Newly discovered proteins protect against progression of diabetic kidney disease

Elevated levels of three specific circulating proteins are associated with protection against kidney failure in diabetes, according to research from the Joslin Diabetes Center that will be published 30th June in Science Translational Medicine.

"As well as acting as biomarkers for advancing kidney disease risk in diabetes, the proteins may also serve as the basis for future therapies against progression to the most serious types of kidney disease," said Andrzej S. Krolewski MD, PhD, senior author on the publication, senior investigator at Joslin Diabetes Center and professor of medicine at Harvard Medical School. This would likely include the delay and prevention of end stage renal disease (ESRD), which is the most serious and advanced stage of diabetic kidney disease.

The study marks a move towards looking for markers associated with protection against, rather than increased individual risk, for the rapid progression of diabetic kidney disease. This should more directly derive potential targets for slowing progression since it is based on the thinking that individuals with slow progression will have protective factors of some sort.

"Our research became possible only recently," said Dr. Krolewski. "We were able to search for these markers thanks to the development of high-throughput proteomic platforms. More importantly, the availability of biobank specimens that we established many years ago in the Joslin Kidney Study was critical."

According to the report, the researchers profiled levels of just over 1000 proteins in the plasma samples that were taken at baseline in the original study. All of them had diabetes and moderately impaired kidney function. They used two cohorts of individuals with either type 1 or type 2 diabetes that were followed for between 7 and 15 years.

The main aim was to identify proteins that were elevated in individuals with slow or minimal decline in kidney function over the follow-up period. Notably they did validate the initial findings in a further cohort of individuals with type 1 diabetes.

Working through potential candidate proteins, they found three proteins that appeared to offer protection against progressive decline. These were fibroblast growth factor 20 (FGF20), angiopoietin-1 (ANGPT1) and tumor necrosis factor ligand superfamily member 12 (TNFSF12).

In each case elevated circulating levels reduced odds of progressive kidney decline and progression towards ESRD. The combined effect of having elevated levels of all three proteins translated to very low risk for ESRD.

"The protective effects of these proteins seem to be independent, which suggests that there are multiple mechanisms involved. They may be causally related to the disease process or represent as-yet unidentified pathways involved in progressive renal decline," said first author Zaipul Md Dom PhD, a research fellow in the Dr. Krolewski's laboratory

The authors go further to look at the current biological knowledge relating to the individual proteins and kidney disease, identifying a number of potential mechanisms that might explain their protective effects. According to Dr. Krolewski these are potential new routes for research that they will follow.

Dr Kevin Duffin, co-author on the publication, and chief operating officer at Eli Lilly, Diabetes and Diabetic Complications said: "Our study identified specific circulating proteins that were depleted in diabetes patients with kidney disease who progressed to ESRD. These results suggest a personalized medicine approach might be possible for treating patients with low levels of the protective proteins. We think that administering protein therapeutic mimetics or treatments that enhance circulating levels of these depleted proteins might be the future." 

Dr. Krolewski added: "We have already started to develop protocols on how to measure concentrations of the protective proteins in clinical settings. We hope that these proteins can then be used to identify patients at risk of progression to ESRD, who can then be treated with new therapies."

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Other contributors to the research include Eiichiro Satake, Jan Skupien, Bozena Krolewski, Kristina O'Neil, Jill Willency, Simon Dillon, Jonathan Wilson, Hiroki Kobayashi, Katsuhito Ihara, Towia Libermann, and Marlon Pragnell. The contributors are based variously at the Joslin Diabetes Center, Harvard Medical School, Jagiellonian University Medical College, Eli Lilly and company, the Beth Israel Deaconess Medical Center and JDRF International. Competing interests are reported in the Science Translational Medicine report.

Funding for the study was provided by JDRF, National Institutes of Health, Novo Nordisk Foundation, Sunstar Foundation, Foundation for Growth Science from Japan, Uehara Memorial Foundation, Japan Society for the Promotion of Science and NIH Diabetes Research Foundation. Full details are available in the Science Translational Medicine report.

Corresponding author: Andrzej S. Krolewski MD, PhD (andrzej.krolewski@joslin.harvard.edu)

Reference: Md Dom et al. Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes. Science Translational Medicine 2021, 13: eabd2699

DOI: 10.1126/scitranslmed.abd2699

About Joslin Diabetes Center

Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 16 NIH-designated Diabetes Research Centers in the U.S.

For more information about the Joslin Diabetes Center, visit http://www.joslin.org or follow @joslindiabetes | One Joslin Place, Boston, MA 617-309-2400

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