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American Journal of Kidney Diseases

Frailty, Kidney Function, and Polypharmacy: The Atherosclerosis Risk in Communities (ARIC) Study

Published:November 21, 2016DOI:https://doi.org/10.1053/j.ajkd.2016.08.034

      Background

      Frail individuals are at increased risk for poor outcomes, including adverse drug events. Kidney function is often compromised in frailty and is a key consideration in medication choice and dosing; however, creatinine-based measures of kidney function may be biased in frail individuals.

      Study Design

      Observational study.

      Setting & Participants

      4,987 community-dwelling older men and women with complete data who participated in visit 5 of the Atherosclerosis Risk in Communities (ARIC) Study (2011-2013).

      Predictors

      Kidney measures included glomerular filtration rate (GFR) estimated using serum creatinine (eGFRcr) and serum cystatin C level (eGFRcys) and urine albumin-creatinine ratio.

      Outcome

      Frailty, defined using established criteria of 3 or more frailty characteristics (weight loss, slowness, exhaustion, weakness, and low physical activity).

      Results

      341 (7%) participants were classified as frail, 1,475 (30%) had eGFRcr < 60 mL/min/1.73 m2, 2,480 (50%) had eGFRcys < 60 mL/min/1.73 m2, and 1,006 (20%) had albuminuria with albumin excretion ≥ 30 mg/g. Among frail participants, prevalences of eGFRcr and eGFRcys < 60 mL/min/1.73 m2 were 45% and 77%, respectively. Adjusted for covariates, frailty showed a moderate association with eGFRcr and a strong association with eGFRcys and albumin-creatinine ratio. Frail individuals with eGFRcr of 60 to <75 mL/min/1.73 m2 were frequently reclassified to lower eGFR categories using eGFRcys (49% to 45-<60, 32% to 30-<45, and 3% to <30 mL/min/1.73 m2). Hyperpolypharmacy (taking ≥10 classes of medications) was more common in frail individuals (54% vs 38% of nonfrail), including classes requiring kidney clearance (eg, digoxin) and associated with falls and subsequent complications (eg, hypnotic/sedatives and anticoagulants).

      Limitations

      Cross-sectional study design.

      Conclusions

      Frail individuals had a high prevalence of reduced kidney function, with large discrepancies when reduced kidney function was classified by eGFRcys versus eGFRcr. Given the substantial medication burden and uncertainty in chronic kidney disease classification, confirmation of kidney function with alternative biomarkers may be warranted to ensure careful prescribing practices in this vulnerable population.

      Index Words

      Frailty is a phenotype of multisystem dysregulation.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      National data from the United States suggest that 15% of community-dwelling persons 65 years or older are frail and 45% are prefrail.
      • Bandeen-Roche K.
      • Seplaki C.L.
      • Huang J.
      • et al.
      Frailty in older adults: a nationally representative profile in the United States.
      The high prevalence of frailty is a significant public health problem. The older adult population is growing, and frailty is associated with increased risk for disability, hospitalization, and mortality.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      • Bandeen-Roche K.
      • Seplaki C.L.
      • Huang J.
      • et al.
      Frailty in older adults: a nationally representative profile in the United States.
      • Zaslavsky O.
      • Cochrane B.B.
      • Thompson H.J.
      • Woods N.F.
      • Herting J.R.
      • LaCroix A.
      Frailty: a review of the first decade of research.
      • Shamliyan T.
      • Talley K.M.
      • Ramakrishnan R.
      • Kane R.L.
      Association of frailty with survival: a systematic literature review.
      Frail individuals are more susceptible to adverse outcomes, including adverse drug effects such as delirium and falls. These risks may be aggravated by inappropriate use and dosing of individual drugs, as well as polypharmacy, a common issue in frail individuals.
      • Hubbard R.E.
      • O'Mahony M.S.
      • Woodhouse K.W.
      Medication prescribing in frail older people.
      A recent study estimated that 39% of adults 65 years and older were taking 5 or more medications.
      • Kantor E.D.
      • Rehm C.D.
      • Haas J.S.
      • Chan A.T.
      • Giovannucci E.L.
      Trends in prescription drug use among adults in the United States from 1999-2012.
      Chronic kidney disease (CKD) is another public health problem that disproportionately affects older adults, has significant consequences for drug dosing, and has been associated with a higher prevalence of frailty.
      • Coresh J.
      • Selvin E.
      • Stevens L.A.
      • et al.
      Prevalence of chronic kidney disease in the United States.
      • Hallan S.I.
      • Coresh J.
      • Astor B.C.
      • et al.
      International comparison of the relationship of chronic kidney disease prevalence and ESRD risk.
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • et al.
      Kidney function and prevalent and incident frailty.
      • Shlipak M.G.
      • Stehman-Breen C.
      • Fried L.F.
      • et al.
      The presence of frailty in elderly persons with chronic renal insufficiency.
      • Bowling C.B.
      • Muntner P.
      Epidemiology of chronic kidney disease among older adults: a focus on the oldest old.
      • Walker S.R.
      • Brar R.
      • Eng F.
      • et al.
      Frailty and physical function in chronic kidney disease: the CanFIT study.
      • Wilhelm-Leen E.R.
      • Hall Y.N.
      • Tamura M.K.
      • Chertow G.M.
      Frailty and chronic kidney disease: the Third National Health and Nutrition Evaluation Survey.
      • Bohm C.
      • Storsley L.
      • Tangri N.
      The assessment of frailty in older people with chronic kidney disease.
      • Chang S.S.
      • Weiss C.O.
      • Xue Q.L.
      • Fried L.P.
      Association between inflammatory-related disease burden and frailty: results from the Women's Health and Aging Studies (WHAS) I and II.
      • Roshanravan B.
      • Khatri M.
      • Robinson-Cohen C.
      • et al.
      A prospective study of frailty in nephrology-referred patients with CKD.
      • Reese P.P.
      • Cappola A.R.
      • Shults J.
      • et al.
      Physical performance and frailty in chronic kidney disease.
      However, previous studies have relied on serum creatinine level for estimating kidney function, which is problematic in frailty because estimation of glomerular filtration rate (GFR) from serum creatinine level assumes similar muscle mass across all individuals of the same age, sex, and race; frail individuals often have sarcopenia. Few studies have examined the relationship between frailty and kidney function measured by level of cystatin C, an alternative kidney filtration marker less influenced by muscle mass and diet.
      • Dalrymple L.S.
      • Katz R.
      • Rifkin D.E.
      • et al.
      Kidney function and prevalent and incident frailty.
      • Roshanravan B.
      • Khatri M.
      • Robinson-Cohen C.
      • et al.
      A prospective study of frailty in nephrology-referred patients with CKD.
      In addition, little has been done to investigate the independent association between frailty and albuminuria, a key component of the new CKD classification system.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      Thus, the relationship between frailty and kidney function assessed with different filtration markers could have significant public health impact in the prescription of medications requiring adjustment in dosing or monitoring in kidney disease.
      We investigated the cross-sectional association of frailty with kidney function as measured by both established and novel biomarkers (creatinine, cystatin C, and urine albumin) in a biracial population-based cohort of men and women 66 years or older, comparing the strength of associations between the alternative biomarkers. We then investigated the clinical implications of accurate assessment of kidney function in frail individuals by quantifying medication use and in particular, medications that are cleared by the kidney.

