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J Am Soc Nephrol. 2017 Sep;28(9):2786-2793. doi: 10.1681/ASN.2016101101. Epub 2017 May 5.

Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease.

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Division of Nephrology, Department of Medicine, and
Division of Nephrology, Department of Medicine, and.
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
Program of Applied Translational Research, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Institute for Healthcare Delivery Science, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.
Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and.
Epidemiology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut;


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-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (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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