Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown.

To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2–4) and a urinary albumin creatinine ratio (UACR) of 300–5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD.

UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata.

Our findings do not support UACR response as a causal predictor of atrasentan’s treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.

阿曲生坦治疗早期减少蛋白尿是否能预测其长期肾脏保护作用尚不清楚。

为了在 SONAR 试验中评估阿曲生坦与安慰剂对肾脏结局的长期影响，我们招募了患有 2 型糖尿病和 CKD（2-4 期）且尿白蛋白肌酐比值 (UACR) 为 300-5000 mg/ G; 参与者正在接受最大耐受的肾素-血管紧张素系统抑制。在暴露于 0.75 mg/天的阿曲生坦 6 周后（强化期），参与者被随机分配（根据强化期间的 UACR 反应分层，范围从≤60% 到 >0%）继续阿曲生坦或过渡到安慰剂。主要肾脏结局是持续血清肌酐倍增或 ESKD 的复合结果。

在整个双盲治疗阶段，U​​ACR 对阿特拉生坦的反应在整个双盲治疗阶段持续存在，并预测了主要肾脏结果，而安慰剂组的 UACR 水平在两个最高 UACR 反应层中仍低于富集前值，并且在两个最低的 UACR 响应层中超过了富集前值地层。因此，在强化期间对 atrasentan 的早期 UACR 反应也与安慰剂期间的主要肾脏结果相关。因此，安慰剂校正后消除了阿曲生坦期间早期白蛋白尿变化的预测作用，导致与安慰剂相比，阿曲生坦主要肾脏结局的相对风险一致降低，无论初始 UACR 反应如何。

我们的研究结果不支持将 UACR 反应作为 atrasentan 治疗效果的因果预测因子。然而，安慰剂组 UACR 的变化轨迹、试验设计的各个方面、白蛋白尿的日常变异性以及阿曲生坦的潜在长期作用可能有所贡献。