For Medical Professionals

Background for the PERL study
Diabetic nephropathy is the long-term complication of type 1 diabetes that imposes the highest social and economic burden.  After 40 years of diabetes, about one in three patients with type 1 diabetes will have developed kidney abnormalities, which frequently progress to end stage renal disease (ESRD). Despite improvements during the past 20 years in glycemic and blood pressure control, and the introduction of ‘renoprotective’ drugs such as renin–angiotensin system blockers, the overall incidence of diabetic nephropathy is not declining. Thus, diabetic nephropathy remains one of the most important causes of excess morbidity and mortality in patients with diabetes mellitus, and novel therapies to complement and increase the therapeutic effects of glycemic control and inhibition of the renin-angiotensin system are urgently needed. 

Mounting evidence from epidemiological studies indicates that serum uric acid levels are strong risk factors for the development of chronic kidney disease and loss of kidney function among persons with type 1 diabetes.  Prospective data from the Second Joslin Kidney Study identified elevated baseline serum uric acid as one of the strongest independent predictors of early glomerular filtration rate (GFR) loss among patients with type 1 diabetes who had microalbuminuria and normal renal function at baseline (Ficociello). Investigators at the University of Colorado also found that serum uric acid levels predicted the transition from normoalbuminuria to micro- or macro-albuminuria, as well as the progression of subclinical atherosclerosis in the CACTI study (Jalal; Rodrigues). An association between uric acid and development of persistent macroalbuminuria has also been reported by the Steno group (Hovind).

These studies and others strongly support the concept that moderately elevated serum uric acid has a pathogenetic role in diabetic nephropathy development and in the deterioration of kidney function observed in type 1 diabetes. Two small clinical trials have recently provided proof of concept data for translating these findings into a novel intervention by showing that the urate-lowering agent allopurinol was effective in slowing the progression of non-diabetic renal disease among hyperuricemic as well as normouricemic individuals with moderately reduced GFR (Siu; Goicoechea). These findings, along with the observational data discussed above, strongly suggest that lowering serum uric acid levels may prevent or slow the loss of kidney function among subjects with diabetes.

To test this hypothesis, we have established a consortium of investigators from academic centers with interest and expertise in diabetic nephropathy. The Consortium, led by Dr. Alessandro Doria from the Joslin Kidney Study, and by Dr. Michael Mauer, who recently led the Renin Angiotensin System Study (RASS) clinical trial, has been named PERL (Preventing Early Renal Loss in Diabetes) to emphasize the Consortium’s focus on intervening early in the course of kidney disease, when renal damage is most likely to be arrested or reversed and interventions are more likely to be effective.  PERL is conducting this 3-year clinical trial to test whether the uric acid lowering drug allopurinol can preserve kidney function among type 1 diabetic patients.

References

Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, Eckfeldt JH, Stanton RC, Galecki AT, Doria A, Warram JH, Krolewski AS. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010 Jun;33(6):1337-43. doi: 10.2337/dc10-0227.

Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, Arroyo D, Luño J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010 Aug;5(8):1388-93. doi:10.2215/ CJN01580210.

Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH.  Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes. 2009 Jul;58(7):1668-71. doi: 10.2337/db09-0014. Erratum in: Diabetes. 2010 Oct;59(10):2695.

Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, Snell-Bergeon JK. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant 25, 1865-1869, 2010.

Levy GD, Rashid N, Niu F, Cheetham TC. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia.  J Rheumatol. 2014 May;41(5):955-62. doi: 10.3899/jrheum.131159.

Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A; PERL Consortium.  Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013 Aug;13(4):550-9. doi: 10.1007/s11892-013-0381-0.

Rodrigues TC, Maahs DM, Johnson RJ, Jalal DI, Kinney GL, Rivard C, Rewers M, Snell-Bergeon JK. Serum uric acid predicts progression of subclinical coronary atherosclerosis in individuals without renal disease. Diabetes Care 33, 2471-2473, 2010.

Siu YP, Leung KT, Tong MK, Kwan TH.  Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis. 2006 Jan;47(1):51-9.

Zoppini G, Targher G, Chonchol M, Ortalda V, Abaterusso C, Pichiri I, Negri C, Bonora E. Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care. 2012 Jan;35(1):99-104. doi: 10.2337/dc11-1346

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What PERL Study’s Principal Investigators and Sponsors Have to Say 
“Diabetes is the leading cause of ESRD, responsible for more than 45% of the more than 115,000 new ESRD cases in the USA and the number of people with diabetes, including type 1 and type 2, and kidney failure rose by 61 percent between 2000 and 2010. Thus, this study has large human suffering, public health and health cost implications,” said co-Principal Investigator, Michael Mauer, M.D., Professor of Pediatrics and Medicine at the University of Minnesota Medical School.

“The goal of this study is to see if we can slow down the decline of kidney function by decreasing uric acid and find a new way of preventing kidney complications in people with diabetes,” said co-Principal Investigator Alessandro Doria, M.D., Ph.D., M.P.H., an Investigator in the Section on Genetics and Epidemiology, Associate Professor of Medicine at Harvard Medical School and Associate Professor in the Department of Epidemiology at the Harvard School of Public Health. “Data indicates that moderately high serum uric acid levels predispose to diabetic kidney disease. However, we don’t know whether this is due to uric acid itself or to something else that goes together with it. That’s why this study is important – to determine if uric acid is the culprit or not.”
“Smaller studies have suggested benefit in slowing kidney function decline in patients with chronic kidney disease, but PERL is positioned to provide a much more definitive answer to this important question,” said Dr. Mauer.

“If we see a robust effect [from this study, allopurinol] will become a standard addition to the treatment of diabetic kidney complications,” said Drs. Doria and Mauer. “Also, given that allopurinol is relatively inexpensive and safe, perhaps many more people with diabetes could be treated with it, even if they are not at high risk for kidney complications. It will make a huge difference in the array of tools we have to prevent ESRD.”

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Related Sites

http://www.niddk.nih.gov - The National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts, supports, and coordinates research on many of the most serious diseases affecting public health. The Institute supports clinical research on the diseases of internal medicine and related subspecialty fields, as well as many basic science disciplines.  NIDDK is a sponsor of the PERL study and their website provides valuable information about type 1 diabetes.

http://jdrf.org/ - JDRF is the leading global organization funding type 1 diabetes research. JDRF’s goal is to progressively remove the impact of type 1 diabetes from people’s lives until we achieve a world without type 1 diabetes.  JDRF is a sponsor of the PERL study and their website provide valuable information about type 1 diabetes.

http://clinicaltrials.gov/ct2/show/NCT02017171?term=PERL&rank=4 - More information about the PERL study may also be found on the NIH-sponsored ClinicalTrials.gov, a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. Learn more About Clinical Studies and About This Site, including relevant History, Policies, and Laws.  The PERL study is registered on ClinicalTrials.gov.


 

 

 

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