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The critical injury causing graft failure after prolonged liver storage involves reperfusion-induced killing of sinusoidal endothelial cells and activation of Kupffer cells. Treatment of stored livers with Carolina rinse solution (CRS) prevents endothelial cell killing, reduces Kupffer cell activation, and improves graft survival. Accordingly, our aim was to evaluate the components of CRS and other agents for protection against reperfusion injury to rat livers stored 24 hr in University of Wisconsin solution. CRS virtually abolished endothelial cell killing, prevented denudation of the sinusoidal lining, and decreased structural changes in Kupffer cells indicative of activation. The only component of CRS preventing endothelial cell killing was acidic pH of 6.5. However, when pH was subsequently increased to 7.4, antioxidants (allopurinol, deferoxamine mesylate, and glutathione), vasodilators (adenosine and nicardipine), and possibly energy substrates (fructose, glucose, and insulin) partially blocked pH-dependent cell killing (pH paradox). Na+/H+ exchange inhibition, protease inhibition, and Ca(2+)-free buffer did not decrease reperfusion injury, but the amino acid glycine protected strongly. Strychnine, which binds to glycine receptors in the central nervous system, protected equally well. Protection by glycine and CRS was synergistic, virtually.

Nephrotoxicity represents a serious side-effect of immunosuppression following orthotopic liver transplantation. In order to preserve the therapeutic potential of cyclosporin (CsA) and FK 506 in human liver transplantation and to differentiate the nephrotoxic action of either drug in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 randomly assigned to CsA- and 61 to FK 506-based immunosuppression. Early postoperative renal insufficiency (between POD0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (36.7%) and FK 506 (42.6%). Early postoperative acute renal failure (ARF; SCr > 3 mg/dl) occurred in 18.3%, regardless of the immunosuppressive management. Approximately 50% of patients with ARF required hemodialysis (CsA: 11.7%; and FK 506: 8.3%). Mean onset of hemodialysis in CsA-treated patients was POD1 and in FK 506-treated patients, POD6, which demonstrated a different time course of drug-specific nephrotoxicity of CsA and FK 506 in early ARF. All patients with early postoperative ARF requiring hemodialysis survived more than 1 year (100% survival). New onset of late ARF (between POD30 and 365), however, occurred in 6.5% under FK 506 and in 1.7% under CsA immunosuppression due to severe infections with the multiple organ failure syndrome. This observation was consistent with the assumption of over-immunosuppression rather than a primary nephrotoxic effect. Mortality of patients with late ARF requiring hemodialysis was 100%. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK 506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity. These preliminary results demonstrated a similar outcome in terms of early and late nephrotoxicity, but longer follow-up will delineate its overall efficacy and toxicity in humans.

Within a 17-month period, 130 orthotopic liver transplantations were performed in our hospital. Nine of these were retransplantations and were not included in our analysis. In the remaining 121 patients, splenectomy was performed in 34 patients, either synchronously with the transplant procedure (27 patients) or in the postoperative period (7 patients). Indications for splenectomy were lienalis-steal syndrome in 15 patients and hypersplenism in 15 cases. The number of rejection episodes was fairly equal in both groups (splenectomized vs. non-splenectomized, 61.7% vs. 63.9%, respectively). There was a marked difference in the frequency of infectious episodes (61.7% vs. 25.3%) that resulted in a decreased survival rate (77.5% vs. 95.4%) for splenectomized patients. Therefore, we recommend splenectomy only for very selected patients and investigate the banding of the splenic artery as an alternative.

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