Rationale and Objective: Although low estimated glomerular filtration rate (eGFR) is associated with cardiovascular disease (CVD) events and mortality, the clinical significance of variability in eGFR over time is uncertain. This study aimed to evaluate the associations between variability in eGFR and the risk of CVD events and all-cause mortality. Study Design: Longitudinal analysis of clinical trial participants. Settings and Participants: 7,520 Systolic Blood Pressure Intervention Trial (SPRINT) participants ≥50 year of age with 1 or more CVD risk factors. Predictors: eGFR variability, estimated by the coefficient of variation of eGFR assessments at the 6th, 12th, and 18-month study visits. Outcomes: The SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death) and all-cause mortality from month 18 to the end of follow-up. Analytical Approach: Cox models were used to evaluate associations between eGFR variability and CVD outcomes and all-cause mortality. Models were adjusted for demographics, randomization arm, CVD risk factors, albuminuria, and eGFR at month 18. Results: Mean age was 68 ± 9 years; 65% were men; and 58% were White. The mean eGFR was 73 ± 21 (SD) mL/min/1.73 m2 at 6 months. There were 370 CVD events and 154 deaths during a median follow-up of 2.4 years. Greater eGFR variability was associated with higher risk for all-cause mortality (hazard ratio [HR] per 1 SD greater variability, 1.29; 95% CI, 1.14-1.45) but not CVD events (HR, 1.05; 95% CI, 0.95-1.16) after adjusting for albuminuria, eGFR, and other CVD risk factors. Associations were similar when stratified by treatment arm and by baseline CKD status, when accounting for concurrent systolic blood pressure changes, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and diuretic medications during follow up. Limitations: Persons with diabetes and proteinuria > 1 g/d were excluded. Conclusions: In trial participants at high risk for CVD, greater eGFR variability was independently associated with all-cause mortality but not CVD events.
Bibliographical noteFunding Information:
Rakesh Malhotra, MD, MPH, Ronit Katz, PhD, Vasantha Jotwani, MD, Adhish Agarwal, MD, Debbie L. Cohen, MD, William C. Cushman, MD, Areef Ishani, MD, MS, Anthony A. Killeen, MD, PhD, Dalane W. Kitzman, MD, Suzanne Oparil, MD, Vasilios Papademetriou, MD, Chirag R. Parikh, MD, PhD, Kalani L. Raphael, MD, Michael V. Rocco, MD, Leonardo J. Tamariz, MD, Paul K. Whelton, MD, MSc, Jackson T. Wright Jr, MD, PhD, Michael G. Shlipak, MD, MPH, and Joachim H. Ix, MD, MAS. Research idea and study design: JHI, RM, RK, MGS; data acquisition: RM, RK; statistical analysis: RK; data interpretation: RM, RK, JHI, MGS; intellectual contribution: RM, VJ, AA, DLC, WCC, AI, AAK, DWK, SO, VP, CP, KLR, MVR, LJT, PKW, JTW, MGS, JHI; supervision: JHI, MGS. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate, This work was supported by the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK098234-04 and K24DK110427 for JHI), the American Heart Association (14EIA18560026 for JHI), the Satellite Coplon award for RM and the Academic Community UCSD grant for RM. SPRINT is funded with federal funds from the NIH, including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. We also acknowledge the support from the following CTSAs funded by National Center for Advancing Translational Sciences (NCATS) to Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston: UL1RR025771, Stanford: UL1TR000093; Tufts University: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1 TR000445; George Washington University: UL1TR000075; University of California Davis: UL1 TR000002; University of Florida: UL1 TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 Centers of Biomedical Research Excellence (COBRE) Award National Institute of General Medical Sciences; and Wake Forest University: UL1TR001420. The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. Dr Shlipak is a Scientific Advisor and holds stock in TAI Diagnostics and has received compensation from Cricket Health, Inc. Dr Ix is principal investigator of an investigator-initiated research study sponsored by Baxter International. Dr Cushman received and institutional grant from Eli Lilly. The remaining authors declare that they have no relevant financial interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. A full list of contributors to SPRINT is available at https://www.sprinttrial.org/public/dspScience.cfm. All components of the SPRINT protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. Received April 27, 2020. Evaluated by 2 external peer reviewers and a statistician, with direct editorial input from an International Editor, who served as Acting Editor-in-Chief. Accepted in revised form October 16, 2020. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
- all-cause mortality
- cardiovascular disease
- cardiovascular event
- eGFR variability
- estimated glomerular filtration rate
- renal function
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't