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Translational Research Approach Leads to PERL Study to Reduce Renal Disease

Monday, March 31, 2014

The complexities of diabetes can’t be fully understood in a lab or in a clinic alone. Sometimes, information coming from the lab informs clinical researchers about what they should study in people with diabetes. Other times, trends noticed in patient visits can lead to an important study at the bench.

The back-and-forth, cross-disciplinary nature of diabetes research and medical research in general is known as translational research.

“It is a reciprocal journey from initial observation in lab or clinic to understanding the relevance of the finding to patients, practice and population health,” said Allison Goldfine, M.D., Head of the Section on Clinical, Behavioral and Outcomes Research.

Joslin Diabetes Center is dedicated to translational research; so much so that Joslin will soon open the doors to the newly constructed Translational Research Center for the Cure of Diabetes. This center will improve communication and encourage collaboration between basic science researchers and clinical researchers.

But Joslin hasn’t been waiting for the Translational Center’s unveiling to do this type of important work. Translational research has been part of Joslin’s approach to understanding more about diabetes for years.

One such translational research endeavor is looking to find a treatment for kidney disease. Kidney disease poses one of the greatest burdens for people with type 1 diabetes, with 10 to 15 percent of patients developing end stage renal disease (ESRD), meaning that they need hemodialysis or a renal transplant to survive.

Diabetes is the leading cause of ESRD, and the number of people with both diabetes (including type 1 and type 2) and kidney failure rose by 61 percent between 2000 and 2010. Currently, tight control of blood sugar and blood pressure are the only prevention tools. However, as high as 50 percent of people with diabetes cannot achieve optimal blood sugar control and blood pressure control is only partially effective.

Research into the potential for a new treatment began with a study that started in 2004 and was published in June 2010 by the lab of Andrezej Krolewski, M.D., Ph.D., Head of the Section on Genetics and Epidemiology at Joslin. Dr. Krolewski and his colleagues had previously noted that declining kidney function seemed to be linked in some way with levels of uric acid, which is a chemical found in the blood created by DNA breakdown. This prompted them to ask if this was a coincidence, or if uric acid levels impacted the risk of early progressive renal function loss.

The June 2010 paper detailed the Second Joslin Study on the Natural History of Microalbuminuria in Type 1 Diabetes. The Second Joslin Study followed more than 400 people with type 1 diabetes and kidney disease for 4 to 6 years to see if there was a definitive link between high uric acid levels and reduced glomerular filtration rate (GFR), which is the measure of how well kidneys filter blood.

“We found that serum uric acid was a significant independent predictor of the development of early GFR loss,” they wrote in the paper. “For each 1 mg/dl increase in serum uric acid, there was a 40 percent increase in the odds of developing early GFR loss.”

But just because the study found a correlation between high uric acid levels and decreasing GFR doesn’t necessarily mean the former caused the latter. This finding from the Second Joslin Study (and data from two other studies, one from the Steno Diabetes Center in Denmark and one from the University of Colorado) inspired the current clinical trial known as Preventing Early Renal Function Loss in Diabetes Consortium (or PERL) to study this correlation in depth within a population of people with type 1 diabetes who are at a higher risk of losing kidney function.

“This is an association, we don’t know whether there is a causal link,” said Alessandro Doria, M.D., Ph.D., M.P.H., Senior Investigator in the Section on Genetics and Epidemiology. Dr. Doria did research in the Second Joslin Study and is a co-principal investigator of PERL, along with Michael Mauer, M.D., from the University of Minnesota Medical School. “But that’s why we’re doing this study, to try to see if by decreasing uric acid we can slow down this decline of kidney function,” he continued.

The PERL study will examine if using allopurinol, a drug commonly prescribed for gout that prevents the formation of uric acid, will halt or slow the reduction in GFR. If the patients taking allopurinol don’t show declining GFR, the path that started with the Second Joslin Study in 2004 could culminate in an effective treatment for kidney disease.

“This shows how well-positioned we are to translate what we are finding from the laboratory to the patients, and this exemplifies what we do best [here at Joslin],” said George King, M.D., Chief Scientific Officer at Joslin. “This is the absolute epitome of translational research.” 

Find out more about participating in the PERL study here, and learn more about research at Joslin Diabetes Center at Joslinresearch.org.

Page last updated: July 25, 2014