TY - JOUR
T1 - Plasma biomarkers and kidney function decline in early and established diabetic kidney disease
AU - Coca, Steven G.
AU - Nadkarni, Girish N.
AU - Huang, Yuan
AU - Moledina, Dennis G.
AU - Rao, Veena
AU - Zhang, Jane
AU - Ferket, Bart
AU - Crowley, Susan T.
AU - Fried, Linda F.
AU - Parikh, Chirag R.
N1 - Funding Information:
This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grant no. R01DK096549 to S.G.C.). G.N.N. is supported by a career development award from the National Institutes of Health (NIH) (K23DK107908). C.R.P. is supported by the NIH (K24-DK090203) and P30-DK079310-07 O’Brien Center grant. S.G.C., G.N.N., B.F., and C.R.P. are members and are supported in part by the Chronic Kidney Disease Biomarker Consortium (1U01DK106962-01). D.G.M. is a Yale Investigative Medicine program graduate student and is supported by Clinical and Translational Science Award grant number UL1 TR000142 from the National Center for Advancing Translational Science, a component of the NIH. B.F. is supported by an American Heart Association grant (#16MCPRP31030016). The manuscript contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. ACCORD was supported by contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010 from the National Heart, Lung, and Blood Institute; by other components of the NIH, including the NIDDK, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The VA-NEPHRON D trial was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, VA-NEPHRON-D ClinicalTrials.gov number, NCT00555217. The Investigator-Initiated Studies Program of Merck donated the study medications, losartan and lisinopril/placebo, for the VA-NEPHROND study.
Publisher Copyright:
Copyright © 2017 by the American Society of Nephrology.
PY - 2017/9
Y1 - 2017/9
N2 - Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1were roughly two-fold higher in the advancedDKD population (NEPHRON-D) than in the earlyDKDpopulation (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.
AB - Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1were roughly two-fold higher in the advancedDKD population (NEPHRON-D) than in the earlyDKDpopulation (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.
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U2 - 10.1681/ASN.2016101101
DO - 10.1681/ASN.2016101101
M3 - Article
C2 - 28476763
AN - SCOPUS:85028713939
VL - 28
SP - 2786
EP - 2793
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 9
ER -