Despite advancements in blood sugar control and kidney therapies, patients with type 1 or type 2 diabetes still face a high risk of diabetic kidney disease. This condition can eventually progress to end-stage kidney disease, but some patients show slower kidney decline than others. 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. This would likely include the delay and prevention of end stage kidney disease (ESKD), which is the most serious and advanced stage of diabetic kidney disease. Now, a 7- to 15-year longitudinal study of 358 diabetics has linked 3 proteins in blood with a slower progression of diabetic kidney disease and progressive kidney failure. The results from Zaipul Md Dom and colleagues suggest that the proteins could help researchers identify diabetics most at risk of kidney damage, potentially enabling earlier interventions and treatment.
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. 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. 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 angiopoietin-1 (ANGPT1), fibroblast growth factor 20 (FGF20) and tumor necrosis factor ligand superfamily member 12 (TNFSF12).
In each case elevated circulating levels reduced odds of progressive kidney decline and progression towards IRC. The combined effect of having elevated levels of all three proteins translated to very low risk for ESKD. The team confirmed this protective link in an independent group of 294 type 1 diabetics; they also found that FGF20 was elevated in healthy, non-diabetic parents of type 1 diabetics who remained free of kidney complications. 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 kidney failure. 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. For example, FGF20 and angioproeitin-1 have specific receptors that may work like growth factor receptors promoting cellular proliferation or sppression of cell death after dangerous stimulation.
Andrzej S. Krolewski MD, PhD, senior investigator at Joslin Diabetes Center and professor of Medicine at Harvard Medical School, explained: “Our research became possible only recently. 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. 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 ESKD, who can then be treated with new therapies.” Dr. Kevin Duffin, co-author on the publication, and chief operating officer at Eli Lilly, said: “Our study identified specific circulating proteins that were depleted in diabetes patients with kidney disease who progressed to ESKD. 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”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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