Journal
KIDNEY INTERNATIONAL
Volume 102, Issue 2, Pages 370-381Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.04.022
Keywords
circulating biomarker; diabetes; diabetic kidney disease; end-stage kidney disease; proteomics analysis
Categories
Funding
- National Institutes of Health (NIH) [DK041526, DK110350, DK126799]
- Novo Nordisk Foundation [NNF14OC0013659]
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science
- Mary K. Iacocca Fellowship
- Sunstar Foundation, Japan (Hiroo Kaneda Scholarship)
- Foundation for Growth Science from Japan
- Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases
- NIH DERC grant [P30 DK036836]
- American Diabetes Association [1-08-CR-42]
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This study utilizes a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. The researchers identified 11 proteins that were significantly associated with the progression to kidney failure and found that some of these proteins were related to neuron development and kidney fibrosis. Further investigation is needed to understand the specific mechanisms of these proteins in the progression of diabetic kidney disease.
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.
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