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Abstract: TH-PO007

Human Recombinant α-1-Microglobulin Protects Against AKI in Rat Models of Ischemia-Reperfusion Injury (IRI)

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gram, Magnus, A1M Pharma AB, Lund, Sweden
  • Larsson, Tobias E., A1M Pharma, Lund, Sweden
  • Campos-bilderback, Silvia B., Indiana University, Indianapolis, Indiana, United States
  • Sandoval, Ruben M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Molitoris, Bruce A., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Acute kidney injury (AKI) is a global health concern associated with high morbidity, mortality, and progressive chronic kidney disease (CKD). RMC-035, a recombinant human α1-microglobulin (A1M), has demonstrated protective antioxidant effects in several injury models. The principal mechanisms of RMC-035 are heme binding, reductase activity, radical scavenging and protection of mitochondria. RMC-035 is being developed for the prevention of cardiac surgery associated-AKI, and are currently evaluated in a Phase 1 study. We present preclinical data for RMC-035, supporting its protective effect in ischemic AKI and AKI on a CKD background.

Methods

RMC-035 (0-5 mg/kg, i.v.) was administered at various time-points and doses prior and/or post renal ischemia in rats exposed to unilateral nephrectomy followed by a 30 minute pedicle clamp ischemia. AKI was evaluated at 1-5 days post injury by serum creatinine (sCr), BUN and 24 hr urinary creatinine clearances (CrCl). Furthermore, RMC-035 (2 mg/kg, i.v.) was administered prior to and post renal clamp ischemia in rats previously subjected to unilateral and renal ischemia (“AKI on CKD model”). Texas Red-x labeled RMC-035 (TR-RMC-035) trafficking and handling by proximal tubule cells (PTC) was studied via intravital imaging.

Results

RMC-035 caused a dose-dependent decrease in AKI measured as reduced proteinuria, sCr and BUN levels, and improved 24 hr CrCl, in rats subjected to a single renal IRI episode. RMC-035 given prior and post renal IRI was more effective for protection vs a single dose given either before or after IRI. In a CKD model with two successive episodes of AKI over 28 days, RMC-035 given at the second IRI episode significantly reduced renal injury by sCr and CrCl. TR-RMC-035 was rapidly filtered and bound to the apical brush border in PTC. Accumulation of RMC-035, tubular-vesicular extensions and vesicular trafficking was seen from 30 minutes through 24 hr post infusion. Cytosolic release was seen as early as 70 minutes.

Conclusion

RMC-035 demonstrates dose-dependent protective effects against AKI in multiple IRI models including AKI on CKD, had a prolonged PTC half-life including release into the cytosol, thus being a novel and promising therapeutic candidate for the treatment of cardiac surgery associated-AKI.

Funding

  • NIDDK Support