慢性肾病临床试验中肾小球滤过率斜率的临床意义

IF 8.5 1区医学 Q1 UROLOGY & NEPHROLOGY

Clinical Journal of the American Society of Nephrology Pub Date : 2025-04-15 DOI:10.2215/cjn.0000000662

Tom Greene,Willem Collier,Benjamin Haaland,Chong Zhang,Sunil V Badve,Fernando Caravaca-Fontán,Lucia Del Vecchio,Jürgen Floege,Thierry Hannedouche,Enyu Imai,Tazeen H Jafar,Julia B Lewis,Philip K T Li,Francesco Locatelli,Bart D Maes,Brendon L Neuen,Ronald D Perrone,Francesco P Schena,Robert Toto,Christoph Wanner,Mark Woodward,Arjan van Zuilen,Hiddo J L Heerspink,Lesley A Inker,

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引用次数: 0

摘要

背景肾小球滤过率（GFR）斜率被认为是慢性肾脏疾病（CKD）试验的有效替代终点。然而，不同的短期和长期治疗对GFR斜率的影响可能会造成评估斜率的适当时间范围的模糊性，部分原因是目前的方法无法区分急性（三个月前）和慢性（三个月后）斜率对临床终点治疗效果的不同贡献。方法：我们从以往CKD临床试验的66个随机治疗比较中评估了治疗对急性和慢性GFR斜率的影响，以及对既定临床终点（CE）肾衰竭或血清肌酐加倍的影响。我们使用了一个新的贝叶斯元回归框架，在一个单一的多变量模型中将治疗效果与急性和慢性斜坡联系起来，以确定急性和慢性斜坡的独立贡献。结果治疗对急慢性斜坡的效果独立预测了治疗对既定CE的效果，中位R2（95%可信区间）为0.95（0.79,1.00）。对于慢性斜坡的固定治疗效果，与对照组相比，治疗组急性GFR下降每增加1 mL/min/1.73m2，既定CE的HR比治疗组增加11.4%（7.9%,15.0%）。急性和慢性坡度的最佳权重与三年总坡度一致，总坡度定义为从基线到三年的平均坡度。结论：治疗对急性和慢性GFR斜坡的影响是对既定CE影响的独立决定因素，在以往的试验中，急性效应的变化在很大程度上解释了治疗对CE影响的变化。我们的研究结果表明，急性效应对CE的影响独立于慢性斜坡的治疗效果，并支持在随机试验中，三年总坡度作为主要的基于坡度的结局。

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The Clinical Implications of Slope of Glomerular Filtration Rate in Clinical Trials of Chronic Kidney Disease.

BACKGROUND Slope of the glomerular filtration rate (GFR) is considered a validated surrogate endpoint for chronic kidney disease (CKD) trials. However, differing short and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate time period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before three months) and chronic (after three months) slopes for treatment effects on clinical endpoints. METHODS We estimated treatment effects on the acute and chronic GFR slopes and on the established clinical endpoint (CE) of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. RESULTS Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79,1.00). For a fixed treatment effect on the chronic slope, each 1 mL/min/1.73m2 greater acute GFR decline for the treatment vs. control increased the HR for the established CE by 11.4% (7.9%, 15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the three-year total slope defined as the average slope extending from baseline to three years. CONCLUSION Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects impact the CE independently of treatment effects on the chronic slope, and support the three-year total slope as the primary slope-based outcome in randomized trials.

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来源期刊

Clinical Journal of the American Society of Nephrology 医学-泌尿学与肾脏学

CiteScore

12.20

自引率

3.10%

发文量

514

审稿时长

3-6 weeks

期刊介绍： The Clinical Journal of the American Society of Nephrology strives to establish itself as the foremost authority in communicating and influencing advances in clinical nephrology by (1) swiftly and effectively disseminating pivotal developments in clinical and translational research in nephrology, encompassing innovations in research methods and care delivery; (2) providing context for these advances in relation to future research directions and patient care; and (3) becoming a key voice on issues with potential implications for the clinical practice of nephrology, particularly within the United States. Original manuscript topics cover a range of areas, including Acid/Base and Electrolyte Disorders, Acute Kidney Injury and ICU Nephrology, Chronic Kidney Disease, Clinical Nephrology, Cystic Kidney Disease, Diabetes and the Kidney, Genetics, Geriatric and Palliative Nephrology, Glomerular and Tubulointerstitial Diseases, Hypertension, Maintenance Dialysis, Mineral Metabolism, Nephrolithiasis, and Transplantation.