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, with the advent of better ways to control blood glucose (sugar) levels and improved blood pressure drugs, "but diabetic kidney disease 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 (NEJM), the leading clinical research journal. 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."
A second trial by Australian researchers on patients with a variety of chronic kidney diseases, some with diabetes, published alongside the PERL study in the NEJM, found similar results.
The PERL trial grew out of several studies that followed a cohort of people with type 1 diabetes, including one in which Doria partnered with Andrzej Krolewski, MD, PhD, head of the Section on Genetics and Epidemiology. In a 2011 paper, the Joslin scientists demonstrated that in this cohort, people with higher levels of uric acid in their blood were more likely to display a high rate of kidney function loss. Two other research groups in Denver, Colorado and Copenhagen, Denmark obtained similar results.
This was an actionable discovery, because allopurinol, a drug that's been on the market since the 1960s, can easily reduce uric acid."
Alessandro Doria, Professor of Medicine at Harvard Medical School
Allopurinol is prescribed for gout, an inflammatory condition caused by excess uric acid, he explains. It's an inexpensive generic drug with known side effects that can largely be avoided. Additionally, allopurinol 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 (NIDDK) 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.
The key measurement of kidney function for PERL was glomerular filtration rate (GFR), a measure of how much blood is filtered every minute by the kidneys. GFR drops as kidney disease progresses.
Over the three years 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 effect on GFR," Doria says.
He and his colleagues will continue to follow participants through their medical records and through national databases that track people who eventually progress to dialysis or kidney transplants.
Researchers at Joslin and other institutions continue to examine other potential routes to guard against kidney disease among people with type 1 diabetes.
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."
Doria, A., et al. (2020) Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. New England Journal of Medicine. doi.org/10.1056/NEJMoa1916624.