Frailty, Inflammatory Markers, and Waitlist Mortality Among Patients with End-Stage Renal Disease in a Prospective Cohort Study

Background Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among ESRD patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant (KT) waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction. Methods We studied 1,975 ESRD patients on the KT waitlist (11/1/09-2/28/17) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1SD change in log IL-6, sTNFR1, CRP, or inflammatory index). Results The registry-based model had moderate predictive ability (c-statistic=0.655). Frailty was associated with increased mortality (2.19, 95%CI:1.26-3.79) but did not improve risk prediction (c-statistic=0.646; P=0.65). Like frailty, IL-6 (2.13, 95%CI:1.41-3.22), sTNFR1 (1.70, 95%CI:1.12-2.59), CRP (1.68, 95%CI:1.06-2.67), and the inflammatory index (2.09, 95%CI:1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic=0.777; P=0.02), CRP (c-statistic=0.728; P=0.02), or inflammatory index (c-statistic=0.777; P=0.02) substantially improved mortality risk prediction. Conclusion Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy to measure markers of increased waitlist mortality risk. Contact Information: Mara McAdams-DeMarco, Ph.D. Department of Epidemiology, 615, N. Wolfe St, W6033, Baltimore, MD 21205 (410) 502-1950 email: mara@jhu.edu Authorship Mara A. McAdams-DeMarco: Research design, data analysis, writing of the paper and review of the paper Hao Ying: Performance of the research, data analysis, writing of the paper and review of the paper Alvin Thomas: Writing of the paper and review of the paper Fatima Warsame: Performance of the research, writing of the paper and review of the paper Ashton A. Shaffer: Writing of the paper and review of the paper Christine E. Haugen: Performance of the research, writing of the paper and review of the paper Jacqueline M. Garonzik-Wang: Performance of the research, writing of the paper and review of the paper Niraj M. Desai: Performance of the research, writing of the paper and review of the paper Ravi Varadhan: Performance of the research, writing of the paper and review of the paper Jeremy D. Walston: Writing of the paper and review of the paper Silas P. Norman: Performance of the research, writing of the paper and review of the paper Dorry L. Segev: Research design, writing of the paper and review of the paper Disclosure The authors declare no conflicts of interest. Funding This study was supported by NIH grant R01AG042504 (PI: Dorry Segev), R01AG055781 (PI: McAdams-DeMarco) and K24DK101828 (PI: Dorry Segev). Mara McAdams-DeMarco was also supported by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center (P30AG021334), National Institute on Aging (K01AG043501). Christine Haugen was supported by the National Institute on Aging (F32AG053025). Ashton Shaffer was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (F30DK116658). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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