Hydrogen sulphide as a novel therapy to ameliorate cyclosporine nephrotoxicity

Abstract

BackgroundCalcineurin inhibitors have significant nephrotoxic side effects, which can exacerbate ischemia–reperfusion injury in renal transplantation. Novel therapeutic agents such as hydrogen sulphide (H2S) may reduce these harmful effects. This study investigated the effects of H2S on cyclosporine (CsA) induced nephrotoxicity. Materials and methodsPorcine kidneys were subjected to 15 min of warm ischemia and 2 h of static cold storage. They were reperfused for 3 h with oxygenated normothermic autologous whole blood on an isolated organ reperfusion apparatus. Kidneys were treated with CsA during reperfusion (n = 6) or cyclosporine and 0.25 mmol/L of H2S infused 10 min before and 20 min after reperfusion (n = 6). These were compared with untreated controls (n = 7). ResultsCsA caused a significant reduction in renal blood flow during reperfusion, which was reversed by H2S (area under the curve renal blood flow CsA 257 ± 93 versus control 477 ± 206 versus CsA + H2S 478 ± 271 mL/min/100 g.h; P = 0.024). Urine output was higher after 2 h of reperfusion in the CsA + H2S group (CsA + H2S 305 ± 218 versus CsA 78 ± 180 versus control 210 ± 45 mL; P = 0.034). CsA treatment was associated with an increase in tubular injury, which was not reversed by H2S (area under the curve fractional excretion of sodium, control 77 ± 53 versus CsA 100 ± 61 versus CsA + H2S 111 ± 57%.h; P = 0.003). Histologic evaluation showed significant vacuolation and glomerular shrinkage in the CsA group. These were significantly reduced by H2S (P = 0.005, 0.002). ConclusionsH2S reversed the vasoconstriction changes associated with CsA treatment during reperfusion.