FC 043SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (SUPAR) DETERMINES OUTCOMES IN CLINICAL AND EXPERIMENTAL SEPTIC ACUTE KIDNEY INJURY. (29th May 2021)

• Record Type: Journal Article
• Authors: Nusshag, Christian; Wei, Changli; Hahm, Eunsil; Szudarek, Roman; Kälble, Florian; Speer, Claudius; Uhle, Florian; Eugen-Olsen, Jesper; Weigand, Markus A; Zeier, Martin; Morath, Christian; Brenner, Thorsten; Reiser, Jochen
• Is Part Of: Nephrology dialysis transplantation. Volume 36(2021)Supplement 1
• Publication Date: 2021-05-29
• Subjects: Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfab119.003
• Languages: English
• ISSNs: 0931-0509

Abstract

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.