TY - JOUR
T1 - The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury
AU - Bullen, Alexander L.
AU - Katz, R.
AU - Lee, Alexandra K.
AU - Anderson, Cheryl A.M.
AU - Cheung, Alfred K.
AU - Garimella, Pranav S.
AU - Jotwani, Vasantha
AU - Haley, William E.
AU - Ishani, A.
AU - Lash, James P.
AU - Neyra, Javier A.
AU - Punzi, H.
AU - Rastogi, A.
AU - Riessen, Erik
AU - Malhotra, Rakesh
AU - Parikh, Chirag R.
AU - Rocco, Michael V.
AU - Wall, Barry M.
AU - Bhatt, Udayan Y.
AU - Shlipak, Michael G.
AU - Ix, Joachim H.
AU - Estrella, Michelle M.
N1 - Funding Information:
The primary funding sources for this ancillary study were supported by an R01 award from the National Institutes of Diabetes and Digestive and Kidney Diseases to JHI and MGS (NIDDK; R01DK098234) and an American Heart Association award to JHI (I4EIA18560026). Dr. Alexander L. Bullen was supported by a Ruth L. Kirschstein training grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; T32DK104717). Dr. Joachim H. Ix was supported by a mid-career mentoring award from the NIDDK (K24DK110427). Dr. Michelle Estrella is supported by an R01 from the NIDDK (R01DK103574).
Funding Information:
The Systolic Blood Pressure Intervention Trial is funded with federal funds from the National Institutes of Health, 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, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and inter-agency agreement number A-HL-13-002-001. It also was 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, Osaka, Japan. 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 National Institutes of Health, 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 at https://www.sprinttrial.org/public/dspScience.cfm .
Funding Information:
We also acknowledge support from the following clinical and translational science awards funded by the National Center for Advancing Translational Sciences:
PY - 2019/8
Y1 - 2019/8
N2 - Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and β-2-microglobulin [β2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.
AB - Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and β-2-microglobulin [β2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.
KW - acute kidney injury
KW - alpha-1 microglobulin
KW - beta-2 microglobulin
KW - chitinase-3-like protein
KW - interleukin-18
KW - kidney injury molecule-1
KW - monocyte chemoattractant protein-1
KW - neutrophil gelatinase-associated lipocalin
KW - uromodulin
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U2 - 10.1016/j.kint.2019.03.024
DO - 10.1016/j.kint.2019.03.024
M3 - Article
C2 - 31262489
AN - SCOPUS:85068002183
VL - 96
SP - 470
EP - 479
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 2
ER -