William R. Zhang, BS; Timothy E. Craven, MSPH; Rakesh Malhotra, MD; Alfred K. Cheung, MD; Michel Chonchol, MD; Paul Drawz, MD; Mark J. Sarnak, MD, MS; Chirag R. Parikh, MD, PhD; Michael G. Shlipak, MD, MPH *; Joachim H. Ix, MD, MAS *; for the SPRINT Research Group †
Note: 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.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH), the U.S. Department of Veterans Affairs, or the U.S. government.
Acknowledgment: The SPRINT investigators thank Takeda Pharmaceuticals International for contributing study medications (azilsartan and azilsartan combined with chlorthalidone).
Grant Support: This ancillary study was supported by grant R01DK098234 from the NIDDK to Drs. Ix and Shlipak. Mr. Zhang is supported by grant TL1TR001871 from NIH/National Center for Advancing Translational Sciences (NCATS). The SPRINT study is funded by the NIH, including the National Heart, Lung, and Blood Institute (NHLBI); NIDDK; National Institute on Aging; and National Institute of Neurological Disorders and Stroke, under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and Inter-Agency Agreement A-HL-13-002-001. It also is partly supported with resources and use of facilities through the U.S. Department of Veterans Affairs. The SPRINT investigators are supported by the following NCATS-funded Clinical and Translational Science Awards: 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; 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, Centers of Biomedical Research Excellence Award P30GM103337, National Institute of General Medical Sciences; and Wake Forest University, UL1TR001420.
Disclosures: Mr. Craven reports grant support from NIH/NHLBI/NIDDK during the conduct of the study. Dr. Cheung reports grant support from NIH during the conduct of the study. Dr. Sarnak serves on the steering committee for an anemia treatment study funded by Akebia; funds for his involvement are payed to Tufts Medical Center. Dr. Shlipak reports grant support from Cricket Health and TAI Diagnostics outside the submitted work. Dr. Ix reports grant support from NIDDK during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-1037.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See the Supplement. Statistical code: Available from Mr. Craven (e-mail, firstname.lastname@example.org). Data set: Available from SPRINT Coordinating Center (e-mail, email@example.com).
Corresponding Author: Michael G. Shlipak, MD, MPH, Kidney Health Research Collaborative, 4150 Clement Street, Building 2, Room 145, San Francisco, CA 94121; e-mail, firstname.lastname@example.org.
Current Author Addresses: Mr. Zhang and Dr. Shlipak: Kidney Health Research Collaborative, 4150 Clement Street, Building 2, Room 145, San Francisco, CA 94121.
Mr. Craven: Wake Forest University Health Sciences, Department of Biostatistical Sciences, Medical Center Boulevard, Room 4303, Winston-Salem, NC 27157.
Dr. Malhotra: University of California, San Diego, 9500 Gilman Drive, #9111H, La Jolla, CA 92093.
Dr. Cheung: Division of Nephrology and Hypertension, 30 North 1900 East, Room 4R312, Salt Lake City, UT 84132.
Dr. Chonchol: University of Colorado Hospital, 12605 East 16th Avenue, Aurora, CO 80045.
Dr. Drawz: Division of Renal Diseases and Hypertension, 717 Delaware Street Southeast, Suite 353, MMC 1932, Minneapolis, MN 55414.
Dr. Sarnak: Division of Nephrology, Tufts Medical Center, 800 Washington Street, Box 391, Boston, MA 02111.
Dr. Parikh: Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 416, Baltimore, MD 21287.
Dr. Ix: University of California, San Diego, 3350 La Jolla Village Drive, Mail Code 111-H, San Diego, CA 92161.
Author Contributions: Conception and design: M. Chonchol, P. Drawz, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Analysis and interpretation of the data: W.R. Zhang, T.E. Craven, R. Malhotra, A.K. Cheung, M. Chonchol, P. Drawz, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Drafting of the article: W.R. Zhang, T.E. Craven, R. Malhotra, M.G. Shlipak.
Critical revision for important intellectual content: W.R. Zhang, R. Malhotra, A.K. Cheung, M. Chonchol, P. Drawz, M.J. Sarnak, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Final approval of the article: W.R. Zhang, T.E. Craven, R. Malhotra, A.K. Cheung, M. Chonchol, P. Drawz, M.J. Sarnak, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Provision of study materials or patients: A.K. Cheung, J.H. Ix.
Statistical expertise: T.E. Craven, J.H. Ix.
Obtaining of funding: A.K. Cheung, M. Chonchol, M.J. Sarnak, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Administrative, technical, or logistic support: W.R. Zhang, A.K. Cheung, M.G. Shlipak, J.H. Ix.
Collection and assembly of data: A.K. Cheung, M. Chonchol, C.R. Parikh, M.G. Shlipak, J.H. Ix.
Whether the increased incidence of chronic kidney disease (CKD) during intensive systolic blood pressure (SBP) lowering is accompanied by intrinsic kidney injury is unknown.
To compare changes in kidney damage biomarkers between incident CKD case participants and matched control participants as well as between case participants in the intensive (<120 mm Hg) versus the standard (<140 mm Hg) SBP management groups of SPRINT (Systolic Blood Pressure Intervention Trial).
Nested case–control study within SPRINT.
Adults with hypertension without baseline kidney disease.
Case participants (n = 162), who developed incident CKD during trial follow-up (128 in the intensive and 34 in the standard group), and control participants (n = 162) without incident CKD, who were matched on age, sex, race, baseline estimated glomerular filtration rate, and randomization group.
9 urinary biomarkers of kidney damage were measured at baseline and at 1 year. Linear mixed-effects models were used to estimate 1-year biomarker changes.
Higher concentrations of urinary albumin, kidney injury molecule-1, and monocyte chemoattractant protein-1 at baseline were significantly associated with greater odds of incident CKD (adjusted odds ratio per doubling: 1.50 [95% CI, 1.14 to 1.98], 1.51 [CI, 1.05 to 2.17], and 1.70 [CI, 1.13 to 2.56], respectively). After 1 year of blood pressure intervention, incident CKD case participants in the intensive group had significantly greater decreases in albumin–creatinine ratio (ACR), interleukin-18, anti–chitinase-3-like protein 1 (YKL-40), and uromodulin than the matched control participants. Compared with case participants in the standard group, those in the intensive group had significantly greater decreases in ACR, β2-microglobulin, α1-microglobulin, YKL-40, and uromodulin.
Biomarker measurements were available only at baseline and 1 year.
Incident CKD in the setting of intensive SBP lowering was accompanied by decreases, rather than elevations, in levels of kidney damage biomarkers and thus may reflect benign changes in renal blood flow rather than intrinsic injury.
National Institute for Diabetes and Digestive and Kidney Diseases.
Zhang WR, Craven TE, Malhotra R, et al, for the SPRINT Research Group. Kidney Damage Biomarkers and Incident Chronic Kidney Disease During Blood Pressure Reduction: A Case–Control Study. Ann Intern Med. 2018;169:610–618. [Epub ahead of print 23 October 2018]. doi: https://doi.org/10.7326/M18-1037
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Published: Ann Intern Med. 2018;169(9):610-618.
Published at www.annals.org on 23 October 2018
Chronic Kidney Disease, Hospital Medicine, Nephrology.
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