SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (SUPAR) DETERMINES OUTCOMES IN CLINICAL AND EXPERIMENTAL SEPTIC ACUTE KIDNEY INJURY

Abstract Background and Aims Sepsis is the main contributor to the development of acute kidney injury (AKI) in critically ill patients. Plasma soluble urokinase plasminogen activator receptor (suPAR) is a circulating risk factor for AKI and a new prognostic marker for renal outcome prediction. We analyzed the pathophysiological role and kinetic properties of suPAR in septic AKI in critically ill patients and in a murine model of septic AKI. Method 200 critically ill patients were enrolled prospectively after meeting Sepsis-3 criteria. Serum suPAR levels were measured at 0, 12, 24, 48, 72, 96, 120 and 168-hour after enrollment (n=1440) and the need for RRT within 7 days (predefined criteria) was assessed as the primary outcome measure. Polybacterial sepsis was induced by cecal slurry injection in three mouse strains, respectively wild type (WT, N=16), uPAR-knockout (KO, N=15), and suPAR transgenic overexpression (OE, N=14). Results No or mild AKI occurred in 62 patients (31.0%), moderate or severe AKI without the need for RRT in 102 patients (51.0%), criteria for RRT were met in 36 patients (18.0%) and 7 patients (3.5%) died within the 7-day period. Compared to all other maximum AKI stages and AKI disease courses within 7 days, patients requiring RRT showed significantly higher suPAR levels at all time-points. Patients with suPAR levels ≥ 12.7 ng/mL (highest quartile) had an unadjusted odds ratio (OR) of 9.73 (95% confidence interval [CI], 4.31-21.98) and an adjusted odds ratio of 5.22 (95% CI, 2.16-12.65) for the need for RRT; and 7.47 (95% CI, 3.54-15.74) and 4.44 (95% CI, 1.98-9.97) for RRT or death within 7 days compared to patients with levels < 12.7 ng/mL. Compared to KO mice, WT and OE mice showed a significantly greater impairment of renal function, structure and tubular apoptosis 24 hours after induction of sepsis. The inflammation levels with respect to Interleukin 6 were comparable between different strains. Kaplan-Meier analysis revealed a survival benefit of KO mice over OE mice within 24h (86.7% vs. 50.0%, p=0.033). Conclusion SuPAR distinguishes between divergent AKI stages/courses and the need for RRT at any time within 7 days after sepsis diagnosis. Our experimental data suggest that suPAR is a pathophysiological driver of septic AKI and may serve as a target for future interventional strategies.