Order of Onset of Physical Frailty and Cognitive Impairment and Risk of Repeated Falls in Community-Dwelling Older Adults.

OBJECTIVES: To examine whether physical frailty onset before, after, or in concert with cognitive impairment is differentially associated with fall incidence in community-dwelling older adults. DESIGN: A longitudinal observational study. SETTING AND PARTICIPANTS: Data from 1337 older adults age ≥65 years and free of physical frailty or cognitive impairment at baseline were obtained from the National Health Aging Trends Study (2011‒2017), a nationally representative cohort study of US older adult Medicare beneficiaries. METHODS: Participants were assessed annually for frailty (physical frailty phenotype) and cognitive impairment (bottom quintile of clock drawing test or immediate and delayed recall; or proxy-report of diagnosis of dementia or AD8 score of ≥2). Incident falls were ascertained annually via self-report. Multinomial logistic regression was performed to estimate the association between order of first onset of cognitive impairment and/or frailty and incident single or repeated falls in the 1-year interval following their first onset. RESULTS: Of the 1,337, 832 developed cognitive impairment first (termed "CI first"), 286 developed frailty first (termed "frailty first") and 219 had co-occurrence of cognitive impairment and frailty within one year (termed "CI-frailty co-occurrence") over 5 years. Overall, 491 (34.5%) had at least 1 fall during the 1-year interval following the onset of physical frailty and/or cognitive impairment. After adjustment, "CI-frailty co-occurrence" was associated with a more than 2-fold increased risk of repeated falls than "CI first" (odds ratio 2.35, 95% confidence interval 1.51‒3.67; P < .001). No significant difference was found between participants with "frailty first" and "CI first" (P = .07). In addition, the order of onset was not associated with risk of a single fall. CONCLUSIONS AND IMPLICATIONS: Older adults experiencing "CI-frailty co-occurrence" had the greatest risk of repeated falls compared with those with "CI first" and "frailty first". Fall risk screening should consider the order and timing of onset of physical frailty and cognitive impairment.

Domains for a Comprehensive Geriatric Assessment of Older Adults with Chronic Kidney Disease: Results from the CRIC Study.

INTRODUCTION: A comprehensive geriatric assessment (CGA) tailored to the chronic kidney disease (CKD) population would yield a more targeted approach to assessment and care. We aimed to identify domains of a CKD-specific CGA (CKD-CGA), characterize patterns of these domains, and evaluate their predictive utility on adverse health outcomes. METHODS: We used data from 864 participants in the Chronic Renal Insufficiency Cohort aged ≥55 years and not on dialysis. Constituents of the CKD-CGA were selected a priori. Latent class analysis informed the selection of domains and identified classes of participants based on their domain patterns. The predictive utility of class membership on mortality, dialysis initiation, and hospitalization was examined. Model discrimination was assessed with C-statistics. RESULTS: The CKD-CGA included 16 domains: cardiovascular disease, diabetes, five frailty phenotype components, depressive symptoms, cognition, five kidney disease quality-of-life components, health literacy, and medication use. A two-class latent class model fit the data best, with 34.7% and 65.3% in the high- and low-burden of geriatric conditions classes, respectively. Relative to the low-burden class, participants in the high-burden class were at increased risk of mortality (aHR = 2.09; 95% CI: 1.56, 2.78), dialysis initiation (aHR = 1.63; 95% CI: 1.06, 2.52), and hospitalization (aOR = 2.00; 95% CI: 1.38, 2.88). Model discrimination was the strongest for dialysis initiation (C-statistics = 0.86) and moderate for mortality and hospitalization (C-statistics = 0.70 and 0.66, respectively). CONCLUSION: With further validation in an external cohort, the CKD-CGA has the potential to be used in nephrology practices for assessing and managing geriatric conditions in older adults with CKD.

Delirium, changes in cognitive function, and risk of diagnosed dementia after kidney transplantation.

