Kidney Function And Disability-Free Survival in Older Women

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Alyson M. Cavanaugh, et al

OBJECTIVES: To examine the prospective association between kidney function and three outcomes: survival to age 85 with functional independence, survival to age 85 with a disability, and death before age 85. DESIGN: Prospective study. SETTING: Women's Health Initiative, conducted at 40 U.S. clinical centers. PARTICIPANTS: Postmenopausal women enrolled between 1993 and 1998 with baseline biomarker assessments who had the potential to reach age 85 before September 2013 (N = 7,178). MEASUREMENTS: Kidney function was measured according to the estimated glomerular filtration rate (eGFR) calculated from serum creatinine collected at baseline. Outcomes were survival to age 85 with functional independence, survival with a disability, or death before age 85. Disability was defined as mobility or activity of daily living limitations measured by questionnaire. RESULTS: eGFR was greater than 90 mL/min per 1.73 m2 in 22.7% of women, 60 to 89 mL/min per 1.73 m2 in 66.5%, 45 to 59 mL/min per 1.73 m2 in 8.7%, and less than 45 mL/min per 1.73 m2 in 2.0%. The Median follow-up was 15 years. Of 4,953 survivors, 3,155 reported no physical disability at age 85. Two thousand two hundred twenty-five participants died before age 85. Women with an eGFR of 90 mL/min per 1.73 m2 or greater had 2.71 times greater odds of survival to age 85 with functional independence than of dying before 85 (95% confidence interval (CI) = 1.62–4.51) than those with an eGFR less than 45 mL/min per 1.73 m2, women with an eGFR of 60 to 89 mL/min per 1.73 m2 had 3.04 times (95% CI = 1.85–5.00) greater odds, and women with an eGFR of 45 to 59 mL/min per 1.73 m2 had 2.22 times (95% CI = 1.31–3.76) greater odds. Similar, but slightly weaker odds were seen for survival to age 85 with disability. Better kidney function was not significantly associated with a greater likelihood of survival to age 85 with independent function than of surviving with disability. CONCLUSION: Better kidney function was associated with a greater likelihood of survival to age 85 with and without disability. J Am Geriatr Soc 65:98–106, 2017.

Keywords: eGFR; disability; physical function; successful aging

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The number of adults aged 85 and older in the United States is expected to triple by 2050, totaling more than 18 million.1 This expanding population of the oldest old adults highlights the importance of understanding how to remain healthy, physically and mentally active, and free of disability in older age. Although chronic disease and disability prevalence rates are high in older adults, some adults live to late age without major disabling health problems.2–4 This subset of the population may provide valuable information about factors predicting survival and intact functioning in later life.

Impaired physical function, including limitations in mobility and activities of daily living (ADLs), can greatly affect the quality of life of older adults and the prospects of remaining independent. Chronic kidney disease (CKD) is a well-established risk factor for mortality,5–7 but emerging evidence suggests that poor kidney function also negatively affects physical function and successful aging.8–14 Mild reductions in kidney function have been associated with poorer performance in functional testing, including poor muscle strength and slower walking speed.8,9 In several prospective studies, impaired kidney function has been associated with subsequent functional limitations and disability in community-dwelling older populations.10–12 In the Health, Aging and Body Composition study, poor kidney filtration was associated with a greater risk of developing mobility limitations during the 4.5-year follow-up period.10 Similarly, in a 6-year longitudinal analysis of the Cardiovascular Health Study, poorer kidney function was associated with fewer years living free of disability and major chronic diseases.11

Impaired kidney function, a strong predictor of mortality in older adults,5–7 may also negatively affect physical function with aging.8–14 The role of kidney function in predicting functional independence in late-age survival is not known. The purpose of this study was to assess the relationship between kidney function and disability-free survival to age 85 in a large prospective cohort of community-dwelling postmenopausal women.

METHODS

Study Population

This was an analysis of postmenopausal women from the Women’s Health Initiative (WHI) program enrolled in the WHI Observational Study (OS) or Clinical Trials (CTs). Details about the study have been previously published.15,16 Brieflfly, 40 U.S. clinical centers recruited 161,808 post-menopausal women aged 50 to 79 between October 1993 and December 1998. Institutional review boards at participating institutions approved study protocols. Each study participant provided written informed consent. Health information was updated annually for women in the OS and semiannually for women in the CTs by mail or telephone questionnaires through 2005. Women surviving in 2005 were recruited for an extensive study from 2005 to 2010; 76.9% of 150,075 eligible women consented to participate. A second extension study followed from 2010 to 2015; 86.8% of 107,706 eligible women consented to participate. Women enrolled in the extension studies were followed annually through mailed questionnaires for health updates, changes in functional status, and death.