      Methods

      Study Population

      The Atherosclerosis Risk in Communities (ARIC) Study cohort was established in 1987 as a prospective cohort of 15,792 men and women aged 45 to 64 years from the following 4 communities in the United States: suburban Minneapolis, MN; Forsyth County, NC; Washington County, MD; and Jackson, MS. Extensive physical examinations were performed at baseline and at 4 subsequent clinic visits. Participants in the ARIC cohort were selected for the present study if they completed the fifth clinical examination (visit 5, 2011-2013; n = 6,538). We excluded participants whose race was not white or black (n = 18), black participants from Minnesota (n = 9) and Maryland (n = 16), individuals who were missing data for other covariates (n = 1,410), and individuals missing the frailty components (n = 98). Thus, 4,987 participants were included in the final study population. The ARIC Study has been approved by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board (IRB number: H.34.99.07.02.A1), and all participants provided informed consent.

      Frailty Definition

      We identified frail individuals at the visit 5 clinical examination using the operational definition developed by Fried et al,
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      which includes 5 components: (1) weight loss, (2) slowness, (3) exhaustion, (4) weakness, and (5) low physical activity. The ARIC-specific classification of the presence of the components has been previously described.
      • Kucharska-Newton A.
      • Palta P.
      • Burgard S.
      • et al.
      Operationalizing frailty in the Atherosclerosis Risk in Communities (ARIC) Study cohort.
      Briefly, weight loss was classified as an unintentional weight loss of 10% between visits 4 (1996-1998) and 5 (2011-2013) or body mass index (BMI) < 18.5 kg/m2 at visit 5. Slowness was classified as the 20th percentile in sex- and height-adjusted gait speed during a 4-m walk test using previous population-based thresholds.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      Exhaustion was classified as responding “some of the time” or “most of the time” to 2 questions from the 11-item Center for Epidemiologic Studies−Depression scale
      • Radloff L.S.
      The CES-D Scale: a self-report depression scale for research in the general population.
      • Kohout F.J.
      • Berkman L.F.
      • Evans D.A.
      • Cornoni-Huntley J.
      Two shorter forms of the CES-D (Center for Epidemiological Studies Depression) depression symptoms index.
      : “I felt everything I did was an effort” and “I could not get ‘going’.” Weakness was classified as the 20th percentile in sex- and BMI-specific grip strength based on population-based cut points.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      Low physical activity was classified as the 20th percentile in sex-specific Baecke leisure sport activity index.
      • Baecke J.A.
      • Burema J.
      • Frijters J.E.
      A short questionnaire for the measurement of habitual physical activity in epidemiological studies.
      Participants were characterized as frail if 3 or more of the components were present. Using a conservative approach, participants missing information for any of the component characteristics were classified as missing the frailty phenotype unless 3 or 4 frail components were present among the nonmissing components. These participants were classified as frail.

