The relationship between plasma cystatin C, mortality and acute respiratory distress syndrome subphenotype in the HARP-2 trial

To evaluate the performance of cystatin C as a prognostic and predictive marker in a trial of patients with acute respiratory distress syndrome (ARDS). A retrospective analysis was performed on plasma samples from patients included in the HARP-2 (hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction) trial - a multicentre, phase 2b trial carried out in general intensive care units across 40 hospitals in the United Kingdom and Ireland. Cystatin C concentrations in plasma obtained from 466 patients with ARDS (before they were randomly assigned in the trial) were quantified by ELISA (enzyme-linked immunosorbent assay). In a univariate analysis, plasma cystatin C concentrations were significantly higher in patients with ARDS who did not survive past 28 days (odds ratio [OR], 1.39 [95% CI, 1.12-1.72]; = 0.002). In a multivariate model adjusted for selected covariates, cystatin C concentrations remained higher among patients with ARDS who did not survive, although this did not reach statistical significance (OR, 1.28 [95% CI, 0.96-1.71]; = 0.090). Cystatin C concentration was also significantly associated with hyperinflammatory ARDS (OR, 2.64 [95% CI, 1.83-3.89]; < 0.001). In multivariate models adjusted for both cystatin C concentration and ARDS subphenotype, hyperinflammatory ARDS was prognostic for mortality (OR, 2.06 [95% CI, 1.16-3.64]; = 0.013) but cystatin C concentration was not (OR, 1.16 [95% CI, 0.85-1.57]; = 0.346). In a multivariate analysis, hyperinflammatory ARDS was predictive of a beneficial effect of simvastatin on mortality (OR, 2.05 [95% CI, 1.16-3.62]; = 0.014) but cystatin C concentration was not (OR, 1.10 [95% CI, 0.77-1.56]; = 0.614). The association between cystatin C concentration and mortality in ARDS may be dependent on inflammatory subphenotype. Cystatin C concentration does not appear to add to existing prognostic or predictive approaches.