Frailty, but not cognitive impairment, improves mortality risk prediction among those with chronic kidney disease-a nationally representative study.

BACKGROUND: Though older adults with chronic kidney disease (CKD) have a greater mortality risk than those without CKD, traditional risk factors poorly predict mortality in this population. Therefore, we tested our hypothesis that two common geriatric risk factors, frailty and cognitive impairment, and their co-occurrence, might improve mortality risk prediction in CKD. METHODS: Among participants aged ≥ 60 years from National Health and Nutrition Examination Survey (2011-2014), we quantified associations between frailty (physical frailty phenotype) and global/domain-specific cognitive function (immediate-recall [CERAD-WL], delayed-recall [CERAD-DL], verbal fluency [AF], executive function/processing speed [DSST], and global [standardized-average of 4 domain-specific tests]) using linear regression, and tested whether associations differed by CKD using a Wald test. We then tested whether frailty, global cognitive impairment (1.5SD below the mean), or their combination improved prediction of mortality (Cox models, c-statistics) compared to base models (likelihood-ratios) among those with and without CKD. RESULTS: Among 3,211 participants, 1.4% were cognitively impaired, and 10.0% were frail; frailty and cognitive impairment co-occurrence was greater among those with CKD versus those without (1.2%vs.0.1%). Frailty was associated with worse global cognitive function (Cohen's d = -0.26SD,95%CI -0.36,-0.17), and worse cognitive function across all domains; these associations did not differ by CKD (pinteractions > 0.05). Mortality risk prediction improved only among those with CKD when accounting for frailty (p[likelihood ratio test] < 0.001) but not cognitive impairment. CONCLUSIONS: Frailty is associated with worse cognitive function regardless of CKD status. While CKD and frailty improved mortality prediction, cognitive impairment did not. Risk prediction tools should incorporate frailty to improve mortality prediction among those with CKD.

Sleep duration and cognitive function among older adults with chronic kidney disease: results from the National Health and Nutrition Examination Survey (2011-2014).

BACKGROUND: Short and long sleep durations are associated with cognitive dysfunction. Given the increased prevalence of sleep abnormalities in the chronic kidney disease (CKD) population, we tested whether the association between sleep duration and cognitive function differed between older adults with and without CKD. METHODS: This was a study of 3215 older adults (age ≥60 years) enrolled in the National Health and Nutrition Examination Survey (2011-14) evaluating sleep duration, cognitive function (immediate recall, delayed recall, verbal fluency, executive function and processing speed and global cognition) and kidney function. We quantified the association between sleep duration and cognitive function using linear regression and tested whether the associations differed among those with CKD and without using a Wald test for interaction. RESULTS: Among 3215 participants, 13.3% reported 2-5 hours of sleep/day, 75.2% reported 6-8 hours, and 11.5% reported ≥9 hours. Persons with CKD were more likely to sleep ≥9 hours [odds ratio 1.73 (95% confidence interval 1.22-2.46)]. Among participants with CKD, those with a sleep duration ≥9 hours demonstrated worse global cognitive function (P for interaction = .01), immediate recall (P for interaction = .01) and verbal fluency (P for interaction = .004) than those with a sleep duration of 6-8 h; no differences were observed for participants with CKD who slept 2-5 hours. Among participants without CKD, sleep was not associated with any measures of cognitive function. CONCLUSIONS: Longer sleep duration is associated with worse cognitive function only among persons with CKD, and global cognition, delayed recall and verbal fluency are particularly affected. Studies should identify interventions to improve sleep patterns and quality in this population.

Chronic kidney disease, physical activity and cognitive function in older adults-results from the National Health and Nutrition Examination Survey (2011-2014).

