别嘌醇降低血清尿酸与 1 型糖尿病患者的肾功能。
Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.
机构信息
From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston (A.D., A.B.G., S.E.R.); the Division of Geriatrics, Institute of Gerontology (A.T.G., C.W.), the Department of Biostatistics, School of Public Health (A.T.G., C.S.), Statistical Analysis of Biomedical and Educational Research (SABER) (C.S.), and the Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes (R.P.-B.), University of Michigan, Ann Arbor; the Departments of Medicine, Physiology, and Pharmacology and Toxicology (D.Z.C.) and the Division of Endocrinology and Metabolism (B.A.P.), University of Toronto, the Division of Nephrology, University Health Network (D.Z.C.), LMC Diabetes and Endocrinology (R.A.), and Lunenfeld-Tanenbaum Research Institute, Sinai Health System (B.A.P.), Toronto, the Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, AB (R.J.S.), BCDiabetes, Vancouver (T.G.E.), and the Division of Endocrinology, University of Alberta, Edmonton (P.S.) - all in Canada; the Departments of Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (A.P.); Steno Diabetes Center, and the Department of Clinical Medicine, University Copenhagen, Copenhagen (P.R.); the Division of Nephrology, Department of Medicine, University of California, Davis (M.A.), and the Department of Pediatrics and Stanford Diabetes Research Center, Stanford University, Palo Alto (D.M.M.) - both in California; the Departments of Medicine and Pediatrics (M.L.C., W.N.R.. M.M.) and Laboratory Medicine and Pathology (A.B.K.), University of Minnesota, Minneapolis; the Division of Endocrinology and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine (J.P.C.), and JDRF (Juvenile Diabetes Research Foundation) (M.P.), New York; the Department of Medicine (I.H.B., I.B.H.) and the Nephrology Division (K.R.T.), University of Washington, and the Institute of Translational Health Sciences, Kidney Research Institute (K.R.T.), Seattle, and Providence Health Care, Spokane (K.R.T.) - both in Washington; the Department of Medicine, Emory University, Atlanta (J.S.H., G.E.U.); the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis (J.B.M.); the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago (M.E.M., A.W.); the Barbara Davis Center for Diabetes, University of Colorado, Aurora (S.P.); and the Department of Medicine, State University of New York Upstate Medical University, Syracuse (R.S.W.).
出版信息
N Engl J Med. 2020 Jun 25;382(26):2493-2503. doi: 10.1056/NEJMoa1916624.
BACKGROUND
Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.
METHODS
In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.
RESULTS
A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m in the allopurinol group and 67.3 ml per minute per 1.73 m in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m per year with allopurinol and -2.5 ml per minute per 1.73 m per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.
CONCLUSIONS
We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
背景
血清尿酸水平升高与糖尿病肾病风险增加相关。别嘌醇降低血清尿酸水平可能会减缓 1 型糖尿病和早期至中期糖尿病肾病患者肾小球滤过率（GFR）的下降。
方法
在一项双盲试验中，我们随机分配了血清尿酸水平至少为每分升 4.5 毫克、估计肾小球滤过率为每分钟每 1.73 平方米 40.0 至 99.9 毫升且有糖尿病肾病证据的 1 型糖尿病患者接受别嘌醇或安慰剂治疗。主要结局是使用碘海醇测量的 3 年后加 2 个月洗脱期的基线调整后 GFR。次要结局包括洗脱后每年碘海醇基础 GFR 的下降和尿白蛋白排泄率。还评估了安全性。
结果
共有 267 名患者被分配接受别嘌醇治疗，263 名患者接受安慰剂治疗。平均年龄为 51.1 岁，糖尿病平均病程为 34.6 年，糖化血红蛋白水平平均为 8.2%。别嘌醇组的基线碘海醇基础 GFR 平均为每分钟每 1.73 平方米 68.7 毫升，安慰剂组为每分钟每 1.73 平方米 67.3 毫升。在干预期间，别嘌醇组的血清尿酸水平从 6.1 降至 3.9 毫克/分升，而安慰剂组仍保持在 6.1 毫克/分升。洗脱后，碘海醇基础 GFR 的组间差异为每分钟每 1.73 平方米 0.001 毫升（95%置信区间，-1.9 至 1.9；P=0.99）。别嘌醇组碘海醇基础 GFR 每年下降 3.0 毫升/分钟/1.73 平方米，安慰剂组每年下降 2.5 毫升/分钟/1.73 平方米（组间差异，-0.6 毫升/分钟/1.73 平方米/年；95%置信区间，-1.5 至 0.4）。洗脱后，别嘌醇组尿白蛋白排泄率平均升高 40%（95%置信区间，0 至 80）。两组严重不良事件的频率相似。
结论
我们没有发现 1 型糖尿病和早期至中期糖尿病肾病患者别嘌醇降低血清尿酸水平对肾脏结局有临床意义的益处。（由国家糖尿病、消化和肾脏疾病研究所和其他机构资助；PERL 临床试验.gov 编号，NCT02017171）。
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