Greene Tom, Collier Willem, Haaland Benjamin, Zhang Chong, Badve Sunil V, Caravaca-Fontán Fernando, Del Vecchio Lucia, Floege Jürgen, Hannedouche Thierry, Imai Enyu, Jafar Tazeen H, Lewis Julia B, Li Philip K T, Locatelli Francesco, Maes Bart D, Neuen Brendon L, Perrone Ronald D, Schena Francesco P, Toto Robert, Wanner Christoph, Woodward Mark, van Zuilen Arjan, Heerspink Hiddo J L, Inker Lesley A
Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.
Clin J Am Soc Nephrol. 2025 May 1;20(5):632-641. doi: 10.2215/CJN.0000000662. Epub 2025 Apr 15.
Acute effects impact the clinical endpoint independently of treatment effects on the chronic slope. Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials.
Slope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).
We estimated treatment effects on the acute and chronic GFR slopes and on the established 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.
Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m greater acute GFR decline for the treatment versus control increased the hazard ratio 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 3-year total slope defined as the average slope extending from baseline to 3 years.
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 affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.
急性效应独立于对慢性斜率的治疗效果而影响临床终点。我们的研究结果支持将3年总斜率作为随机试验中基于斜率的主要结局。
肾小球滤过率（GFR）斜率被认为是慢性肾脏病（CKD）试验的有效替代终点。然而，对GFR斜率的短期和长期治疗效果不同，可能会在评估斜率的合适时间段方面产生模糊性，部分原因是当前方法无法区分急性（3个月前）和慢性（3个月后）斜率对临床终点（CE）治疗效果的不同贡献。
我们估计了先前CKD临床试验中66项随机治疗比较对急性和慢性GFR斜率以及既定的肾衰竭或血清肌酐翻倍CE的治疗效果。我们使用一种新颖的贝叶斯元回归框架，在单个多变量模型中将对既定CE的治疗效果与急性和慢性斜率相关联，以确定急性和慢性斜率的独立贡献。
对急性和慢性斜率的治疗效果均独立预测了对既定CE的治疗效果，中位数R（95%可信区间）高达0.95（0.79至1.00）。对于对慢性斜率的固定治疗效果，治疗组与对照组相比，急性GFR每1.73 m²每分钟下降1 ml/min，既定CE的风险比就增加11.4%（7.9% - 15.0%）。急性和慢性斜率的最佳权重与定义为从基线到3年的平均斜率的3年总斜率一致。
对急性和慢性GFR斜率的治疗效果都是对既定CE效果的独立决定因素，急性效果的差异在先前试验中对CE治疗效果的观察差异中占很大比例。我们的结果表明，急性效果独立于对慢性斜率的治疗效果而影响CE，并支持将3年总斜率作为随机试验中基于斜率的主要结局。
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