Markers of kidney tubule function and risk of cardiovascular disease events and mortality in the SPRINT trial

Pranav S. Garimella, Alexandra K. Lee, Walter T. Ambrosius, Udayan Bhatt, Alfred K. Cheung, Michel Chonchol, Timothy Craven, Amret T. Hawfield, Vasantha Jotwani, Anthony Killeen, Henry Punzi, Mark J. Sarnak, Barry M. Wall, Joachim H. Ix, Michael G. Shlipak

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Aims: Biomarkers of kidney tubule injury, inflammation and fibrosis have been studied extensively and established as risk markers of adverse kidney and cardiovascular disease (CVD) outcomes. However, associations of markers of kidney tubular function with adverse clinical events have not been well studied, especially in persons with chronic kidney disease (CKD). Methods and results: Using a sample of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit, we evaluated the association of three urine tubular function markers, alpha-1 microglobulin (α1m), beta-2 microglobulin (β2m), and uromodulin, with a composite CVD endpoint (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) and mortality using Cox proportional hazards regression, adjusted for baseline estimated glomerular filtration rate (eGFR), albuminuria, and CVD risk factors. In unadjusted analysis, over a median follow-up of 3.8 years, α1m and β2m had positive associations with composite CVD events and mortality, whereas uromodulin had an inverse association with risk for both outcomes. In multivariable analysis including eGFR and albuminuria, a two-fold higher baseline concentration of α1m was associated with higher risk of CVD [hazard ratio (HR) 1.25; 95% confidence interval (CI): 1.10-1.45] and mortality (HR 1.25; 95% CI: 1.10-1.46), whereas β2m had no association with either outcome. A two-fold higher uromodulin concentration was associated with lower CVD risk (HR 0.79; 95% CI: 0.68-0.90) but not mortality (HR 0.86; 95% CI: 0.73-1.01) after adjusting for similar confounders. Conclusion: Among non-diabetic persons with CKD, biomarkers of tubular function are associated with CVD events and mortality independent of glomerular function and albuminuria.

Original languageEnglish (US)
Pages (from-to)3486-3493
Number of pages8
JournalEuropean heart journal
Volume40
Issue number42
DOIs
StatePublished - Nov 1 2019

Bibliographical note

Funding Information:
This work was supported by the NIH and the National Research Service Award (NRSA) through the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK grant K23 DK114556 to P.G., R01DK098234 and K24DK110427 to J.H.I.), and the American Heart Association (14EIA18560026 to J.H.I.). The Systolic Blood Pressure Intervention Trial is funded with Federal funds from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (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. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analysed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the co-authors. The content is solely the responsibility of the authors and does not necessarily represent the official views of

Funding Information:
We acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134 and UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073, and 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, and Wake Forest University: UL1TR001420.

Funding Information:
the NIH, the U.S. 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.

Publisher Copyright:
© 2019 Published on behalf of the European Society of Cardiology. All rights reserved.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Alpha-1 microglobulin
  • Beta-2 microglobulin
  • Biomarkers
  • Cardiovascular disease
  • Chronic kidney disease
  • Tubular function
  • Uromodulin

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