Historically, half or more of people with type 1 diabetes develop kidney disease, which frequently progresses to kidney failure requiring hemodialysis or a kidney transplant for survival. The high rate of this diabetic complication has dropped slightly in recent years, but is still a huge problem, says Alessandro Doria, MD, PhD, MPH, senior investigator in Joslin Diabetes Center’s Section on Genetics and Epidemiology.
Progression of kidney disease in type 1 diabetes is correlated with increased amounts of a compound in the blood called uric acid. Hoping that a drug that reduces these uric acid levels would slow the disease, Doria and his colleagues launched a multi-institution, randomized clinical trial that enrolled 530 participants with type 1 diabetes and early-to-moderate kidney disease.
Results of the Preventing Early Renal Loss in Diabetes (PERL) study were just published in the New England Journal of Medicine. Unfortunately, this study did not show the desired clinical benefits. “This is not the result that we wanted,” says Doria, “but it does give a very clear answer to an important scientific question.”
The PERL trial grew out of several studies that followed a cohort of people with type 1 diabetes, including one that found people with higher levels of uric acid in their blood were more likely to display a high rate of kidney function loss. “This was an actionable discovery, because allopurinol, a drug that’s been on the market since the 1960s, can easily reduce uric acid,” says Doria, who is also a professor of medicine at Harvard Medical School.
Allopurinol is prescribed for gout, an inflammatory condition caused by excess uric acid, and had produced apparent benefits in much smaller clinical trials among people with chronic kidney disease, a minority of whom had diabetes.
Doria teamed up with S. Michael Mauer, MD, of the University of Minnesota Medical School, to design and carry out a clinical trial with support from the National Institute of Diabetes and Digestive and Kidney Diseases and JDRF. The PERL consortium eventually grew to 16 sites.
Participants in the three-year, placebo-controlled and double-blinded trial received the current standard of care, including a renin-angiotensin system inhibitor—an existing type of drug shown in the 1990s to slow kidney damage, albeit incompletely. Over the course of the study, levels of uric acid dropped about 35% on average among people given allopurinol compared to those who weren’t. “But despite this very nice reduction in uric acid, we could not see any [of the desired] effect on the [glomerular filtration rate]” measuring how much blood is filtered every minute by the kidneys, Doria says.
Despite its disappointing conclusion, “PERL was a textbook example of using epidemiology to find treatment targets, and then designing a study to translate those findings and try to find a new intervention,” Doria says. “In this case, it didn’t work. But this is exactly why we do epidemiological studies, and how our scientific understanding advances.”
Edited by Gary Cramer
