Effect of Defibrotide on Kidney Ischemia Reperfusion Injury in a Preclinical Renal Transplant Model

P. Pine¹, Z. Sun², A. Matas³, J. Shi¹, A. Ebrahimnejad¹, M. Zanette⁴, P. Halloran⁵, J. S. Bromberg⁶, R. Hanvesakul⁷

¹Jazz Pharmaceuticals, Palo Alto, CA, ²Johns Hopkins Medicine, Baltimore, MD, ³Univ of Minnesota, Minneapolis, MN, ⁴Jazz Pharmaceuticals, Philadelphia, PA, ⁵Univ of Alberta, Edmonton, AB, Canada, ⁶Univ of Maryland School of Medicine, Baltimore, MD, ⁷Jazz Pharmaceuticals, Oxford, United Kingdom

Meeting: 2021 American Transplant Congress

Abstract number: 609

Keywords: Graft failure, Kidney/liver transplantation, Nephropathy, Renal ischemia

Topic: Basic Science » Ischemia Reperfusion & Organ Rehabilitation

Session Information

Session Name: Ischemia Reperfusion & Organ Rehabilitation

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*Purpose: Ischemia reperfusion injury (IRI) is a major contributor to graft failure. During organ removal and preservation, ischemia results in anaerobic respiration and cellular damage. At time of renal transplant (tx), oxygen is restored in aerobic respiration; injury is caused by generation of reactive oxygen species and inflammatory cytokines. Cellular activation caused by IRI results in an immune response, leading to further kidney damage. In vitro studies have shown that defibrotide (DF) stabilizes and protects endothelial cells through anti-inflammatory and antioxidant mechanisms. This study investigated the potential of DF to prevent kidney damage from IRI.

*Methods: A beagle dog autologous renal tx model was used to evaluate DF on kidney IRI without immunosuppression. For all dogs, on Day 0, the left kidney was removed, flushed, placed in cold preservation solution (CPS) for 32h, and then transplanted to the same dog. At tx, the right kidney was removed. Control dogs (Group [Gp]1, n=8) received intravenous (IV) saline (4 mL/kg/h). Gp2 (n=8) received IV DF (50 mg/kg/dose q.i.d.) 2h before tx and immediately after tx, continuing until study end (Day 8). For Gp3 (n=8), the kidney was flushed with DF in CPS at removal and IV DF was given as in Gp2. Assessments included histology and daily clinical chemistry. Mixed effects models with repeated measures were used; nominal P values are comparing each DF Gp with control. Histology was assessed qualitatively.

*Results: The combination of DF in CPS flush and IV DF pre-/post-tx reduced elevations of serum creatinine (P=0.0058), urea (P=0.0061), and potassium (P<0.0001), and stabilized urine output (P=0.0124) post-tx compared to controls. Results for IV DF alone were not significant compared to control. Histology revealed that kidneys from Grp 3 DF-treated dogs had reduced tubular necrosis, interstitial fibroplasia, and hemorrhage vs controls.

*Conclusions: In this preclinical dog model, when DF was in flush/CPS and given pre-/post-tx, there was reduced renal impairment, tubular necrosis, interstitial fibroplasia, and hemorrhage vs controls. These results support further DF evaluation in preventing kidney IRI.

To cite this abstract in AMA style:

Pine P, Sun Z, Matas A, Shi J, Ebrahimnejad A, Zanette M, Halloran P, Bromberg JS, Hanvesakul R. Effect of Defibrotide on Kidney Ischemia Reperfusion Injury in a Preclinical Renal Transplant Model [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/effect-of-defibrotide-on-kidney-ischemia-reperfusion-injury-in-a-preclinical-renal-transplant-model/. Accessed November 21, 2024.

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