine whether interventions to address inflammation or posthospitalization rehabilitation can improve the trajectory of frailty.

Predialysis volume overload and patient-reported sleep duration and quality in patients receiving hemodialysis.

INTRODUCTION: Previous studies of patients with end-stage renal disease have examined the role of fluid shifts on apnea-hypopnea episodes, but the association between volume overload and patient-reported sleep quality or duration has not been well-established. METHODS: We studied the association between predialysis bioimpedance spectroscopy-derived volume estimates and self-reported sleep quality and duration in 638 patients in the United States Renal Data System ACTIVE/ADIPOSE study receiving hemodialysis from 2009 to 2011. We used questionnaires to assess self-reported sleep duration and quality. We used relative hydration status (fluid overload/extracellular water; FO/ECW) as the primary predictor and examined associations with hours of sleep duration using linear regression. We used multivariable ordinal logistic regression to determine the association between categories of relative hydration status (normal hydration [FO/ECW < 6.8%], mild overhydration [FO/ECW 6.8%-15%], and hyperhydration [FO/ECW > 15%]) and four levels of difficulty with falling asleep, waking, and returning to sleep. FINDINGS: Higher relative hydration status was associated with fewer hours of sleep (-0.31 hours per 10%, 95% confidence interval (CI) -0.49 to -0.13). Compared to the normal hydration group, there was a statistically significant association between higher relative hydration status category and more frequent nighttime waking (OR: mild overhydration 1.92 [95% CI 1.23-2.99], hyperhydration 1.87 [95% CI 1.16-2.99]), a trend toward more difficulty returning to sleep (OR: mild overhydration 1.46 [95% CI 0.94-2.27], hyperhydration 1.52 [95% CI 0.95-2.43]), and no association between relative hydration category and difficulty falling asleep. DISCUSSION: Hydration status was associated with self-reported sleep duration in patients on dialysis. Future studies should prospectively examine the effects of optimizing fluid status on sleep duration and quality.

Association of Performance-Based and Self-Reported Function-Based Definitions of Frailty with Mortality among Patients Receiving Hemodialysis.

BACKGROUND AND OBJECTIVES: Frailty is common among patients on dialysis and increases vulnerability to dependency and death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the predictive ability of frailty on the basis of physical performance and self-reported function in participants of a US Renal Data System special study that enrolled a convenience sample of 771 prevalent patients on hemodialysis from 14 facilities in the Atlanta and northern California areas from 2009 to 2011. Performance-based frailty was assessed using direct measures of grip strength (weakness) and gait speed along with weight loss, exhaustion, and low physical activity; poor self-reported function was substituted for weakness and slow gait speed in the self-reported function-based definition. For both definitions, patients meeting three or more criteria were considered frail. RESULTS: The mean age of 762 patients included in analyses was 57.1±14.2 years old; 240 patients (31%) met the physical performance-based definition of frailty, and 396 (52%) met the self-reported function-based definition. There were 106 deaths during 1.7 (interquartile range, 1.4-2.4) years of follow-up. After adjusting for demographic and clinical characteristics, the hazard ratio (HR) for mortality for the performance-based definition (2.16; 95% confidence interval [95% CI], 1.41 to 3.29) was slightly higher than that of the self-reported function-based definition (HR, 1.93; 95% CI, 1.24 to 3.00). Patients who met the self-report-based definition but not the physical performance definition of frailty (n=192) were not at statistically significantly higher risk of mortality than those who were not frail by either definition (n=330; HR, 1.41; 95% CI, 0.81 to 2.45), but those who met both definitions of frailty (n=204) were at significantly higher risk (HR, 2.46; 95% CI, 1.51 to 4.01). CONCLUSIONS: Frailty, defined using either direct tests of physical performance or self-reported physical function, was associated with higher mortality among patients receiving hemodialysis. Future studies are needed to determine the utility of assessing frailty in clinical practice.

Time-varying effect modeling with longitudinal data truncated by death: conditional models, interpretations, and inference.

Recent studies found that infection-related hospitalization was associated with increased risk of cardiovascular (CV) events, such as myocardial infarction and stroke in the dialysis population. In this work, we develop time-varying effects modeling tools in order to examine the CV outcome risk trajectories during the time periods before and after an initial infection-related hospitalization. For this, we propose partly conditional and fully conditional partially linear generalized varying coefficient models (PL-GVCMs) for modeling time-varying effects in longitudinal data with substantial follow-up truncation by death. Unconditional models that implicitly target an immortal population is not a relevant target of inference in applications involving a population with high mortality, like the dialysis population. A partly conditional model characterizes the outcome trajectory for the dynamic cohort of survivors, where each point in the longitudinal trajectory represents a snapshot of the population relationships among subjects who are alive at that time point. In contrast, a fully conditional approach models the time-varying effects of the population stratified by the actual time of death, where the mean response characterizes individual trends in each cohort stratum. We compare and contrast partly and fully conditional PL-GVCMs in our aforementioned application using hospitalization data from the United States Renal Data System. For inference, we develop generalized likelihood ratio tests. Simulation studies examine the efficacy of estimation and inference procedures.