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Blood Protein Signature Reported for Severe Diabetic Kidney Disease

NEW YORK (GenomeWeb) – A team from the US, Poland, France, and Italy has identified 17 proteins that appear to turn up at higher-than-usual blood levels in individuals with type 1 or type 2 diabetes who ultimately go on to develop severe kidney disease.

"These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease," senior and co-corresponding author Andrzej Krolewski, a researcher affiliated with the Joslin Diabetes Center and Harvard Medical School, and his co-authors wrote in their study, published online yesterday in Nature Medicine.

In their prospective analysis, the researchers found that this circulating protein set — dubbed the kidney risk inflammatory signature, or KRIS — corresponded with the risk of developing end-stage diabetic kidney disease within a decade in three distinct groups of type 1 diabetes or type 2 diabetes patients.

Based on the documented functions for the KRIS proteins and their reported tissue sources, the team speculated that the proteins likely play a role in inflammatory processes that are involved in diabetes and in the end-stage kidney disease itself.

For their study, the researchers did proteomic profiling on blood samples from individuals in diabetic cohorts assembled for the Joslin Diabetes Center's Joslin Kidney Study that were followed for eight to 11 years in an effort to find markers for end-stage renal disease.

Using a custom SOMAscan array from Boulder, Colorado-based SomaLogic, the team assessed 194 circulating proteins — focusing on inflammatory proteins and proteins previously implicated in diabetic kidney disease — in blood samples from 219 individuals with type 1 diabetes and a validation group of 144 type 2 diabetes patients, all with some level of kidney impairment.

The type 1 diabetes group included 108 individuals who developed end-stage renal disease during the study's follow up time, while 35 of the individuals with type 2 diabetes had kidney disease that advanced to that point, the researchers noted. Half a dozen of the proteins came from tumor necrosis factor receptor super-families, while the remaining proteins represented receptor or secreted proteins.

After narrowing in on 35 inflammatory proteins that appeared to be enhanced in blood samples from the individuals with type 1 diabetes, they validated associations for the 17 KRIS proteins using proteomic patterns in blood samples from the Joslin type 2 diabetes cohort.

The team further verified the signature's association with advanced diabetic kidney disease through SOMAscan array analyses on blood samples from 162 individuals with type 2 diabetes from the Pima Indian population, a Native American group traditionally found in present-day Arizona.

Members of that cohort were followed for 11 years, as a median, and 38 developed end-stage renal disease, the researchers reported. Although all of those participants appeared to have normal kidney function at baseline, those who ultimately developed end-stage renal disease had significantly higher levels of 16 KRIS proteins when the study began, hinting that a rise in circulating levels of the inflammatory proteins may portend disease.

The team's follow-up analyses suggested that at least a dozen of the proteins remained tied to kidney disease risk in the Pima participants, even after adjusting for potential confounders and focusing on an intermediate phenotype.

Along with efforts to untangle the pathways involved in producing the inflammatory blood signature and its potential role in kidney disease and diabetes, the researchers also looked at how well the KRIS protein levels in the blood could predict severe kidney disease, focusing in on a five-protein predictive model. 

The authors cautioned that because the current study focused on individuals with type 1 or type 2 diabetes, "we have no data to evaluate the generalizability of these findings to individuals with other kidney diseases."