TY - JOUR
T1 - Distinct Dimensions of Kidney Health and Risk of Cardiovascular Disease, Heart Failure, and Mortality
AU - Lee, Alexandra K.
AU - Katz, Ronit
AU - Jotwani, Vasantha
AU - Garimella, Pranav S.
AU - Ambrosius, Walter T.
AU - Cheung, Alfred K.
AU - Gren, Lisa H.
AU - Neyra, Javier A.
AU - Punzi, Henry
AU - Raphael, Kalani L.
AU - Shlipak, Michael G.
AU - Ix, Joachim H.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) and the National Research Service Award through the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK; grants R01DK098234 to J.H. Ix and M.G. Shlipak and K24DK110427 to J.H. Ix) and the American Heart Association (14EIA18560026 to J.H. Ix). A.K. Lee was supported by the National Institute on Aging (NIA; grant 2T32AG000212). SPRINT is funded with federal funds from the NIH, including the National Heart, Lung, and Blood Institute, the NIDDK, the NIA, and the National Institute of Neurological Disorders and Stroke (contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200 900049C, and interagency agreement 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 Translation Science Awards funded by 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; University of Texas, Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1 TR000445; George Washington University: UL1TR000075; University of CA, Davis: UL1TR000002; University of Florida: UL1 TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 Centers of Biomedical Research Excellence Award National Institute of General Medical Sciences; and Wake Forest University: UL1TR001420. The content of this manuscript 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.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Chronic kidney disease is a strong risk factor for cardiovascular disease (CVD), but clinical kidney measures (estimated glomerular filtration rate and albuminuria) do not fully reflect the multiple aspects of kidney tubules influencing cardiovascular health. Applied methods are needed to integrate numerous tubule biomarkers into useful prognostic scores. In SPRINT (Systolic Blood Pressure Intervention Trial) participants with chronic kidney disease at baseline (estimated glomerular filtration ratecr&cys <60 mL/minute per 1.73 m2), we measured 8 biomarkers from urine (α1M [α1M microglobulin], β2M [β2M microglobulin], umod [uromodulin], KIM-1 [kidney injury molecule-1], MCP-1 [monocyte chemoattractant protein-1], YKL-40 [chitinase-3-like protein-1], NGAL [neutrophil gelatinase-associated lipocalin], and IL-18 [interleukin 18]) and 2 biomarkers from serum (intact parathyroid hormone, iFGF-23 [intact fibroblast growth factor-23]). We used an unsupervised method, exploratory factor analysis, to create summary scores of tubule health dimensions. Adjusted Cox models evaluated each tubule score with CVD events, heart failure, and all-cause mortality. We examined CVD discrimination using Harrell C-statistic. Factor analysis of 10 biomarkers from 2376 SPRINT-chronic kidney disease participants identified 4 unique dimensions of tubular health: tubule injury/repair (NGAL, IL-18, YKL-40), tubule injury/fibrosis (KIM-1, MCP-1), tubule reabsorption (α1M, β2M), and tubular reserve/mineral metabolism (umod, intact parathyroid hormone, iFGF-23). After adjustment for CVD risk factors, estimated glomerular filtration rate, and albumin-to-creatinine ratio, 2 of the 4 tubule scores were associated with CVD (hazard ratio per SD; reabsorption, 1.21 [1.06-1.38]; reserve, 1.24 (1.08-1.38]), 1 with heart failure (reserve, 1.41 [1.13-1.74]), and none with mortality. Compared with a base model (C-statistic=0.674), adding estimated glomerular filtration rate and albumin-to-creatinine ratio improved the C-statistic (C=0.704; P=0.001); further adding tubule scores additionally improved the C-statistic (C=0.719; P=0.009). In the setting of chronic kidney disease, dimensions of tubule health quantified using factor analysis improved CVD discrimination beyond contemporary kidney measures. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.
AB - Chronic kidney disease is a strong risk factor for cardiovascular disease (CVD), but clinical kidney measures (estimated glomerular filtration rate and albuminuria) do not fully reflect the multiple aspects of kidney tubules influencing cardiovascular health. Applied methods are needed to integrate numerous tubule biomarkers into useful prognostic scores. In SPRINT (Systolic Blood Pressure Intervention Trial) participants with chronic kidney disease at baseline (estimated glomerular filtration ratecr&cys <60 mL/minute per 1.73 m2), we measured 8 biomarkers from urine (α1M [α1M microglobulin], β2M [β2M microglobulin], umod [uromodulin], KIM-1 [kidney injury molecule-1], MCP-1 [monocyte chemoattractant protein-1], YKL-40 [chitinase-3-like protein-1], NGAL [neutrophil gelatinase-associated lipocalin], and IL-18 [interleukin 18]) and 2 biomarkers from serum (intact parathyroid hormone, iFGF-23 [intact fibroblast growth factor-23]). We used an unsupervised method, exploratory factor analysis, to create summary scores of tubule health dimensions. Adjusted Cox models evaluated each tubule score with CVD events, heart failure, and all-cause mortality. We examined CVD discrimination using Harrell C-statistic. Factor analysis of 10 biomarkers from 2376 SPRINT-chronic kidney disease participants identified 4 unique dimensions of tubular health: tubule injury/repair (NGAL, IL-18, YKL-40), tubule injury/fibrosis (KIM-1, MCP-1), tubule reabsorption (α1M, β2M), and tubular reserve/mineral metabolism (umod, intact parathyroid hormone, iFGF-23). After adjustment for CVD risk factors, estimated glomerular filtration rate, and albumin-to-creatinine ratio, 2 of the 4 tubule scores were associated with CVD (hazard ratio per SD; reabsorption, 1.21 [1.06-1.38]; reserve, 1.24 (1.08-1.38]), 1 with heart failure (reserve, 1.41 [1.13-1.74]), and none with mortality. Compared with a base model (C-statistic=0.674), adding estimated glomerular filtration rate and albumin-to-creatinine ratio improved the C-statistic (C=0.704; P=0.001); further adding tubule scores additionally improved the C-statistic (C=0.719; P=0.009). In the setting of chronic kidney disease, dimensions of tubule health quantified using factor analysis improved CVD discrimination beyond contemporary kidney measures. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.
KW - albuminuria
KW - biomarker
KW - cardiovascular diseases
KW - epidemiology
KW - kidney
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U2 - 10.1161/HYPERTENSIONAHA.119.13339
DO - 10.1161/HYPERTENSIONAHA.119.13339
M3 - Article
C2 - 31378102
AN - SCOPUS:85072134125
SN - 0194-911X
VL - 74
SP - 872
EP - 879
JO - Hypertension
JF - Hypertension
IS - 4
ER -