      Kidney Measures

      We estimated GFR from serum creatinine and serum cystatin C using the 2009 CKD-EPI (CKD Epidemiology Collaboration) creatinine equation
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      (eGFRcr) and the 2012 CKD-EPI cystatin C equation
      • Inker L.A.
      • Eckfeldt J.
      • Levey A.S.
      • et al.
      Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values.
      (eGFRcys). Serum creatinine was measured using a creatinase enzymatic method on a Roche Modular P Chemistry Analyzer (Roche Diagnostics) and standardized to isotope-dilution mass spectrometry. Serum cystatin C was measured by a turbidimetric method (Gentian AS), calibrated and standardized to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference.
      • Grubb A.
      • Blirup-Jensen S.
      • Lindstrom V.
      • et al.
      First certified reference material for cystatin C in human serum ERM-DA471/IFCC.
      Albuminuria was defined as the ratio of urine albumin to urine creatinine (ACR). Urine creatinine was measured by the modified kinetic Jaffé method. Albumin was measured from urine samples by a nephelometric method on either the Dade Behring BN100 or the Beckman Image Nephelometer.

      Measurement of Other Covariates

      Trained study personnel and research technicians took all physical measurements and administered all questionnaires following a standardized protocol that included quality control measures during the visit 5 clinical examination. Race was classified as black or white. Education was categorized as less than high school, high school or equivalent, and college/graduate school. Cigarette smoking and alcohol consumption were categorized as current user or never/former user.
      BMI was defined as weight (in kilograms) divided by height (in meters) squared. Diabetes was defined as self-reported history of physician diagnosis, antidiabetic medication use during the past 2 weeks, fasting blood glucose level ≥ 126 mg/dL, or nonfasting blood glucose level ≥ 200 mg/dL. Certified technicians measured blood pressure 3 times with participants in the sitting position after a 5-minute rest, using a validated automatic sphygmomanometer (Omron HEM-907 XL), and the average of the last 2 readings was recorded. Anemia was defined using sex-specific cut points for hemoglobin (based on the World Health Organization definition,
      World Health Organization
      Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System.
       <12 g/dL for nonpregnant women and <13 g/dL for men). C-Reactive protein was included as a marker of inflammation. Prevalent cardiovascular disease (including coronary heart disease, peripheral artery disease, heart failure, and stroke) was established by self-report at visit 1 or an adjudicated event between visits 1 and 5. Reduced kidney function was defined as eGFRcr or eGFRcys < 60 mL/min/1.73 m2.
      All medication use was self-reported by participants and confirmed by staff from medications brought to the visit. Polypharmacy was defined as use of 5 or more medication classes; hyperpolypharmacy was defined as use of 10 or more medication classes. Each drug class was examined in relation to frailty prevalence.

      Statistical Analysis

      Crude proportions and mean values were used to describe demographics, health behaviors, risk factors, and comorbid conditions according to frailty status. Differences between groups in univariate analyses were assessed using χ2 test for categorical variables and 2-sample t test or analysis of variance for continuous variables, as appropriate.
      Associations between kidney measures and frailty were assessed using Poisson regression models to estimate prevalence ratios. eGFR and ACR were analyzed in categories (<30, 30-<45, 45-<60, and ≥60 mL/min/1.73 m2 and <30, 30-<300, and ≥300 mg/g, respectively). When included as covariates in other models, eGFR and ACR (log-transformed ACR) were examined continuously. Prevalence of frailty was also examined by kidney function categorized by eGFR and albuminuria stage according to the KDIGO (Kidney Disease: Improving Global Outcomes) CKD guideline (ie, G1-G5 and A1-A3).
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      Model 1 included age (continuous), sex, race/center, and education. Model 2 included all variables in model 1 plus smoking status and alcohol consumption. Model 3 included all variables in model 2 plus relevant comorbid conditions of BMI, systolic blood pressure, anemia, inflammation, prevalent cardiovascular disease, diabetes, hypertension medication use, and statin medication use. Because diabetes mellitus is one of the most common causes of CKD in older adults and also a strong predictor of frailty,
      • Garcia-Esquinas E.
      • Graciani A.
      • Guallar-Castillon P.
      • Lopez-Garcia E.
      • Rodriguez-Manas L.
      • Rodriguez-Artalejo F.
      Diabetes and risk of frailty and its potential mechanisms: a prospective cohort study of older adults.
      we performed stratified analysis by diabetes status to determine differences by categories of both eGFR and ACR.
      Unadjusted eGFRcr and eGFRcys categories (<30, 30-<45, 45-<60, 60-<75, 75-<90, and ≥90 mL/min/1.73 m2) were cross-tabulated to determine the number of individuals reclassified up or down to different categories when using eGFRcys instead of eGFRcr. We also evaluated the categorical net reclassification improvement for categories of GFR (<30, 30-<45, 45-<60, and ≥60 mL/min/1.73 m2 and <30, 30-<60, and ≥60 mL/min/1.73 m2) with frailty.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      • D'Agostino Jr., R.B.
      • Vasan R.S.
      Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
      Associations of medication classes and frailty were assessed using crude proportions, as well as with unadjusted and demographically adjusted Poisson regression models.
      All P values were 2 sided, and P < 0.05 was considered statistically significant. Statistical analyses were conducted using Stata, version 13.0 (StataCorp LP).

