Assess the respiratory-related parameters associated with subsequent severe acute kidney injury in mechanically ventilated patients with acute respiratory distress syndrome (ARDS).Retrospective cohort, analyzing a large public database-Multiparameter Intelligent Monitoring in Intensive Care-III. Adult patients with at least 48 h of mechanical ventilation (MV), under volume controlled ventilation and an oxygenation index less than 300 mmHg were included.A total of 1,142 patients had complete data and were included in the final analyses. According to a causal directed acyclic graph (DAG) that included respiratory system compliance (C), tidal volume (Vt), driving pressure (ΔP), plateau pressure (P), PEEP, PaO and PaCO as possible exposures related to severe AKI, only C and PEEP levels had significant causal association with severe acute kidney injury (AKI) (OR 0.90, 95% CI: 0.84-0.94 for each 5-mL/cmHO reduction in C; OR, 1.05 95% CI: 1.03-1.10 for each 1-cmHO increase of PEEP). Using mediation analysis, we examined whether any mechanical ventilation, blood gas or hemodynamic parameters could explain the effects of C on AKI. Only PEEP mediated the significant but small effect (less than 5%) of C on severe AKI. The effects of PEEP, in turn, were not mediated by any other evaluated parameter. Several sensitivity analyses with (I) need of renal replacement therapy (RRT) as an alternative outcome and (II) only patients with Vt <8 mL/kg, confirmed our main findings. In trying to validate our DAG assumptions, we confirmed that only ΔP was associated with mortality but not with severe AKI.C and PEEP are the only respiratory-related variables with a direct causal association in severe AKI. No mechanical ventilator or blood gas parameter mediated the effects of C. Approaches reducing Vt and/or ΔP in ARDS can have limited effect on renal protection.