Kidney transplant (KT) recipients with delirium, a preventable surgical complication, are likely to reap cognitive benefits from restored kidney function, but may be more vulnerable to longer-term neurotoxic stressors post-KT (i.e., aging, immunosuppression). In this prospective cohort study, we measured delirium (chart-based), global cognitive function (3MS), and executive function (Trail Making Test Part B minus Part A) in 894 recipients (2009-2021) at KT, 1/3/6-months, 1-year, and annually post-KT. Dementia was ascertained using linked Medicare claims. We described repeated measures of cognitive performance (mixed effects model) and quantified dementia risk (Fine & Gray competing risk) by post-KT delirium. Of 894 recipients, 43(4.8%) had post-KT delirium. Delirium was not associated with global cognitive function at KT (difference = -3.2 points, 95%CI: -6.7, 0.4) or trajectories post-KT (0.03 points/month, 95%CI: -0.27, 0.33). Delirium was associated with worse executive function at KT (55.1 s, 95%CI: 25.6, 84.5), greater improvements in executive function <2 years post-KT (-2.73 s/month, 95%CI: -4.46,-0.99), and greater decline in executive function >2 years post-KT (1.72 s/month, 95%CI: 0.22, 3.21). Post-KT delirium was associated with over 7-fold greater risk of dementia post-KT (adjusted subdistribution hazard ratio = 7.84, 95%CI: 1.22, 50.40). Transplant centers should be aware of cognitive risks associated with post-KT delirium and implement available preventative interventions to reduce delirium risk.

Depressive Symptoms at Kidney Transplant Evaluation and Access to the Kidney Transplant Waitlist.

Introduction: Depressive symptoms, even without a clinical diagnosis of depression, are common in kidney failure patients and may be a barrier to completing the complex process of kidney transplant (KT) evaluation. We assessed depressive symptom burden and association between depressive symptoms and access to KT waitlist by age. Methods: In a prospective cohort of 3728 KT patients (aged 18-88 years), the Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms at evaluation. Depressive symptom severity was defined as follows: none: 0; minimal: 1 to 15; mild: 16 to 20; moderate: 21 to 25; severe: 26 to 60. Hazard ratios (HRs) of active listing within 1 year after evaluation were estimated using Cox proportional hazards models, adjusted for clinical and social factors. Results: At evaluation, 85.8% of the patients reported at least minimal depressive symptoms; the proportion was lower among older patients: 18 to 29 years = 92.0%; 30 to 39 years = 88.3%; 40 to 49 years = 87.2%; 50 to 59 years = 87.0%; 60 to 69 years = 83.4%; and ≥70 years = 82.0%. Chance of active listing decreased with more severe depressive symptoms (log-rank, P < 0.001). After adjustment, every 5-point higher CES-D score (more depressive symptoms) was associated with a 13% lower chance of listing (HR = 0.87, 95% CI: 0.85-0.90); the strongest association was found among patients aged ≥70 years (adjusted HR [aHR] = 0.73, 95% CI: 0.62-0.86). Furthermore, minimal (HR = 0.69, 95% CI: 0.60-0.79), mild (HR = 0.57, 95% CI: 0.44-0.72), moderate (HR = 0.53, 95% CI: 0.39-0.71), and severe (HR = 0.44, 95% CI: 0.34-0.57) depressive symptoms were all associated with a lower chance of listing. Conclusion: Older candidates were less likely to report depressive symptoms at KT evaluation. Regardless of age, candidates who did report depressive symptoms, and even minimal symptoms, had a lower chance of listing. Transplant centers should routinely screen patients for depressive symptoms and refer the affected patients to mental health services to improve access to KT.

Secondary hyperparathyroidism (CKD-MBD) treatment and the risk of dementia.