      Results

      Baseline Characteristics by Frailty Status

      Among the 4,987 participants, 341 were classified as frail (Table 1). Those who were frail were older (mean age, 78.0 vs 75.4 years) and more likely to be women (64.8% vs 55.1%) than participants who were not frail. There was no statistically significant difference in the prevalence of frailty by race. Individuals who were classified as frail had lower levels of education, were less likely to be current alcohol users, and had a slightly higher BMI than participants who were not frail. There was no significant difference in smoking status or systolic blood pressures. Frail individuals were more likely to have diabetes (53.1% vs 37.5%). Among participants with diabetes, frail individuals had similar hemoglobin A1c levels but had a longer duration of disease (mean, 12.5 ± 6.4 [standard deviation] vs 10.7 ± 6.3 years; P < 0.001). Frail individuals were also more likely to have prevalent cardiovascular disease, anemia, and an elevated inflammatory marker (C-reactive protein) level.
      Table 1Characteristics by Frailty Status
      CharacteristicNot FrailFrailP
      No. of participants (%)4,646 (93.2)341 (6.8)
      Age, y75.4 ± 5.178.0 ± 5.6<0.001
      Female sex2,561 (55.1)221 (64.8)0.001
      Black race1,029 (22.1)84 (24.6)0.3
      Education level<0.001
       <HS611 (13.2)76 (22.3)
       HS, GED, or vocational school1,914 (41.2)163 (47.8)
       College, graduate, or professional school2,121 (45.7)102 (29.9)
      Smoking status0.5
       Current271 (5.8)23 (6.7)
       Former/never4,375 (94.2)318 (93.3)
      Alcohol consumption<0.001
       Current2,359 (50.8)115 (33.7)
       Former/never2,287 (49.2)226 (66.3)
      BMI, kg/m228.7 ± 5.629.8 ± 7.1<0.001
      Systolic blood pressure, mm Hg130.6 ± 17.9132.0 ± 20.70.2
      eGFRcr, mL/min/1.73 m269.6 ± 17.161.8 ± 19.9<0.001
      eGFRcys, mL/min/1.73 m261.8 ± 19.147.4 ± 17.4<0.001
      ACR, log-transformed2.3 [1.8-3.1]3.0 [2.1-4.0]<0.001
      DM1,744 (37.5)181 (53.1)<0.001
       Hemoglobin A1c (%)
      For participants with DM.
      6.6 ± 1.16.6 ± 1.20.6
       Duration of DM, y10.7 ± 6.312.5 ± 6.4<0.001
      Prevalent cardiovascular disease1,122 (24.1)143 (41.9)<0.001
      Anemia1,200 (25.8)131 (38.4)<0.001
      C-Reactive protein, mg/L3.9 ± 6.65.3 ± 8<0.001
      Any HTN medication3,516 (75.7)298 (87.4)<0.001
      No. of medications taken8.8 ± 4.610.5 ± 5.0<0.001
      Note: Values for categorical variables are given as number (percent); values for continuous variables are given as mean ± standard deviation or median [interquartile range].
      Abbreviations: ACR, albumin-creatinine ratio; BMI, body mass index; DM, diabetes mellitus; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C−based estimated glomerular filtration rate; GED, General Education Development; HS, high school; HTN, hypertension.
      a For participants with DM.

