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UW Researchers Hope to ID Urine Protein Markers of Diabetic Kidney Disease Progression

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NEW YORK(GenomeWeb) – Researchers from the University of Washington are setting out on a three-year project to identify proteins that mark the progression of diabetic kidney disease to full-blown end-stage kidney failure.

Funded by a $404,500 grant for its first year from the National Institute of Diabetes and Digestive and Kidney Diseases, which was announced last month, the project will use a state-of-the-art, targeted, quantitative proteomics platform to quantify the expression of 179 proteins from 12 biologically promising candidate pathways the group has identified as having a high likelihood of association with diabetic kidney disease.

Maryam Afkarian, the project's principal investigator, told GenomeWeb in an email that the team hopes the effort will lead to identification of new pathways that are involved in DKD progression to its final stages.

"The findings from this work will have to be validated and characterized further in other populations and [in a] much larger number of people," Afkarian wrote. But, if confirmed, pathways identified in the study could yield new therapeutic targets and/or a molecular tool to assess patients' likelihood of progressing to end-stage disease and a need for dialysis.

According to Afkarian, DKD is common — occurring in between 30 and 50 percent of people with type 2 diabetes — and has a significant impact on both lifespan and quality of life.

Meanwhile, current tools for both diagnosis and treatment of DKD are limited. "We cannot diagnose it until urine protein increases, something that happens about 10 [to]15 years after the onset of disease and doesn’t happen at all in [about] 25 percent of people," Afkarian wrote. "Our current treatments are also limited: controlling sugar, blood pressure, and use of renin-angiotensin system inhibitors slows DKD progression but does not stop it."

In the study, Afkarian and her colleagues plan to examine patients' urine for proteins from a defined group of pathways, with the hope that they can identify pathologic mechanisms of the disease at specific stages, primarily, as patients progress from stage 3 kidney disease to dialysis or significant loss of kidney function. 

The researchers have picked 179 proteins from 12 biological pathways that have "tremendous pre-existing evidence of involvement in DKD pathology based on animal models and the limited human data that exists," Afkarian wrote.

Using mass spectrometry, the researchers will examine the concentration of these proteins in the urine as a way of gauging the activity of their corresponding pathways in the kidneys. In earlier research the team used immunoassays and other targeted approaches to examine urine concentrations of 28 proteins from four of the 12 total pathways they hope to study under the new grant.

The group found that the urine concentration of 25 of these 28 proteins, were indeed altered compared to normal levels, evidence that there is dysregulation of the related pathways in the kidneys of DKD patients.

In the new study, Afkarian said she will be working with investigators at th Institute for Systems Biology, who have developed selected reaction monitoring mass spectrometry assays to measure the quantities of their 179 target proteins in subjects' urine.

SRM-MS offers the group a targeted quantitative proteomics approach that covers all the 179 proteins they aim to measure. The technology is supported by the ISB's human SRM atlas and human peptide atlas, which allow the platform to be used to measure 20,000 different human proteins.

First, the team will test the urine of patients from a type 2 diabetes sub-cohort of the Chronic Renal Insufficiency Cohort study. They will then validate any findings from this initial study population in a second independent group from the Seattle Kidney Study.

For the first stage, in the CRIC cohort, Afkarian said the group aims to test samples from 100 people who progress from stage 3 DKD to dialysis and compare those to 100 more patients who have stage 3 DKD but do not progress.

In the validation phase, the group will analyze at least 50 samples of each of these two categories in the SKS cohort, she wrote.

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