BackgroundWe aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes.MethodsWe included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure.ResultsImprovement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64–2.15,p< 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60–0.83,p< 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99–1.04), ACM HR 1.01 (0.99–1.03), HF/renal failure hospitalization HR 0.99 (0.97–1.00)].ConclusionsDespite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF.Graphical abstractCentral illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00392-022-02144-6.