      Frailty and CKD

      Reduced eGFR (<60 mL/min/1.73 m2) was common in frail individuals, but the proportion with eGFRs < 60 mL/min/1.73 m2 was much greater when kidney function was estimated using eGFRcys compared to eGFRcr (77% vs 45%). In univariate analyses, both eGFRcr and eGFRcys were inversely associated with frailty. Compared to eGFRcr ≥ 60 mL/min/1.73 m2, eGFRcr < 30, 30 to <45, and 45 to <60 mL/min/1.73 m2 were significantly associated with frailty in a demographic-adjusted model (model 1; Table 2). This association remained significant when further adjusted for health behaviors (model 2), but was attenuated in the fully adjusted model (model 3) and the only significant category was eGFR < 30 mL/min/1.73 m2; Fig 1). When kidney function was assessed using eGFRcys, categories of <30, 30 to <45, and 45 to <60 mL/min/1.73 m2 were all significantly associated with frailty in a graded manner; this association was present in all models. Although diabetes was associated with frailty in all analyses (prevalence ratios in fully adjusted models for eGFRcr and eGFRcys of 1.35 [95% CI, 1.08-1.68] and 1.32 [95% CI, 1.06-1.65], respectively), relationships between eGFR and frailty were similar within categories of diabetes and no diabetes and consistently stronger when using eGFRcys (Fig S1, available as online supplementary material).
      Table 2Prevalence Ratios for Frailty Associated With eGFRcr, eGFRcys, and ACR
      Unadjusted Prevalence, % Frail (No. Frail/Total No.)PR (95% CI)
      Model 1Model 2Model 3
      eGFRcr category
       ≥605.3% (186/3,512)1.00 (reference)1.00 (reference)1.00 (reference)
       45-<608.5% (86/1,012)1.35
      P ≤ 0.05.
      (1.05-1.74)
      1.34
      P ≤ 0.05.
      (1.04-1.71)
      1.16 (0.90-1.49)
       30-<4512.7% (47/369)1.86
      P ≤ 0.001.
      (1.35-2.55)
      1.84
      P ≤ 0.001.
      (1.34-2.52)
      1.23 (0.89-1.70)
       <3023.4% (22/94)3.40
      P ≤ 0.001.
      (2.21-5.21)
      3.34
      P ≤ 0.001.
      (2.17-5.12)
      1.83
      P ≤ 0.01.
      (1.18-2.84)
      P for trend<0.001<0.0010.02
      eGFRcys category
       ≥603.1% (77/2,507)1.00 (reference)1.00 (reference)1.00 (reference)
       45-<607.9% (110/1,386)2.17
      P ≤ 0.001.
      (1.62-2.90)
      2.10
      P ≤ 0.001.
      (1.57-2.82)
      1.85
      P ≤ 0.001.
      (1.38-2.47)
       30-<4512.3% (103/838)3.08
      P ≤ 0.001.
      (2.29-4.15)
      2.98
      P ≤ 0.001.
      (2.21-4.02)
      2.19
      P ≤ 0.001.
      (1.62-2.97)
       <3019.9% (51/256)4.76
      P ≤ 0.001.
      (3.31-6.83)
      4.62
      P ≤ 0.001.
      (3.21-6.63)
      2.59
      P ≤ 0.001.
      (1.75-3.85)
      P for trend<0.001<0.001<0.001
      ACR
       <305.5% (217/3,981)1.00 (reference)1.00 (reference)1.00 (reference)
       30-<30011.6% (100/865)1.83
      P ≤ 0.001.
      (1.44-2.31)
      1.80
      P ≤ 0.001.
      (1.42-2.27)
      1.53
      P ≤ 0.001.
      (1.21-1.95)
       ≥30017.0% (24/141)2.75
      P ≤ 0.001.
      (1.82-4.15)
      2.78
      P ≤ 0.001.
      (1.84-4.19)
      1.95
      P ≤ 0.01.
      (1.28-2.97)
      P for trend<0.001<0.001<0.001
      Note: eGFRs expressed in mL/min/1.73 m2, and ACRs, in mg/g. Model 1: eGFR or ACR plus demographics (age, sex, race-center, and education); model 2: model 1 plus health behaviors (smoking status and alcohol consumption); model 3: model 2 plus comorbid conditions (body mass index, systolic blood pressure, anemia [hemoglobin], inflammation [C-reactive protein], cardiovascular disease [history of coronary heart disease, peripheral artery disease, heart failure, and stroke], diabetes, hypertension medication use, and statin medication use) and either urine ACR (log-transformed) or eGFR.
      Abbreviations: ACR, albumin-creatinine ratio; CI, confidence interval; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C−based estimated glomerular filtration rate; PR, prevalence ratio.
      a P ≤ 0.05.
      b P ≤ 0.001.
      c P ≤ 0.01.
      Figure thumbnail gr1
      Figure 1Adjusted prevalence ratios for frailty status by estimated glomerular filtration rate (eGFR). Prevalence ratios adjusted for age, sex, race-center, education, smoking status, alcohol consumption, body mass index, systolic blood pressure, anemia (hemoglobin), inflammation (C-reactive protein), cardiovascular disease (history of coronary heart disease, peripheral artery disease, heart failure, and stroke), diabetes, hypertension medications use, statin medication use), and albumin-creatinine ratio (log-transformed). Abbreviations: CI, confidence interval; eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C−based estimated glomerular filtration rate.
      Categories of ACR of 30 to <300 mg/g and ≥300 mg/g were also strongly associated with frailty, and the association remained in the fully adjusted models (Fig 2). Relationships between albuminuria and frailty were similar within categories of diabetes and no diabetes (Fig S2).
      Figure thumbnail gr2
      Figure 2Adjusted prevalence ratios for frailty status by albumin-creatinine ratio (ACR). Prevalence ratios adjusted for age, sex, race-center, education, smoking status, alcohol consumption, body mass index, systolic blood pressure, anemia (hemoglobin), inflammation (C-reactive protein), cardiovascular disease (history of coronary heart disease, peripheral artery disease, heart failure, and stroke), diabetes, hypertension medications use, statin medication use), and estimated glomerular filtration rate. Abbreviation: CI, confidence interval.
      When taking into account both eGFR stage and albuminuria stage, the relationship between eGFR stage and frailty was stronger for eGFRcys compared to eGFRcr (Figs 3 and S3). In demographic-adjusted analyses, prevalence of frailty generally increased with higher stage of eGFRcr and albuminuria (prevalence ratios increasing from 1.4 [95% CI, 1.0-1.9] to 5.5 [95% CI, 3.0-10.3]). The relationship was more pronounced when examining by stage of eGFRcys and albuminuria, with prevalence ratios of frailty increasing from 1.9 (95% CI, 1.1-3.2) to 7.2 (95% CI, 3.9-13.1); reference group: eGFRcys ≥ 60 mL/min/1.73 m2 and ACR < 30 mg/g).
      Figure thumbnail gr3
      Figure 3Demographically adjusted prevalence ratios (95% confidence intervals [CIs]) of frailty by (A) creatinine-based estimated glomerular filtration rate (eGFRcr) or (B) cystatin C−based eGFR (eGFRcys) and albuminuria category. P ≤ 0.05; ∗∗P ≤ 0.01; ∗∗∗P ≤ 0.001.