BACKGROUND: Elevated parathyroid hormone (PTH) levels have been reported as a potential risk factor for cognitive impairment. Compared with the general population, older adults with end-stage renal disease (ESRD) who are frequently affected by secondary hyperparathyroidism (SHPT) are at increased risk of developing dementia. The main objective of our study was to evaluate if the risk of dementia in older (age ≥66 years) ESRD patients differed if they were treated for SHPT. METHODS: Using the United States Renal Data System and Medicare claims, we identified 189 433 older adults without a diagnosis of dementia, who initiated dialysis between 2006 and 2016. SHPT treatment was defined as the use of vitamin D analogs, phosphate binders, calcimimetics or parathyroidectomy. We quantified the association between treated SHPT and incident dementia during dialysis using a multivariable Cox proportional hazards model with inverse probability weighting, considering SHPT treatment as a time-varying exposure. RESULTS: Of 189 433 older ESRD adults, 92% had a claims diagnosis code of SHPT and 123 388 (65%) were treated for SHPT. The rate of incident dementia was 6 cases per 100 person-years among SHPT treated patients compared with 11 cases per 100 person-years among untreated patients. Compared with untreated SHPT patients, the risk of dementia was 42% lower [adjusted hazard ratio (aHR) = 0.58, 95% confidence interval (CI): 0.56-0.59] among SHPT treated patients. The magnitude of the beneficial effect of SHPT treatment differed by sex (Pinteraction = .02) and race (Pinteraction ≤ .01), with females (aHR = 0.56, 95% CI: 0.54-0.58) and those of Asian (aHR = 0.51, 95% CI: 0.46-0.57) or Black race (aHR = 0.51, 95% CI: 0.48-0.53) having a greatest reduction in dementia risk. CONCLUSION: Receiving treatment for SHPT was associated with a lower risk of incident dementia among older patients with ESRD. This work provides additional support for the treatment of SHPT in older ESRD patients.

Frailty-a risk factor of global and domain-specific cognitive decline among a nationally representative sample of community-dwelling older adult U.S. Medicare beneficiaries.

OBJECTIVES: frail older adults may be more vulnerable to stressors, resulting in steeper declines in cognitive function. Whether the frailty-cognition link differs by cognitive domain remains unclear; however, it could lend insight into underlying mechanisms. METHODS: we tested whether domain-specific cognitive trajectories (clock-drawing test, (CDT), immediate and delayed recall, orientation to date, time, president and vice-president naming) measured annually (2011-2016) differ by baseline frailty (physical frailty phenotype) in the National Health and Aging Trends Study (n = 7,439), a nationally representative sample of older adult U.S. Medicare beneficiaries, using mixed effects models to describe repeated measures of each cognitive outcome. To determine if the association between frailty and subsequent cognitive change differed by education, we tested for interaction using the Wald test. RESULTS: we observed steeper declines for frail compared to non-frail participants in each domain-specific outcome, except for immediate recall. Largest differences in slope were observed for CDT (difference = -0.12 (standard deviations) SD/year, 95%CI: -0.15, -0.08). By 2016, mean CDT scores for frail participants were 1.8 SD below the mean (95%CI: -1.99, -1.67); for non-frail participants, scores were 0.8 SD below the mean (95%CI: -0.89, -0.69). Associations differed by education for global cognitive function (Pinteraction < 0.001) and for each domain-specific outcome: CDT (Pinteraction < 0.001), orientation (Pinteraction < 0.001), immediate (Pinteraction < 0.001) and delayed (Pinteraction < 0.001) word recalls. CONCLUSION: frailty is associated with lower levels and steeper declines in cognitive function, with strongest associations for executive function. These findings suggest that aetiologies are multifactorial, though primarily vascular related; further research into its association with dementia sub-types and related pathologies is critical.

Benzodiazepines, Codispensed Opioids, and Mortality among Patients Initiating Long-Term In-Center Hemodialysis.

BACKGROUND AND OBJECTIVES: Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing. RESULTS: Within 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; Pinteraction<0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (Pinteraction=0.72). CONCLUSIONS: Codispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.

Fractures and Subsequent Graft Loss and Mortality among Older Kidney Transplant Recipients.

