Preventing Early Renal Loss in Diabetes (PERL) study: A randomized double-blinded trial of allopurinoldrationale, design, and baseline data

PERL Study Group

doi:10.2337/dc19-0342

Preventing Early Renal Loss in Diabetes (PERL) study: A randomized double-blinded trial of allopurinoldrationale, design, and baseline data

PERL Study Group

Medicine, Endocrinology Division

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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) 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 HbA_1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m², and historical eGFR slope 23.5 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 HbA_1c (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 (24.7 vs. 22.5 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.

Original language	English (US)
Pages (from-to)	1454-1463
Number of pages	10
Journal	Diabetes care
Volume	42
Issue number	8
DOIs	https://doi.org/10.2337/dc19-0342
State	Published - Aug 1 2019

Funding

Acknowledgments. The PERL study investigators thank all the study participants for enormous contributions made to this long and demanding trial. They are also grateful to the PERL data safety and monitoring board (Linda Fried, Ananda Basu, Melanie Blank, Tom Greene, Lawrence Holzman, Charity G. Moore Patterson, and John Sedor) and the National Institutes of Health officer Dr. Teresa Jones for guidance and to Green Mountain Pharmaceuticals and Belmar Pharmacy (Lakewood, CO) for the skilled preparation and distribution of the study drug. The PERL investigators also acknowledge all the PERL research coordinators whose daily commitment and effort has made this study possible (alphabetically): Daphne Adelman, Gayatri Anupindi, Cathy Bagne, Mary Bates, Karen Belanger, Emily Boone, Jane Bulger, Leslie Cham, Jing H. Chao, Theresa Christiansen, Mary Ann Clearwaters, Mary Jane Clifton, Hector Com, Debra Conboy, Kristie DeHaan, Tineke Dineen, Amy Dunlop, Sara Eischen, C. Marcelo Falappa, Lestat Feliciano, Birgit Fink, Benjamin Flagg, Victoria Gage, Jason Gensler, Anne Goodling, Vasundhara Goplani, Monica Hartmuller, Eric Henricks, Jessie Arman Hermann, Madeleine Hermans, Xinli Huang, Karen Hyams, Marla Inducil, Lone Jelstrup, Florence John, Yvette Kowalski, Vesta Lai, Lee-Ann Langkaas, Diane Larsen, Catherine Leiendecker Foster, Virginia Leone, Camilla Levister, Annie Lukkari, Dawn Lum, Caroline Lyster, Maria Maione, Elaine Massaro, Jennifer McCance, Christine Mendonca, Sara R. Meyers, Joan Milton, Cindy A. Murphy, Ariane Nguyen, Andrej Orszag, Cynthia Plunkett, Carmyn Polk, Laurentiu Pop, Danielle Powell, Chinmaya Rajderkar, Clementina Ramos Garrido, Carol Recklein, Marilyn Richardson, Nicole Robinson, Lauri Schafer, Michelle Smith, Trudy Strand, Anna-Kay Thompson, Lindsey Towers, Josephine Tse, Joanie Tsougrianis, Victoria Tully, Sara Vecchi, Katherine Wilder, Tanisha Wilma, and Brittany Williams. Funding. The PERL study is funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R03-DK-094484, R34-DK-097808, and UC4-DK-101108) and JDRF (17-2012-377). The iohexol used for the iGFR measurements was a generous gift of GE Healthcare. Research reported in this publication was supported by the National Center for Advancing Translational Sciences, the NIDDK, and the National Institute on Aging (Claude Pepper Center grants) under award numbers P30-DK-036836, UL1-TR-002494, P30-DK-020572, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, UL1-TR-001105, UL1-TR-002319-02, P30-AG-08808, and P30-AG-024824. The PERL study is funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R03-DK-094484, R34-DK-097808, and UC4-DK-101108) and JDRF (17-2012-377). The iohexol used for the iGFR measurements was a generous gift of GE Healthcare. Research reported in this publication was supported by the National Center for Advancing Translational Sciences, the NIDDK, and the National Institute on Aging (Claude Pepper Center grants) under award numbers P30-DK-036836, UL1-TR-002494, P30-DK-020572, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, UL1-TR-001105, UL1-TR-002319-02, P30-AG-08808, and P30-AG-024824. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, NIDDK, National Institute on Aging, JDRF, or GE Healthcare.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialized Nursing