      Implications of Frailty and Reduced Kidney Function: Reclassification Based on Cystatin C

      Overall, eGFRcr categorized 30% of this older adult study sample as <60 mL/min/1.73 m2 compared to 50% using eGFRcys (Tables S1-S3). Of those with eGFRcr ≥ 60 mL/min/1.73 m2, 33% were reclassified as <60 mL/min/1.73 m2 using eGFRcys. These differences were more pronounced in the frail than in the nonfrail individuals (Table 3). For individuals with eGFRcr ≥ 60 mL/min/1.73 m2, eGFRcys reclassified 31.3% to be <60 mL/min/1.73 m2 among nonfrail individuals and 62.4% to be <60 mL/min/1.73 m2 among frail individuals. Similarly, within the narrow range of eGFRcr of 60 to <75 mL/min/1.73 m2, those who were reclassified to eGFRcys of 45 to <60 mL/min/1.73 m2 were more likely to be frail than those who were not reclassified (7.3% vs 2.1%). The net reclassification improvement was positive (favoring eGFRcys) when using eGFR categories of <30, 30 to <45, 45 to <60, and ≥60 mL/min/1.73 m2 and categories of <30, 30 to <60, and ≥60 mL/min/1.73 m2 with frailty: estimated at 0.153 (95% CI, 0.070-0.235) and 0.092 (95% CI, 0.020-0.163), respectively.
      Table 3Reclassification Across eGFRcys on eGFRcr in Nonfrail and Frail Participants
      eGFRcr CategoryeGFRcys Category
      ≥9075-<9060-<7545-<6030-<45<30Total
      Nonfrail
      ≥90157 (38.2%)134 (32.6%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      92 (22.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      25 (6.1%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      3 (0.7%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      411
      75-<90198 (13.0%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      457 (30.0%)552 (36.2%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      270 (17.7%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      47 (3.1%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      1,524
      60-<7533 (2.4%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      156 (11.2%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      506 (36.4%)560 (40.3%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      131 (9.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      5 (0.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      1,391
      45-<605 (0.5%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      21 (1.9%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      143 (13.1%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      456 (41.7%)431 (39.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      31 (3.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      926
      30-<451 (0.3%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      2 (0.6%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      33 (10.3%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      185 (57.5%)101 (31.4%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      322
      <304 (5.6%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      68 (94.4%)72
      Total3947621,2741,276735205
      Frail
      ≥902 (8.7%)5 (21.7%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      10 (43.5%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      6 (26.1%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      23
      75-<901 (1.4%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      11 (15.1%)27 (37.0%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      27 (37.0%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      7 (9.6%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      73
      60-<753 (3.3%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      11 (12.2%)44 (48.9%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      29 (32.2%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      3 (3.3%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      90
      45-<607 (8.1%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      31 (36.1%)45 (52.3%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      3 (3.5%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      86
      30-<452 (4.3%)
      Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.
      22 (46.8%)23 (48.9%)
      Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      47
      <3022 (100%)22
      Total3195511010351
      Note: Values are given as n (row percentage). eGFRcr categories expressed in mL/min/1.73 m2.
      Abbreviations: eGFRcr, creatinine-based estimated glomerular filtration rate; eGFRcys, cystatin C−based estimated glomerular filtration rate.
      a Reclassification to lower eGFR categories using eGFRcys compared to eGFRcr.
      b Reclassification to higher eGFR categories using eGFRcys compared to eGFRcr.

      Implications of Frailty and Reduced Kidney Function: Medication Use

      Although polypharmacy was seen in the majority of the study population (84%), frail participants took a greater number of medications than participants who were not frail. For example, hyperpolypharmacy was seen in 54.0% of frail individuals versus 38.4% of the nonfrail (P < 0.001). In addition, several medication classes were used more frequently among frail individuals than nonfrail individuals (Table S4). In particular, certain medications requiring precaution or dosing adjustment in CKD were more prevalent in frail individuals, including digoxin (4.4% vs 1.6%), metformin (15.0% vs 11.6%), and anticoagulation (12.0% vs 7.3%), as well as the class of hypnotic/sedatives (10.0% vs 7.2%).

