Maryam Afkarian1, Sarit Polsky2, Afshin Parsa3, Ronnie Aronson4, Maria Luiza Caramori5, David Z Cherney6, Jill P Crandall7, Ian H de Boer8, Thomas G Elliott9, Andrzej T Galecki10,11, Allison B Goldfine12, J Sonya Haw13, Irl B Hirsch8, Amy B Karger14, Ildiko Lingvay15, David M Maahs16, Janet B McGill17, Mark E Molitch18, Bruce A Perkins19, Rodica Pop-Busui20, Marlon Pragnell21, Sylvia E Rosas12, Peter Rossing22,23, Peter Senior24, Ronald J Sigal25, Catherine Spino26, Katherine R Tuttle27,28, Guillermo E Umpierrez13, Amisha Wallia18, Ruth S Weinstock29, Chunyi Wu11, Michael Mauer5, Alessandro Doria. 1. Division of Nephrology, Department of Medicine, University of California, Davis, Davis, CA. 2. Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO. 3. Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. 4. LMC Diabetes & Endocrinology, Toronto, Ontario, Canada. 5. Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN. 6. Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada. 7. Department of Medicine, Albert Einstein College of Medicine, New York, NY. 8. Department of Medicine, University of Washington, Seattle, WA. 9. BCDiabetes, Vancouver, British Columbia, Canada. 10. Division of Geriatrics, Institute of Gerontology, University of Michigan, Ann Arbor, MI. 11. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI. 12. Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA. 13. Department of Medicine, Emory University, Atlanta, GA. 14. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN. 15. Department of Internal Medicine and Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX. 16. Department of Pediatrics, Stanford University, Palo Alto, CA. 17. Department of Medicine, Washington University School of Medicine, St. Louis, MO. 18. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. 19. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada. 20. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. 21. JDRF, New York, NY. 22. Steno Diabetes Center Copenhagen, Gentofte, Denmark. 23. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 24. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 25. Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada. 26. Statistical Analysis of Biomedical and Educational Research, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI. 27. Providence Health Care, Spokane, WA. 28. Institute of Translational Health Sciences, Kidney Research Institute, and Division of Nephrology, University of Washington, Seattle, WA. 29. Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY.
Abstract
OBJECTIVE:Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) toallopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS:Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated withrenin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.
RCT Entities:
OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS:Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.
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