WHI participants born before September 1, 1928, who therefore had the potential to survive to their 85th birthday by August 31, 2013, were included in this study population (Figure 1). Cardiovascular disease (CVD) biomarkers were assessed in a subcohort of WHI participants selected to be representative of WHI Hormone Therapy Trial participants, with the inclusion of all eligible Hispanic and African-American women and a comparable group of nonminority Hormone Therapy Trial participants matched on age, hysterectomy status, and date of enrollment; 8,815 African Americans, 3,642 Hispanics, and 10,306 European Americans had serum samples collected. Women without baseline serum creatinine measurements (n = 43,555) and women with baseline mobility or ADL disability (n = 270) were excluded from this analysis. To prevent misclassification of survival with functional independence, women without a completed questionnaire assessing mobility and ADL independence within 1 year of turning age 85 were also excluded from the analyses (n = 1,435). After these exclusions, 7,178 women remained in the analytical study population.

Classification of Function and Disability

Women were assessed for incident disability or death from study baseline through September 2013 for this analysis. Follow-up time for study participants ranged from 1 to 19 years (median 15 years). WHI participants were contacted annually or semiannually for medical updates. A family member of a participant who died typically returned the mailed survey form to notify study personnel of the death. The National Death Index and obituary notices were searched when a participant or proxy information was not received.

Disability status was determined through mailed surveys collecting information on self-reported physical function. For OS participants, disability was assessed at baseline and 3 years after baseline. For CT participants, disability was assessed at baseline, 1 year after baseline, and at study close. In a subset of CT participants, information on disability measures was collected every 3 years until the study closed. Disability was then evaluated annually for participants enrolled in the extension studies. Proxy reporting was used when a participant’s illness or disability prevented her from completing the questionnaire independently. Women who reported using a walker, crutches, or a wheelchair to move on a level surface or who responded that their health greatly limited their ability to walk one block or climb one flight of stairs were categorized with mobility disability. Women who reported inability to eat, dress, get in and out of bed, or take a bath or shower independently were classified with ADL disability. Women who lived to age 85 but reported mobility or ADL disability before reaching age 85 were categorized as surviving to 85 with disability (n = 1,798). Women who survived to age 85 without reporting mobility or ADL disability were categorized as surviving with functional independence (n = 3,155). Measures of disability within 1 year of reaching age 85 were required for the classification of functional independence.

Laboratory Methods A 12-hour fasting serum sample was obtained during the baseline examination, processed, and stored at - 70°C according to strict quality control procedures. Stored frozen serum specimens were sent to the University of Minnesota Fairview laboratory for assay of biomarkers, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), glucose, and C-reactive protein using standard laboratory methods (Roche Diagnostics, Indianapolis, IN). Creatinine was assayed using the Creatinine Plus Reagent (Roche Diagnostics) on the Modular P Chemistry Analyzer (Roche Diagnostics). Low-density lipoprotein cholesterol concentration was calculated from total cholesterol, HDL-C, and triglyceride concentrations using the Friedewald equation.17

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Covariate Data Collection

Demographic and health information was collected using questionnaires at baseline clinic visits. Demographic information included age, race and ethnicity (white, black, Hispanic, American Indian or Alaskan Native, Asian or Pacific Islander), annual income (<$20,000, $20,000– 49,999, ≥$50,000), and educational attainment (<high school, high school, some vocational/college education, college graduate). Socioeconomic status (SES) was also assessed using a neighborhood SES (NSES) variable based on 2000 census tract-level data on income, poverty, education, and other SES variables within geographical regions.18 Scores ranged from 0 to 100, with higher NSES scores indicating more-affluent census tracts. Lifestyle and health behaviors, including alcohol consumption (frequency and amounts of wine, beer, and hard liquor) and smoking status (current, past, nonsmoker), were ascertained by the questionnaire. Medical history at baseline was based on self-reported physician diagnosis of cardiovascular disease, diabetes mellitus, hypertension, congestive heart failure, or past cerebrovascular accident. Interviewers ascertained current prescription medications recorded the names of medications directly from medication containers and entered these into the Medispan database.15 Analyses for this study included the use of any antihypertensive medication and, specifically, the use of angiotensin-converting enzyme inhibitors because of potential influence on estimated glomerular filtration rate (eGFR).

