OPTIMIZING IMMEDIATE GRAFT FUNCTION IN KIDNEY TRANSPLANTATION

R. Sucher¹, G. Rumberg², P. Gehwolf¹, I. Kronberger¹, C. Margreiter³, R. Öllinger⁴, S. Schneeberger², E. Werner¹, B. Zelger⁵, J. Pratschke¹, G. Brandacher^1
1Department Of Visceral, Transplant And Thoracic Surgery, Innsbruck Medical University, Innsbruck/AUSTRIA, ²Department Of Visceral Transplant And Thoracic Surgery, Innsbruck Medical University, Innsbruck/AUSTRIA, ³Department Of Visceral, Transplant, And Thoracic Surgery, Innsbruck Medical University, Innsbruck/AUSTRIA, ⁴Visceral, Transplant And Thoracic Surgery, Medical University Innsbruck, Innsbruck/AUSTRIA, ⁵Department Of Pathology, Innsbruck Medical University, Innsbruck/AUSTRIA

Body: Introduction: Tetrahydrobiopterin (BH4) is a rate-limiting factor of NO production. BH4 depletion during ischemia and reperfusion leads to uncoupling of nitric oxide synthases (NOS) and increased ROS formation instead of NO. This results in activation of MAPK leading to graft injury (IRI) and DGF. The effects of BH4 on MAPKs, however, are currently unknown. Methods: Syngeneic kidneys were either clamped in situ or transplanted orthotopically into nephrectomized Lewis rats following cold flush and storage in UW solution (120min). Animals received either BH4 (20mg/kg) prior to clamping or organ harvest/transplantation. Vector treated animals served as controls. Renal function (creatinine/urea), BH4 tissue levels (HPLC), MAPK (ERK, JNK, p38) activation and graft morphology (H&E, nitrotyrosine immunostaining) were assessed at various time points after reperfusion/transplantation. Results: During both renal clamping and transplantation, BH4 tissue levels significantly decreased after ischemia and reperfusion (p<0.05). Stress activated MAPK’s (SAMPK) JNK and p38 were significantly induced during reperfusion whereas tissue protective ERK was decreased (p<0.01) resulting in DGF. BH4 treatment prior to ischemia reversed SAMPK activation patterns (p<0.05) and improved renal function, (p<0.001), reduced histologic damage (interstitial edema, tubular atrophy and focal necrosis) and attenuated ROS formation assessed by nitrotyrosine staining. Conclusions: This is the first data suggesting that BH4 treatment reverses IRI-induced SAMPK activation and thereby protects from DGF.

Disclosure: All authors have declared no conflicts of interest.