Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD

Alexander L. Bullen, Simon B. Ascher, Rebecca Scherzer, Pranav S. Garimella, Ronit Katz, Stein I. Hallan, Alfred K. Cheung, Kalani L. Raphael, Michelle M. Estrella, Vasantha K. Jotwani, Rakesh Malhotra, Jesse C. Seegmiller, Michael G. Shlipak, Joachim H. Ix

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment.

METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m 2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia).

RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups.

CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Original languageEnglish (US)
Pages (from-to)1915-1926
Number of pages12
JournalJournal of the American Society of Nephrology
Issue number10
StatePublished - Oct 2022

Bibliographical note

Funding Information:
SPRINT is funded with federal funds from the National Institutes of Health (NIH), 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 HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency 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 azil-sartan 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 NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgment list: public/dspScience.cfm. We also acknowledge the support from the following Clinical and Translational Science awards funded by the National Center for Advancing Translational Sciences: Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston University: UL1RR025771; Stanford University: UL1TR000093; Tufts University: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; UT Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1TR000445; George Washington University: UL1TR000075; University of California, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 COBRE award NIGMS; and Wake Forest University: UL1TR001420.

Funding Information:
A. Bullen reports research funding from the Veterans Affairs’ Office of Research and Development. A. Cheung reports consultancy fees and honoraria from Boehringer Ingelheim, Calliditas, and UptoDate; and reports ownership interest with Merck. M. Estrella reports consultancy fees from Eiland & Bonnin, PC; reports research funding from Bayer and Booz Allen Hamilton; reports honoraria from American Kidney Fund, AstraZeneca, Boehringer Ingelheim, and National Kidney Foundation,; and has other interests or relationships with American Journal of Kidney Diseases, CJASN, and National Kidney Foundation. P. Garimella reports honoraria from DCI, Inc.; reports advisory or leadership role for BMC Nephrology (Associate Editor) and Kidney Medicine (Editorial Board Member); and is on the speakers’ bureau for Otsuka. J. Ix reports consultancy fees from Akebia, AstraZeneca, and Sanifit; reports research funding from Baxter International; and has an advisory or leadership role with AlphaYoung. R. Katz reports consultancy fees from University of California San Diego and University of Pennsylvania; and is on the editorial board for CJASN. K. Raphael reports consultancy fees from AstraZeneca. R. Scherzer is on the editorial boards for CJASN, Journal of Acquired Immune Deficiency Syndromes, and Kidney360. M. Shlipak reports consultancy fees from Cricket Health and Intercept Pharmaceuticals; reports ownership interest with TAI Diagnostics; reports research funding from Bayer; reports honoraria from AstraZeneca, Bayer, and Boehringer Ingelheim; and reports advisory or leadership roles with American Journal of Kidney Disease, Circulation, and JASN; and is a board member of Northern California Institute for Research and Education. All remaining authors have nothing to disclose. Because Alexander Bullen is an editorial fellow for JASN, he was not involved in the peer review process for this manuscript. Another editor oversaw the peer review and decision-making process for this manuscript. All remaining authors have nothing to disclose.

Funding Information:
A. Bullen was supported by a mentored career development award from the Veterans Affairs San Diego Healthcare System (5IK2BX004986) and a pilot grant from the University of Alabama at Birmingham and the University of California San Diego2O’Brien Center for Acute Kidney Injury Research (P30DK079337); J. Ix was supported by a midcareer mentoring award from the National Institute of Diabetes and Digestive and Kidney Diseases (K24DK110427). For the ancillary study measurements and data analysis, J. Ix and M. Shlipak were supported by an R01 award from the National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK098234), and J. Ix was supported by an award from the American Heart Association (14EIA18560026).

Publisher Copyright:
Copyright © 2022 by the American Society of Nephrology.


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