Trained clinic staff recorded blood pressure and anthropometric measurements at the baseline clinic visit. Blood pressure was measured in the right arm using a conventional mercury sphygmomanometer in a seated position after 5 minutes of rest. Two blood pressure measurements were taken at least 30 seconds apart, and the average was used for the current analyses. Height was measured to the nearest 0.1 cm using a wall-mounted stadiometer. Weight was measured to the nearest 0.1 kg on a balance beam scale with the participant wearing light clothes without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared and categorized as underweight (<18.5 kg/m2 ), healthy weight (18.0– 24.9 kg/m2 ), overweight (25.0–29.9 kg/m2 ), obese I (30.0– 34.9 kg/m2 ), obese II (35.0–39.9 kg/m2 ), and obese III (≥40.0 kg/m2 ) using standard World Health Organization cut points.19 For stratification purposes, Obese I to Obese III were combined into one category.

Statistical Analysis

The primary exposure of interest was eGFR based on serum creatinine measurements collected at baseline and calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation20 with the formula: eGFRCKD_EPI_cr = 141 9 min(Scr/0.7, 1)
0.329 9 max(Scr/0.7, 1)
1.209 9 0.993Age 9 1.018 x (1.159 if African American). eGFR is expressed in mL/min per 1.73 m2 of body surface area. Participants were divided into four eGFR strata (≥90, 60–89, 45–59, <45 mL/min per 1.73 m2 ) according to 2012 Kidney Disease: Improving Global Outcomes cut-points.21

Baseline demographic and health information were compared according to baseline kidney function and outcomes. Pearson chi-square tests were used to test for significant differences in categorical and analysis of variance for significant differences in continuous data.

Kaplan-Meier curves were plotted to visualize survival over time of women according to eGFR. The association between kidney function and the outcome was assessed using polychotomous logistic regression with three outcomes: survival to age 85 with functional independence, survival to age 85 with a disability, and death before age 85 (reference). To determine odds of survival with functional independence versus survival with a disability, a disability at age 85 was assigned as the reference group. A series of nested models were used to explore potential confounders. An initial model was adjusted for age and ethnicity. A fully adjusted model included all covariates significantly associated with kidney function and survival with functional independence, as well as biologically plausible potential confounders. Covariates not normally distributed were log-transformed. Because muscle mass influences serum creatinine, multiplicative interaction terms between kidney function and BMI were added to the fully adjusted model to assess effect modification according to BMI. Interactions were tested using indicator variables because of evidence of nonlinearity in the associations being evaluated. A likelihood ratio test comparing the full and reduced models, with 18 degrees of freedom (4 categories of eGFR by 4 categories of BMI) was used to test the significance of interactions.

Two sensitivity analyses were performed to determine whether alternative adjustments for socioeconomic status changed the results. The first sensitivity analysis added the annual household income variable to the fully adjusted model. The second sensitivity analysis used NSES as an alternate to the education and income variables. NSES, which takes into consideration neighborhood-level characteristics, including access to medical and social services, exposure to chronic environmental pollutants and stressors, and physical accessibility and walkability of the environment, may influence health and mortality risk differently than individual-level SES characteristics.18,22

All analyses were completed using SAS version 9.3 (SAS Institute, Inc., Cary, NC). A nominal P<.05 was considered statistically significant.

RESULTS

Comparisons of baseline participant characteristics according to kidney function are shown in Table 1. Statistically, significant differences according to the level of kidney function were observed for most baseline variables, with the exception of medication use and HDL-C levels. Women with the poorest kidney function (eGFR <45 mL/min per 1.73 m2 ) were more likely to have diagnoses of hypertension, CVD, congestive heart failure, and diabetes mellitus and have higher blood pressure, C-reactive protein, cholesterol, and blood glucose levels at baseline.

Table 2 displays baseline characteristics according to the aging outcome. Comparisons showed that participants who died before age 85 had a higher burden of CVD biomarkers and disease comorbidity at baseline. Levels of covariates tended to be intermediate in the group that survived with disability.

