Promising treatment to slow kidney disease doesn’t prove out in clinical trial
Scientists find that reducing levels of uric acid in the blood does not guard against complication in patients with type 1 diabetes.
Ann Arbor – (June 25, 2020) – 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. This 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 better blood pressure control, including blood pressure drugs that block the renin-angiotensin system, “but diabetic kidney disease remains a huge problem,” says Rodica Pop-Busui, MD, PhD, Professor of Internal Medicine, Metabolism, Endocrinology and Diabetes, Vice Chair of Clinical Research in the Department of Internal Medicine and Director of Clinical Research, Mentoring and Development in the Elizabeth Wiser Caswell Diabetes Institute at Michigan Medicine.
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, Drs Alessandro Doria MD, PhD, MPH, Senior Investigator in Joslin Diabetes Center’s Section on Genetics and Epidemiology and Professor of Medicine, Harvard Medical School and Michael Mauer, MD, Professor of Pediatrics and Medicine at the University of Minnesota, co-principal investigators of the PERL trial, together with colleagues from several other academic centers including University of Michigan designed and launched a multi-institution randomized clinical trial that enrolled 530 participants with type 1 diabetes and early-to-moderate kidney disease. “We wanted to intervene early in the disease, because the earlier you start, the more you can gain,” Drs. Doria and Mauer note.
The Preventing Early Renal Loss in Diabetes (PERL) study was just published in the New England Journal of Medicine (NEJM), the leading clinical research journal. Unfortunately, this study did not show a clinical benefit for allopurinol. “This is not the result that we have hoped for,” says Pop-Busui, “but it does give a very clear answer to an important scientific question.” A second study from Australia on patients with a variety of chronic kidney diseases, some with diabetes, published alongside the PERL study in this edition of 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 Alessandro 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 groups in Denver, Colorado, USA and Copenhagen, Denmark obtained similar results. Also, allopurinol seemed to produce benefits in two much smaller clinical trials in people with chronic kidney disease, a minority of whom had diabetes, indicating the need for a more definitive large-scale trial to answer this important question. “This was an actionable discovery, because allopurinol, a drug that’s been on the market since the 1960s, prescribed for gout, an inflammatory condition caused by excess uric acid, can easily reduce uric acid,” says Dr. Alessandro Doria.
Drs. Doria and Mauer teamed up with several other co-senior investigators including University of Michigan investigators Drs. Rodica Pop-Busui (Site Director and PI at Michigan) and Frank Brosius (co-I), and Drs. Andrzej Galecki (DOIM) and Cathie Spino (School of Public Health) (Co-Directors of the Data Coordinating Center) 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 (majority from US, 3 from Canada and one from Denmark).
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.
“PERL was a textbook example of using basic science, epidemiology findings and preliminary pilot studies to identify a treatment target, and then to design a study to answer an important question," Doria and Mauer say.
“In this case, it didn’t work. But this is exactly why we do epidemiological studies, and how our scientific understanding advances.” Pop-Busui says.
We will continue to follow participants through their medical records and through national databases that track people who eventually progress to dialysis or kidney transplants.
“University of Michigan main site also included participants from the Ann Arbor VA and Henry Ford Health System as sub sites, demonstrating the strength of a teamwork that overcame barriers across healthcare systems in our efforts to fight diabetes complications and help all patients with diabetes have a better life,” Pop-Busui says. Other University of Michigan investigators included: Lynn Ang MD, Nazanene Esfandiari MD, Kara Mizokami-Stout MD, Cynthia Plunkett RN, Virginia Leone MS, Brittany Williams (Michigan Medicine), Rachel Perlman and Karen Belanger NP (Ann Arbor VA), and Arti Bhan MD, Davida Kruger NP, CDE, Heather Remtema (Henry Ford Health System).
Other co-senior authors on the NEJM paper were Allison Goldfine and Sylvia Rosas at Joslin’s, David Cherney and Bruce Perkins of the University of Toronto; Ildiko Lingvay of University of Texas Southwestern Medical School; Afshin Parsa of the National Institutes of Health; Peter Rossing of the University of Copenhagen; Ronald Sigal of the University of Calgary; Maryam Afkarian of the University of California at Davis; Ronnie Aronson of LMC Diabetes & Endocrinology in Toronto; Luiza Caramori, Amy Karger and William Robiner of the University of Minnesota; Jill Crandall of the Albert Einstein College of Medicine; Ian de Boer, Irl Hirsch and Katherine of the University of Washington; Thomas Elliott of BCDiabetes in Vancouver; Jeehea Haw and Guillermo Umpierrez of Emory University; David Maahs and Sarit Polsky of the University of Colorado; Janet McGill of Washington University; Mark Molitch and Amisha Wallia of Northwestern University; Marlon Pragnell of JDRF; Peter Senior of the University of Alberta; and Ruth Weinstock of SUNY Upstate Medical University.