Systems Biology–Derived Biomarkers to Predict Progression of Renal Function Decline in Type 2 Diabetes Diabetes Care 2017;40:391–397 | DOI: 10.2337/dc16-2202 OBJECTIVE Chronic kidney disease (CKD) in diabetes has a complex molecular and likely multifaceted pathophysiology. We aimed to validate a panel of biomarkers iden- tified using a systems biology approach to predict the individual decline of esti- mated glomerular filtration rate (eGFR) in a large group of patients with type 2 diabetes and CKD at various stages. RESEARCH DESIGN AND METHODS We used publicly available “omics” data to develop a molecular process model of CKD in diabetes and identified a representative parsimonious set of nine molec- ular biomarkers: chitinase 3-like protein 1, growth hormone 1, hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP7, MMP8, MMP13, tyrosine ki- nase, and tumor necrosis factor receptor-1. These biomarkers were measured in baseline serum samples from 1,765 patients recruited into two large clinical trials. eGFR decline was predicted based on molecular markers, clinical risk factors (in- cluding baseline eGFR and albuminuria), and both combined, and these predic- tions were evaluated using mixed linear regression models for longitudinal data. RESULTS The variability of annual eGFR loss explained by the biomarkers, indicated by the ad- justed R 2 value, was 15% and 34% for patients with eGFR ‡60 and <60 mL/min/1.73 m 2 , respectively; variability explained by clinical predictors was 20% and 31%, respec- tively. A combination of molecular and clinical predictors increased the adjusted R 2 to 35% and 64%, respectively. Calibration analysis of marker models showed sig- nificant (all P < 0.0001) but largely irrelevant deviations from optimal calibration (calibration-in-the-large: 21.125 and 0.95; calibration slopes: 1.07 and 1.13 in the two groups, respectively). CONCLUSIONS A small set of serum protein biomarkers identified using a systems biology ap- proach, combined with clinical variables, enhances the prediction of renal func- tion loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD. 1 Department of Internal Medicine IV (Nephrol- ogy and Hypertension), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Clinical Pharmacy and Pharmacol- ogy, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands 3 Department of Nephrology, Medical University of Vienna, Vienna, Austria 4 emergentec biodevelopment GmbH, Vienna, Austria 5 Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria 6 Steno Diabetes Center, Gentofte, University of Copenhagen, Copenhagen, Denmark Corresponding author: Rainer Oberbauer, rainer. oberbauer@meduniwien.ac.at. Received 13 October 2016 and accepted 20 December 2016. Clinical trial reg. nos. NCT00252694 and NCT00130312, clinicaltrials.gov. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc16-2202/-/DC1. G.M. and H.J.L.H. contributed equally to this study. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- mation is available at http://www.diabetesjournals .org/content/license. Gert Mayer, 1 Hiddo J.L. Heerspink, 2 Constantin Aschauer, 3 Andreas Heinzel, 4 Georg Heinze, 5 Alexander Kainz, 3 Judith Sunzenauer, 3 Paul Perco, 4 Dick de Zeeuw, 2 Peter Rossing, 6 Michelle Pena, 2 and Rainer Oberbauer, 3 for the SYSKID Consortium Diabetes Care Volume 40, March 2017 391 PATHOPHYSIOLOGY/COMPLICATIONS Downloaded from http://diabetesjournals.org/care/article-pdf/40/3/391/548626/dc162202.pdf by guest on 15 August 2023