Survival curves for participants based on eGFR levels are displayed in Figure 2. Women with eGFR of 60 to 89 mL/min per 1.73 m2 had the highest survival rates throughout the follow-up period, with more than 72% surviving at 15 years of follow-up. Women with eGFR less than 45 mL/min per 1.73 m2 had significantly lower survival over time (P<.001), with fewer than 33% surviving at 15 years of follow-up. In unadjusted polychotomous logistic regression, an inverted U-shaped association was observed between eGFR and odds of survival to 85 with or without disability relative to death before age 85, with lower odd ratios noted in the highest and lowest categories of kidney function (Table 3). Women with an eGFR of 60 to 89 mL/min per 1.73 m2 had the highest odds of survival (vs the lowest eGFR category: OR = 6.04, 95% CI = 3.95–9.25 for functional independence; OR = 4.45, 95% CI = 2.73—7.24 for survival with disability). A weaker association was noted between women with an eGFR of 90 mL/min per 1.73 m2 and higher relative to those in the lowest eGFR category (OR = 3.70, 95% CI = 2.40–5.72 for functional independence; OR = 4.01, 95% CI = 2.44–6.59 for survival with disability). With full adjustment of confounders, odds of survival to 85 with independent function for eGFR categories of 60 to 89 and 90 mL/min per 1.73 m2 and higher were similar. Women with baseline eGFR of 90 mL/min per 1.73 m2 or greater had 2.71 times (95% CI = 1.62–4.51) higher odds of surviving with independent function relative to death before 85, and women with eGFR of 60 to 89 mL/min per 1.73 m2 had 3.04 times (95% CI 1.85–5.00) higher odds than women in the reference group in the fully adjusted model. Similar but somewhat weaker odds were observed for kidney function categories when comparing women who survived to age 85 with disability with women who died before age 85 (Table 3).

When comparing the outcome of surviving with functional independence with that of living to age 85 with a disability, higher eGFR was weakly and nonsignificantly associated with greater odds of functional independence (OR = 1.18, 95% CI = 0.62–2.25 for eGFR ≥90 mL/min per 1.73 m2; OR = 1.43, 95% CI = 0.73– 2.80 for eGFR 45–59 mL/min per 1.73 m2 ) in the fully adjusted model.

The association between kidney function and aging outcomes did not differ significantly according to BMI (P = .55). Sensitivity analyses showed no substantive differences in associations between kidney function and survival outcomes when the income variable was added to the fully adjusted model or when the NSES variable replaced the income and education variables.

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DISCUSSION

Better kidney function was associated with greater odds of surviving to age 85 with functional independence than of dying before 85 in this community-dwelling population of postmenopausal women. Better kidney function was similarly associated with greater odds of survival to age 85 with disability than with death before age 85, although this association was slightly weaker. Better kidney function was predictive of survival to age 85 with or without disability, independent of cardiometabolic disease and CVD biomarkers. When comparing the two groups of women who lived to age 85 (those with functional independence vs those with disability), there was a trend toward an association between better kidney function and functional independence, although none of the odds ratios were statistically significant.

Women with kidney function above the cutpoint for CKD (60 mL/min per 1.73 m2) 23 had the greatest odds of surviving to age 85 with or without disability. Specifically, the results demonstrated the highest likelihood of survival to age 85 with an eGFR of 60 to 89 mL/min per 1.73 m2. Consistent with the results of other studies,5,7 creatinine-based eGFR of 90 mL/min per 1.73 m2 or greater was not associated with better survival odds than eGFR of 60 to 89 mL/min per 1.73 m2. Although it is likely that higher kidney filtration is advantageous for healthy aging, the highest eGFR categorization may also include women in a state of hyperfiltration and those with low muscle mass or malnutrition, contributing to lower odds of survival with functional independence, particularly in the unadjusted model. Hyperfiltration may occur in some older adults with diabetes mellitus or metabolic syndrome and may be an initial step in the progression of nephropathy.24,25 Erroneous overestimates of kidney filtration rates can occur with conditions including sarcopenia, malnutrition, and frailty because of lower creatinine production.24,26 With full adjustment to account for BMI and other health characteristics, the odds of survival with functional independence were similar in women with an eGFR of 60 to 89 mL/min per 1.73 m2 and those with an eGFR of 90 mL/min per 1.73 m2 or greater.

These findings reveal that women with good kidney function are more likely to survive to age 85, with or without disability than those with poor kidneys, although baseline eGFR did not significantly predict the disability status of survivors. There are several potential explanations for these findings. First, kidney function may not predict disability with aging because of the heterogeneity of pathologies leading to disability at age 85. For example, osteoarthritis is the most prevalent cause of disability in older adults,27 but it is not linked to kidney dysfunction. Second, the possibility cannot be excluded that the use of serum creatinine for eGFR calculations may have reduced the ability to detect differences in odds of survival with and without disability. Although several confounders were adjusted for and interaction between kidney function and BMI was assessed, there may be residual confounding according to muscle mass, body size, and frailty, obscuring an association between kidney function and disability. In two previous studies, significant associations between frailty and kidney function were greatly attenuated when creatinine-based eGFR was used instead of cystatin C–based calculations.13,14 Third, selective retention of healthier women in WHI who lived to age 85 irrespective of their disabilities may have reduced the ability to detect a significant difference in kidney function between the survivor groups with and without disability. WHI

investigators have shown that women who remained in the study past their 80th birthday tended to be healthier than their counterparts who did not consent to the two extension study re-enrollment periods.28

