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Publication Information
Affiliation
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Division of Nephrology, Hypertension, and Endocrinology, Nihon University School of Medicine, Tokyo, Japan.; Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA; Centre Hospitalier Universitaire, Centre d Investigation Clinique Poitiers, France.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Cognitive Health Services Research Program, University of Michigan, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Diabetes and Complication Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Diabetes and Complication Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.; Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA. Electronic address: rnelson@phx.niddk.nih.gov.; Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: Andrzej.Krolewski@joslin.harvard.edu.
Authors
Kobayashi Hiroki, Looker Helen C, Satake Eiichiro, Saulnier Pierre Jean, Md Dom Zaipul I, O'Neil Kristina, Ihara Katsuhito, Krolewski Bozena, Galecki Andrzej T, Niewczas Monika A, Wilson Jonathan M, Doria Alessandro, Duffin Kevin L, Nelson Robert G, Krolewski Andrzej S
Studies
Abstract
This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.