Urinary biomarkers of tubular damage are associated with mortality but not cardiovascular risk among systolic blood pressure intervention trial participants with chronic kidney disease

Vasantha K. Jotwani, Alexandra K. Lee, Michelle M. Estrella, Ronit Katz, Pranav S. Garimella, Rakesh Malhotra, Dena E. Rifkin, Walter Ambrosius, Barry I. Freedman, Alfred K. Cheung, Kalani L. Raphael, Paul Drawz, Javier A. Neyra, Suzanne Oparil, Henry Punzi, Michael G. Shlipak, Joachim H. Ix

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Kidney tubulointerstitial fibrosis on biopsy is a strong predictor of chronic kidney disease (CKD) progression, and CKD is associated with elevated risk of cardiovascular disease (CVD). Tubular health is poorly quantified by traditional kidney function measures, including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of tubular injury, inflammation, and repair would be associated with higher risk of CVD and mortality in persons with CKD. <bold><italic>Methods:</italic></bold> We measured urinary concentrations of interleukin-18 (IL-18), kidney injury molecule-1, neutrophil gelatinase-Associated lipocalin, monocyte chemoattractant protein-1, and chitinase-3-like protein-1 (YKL-40) at baseline among 2,377 participants of the Systolic Blood Pressure Intervention Trial who had an eGFR < 60 mL/min/1.73 m<2. We used Cox proportional hazards models to evaluate biomarker associations with CVD events and all-cause mortality. <bold><italic>Results:</italic></bold> At baseline, the mean age of participants was 72 ± 9 years, and eGFR was 48 ± 11 mL/min/1.73 m<2. Over a median follow-up of 3.8 years, 305 CVD events (3.6% per year) and 233 all-cause deaths (2.6% per year) occurred. After multivariable adjustment including eGFR, albuminuria, and urinary creatinine, none of the biomarkers showed statistically significant associations with CVD risk. Urinary IL-18 (hazard ratio [HR] per 2-fold higher value, 1.14; 95% CI 1.01-1.29) and YKL-40 (HR per 2-fold higher value, 1.08; 95% CI 1.02-1.14) concentrations were each incrementally associated with higher mortality risk. Associations were similar when stratified by randomized blood pressure arm. <bold><italic>Conclusions:</italic></bold> Among hypertensive trial participants with CKD, higher urinary IL-18 and YKL-40 were associated with higher risk of mortality, but not CVD.

Original languageEnglish (US)
Pages (from-to)346-355
Number of pages10
JournalAmerican Journal of Nephrology
Issue number5
StatePublished - Apr 1 2019

Bibliographical note

Funding Information:
This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098234 for MGS/JHI, K24DK110427 for JHI, and K23DK109868 for VJ) and the American Heart Association (14EIA18560026 for JHI). The authors thank the participants and staff members of the SPRINT, which was funded with Federal funds from the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under Contract Numbers HH-SN268200900040C, 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. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the US Department of Veterans Affairs, or the United States Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: https://www.sprinttrial.org/public/ dspScience.cfm.

Funding Information:
We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017-06, University of Utah: UL1TR000105-05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420.

Funding Information:
M.G.S.: has worked as a consultant for the University of Washington and has equity in TAI Diagnostics and Cricket Health, Inc. J.H.I.: holds an investigator initiated research grant from Baxter International Inc. The results presented in this paper have not been published previously in whole or part, except in abstract form.


  • Chitinase-3-like protein-1
  • Interleukin-18
  • Kidney injury
  • Urinary biomarkers

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