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 typediabetes.

Date:
June 27, 2020
Source:
Joslin Diabetes Center
Summary:
Progression of kidney disease in type 1 diabetes is correlated with
increased amounts of uric acid. A drug that reduces uric acid levels
was tested in a multi-institution randomized clinical trial. Though
the study did not show the desired clinical benefit, it did provide
a very clear answer to an important scientific question.



FULL STORY ========================================================================== 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," 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, 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."

========================================================================== Story Source: Materials provided by Joslin_Diabetes_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Alessandro Doria, Andrzej T. Galecki, Cathie Spino, Rodica
Pop-Busui,
David Z. Cherney, Ildiko Lingvay, Afshin Parsa, Peter Rossing,
Ronald J.

Sigal, Maryam Afkarian, Ronnie Aronson, M. Luiza Caramori, Jill P.

Crandall, Ian H. de Boer, Thomas G. Elliott, Allison B. Goldfine, J.

Sonya Haw, Irl B. Hirsch, Amy B. Karger, David M. Maahs, Janet
B. McGill, Mark E. Molitch, Bruce A. Perkins, Sarit Polsky, Marlon
Pragnell, William N. Robiner, Sylvia E. Rosas, Peter Senior,
Katherine R. Tuttle, Guillermo E. Umpierrez, Amisha Wallia, Ruth
S. Weinstock, Chunyi Wu, Michael Mauer.

Serum Urate Lowering with Allopurinol and Kidney Function in
Type 1 Diabetes. New England Journal of Medicine, 2020; 382 (26):
2493 DOI: 10.1056/NEJMoa1916624 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200627112431.htm

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