Objective: The prevention of IRI is important for both early and long-term graft function, especially when using extended-criteria or donation after cardiac donors. H2S has recently been reported to have both anti-inflammatory and cytoprotective effects. However, the efficacy and safety of H2S has yet to be elicited in a large animal model. We investigated the effectiveness and optimal method of administration of H2S for renal IRI using miniature swine.

Methods: Nine CLAWN swine underwent renal ischemia for 120 minutes (min) by clamping the left renal artery and vein. Group 1 (G1; n=3) underwent renal ischemia without any additional treatment. Group 2 (G2; n=3) received 1.1 mg/kg of intravenous Na2S (H2S donor) 10 min prior to reperfusion, followed by an additional 1.1 mg/kg of Na2S 30 min post-reperfusion. Group 3 (G3; n=3) received 1.1 mg/kg of Na2S 10 min prior to reperfusion via renal artery, followed by an additional 1.1 mg/kg of Na2S 30 min post-reperfusion via the supra-renal aorta with concomitant occlusion of the infra-renal aorta; thus allowing for exclusive renal administration. Renal function was monitored by daily serum creatinine (Cre) and renal biopsies obtained on post-operative days (POD) 2, 7 and 14. Serum cytokines were measured to characterize the inflammatory response to IRI.

Results: H2S did not result in any adverse effects (G2 and G3). Animals in G1 had significantly higher Cre than G3 at POD4 (4.4 vs 8.6 mg/dl, p<0.001). Histology showed diffuse epithelial flattening, vacuolations, congestion and condensed nuclei of proximal tubule cells at PODs 2 and 7 while specimens of G2 showed less obvious tubular changes at the same time points. Notably, specimens of G3 showed markedly less tubular damage at POD2, and no remarkable findings were present at POD7. The mRNA expression of IL-1β in the specimens of G3 at 2 hours and POD2 were markedly lower than those of G2. Furthermore, serum TNF-α and HMGB1 levels in G3 were significantly lower than G2 (TNF-α: 30.6 vs 85.4 pg/ml, p<0.05, HMGB1: 2.6 vs 11.4 ng/ml, p<0.05).

Conclusion: To our knowledge, this is the first demonstration of the beneficial effects of H2S on reducing renal IRI in a large animal model. This effect was most profound with selective renal artery administration. Further work investigating the benefits of H2S for organ procurement and preservation may allow for improved outcomes of renal transplantation.

CITATION INFORMATION: Ariyoshi Y, Sekijima M, Sahara H, Murokawa T, Shimizu A, Yamada K. Beneficial Effects of Hydrogen Sulfide (H2S) on Renal Ischemia-Reperfusion Injury (IRI) in CLAWN Miniature Swine. Am J Transplant. 2017;17 (suppl 3).

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