      Discussion

      In this biracial cohort of older men and women, frailty was present in 6.8% of the population and was associated with kidney disease. Lower levels of both eGFRcr and eGFRcys and higher albuminuria were independently associated with frailty, with much stronger associations between frailty and eGFR based on cystatin C compared to creatinine. This suggests that there may be uniform overestimation of kidney function among frail individuals given that eGFR is most commonly estimated using serum creatinine level in clinical practice. The implications of overestimation of kidney function in frail individuals could be substantial: we demonstrated that hyperpolypharmacy was common in frail individuals, including many medication classes with clear warnings for use in CKD. Current KDIGO guidelines suggest confirmation of kidney function testing in the diagnosis of CKD; for frail individuals, clinicians may consider repeat testing with an alternative filtration marker or direct measurement of GFR.
      Our results expand on the current literature by providing clear contrasts in the associations between frailty and kidney function based on creatinine level to those based on cystatin C level and presenting detailed data for stage of albuminuria. Serum creatinine level may be inaccurately low in persons with low muscle mass, which can accompany the weakness and weight loss that are part of the definition of frailty. Cystatin C level may be high in the setting of inflammation, but associations between frailty and eGFR based on cystatin C level remained strong even after adjustment for level of C-reactive protein, a measure of inflammation. Given the strength of associations, our results suggest that eGFRcys may be a better marker of kidney function in frail individuals. This could be important in medication dosing, but also in patient counseling. eGFRcys has been shown to have stronger associations with prognosis than eGFRcr, even in the general population.
      • Shlipak M.G.
      • Matsushita K.
      • Arnlov J.
      • et al.
      Cystatin C versus creatinine in determining risk based on kidney function.
      Previous work on the association of albuminuria and frailty was in a referred population of almost all men (81%) and examined only the presence/absence of microalbuminuria without concomitant evaluation of a range of eGFR categories.
      • Roshanravan B.
      • Khatri M.
      • Robinson-Cohen C.
      • et al.
      A prospective study of frailty in nephrology-referred patients with CKD.
      We demonstrated that albuminuria had independent associations with frailty beyond that of eGFR. These findings highlight the importance of increasing awareness for the frailty phenotype and perhaps suggest a need for enhanced albuminuria testing in this vulnerable population. Elevated albuminuria has been shown to have a strong association with risk for bone fractures, cardiovascular disease, end-stage renal disease, and mortality in the general population
      • Matsushita K.
      • van der Velde M.
      • Astor B.C.
      • et al.
      Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
      • Gansevoort R.T.
      • Matsushita K.
      • van der Velde M.
      • et al.
      Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.
      • Daya N.R.
      • Voskertchian A.
      • Schneider A.L.
      • et al.
      Kidney function and fracture risk: the Atherosclerosis Risk in Communities (ARIC) Study.
      and significant absolute risk increases in the older adult population.
      • Hallan S.I.
      • Matsushita K.
      • Sang Y.
      • et al.
      Age and association of kidney measures with mortality and end-stage renal disease.
      The association between CKD and frailty has a number of possible mechanisms. First, associations may be driven by common causes of CKD rather than CKD itself.
      • Walker S.R.
      • Wagner M.
      • Tangri N.
      Chronic kidney disease, frailty, and unsuccessful aging: a review.
      For example, diabetes is one of the most common causes of CKD and has been shown to be associated with increased risk for frailty.
      • Garcia-Esquinas E.
      • Graciani A.
      • Guallar-Castillon P.
      • Lopez-Garcia E.
      • Rodriguez-Manas L.
      • Rodriguez-Artalejo F.
      Diabetes and risk of frailty and its potential mechanisms: a prospective cohort study of older adults.
      However, we demonstrate consistent associations between kidney function and frailty in the presence and absence of diabetes. Alternatively, downstream effects of CKD could mediate the relationship. Often CKD is characterized by an inflammatory state, and higher inflammatory burden has been associated with frailty.
      • Chang S.S.
      • Weiss C.O.
      • Xue Q.L.
      • Fried L.P.
      Association between inflammatory-related disease burden and frailty: results from the Women's Health and Aging Studies (WHAS) I and II.
      In addition, low GFR is associated with erythropoietin deficiency and shortened erythrocyte survival, and lower hemoglobin levels have been associated with frailty, possibly by limiting participation in physical activities or the development of left ventricular hypertrophy.
      • Chaves P.H.
      • Semba R.D.
      • Leng S.X.
      • et al.
      Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II.
      • Pires Corona L.
      • Drumond Andrade F.C.
      • de Oliveira Duarte Y.A.
      • Lebrao M.L.
      The relationship between anemia, hemoglobin concentration and frailty in Brazilian older adults.
      However, our study found that the association between CKD and frailty generally persisted when adjusting for these comorbid diseases, indicating that there may be an independent contribution of CKD to frailty.
      Mitigating polypharmacy and adhering to careful medication dosing may be an important aspect in the management of frail individuals. In our study, >50% of frail individuals were taking 10 or more medications, which is consistent with previous research demonstrating higher medication burden among frail individuals.
      • Gnjidic D.
      • Hilmer S.N.
      • Blyth F.M.
      • et al.
      High-risk prescribing and incidence of frailty among older community-dwelling men.
      • Bennett A.
      • Gnjidic D.
      • Gillett M.
      • et al.
      Prevalence and impact of fall-risk-increasing drugs, polypharmacy, and drug-drug interactions in robust versus frail hospitalised falls patients: a prospective cohort study.
      • Crentsil V.
      • Ricks M.O.
      • Xue Q.L.
      • Fried L.P.
      A pharmacoepidemiologic study of community-dwelling, disabled older women: factors associated with medication use.
      Although frail individuals are more likely to have more comorbid illness warranting the use of prescription medications, these individuals are also at higher risk for adverse events. Frail individuals are at high risk for fractures and falls, which may be precipitated and/or exacerbated by certain medications, such as hypnotic/sedatives, central nervous system–altering medications, and glucocorticoids, all of which were more commonly prescribed among frail persons in our study.
      • Jette N.
      • Lix L.M.
      • Metge C.J.
      • Prior H.J.
      • McChesney J.
      • Leslie W.D.
      Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis.
      • Vestergaard P.
      • Rejnmark L.
      • Mosekilde L.
      Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture.
      • Ensrud K.E.
      • Blackwell T.
      • Mangione C.M.
      • et al.
      Central nervous system active medications and risk for fractures in older women.
      • Buehring B.
      • Viswanathan R.
      • Binkley N.
      • Busse W.
      Glucocorticoid-induced osteoporosis: an update on effects and management.
      In addition, frail individuals in our study were more likely to be taking anticoagulants, which increase bleeding risk after falls.
      • Ho P.
      • Brooy B.L.
      • Hayes L.
      • Lim W.K.
      Direct oral anticoagulants in frail older adults: a geriatric perspective.
      They may also be particularly vulnerable to drug accumulation with medications such as digoxin and other renally cleared medications, particularly if kidney function is misclassified using serum creatinine level.
      • Hubbard R.E.
      • O'Mahony M.S.
      • Woodhouse K.W.
      Medication prescribing in frail older people.
      Greater provider awareness of the frailty phenotype and its associated risks may lead to improved prognosis.
      In considering these results, there are certain strengths and limitations of our study that should be mentioned. The ARIC Study is a community-based cohort of predominantly white and black individuals; other races and ethnicities were not represented in our analyses. This study is also limited to older adults and results may not be generalizable to younger individuals; however, the ARIC population may be representative of the population with the greatest burden of both CKD and frailty. Urine ACR, eGFRcr, and eGFRcys were measured per protocol, limiting confounding by indication for measurement. There is heterogeneity in the existing frailty instruments, but the frailty variable used in these analyses was rigorously derived to accurately capture the frailty phenotype using component measures that are comparable to other study definitions.
      • Buta B.J.
      • Walston J.D.
      • Godino J.G.
      • et al.
      Frailty assessment instruments: systematic characterization of the uses and contexts of highly-cited instruments.
      Although we found strong and statistically significant cross-sectional associations, it is not possible to establish the temporality of the observed associations. We were only able to evaluate relationships in participants attending visit 5 of the ARIC Study, who represent a healthier subset of the surviving ARIC population that may have less severe disease. Medications are typically dosed by creatinine clearance rather than clinically used eGFR, although recent US Food and Drug Administration issuances have amended drug labeling to incorporate eGFR in drug dosage.