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/dc19-0342

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@article{97794417af8b4e6ebdec71a767697a03,

title = "Preventing Early Renal Loss in Diabetes (PERL) study: A randomized double-blinded trial of allopurinoldrationale, design, and baseline data",

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) 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 23.5 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 (24.7 vs. 22.5 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.",

author = "{PERL Study Group} and Maryam Afkarian and Sarit Polsky and Afshin Parsa and Ronnie Aronson and Caramori, {Maria Luiza} and Cherney, {David Z.} and Crandall, {Jill P.} and {De Boer}, {Ian H.} and Elliott, {Thomas G.} and Galecki, {Andrzej T.} and Goldfine, {Allison B.} and {Sonya Haw}, J. and Hirsch, {Irl B.} and Karger, {Amy B.} and Ildiko Lingvay and Maahs, {David M.} and McGill, {Janet B.} and Molitch, {Mark E.} and Perkins, {Bruce A.} and Rodica Pop-Busui and Marlon Pragnell and Rosas, {Sylvia E.} and Peter Rossing and Peter Senior and Sigal, {Ronald J.} and Catherine Spino and Tuttle, {Katherine R.} and Umpierrez, {Guillermo E.} and Amisha Wallia and Weinstock, {Ruth S.} and Chunyi Wu and Michael Mauer and Alessandro Doria and Linda Fried and Ananda Basu and Melanie Blank and Tom Greene and Lawrence Holzman and {Moore Patterson}, {Charity G.} and John Sedor and Daphne Adelman and Gayatri Anupindi and Cathy Bagne and Mary Bates and Karen Belanger and Emily Boone and Jane Bulger and Leslie Cham and Chao, {Jing H.} and Theresa Christiansen",

note = "Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.",

year = "2019",

month = aug,

day = "1",

doi = "10.2337/dc19-0342",

language = "English (US)",

volume = "42",

pages = "1454--1463",

journal = "Diabetes care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "8",

}

TY - JOUR

T1 - Preventing Early Renal Loss in Diabetes (PERL) study

T2 - A randomized double-blinded trial of allopurinoldrationale, design, and baseline data

AU - PERL Study Group

AU - Afkarian, Maryam

AU - Polsky, Sarit

AU - Parsa, Afshin

AU - Aronson, Ronnie

AU - Caramori, Maria Luiza

AU - Cherney, David Z.

AU - Crandall, Jill P.

AU - De Boer, Ian H.

AU - Elliott, Thomas G.

AU - Galecki, Andrzej T.

AU - Goldfine, Allison B.

AU - Sonya Haw, J.

AU - Hirsch, Irl B.

AU - Karger, Amy B.

AU - Lingvay, Ildiko

AU - Maahs, David M.

AU - McGill, Janet B.

AU - Molitch, Mark E.

AU - Perkins, Bruce A.

AU - Pop-Busui, Rodica

AU - Pragnell, Marlon

AU - Rosas, Sylvia E.

AU - Rossing, Peter

AU - Senior, Peter

AU - Sigal, Ronald J.

AU - Spino, Catherine

AU - Tuttle, Katherine R.

AU - Umpierrez, Guillermo E.

AU - Wallia, Amisha

AU - Weinstock, Ruth S.

AU - Wu, Chunyi

AU - Mauer, Michael

AU - Doria, Alessandro

AU - Fried, Linda

AU - Basu, Ananda

AU - Blank, Melanie

AU - Greene, Tom

AU - Holzman, Lawrence

AU - Moore Patterson, Charity G.

AU - Sedor, John

AU - Adelman, Daphne

AU - Anupindi, Gayatri

AU - Bagne, Cathy

AU - Bates, Mary

AU - Belanger, Karen

AU - Boone, Emily

AU - Bulger, Jane

AU - Cham, Leslie

AU - Chao, Jing H.

AU - Christiansen, Theresa

N1 - Publisher Copyright: © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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 23.5 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 (24.7 vs. 22.5 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.

AB - 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 23.5 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 (24.7 vs. 22.5 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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Preventing Early Renal Loss in Diabetes (PERL) study: A randomized double-blinded trial of allopurinoldrationale, design, and baseline data

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