Department of Medicine, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
MathurConsulting LLC, Woodside, California.
J Am Soc Nephrol. 2024 Mar 1;35(3):311-320. doi: 10.1681/ASN.0000000000000292. Epub 2024 Jan 23.
Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated.
Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate.
In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure.
The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups.
Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis.
VALOR-CKD, NCT03710291 .
代谢性酸中毒是 CKD 的常见并发症，与肾功能更快下降有关，但尚未进行过充分的对照随机试验来检验治疗代谢性酸中毒对减缓 CKD 进展的效果。VALOR-CKD 研究将 1480 名 CKD 合并代谢性酸中毒的患者，在 320 个地点随机分为安慰剂或维维拉米（一种新型盐酸结合剂）组。研究结果并未显示维维拉米在减缓 CKD 进展方面的疗效，但安慰剂组和药物组之间血清碳酸氢盐的差异仅约为 1 mEq/L。维维拉米安全且耐受良好。
代谢性酸中毒在 CKD 中很常见，但尚不清楚其治疗是否会减缓 CKD 进展。维维拉米是一种新型的盐酸结合剂，可从胃肠道中去除酸，从而导致血清碳酸氢盐增加。
在一项 3 期、双盲、安慰剂对照试验中，来自 35 个国家的 CKD（eGFR 为 20-40 ml/min/1.73 m 2 ）和代谢性酸中毒（血清碳酸氢盐为 12-20 mEq/L）的患者被随机分为维维拉米或安慰剂组。主要终点是 CKD 进展的复合终点，定义为进展为 ESKD（肾移植或维持性透析）、eGFR 从基线下降≥40%或因肾功能衰竭死亡。
基线时平均（±SD）eGFR 为 29.2±6.3 ml/min/1.73 m 2 ，血清碳酸氢盐为 17.5±1.4 mEq/L；经过活性药物导入期后增加至 23.4±2.0 mEq/L。随机停药后，维维拉米组和安慰剂组的平均血清碳酸氢盐分别为治疗后 3 个月时的 22.0±3.0 mEq/L 和 20.9±3.3 mEq/L，这一约 1 mEq/L 的差异在最初 24 个月内保持稳定。维维拉米组和安慰剂组分别有 149/741 例和 148/739 例患者发生主要终点事件（风险比，0.99；95%置信区间，0.8 至 1.2；P=0.90）。两组严重和总体不良事件发生率无差异。
在 CKD 合并代谢性酸中毒的患者中，维维拉米治疗并未减缓 CKD 进展。预期的碳酸氢盐分离较低可能阻碍了检验假设的能力。
VALOR-CKD，NCT03710291。
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