TY - JOUR
T1 - Urine markers of kidney tubule cell injury and kidney function decline in sprint trial participants with ckd
AU - Malhotra, Rakesh
AU - Katz, Ronit
AU - Jotwani, Vasantha
AU - Ambrosius, Walter T.
AU - Raphael, Kalani L.
AU - Haley, William
AU - Rastogi, Anjay
AU - Cheung, Alfred K.
AU - Freedman, Barry I.
AU - Punzi, Henry
AU - Rocco, Michael V.
AU - Ix, Joachim H.
AU - Shlipak, Michael G.
N1 - Funding Information:
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. We also acknowledge the support from the following Clinical and Translational Science Awards funded by the National Center for Advancing Translational Sciences: Case Western Researve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston University Medical Center: 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: UL1TR000445; GeorgeWashingtonUniversity:UL1TR000075;UniversityofCalifornia, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 Centers of Biomedical Research Excellence Award National Institute of General Medical Sciences; Wake Forest University: UL1TR001420. Dr. Ambrosius is supported by a grant from the NIH. Dr. Freedman is supported by a grant from the NIH. Dr. Ix is supported by NIDDK grants R01DK098234 and K24DK110427, and American Heart Association grant 14EIA18560026. Dr. Katz is supported by a grant from Veterans Medical Research Foundation San Diego. Dr. Malhotra is supported by the Satellite Coplon award and a grant from the Academic Community of the University of California, San Diego. Dr. Punzi is supported by a grant from the NIH. Dr. Rastogi is supported by a grant from the NIH. Dr. Rocco is supported by a grant from the NIH.
Funding Information:
This study was funded by National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK098234 (to J. Ix and M. Shlipak). The Systolic Blood Pressure Intervention Trial is funded by federal funds from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute, the NIDDK, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under contract numbers HHSN268200900040C,
Funding Information:
Dr. Freedman reports receiving consultant fees from AstraZeneca and RenalytixAI and an issued patent for APOL1 gene testing, outside of the submitted work. Dr. Ix reports receiving a grant from Baxter outside of the submitted work. Dr. Rastogi reports receiving research grants and speaker’s bureau fees from and an advisory board position with both AstraZeneca and Sanofi; receiving a research grant from and an advisory board position with GlaxoSmithKline; and a research grant from Pfizer, all outside of the submittedwork.Dr.Roccoreportsreceivingclinicaltrialgrantsfrom Bayer, Boehringer Ingelheim, and GlaxoSmithKline; receiving consultant fees from Baxter; and positions on an adjudication committee at Abbvie, Beacon Bioscience, and George Clinical, all outside of the submitted work. Dr. Shlipak reports a position of Scientific Advisor at and holds stock options with Cricket Health, Inc. and TAI Diagnostics. Dr. Ambrosius, Dr. Cheung, Dr. Haley, Dr. Jotwani, Dr. Katz, Dr. Malhotra, Dr. Punzi, and Dr. Raphael have nothing to disclose.
Publisher Copyright:
© 2020, American Society of Nephrology. All rights reserved.
PY - 2020/3/6
Y1 - 2020/3/6
N2 - Background and objectives eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, setting, participants, & measurements Among 2428 SPRINT participants with CKD (eGFR,60 ml/min per 1.73 m2 ) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. Results Mean participant age was 7369 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46611 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (20.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, 21.44 to 20.38), a finding that was stronger in the standard arm of SPRINT. Conclusions Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.
AB - Background and objectives eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, setting, participants, & measurements Among 2428 SPRINT participants with CKD (eGFR,60 ml/min per 1.73 m2 ) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. Results Mean participant age was 7369 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46611 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (20.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, 21.44 to 20.38), a finding that was stronger in the standard arm of SPRINT. Conclusions Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.
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U2 - 10.2215/CJN.02780319
DO - 10.2215/CJN.02780319
M3 - Article
C2 - 32111704
AN - SCOPUS:85081938359
SN - 1555-9041
VL - 15
SP - 349
EP - 358
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 3
ER -