TY - JOUR
T1 - Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT
AU - Ascher, Simon B.
AU - Scherzer, Rebecca
AU - Estrella, Michelle M.
AU - Berry, Jarett D.
AU - de Lemos, James A.
AU - Jotwani, Vasantha K.
AU - Garimella, Pranav S.
AU - Malhotra, Rakesh
AU - Bullen, Alexander L.
AU - Katz, Ronit
AU - Ambrosius, Walter T.
AU - Cheung, Alfred K.
AU - Chonchol, Michel
AU - Killeen, Anthony A.
AU - Ix, Joachim H.
AU - Shlipak, Michael G.
N1 - Funding Information:
The authors thank the participants and staff members of the SPRINT, which is sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268 200900048C, 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 NIH, the US Department of Veterans Affairs or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: https://www.sprinttrial. org/public/dspScience.cfm. We also 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. This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK098234 for M.G.S./J.H.I. and K24DK110427 for J.H.I.) and the American Heart Association (14EIA18560026 for J.H.I.).
Publisher Copyright:
© The Author(s) 2021.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Background. Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. Methods. Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). Results. At baseline, the mean age was 73 6 9 years and mean estimated glomerular filtration rate (eGFR) was 46 6 11 mL/ min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) ¼ 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03–1.13], higher MCP-1 (HR ¼ 1.11, 95% CI 1.03–1.19) and lower UMOD (HR ¼ 0.91, 95% CI 0.85–0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). Conclusions. Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.
AB - Background. Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. Methods. Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). Results. At baseline, the mean age was 73 6 9 years and mean estimated glomerular filtration rate (eGFR) was 46 6 11 mL/ min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) ¼ 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03–1.13], higher MCP-1 (HR ¼ 1.11, 95% CI 1.03–1.19) and lower UMOD (HR ¼ 0.91, 95% CI 0.85–0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). Conclusions. Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.
KW - adverse events
KW - biomarkers
KW - chronic kidney disease
KW - hypertension
KW - kidney tubule
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U2 - 10.1093/ndt/gfab255
DO - 10.1093/ndt/gfab255
M3 - Article
C2 - 34473302
AN - SCOPUS:85137008911
SN - 0931-0509
VL - 37
SP - 1637
EP - 1646
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 9
ER -