Although this study found that poor kidney function is a strong predictor of death before age 85, the relationship between kidney function and time of incident disability could not be assessed. Because there were few measurements of functional status before 2005, it was not possible to determine whether disability preceded death in the cohort of women who died before age 85. Prior longitudinal studies have found that poorer kidney function in community-dwelling older adults predicted incident disability over 4 to 6 years of follow-up.10,11 Mobility and ADL disability, strong risk factors for death,29,30 have been found to shorten life expectancy by up to 10 years.31 Women with better kidney function may have greater resilience that extends their survival in spite of mobility and ADL disability than women with poorer kidney function who develop disability.

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Aligned with the latter explanation, consistent associations between poor kidney function, cardiovascular disease, and mortality have been firmly established, although the exact biological mechanisms are undetermined. The kidneys may be particularly susceptible to damage from vascular stressors and thus serve as a sensitive marker of cardiovascular disease.32 Conversely, impaired kidney function resulting in improper fluid retention and filtration may lead to greater hemodynamic stress, hypertension, and high circulatory levels of inflammatory markers.33,34 Regardless of the directionality of the relationship between cardiovascular impairment and kidney dysfunction, poor kidney filtration, even at subclinical levels, may signal cellular and organ senescence and a faster rate of biological aging.35 In proposed phenotypes for healthy aging, kidney function consistently serves as an integral component of physiological health.36–38 Poor kidney function may be indicative of cumulative damage to the body and accelerated aging.36 Kidney dysfunction, in turn, may lead to impaired regulation of electrolytes, inflammation, anemia, and insulin resistance, contributing to physiological deterioration. It is not clear whether impaired kidney function contributes directly to accelerated aging or serves as a marker of the severity of cumulative effects of clinical and subclinical disease morbidity. Therefore, it is uncertain whether interventions to improve kidney function in older adults may protect the body from physiological decline, but this potential clinical implication deserves further study.

There are several limitations of this study that warrant consideration. The study population included only women, and it is unknown whether these results can be generalized to older men, although women tend to live longer than men, and findings that pertain to women's aging hold inherent public health value. The study used creatinine measures and other health characteristics collected at a single baseline visit. In this sample, alternate biomarkers of kidney function including urinary albumin and cystatin C levels were not available. As discussed previously, muscle mass influences creatinine, a well-known limitation of using this biomarker, but kidney function assessed using cystatin C in WHI has also been found to be associated with BMI,39 and it is uncertain whether cystatin C is superior to serum creatinine in predicting mobility independence in older age. In addition, serum creatinine remains the most commonly used biomarker for estimating GFR clinically. The analysis presented in this study is more directly translatable to geriatric clinical practice than the use of cystatin C–based eGFR. Future studies comparing cystatin C and serum creatinine equations in assessing kidney function and mobility in older age would be informative.

This study has several strengths. It included a large sample of ethnically diverse, community-dwelling, post-menopausal women from the well-characterized WHI. Participants were followed for an average of 13.5 years, and the retention rate was high. Detailed information on potential confounders and disease mediators was collected and analyzed. The study had a substantially longer follow-up than previous studies examining eGFR and physical functioning, which allowed the long-term health effects of kidney function to be studied.

In conclusion, better kidney function as measured using serum creatinine-based eGFR was predictive of survival to age 85 with functional independence, and to a lesser extent survival to age 85 with a disability, in postmenopausal community-dwelling women. Results of this study suggest that eGFR may be used as a clinical marker of prospects for longevity in older women.

ACKNOWLEDGMENTS

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN 268201100004C).

Conflict of Interest:

None.

Author Contributions:

Cavanaugh: design of statistical analysis and manuscript, data analysis and interpretation, drafting and revising the manuscript, approval of the final version. LaCroix, Kritz-Silverstein, Rifkin: design of statistical analysis and manuscript, data interpretation, revising the manuscript, approval of the final version. Rillamas-Sun: design of statistical analysis and manuscript, data analysis and interpretation, revising the manuscript, approval of the final version.

Sponsor's Role:

The sponsors did not play a role in the analysis or preparation of this manuscript.

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