Hydrogen sulphide as a novel therapy to ameliorate cyclosporine nephrotoxicity

Abstract

Background: Calcineurin 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 methods: Porcine 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).

Results: CsA 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).

Conclusions: H₂S reversed the vasoconstriction changes associated with CsA treatment during reperfusion.

Keywords: Cyclosporine; Hydrogen sulphide; Ischemia–reperfusion injury; Kidney.