Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.
Division of Nephrology, Nanfang Hospital, Guangzhou, China.
J Am Soc Nephrol. 2021 Nov;32(11):2900-2911. doi: 10.1681/ASN.2021030391. Epub 2021 Sep 22.
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.
阿曲生坦治疗早期降低蛋白尿是否能预测其长期肾脏保护作用尚不清楚。
为评估 SONAR 试验中阿曲生坦与安慰剂对肾脏结局的长期影响，我们纳入了患有 2 型糖尿病和 CKD（2-4 期）且尿白蛋白肌酐比（UACR）为 300-5000mg/g 的患者；参与者正在接受最大耐受的肾素-血管紧张素系统抑制。在 0.75mg/天阿曲生坦（富集期）治疗 6 周后，参与者根据富集期 UACR 反应（范围为≤60%至>0%）分层，随机继续接受阿曲生坦或转换为安慰剂。主要肾脏结局为血清肌酐持续倍增或终末期肾病（ESKD）复合终点。
阿曲生坦在富集期的 UACR 反应在双盲治疗阶段持续存在，并预测了主要肾脏结局，而安慰剂组在两个 UACR 反应最高的分层中 UACR 水平仍低于富集前水平，在两个 UACR 反应最低的分层中则超过了富集前水平。因此，阿曲生坦富集期早期 UACR 反应也与安慰剂期间的主要肾脏结局相关。因此，在安慰剂校正后，阿曲生坦早期白蛋白尿变化的预测作用被消除，导致阿曲生坦与安慰剂相比，主要肾脏结局的相对风险降低持续存在，与初始 UACR 反应无关。双盲治疗期间阿曲生坦与安慰剂在 UACR 方面的差异也在 UACR 反应分层中保持一致。
我们的研究结果不支持 UACR 反应作为阿曲生坦治疗效果的因果预测因素。然而，安慰剂治疗中 UACR 的可变轨迹、试验设计的各个方面、白蛋白尿的日常变化以及阿曲生坦可能产生的长期影响可能对此有影响。
