gms | German Medical Science

Introduction: Ischemia-reperfusion-injury (IRI) is known to affect graft survival. In various transplantation models administration of tetrahydrobiopterin (H4B) resulted in protection form IRI. Herein we present first results using a porcine kidney autotransplantation model.

Materials and methods: Male common house pigs (50–60 kg b.w.) were used. For pharmacokinetic studies H4B (BioMarin, Novato, CA, USA) distribution in renal tissue was analysed (n=3). To avoid confounding alloimmune effects a porcine kidney autotransplantation model was performed. Pigs were either pre-treated with H4B 20 mg/kg b.w. (n=3) or were untreated (n=3). Left kidney was explanted and stored on ice for 24h. Before implantation of the autograft, contralateral nephrectomy was performed. Parenchymal damage was evaluated by H&E histology and nitrotyrosine western blot, H4B renal tissue levels by HPLC.

Results: Maximal H4B tissue levels were observed 15 min post application (22,840 nmol/mg). Compared to non treated animals H4B treated pigs displayed numerically higher creatinine (1.8±0.6 vs 4.3±2.4; p=0.15) and urea levels (32.3±2.7 vs 74.0±32.1; p=0.09) before reperfusion, indicating possible nephrotoxic effects. However, in contrast to non treated pigs, H4B treated animals showed urine production immediately following kidney reperfusion. Two out of three treated animals survived the entire 7-day observation period. One animal died two days after transplantation because of a gastrointestinal bleeding. Peak creatinine (18.5 mg/dl and 19.7 mg/dl) and urea (284.8 mg/dl and 338.6 mg/dl) levels were reached at day 3 and 5, respectively. In contrast, only one non treated animal survived for 7 days with creatinine and urea levels still rising at day seven (24.5 mg/dl and 246.7 mg/dl, respectively). Two animals died anuric two days post transplantation. Histopathology and nitrotyrosine western blots revealed no differences two hours post reperfusion.

Conclusion: To our knowledge this is the first study observing nephrotoxic effects of H4B. Despite this finding, immediate urine production and better survival confirm the protective effect of this pterin in IRI. Further dose finding studies have to be performed.