BACKGROUND: Cognitive impairment is common among persons with chronic kidney disease (CKD), due in part to reduced kidney function. Given that physical activity (PA) is known to mitigate cognitive decline, we examined whether associations between CKD stage and global/domain-specific cognitive function differ by PA. METHODS: We leveraged 3223 participants (≥60 years of age) enrolled in National Health and Nutrition Examination Survey (NHANES, 2011-2014), with at least one measure of objective cognitive function [immediate recall (CERAD-WL), delayed recall (CERAD-DR), verbal fluency (AF), executive function/processing speed (DSST), global (average of four tests) or self-perceived memory decline (SCD)]. We quantified the association between CKD stage {no CKD: estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 and albuminuria [albumin:creatinine ratio (ACR)] <30 mg/g; stages G1-G3: eGFR ≥60 mL/min/1.73 m2 and ACR ≥30 mg/g or eGFR 30-59 mL/min/1.73 m2; stages G4 and G5: eGFR <30 mL/min/1.73 m2} and cognitive function using linear regression (objective measures) and logistic regression (SCD), accounting for sampling weights for nationally representative estimates. We tested whether associations differed by PA [Global Physical Activity Questionnaire, high PA ≥600 metabolic equivalent of task (MET) · min/week versus low PA <600 MET · min/week] using a Wald test. RESULTS: Among NHANES participants, 34.9% had CKD stages G1-G3, 2.6% had stages G4 and G5 and 50.7% had low PA. CKD stages G4 and G5 were associated with lower global cognitive function {difference = -0.38 standard deviation [SD] [95% confidence interval (CI) -0.62 to -0.15]}. This association differed by PA (Pinteraction = 0.01). Specifically, among participants with low PA, those with CKD stages G4 and G5 had lower global cognitive function [difference = -0.57 SD (95% CI -0.82 to -0.31)] compared with those without CKD. Among those with high PA, no difference was found [difference = 0.10 SD (95% CI -0.29-0.49)]. Similarly, the CKD stage was only associated with immediate recall, verbal fluency, executive function and processing speed among those with low PA; no associations were observed for delayed recall or self-perceived memory decline. CONCLUSIONS: CKD is associated with lower objective cognitive function among those with low but not high PA. Clinicians should consider screening older patients with CKD who have low PA for cognitive impairment and encourage them to meet PA guidelines.

Retinopathy and Risk of Kidney Disease in Persons With Diabetes.

RATIONALE & OBJECTIVE: Retinopathy and chronic kidney disease (CKD) are typically considered microvascular complications of diabetes, and cardiovascular and cerebrovascular diseases are considered macrovascular complications; however, all may share common pathological mechanisms. This study quantified the association of retinopathy with risk of kidney disease and compared with the association with cardiovascular disease in persons with diabetes. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,759 participants in the ARIC study who had diabetes at visit 4 and underwent retinal examination at visit 3. EXPOSURE: Retinopathy. OUTCOME: Prevalent CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2), prevalent albuminuria (urinary albumin-creatinine ratio [UACR] > 30 mg/g), incident CKD, incident end-stage kidney disease (ESKD), incident coronary heart disease (CHD), and incident stroke. ANALYTICAL APPROACH: The cross-sectional association of retinopathy with prevalent CKD and albuminuria was assessed by logistic regression. The associations between retinopathy, incident CKD, incident ESKD, incident CHD, and incident stroke were examined using Cox proportional hazards models. Seemingly unrelated regression was used to compare the strength of association between retinopathy and outcomes. RESULTS: During the median follow-up period of 14.2 years, 723 participants developed CKD, and there were 109 ESKD events, 399 CHD events, and 196 stroke events. Compared with the participants without retinopathy, participants with retinopathy were more likely to have reduced eGFR (OR, 1.56 [95% CI, 1.09-2.23]) and UACR > 30 mg/g (OR, 1.61 [95% CI, 1.24-2.10]). Retinopathy was associated with risk of incident CKD (HR, 1.22 [95% CI, 1.02-1.46]), ESKD (HR, 1.69 [95% CI, 1.11-2.58]), CHD (HR, 1.46 [95% CI, 1.15-1.84]), and stroke (HR, 1.43 [95% CI, 1.03-1.97]). A stronger relationship was found between retinopathy and CHD when compared with retinopathy and CKD (P = 0.03); all other associations were similar. LIMITATIONS: Retinal examination and kidney measurements were taken at different visits. CONCLUSIONS: The presence of retinopathy was associated with higher prevalence of kidney disease and higher risk of incident CKD, ESKD, and CHD. These results may suggest that a similar mechanism underlies the development of retinopathy and other adverse outcomes in diabetes.

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.