OBJECTIVES: Older adults who undergo kidney transplantation (KT) are living longer with a functioning graft and are at risk for age-related adverse events including fractures. Understanding recipient, transplant, and donor factors and the outcomes associated with fractures may help identify older KT recipients at increased risk. We determined incidence of hip, vertebral, and extremity fractures; assessed factors associated with incident fractures; and estimated associations between fractures and subsequent death-censored graft loss (DCGL) and mortality. DESIGN: This was a prospective cohort study of patients who underwent their first KT between January 1, 1999, and December 31, 2014. SETTING: We linked data from the Scientific Registry of Transplant Recipients to Medicare claims through the US Renal Data System. PARTICIPANTS: The analytic population included 47 815 KT recipients aged 55 years or older. MEASUREMENTS: We assessed the cumulative incidence of and factors associated with post-KT fractures (hip, vertebral, or extremity) using competing risks models. We estimated risk of DCGL and mortality after fracture using adjusted Cox proportional hazards models. RESULTS: The 5-year incidence of post-KT hip, vertebral, and extremity fracture for those aged 65 to 69 years was 2.2%, 1.0%, and 1.7%, respectively. Increasing age was associated with higher hip (adjusted hazard ratio [aHR] = 1.37 per 5-y increase; 95% confidence interval [CI] = 1.30-1.45) and vertebral (aHR = 1.31; 95% CI = 1.20-1.42) but not extremity (aHR = .97; 95% CI = .91-1.04) fracture risk. DCGL risk was higher after hip (aHR = 1.34; 95% CI = 1.12-1.60) and extremity (aHR = 1.30; 95% CI = 1.08-1.57) fracture. Mortality risk was higher after hip (aHR = 2.31; 95% CI = 2.11-2.52), vertebral (aHR = 2.80; 95% CI = 2.44-3.21), and extremity (aHR = 1.85; 95% CI = 1.64-2.10) fracture. CONCLUSION: Our findings suggest that older KT recipients are at higher risk for hip and vertebral fracture but not extremity fracture; and those with hip, vertebral, or extremity fracture are more likely to experience subsequent graft loss or mortality. These findings underscore that different fracture types may have different underlying etiologies and risks, and they should be approached accordingly. J Am Geriatr Soc 67:1680-1688, 2019.

Comorbidity, Frailty, and Waitlist Mortality among Kidney Transplant Candidates of All Ages.

BACKGROUND: Kidney transplantation (KT) candidates often present with multiple comorbidities. These patients also have a substantial burden of frailty, which is also associated with increased mortality. However, it is unknown if frailty is merely a surrogate for comorbidity, itself an independent domain of risk, or if frailty and comorbidity have differential effects. Better understanding the interplay between these 2 constructs will improve clinical decision making in KT candidates. OBJECTIVE: To test whether comorbidity is equally associated with waitlist mortality among frail and nonfrail KT candidates and to test whether measuring both comorbidity burden and frailty improves mortality risk prediction. METHODS: We studied 2,086 candidates on the KT waitlist (November 2009 - October 2017) in a multicenter cohort study, in whom frailty and comorbidity were measured at evaluation. We quantified the association between Charlson comorbidity index (CCI) adapted for end-stage renal disease and waitlist mortality using an adjusted Cox proportional hazards model and tested whether this association differed between frail and nonfrail candidates. RESULTS: At evaluation, 18.1% of KT candidates were frail and 51% had a high comorbidity burden (CCI score ≥2). Candidates with a high comorbidity burden were at 1.38-fold (95% CI 1.01-1.89) increased risk of waitlist mortality. However, this association differed by frailty status (p for interaction = 0.01): among nonfrail candidates, a high comorbidity burden was associated with a 1.66-fold (95% CI 1.17-2.35) increased mortality risk; among frail candidates, here was no statistically significant association (HR 0.75, 95% CI 0.44-1.29). Adding this interaction between comorbidity and frailty to a mortality risk estimation model significantly improved prediction, increasing the c-statistic from 0.640 to 0.656 (p < 0.001). CONCLUSIONS: Nonfrail candidates with a high comorbidity burden at KT evaluation have an increased risk of waitlist mortality. Importantly, comorbidity is less of a concern in already high-risk patients who are frail.