Early Response in Albuminuria and Long-Term Kidney Protection during Treatment with an Endothelin Receptor Antagonist: A Prespecified Analysis from the SONAR Trial
Authors: Heerspink Hiddo J. L. , Xie Di , Bakris George , Correa-Rotter Ricardo , Hou Fan-Fan , Kitzman Dalane W. , Kohan Donald , Makino Hirofumi , McMurray John J. V. , Perkovic Vlado , Rossing Peter , Parving Hans-Henrik , de Zeeuw Dick ,   on behalf on the SONAR Investigators
Published: September 2021

Significance Statement
This prespecified analysis of the SONAR trial in patients with type 2 diabetes and CKD demonstrated the early albuminuria reduction during an open-label, 6-week run-in period with atrasentan was associated with a reduced risk for long-term kidney outcomes in patients who continued atrasentan after randomization. But because the early albuminuria reduction also associated with long-term kidney outcomes in patients who transitioned from atrasentan to placebo at randomization, atrasentan’s effect on the primary kidney outcome was consistent, regardless of the early albuminuria change, suggesting the early albuminuria response is not a causal predictor for atrasentan’s nephroprotective effect. However, the variable UACR trajectory in the placebo arm, aspects of the SONAR trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.

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

Methods
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.

Results
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.

Conclusions
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.