      US Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. April 8, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm. Accessed July 12, 2016.

      Finally, for several important measures (eg, smoking status, alcohol consumption, and physical activity), analyses relied on self-reported information.
      In conclusion, this study provides evidence of an independent relationship of reduced kidney function and albuminuria with elevated frailty prevalence in an older biracial community-dwelling cohort, with stronger associations observed using the alternative filtration marker cystatin C compared to creatinine. We demonstrate the clear clinical importance of this finding: frail individuals were commonly taking medications requiring caution or dose adjustment in CKD. Further studies are needed to determine whether greater awareness of the frailty phenotype and more careful assessment of kidney function in frail individuals could improve prognosis.

      Acknowledgements

      The authors thank the staff and participants of the ARIC Study for important contributions.
      Support: The ARIC Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts ( HHSN268201100005C , HHSN268201100006C , HHSN268201100007C , HHSN268201100008C , HHSN268201100009C , HHSN268201100010C , HHSN268201100011C , and HHSN268201100012C ). Neurocognitive data are collected with support by U01 HL096812, HL096814, HL096899, HL096902, and HL096917, with previous brain magnetic resonance imaging examinations funded by R01-HL70825. Dr. McAdams-DeMarco is supported by National Institute on Aging grant K01AG043501 . Dr Selvin was supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants K24DK106414 and 2R01DK089174 . Dr Grams is supported by NIH/NIDDK grant K08DK092287. The funders of this study had no role in the study design; collection, analyses, and interpretation of data; writing of the report; or decision to submit the report for publication.
      Financial Disclosure: The authors declare that they have no other relevant financial interests.
      Contributions: Research idea and study design: SHB, JGG, BGW, JC, ES, MEG; data acquisition: BGW, JC, ES; data analysis/interpretation: SHB, YC, NRD, JGG, BGW, MM-D, JC, ES, MEG; statistical analysis: SHB, YC, NRD; supervision or mentorship: JC, ES, MEG. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. SHB takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
      Peer Review: Evaluated by 3 external peer reviewers, a Statistical Editor, a Co-Editor, and an Acting Editor-in-Chief.

      Supplementary Material

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