Bjorn Nashan

Large‐scale clinical trials using C₂ monitoring of cyclosporine (CsA) microemulsion (Neoral) in renal transplant recipients have demonstrated low acute rejection rates and good tolerability with a low adverse event profile in a variety of settings: with or without routine induction therapy; in combination with mycophenolate mofetil; with standard‐exposure or low‐exposure Neoral; and in patients with immediate or delayed graft function. In liver transplantation, C₂ monitoring significantly reduces the severity and incidence of acute rejection compared with C₀ monitoring, without adverse consequences in terms of renal function or tolerability. Different C₂ targets are appropriate depending on adjunctive immune suppression, level of immunologic risk, CsA tolerability, risk of renal toxicity and time since transplantation. CsA absorption may increase substantially in most patients during the first 1–2 weeks post‐transplant, and this should be taken into account to avoid overshooting C₂ target range. A patient with a low C₂ value may be either a low or a delayed absorber of CsA, or be a normal absorber who is receiving too low a dose of Neoral. C₂ monitoring alone is insufficient to differentiate between these types of patients, and measurement of additional timepoints is recommended. Adopting C₂ monitoring in maintenance transplant patients identifies those who are overexposed to CsA. In summary, randomized, prospective, multicenter studies and single‐center trials have evaluated Neoral C₂ monitoring within a range of regimens in different organ types, providing a robust evidence base for the benefits of this sensitive monitoring technique.

Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with a lymphocyte-depleting agent or an interleukin-2 receptor (IL-2R) antagonist can provide effective protection against rejection in the first critical weeks and months post-transplant. Polyclonal lymphocyte-depleting antibodies are associated with a low incidence of rejection but evidence of their benefit in terms of graft survival is lacking. Thymoglobulin® appears to offer superior graft outcomes compared with generic antithymocyte globulin (ATG). The most frequent adverse events are symptoms of cytokine release syndrome, leukopenia, thrombocytopenia, and tachycardia; data on whether polyclonal antibody use increases the risk of lymphoma are conflicting. Muromonab CD3 (OKT3), a monoclonal lymphocyte-depleting antibody, is efficacious but a high incidence of cytokine release syndrome and increased risk of post-transplant lymphoproliferative disease have limited its use. Following their recent introduction, the IL-2R antagonists basiliximab and daclizumab are now used widely, after randomized trials demonstrated that addition to calcineurin inhibitor-based therapy significantly reduced acute rejection by approximately 30–40%. Meta-analyses and registry analysis suggest that addition of an IL-2R antagonist may improve graft survival. The safety profile of IL-2R antagonists is indistinguishable from placebo, with no apparent difference in incidence of infection or post-transplant lymphoproliferative disease. IL-2R antagonists and polyclonal lymphocyte-depleting antibodies (with delayed cyclosporine) offer equivalent efficacy in standard-risk populations; in a trial of high-risk patients, acute rejection rate and graft outcomes were improved with Thymoglobulin®. Tolerability is superior with IL-2R antagonists: cytokine release syndrome and hematologic disturbances (notably leukopenia) are significantly more frequent with polyclonal antibodies. Cytomegalovirus infection may also be more common with lymphocyte-depleting antibodies. Thus, in patients at high risk of graft loss, Thymoglobulin® may be the preferred choice for induction therapy, while for all other patients, IL-2R antagonists should be considered first-line choice for induction therapy.

Everolimus and cyclosporine (CsA) exhibit synergistic immunosuppressive activity when used in combination. We explored the use of everolimus with a CsA-sparing strategy in de novo renal-transplant recipients. A phase II, randomized, open-label 3-year study was performed in 111 patients to compare the efficacy and tolerability of everolimus (3 mg/day) in combination with basiliximab, steroids, and either full-dose Neoral (FDN) or reduced-dose Neoral (RDN) (CsA trough levels 125–250 ng/mL and 50–100 ng/mL, respectively). Efficacy failure (biopsy-proven acute rejection, death, graft loss, or loss to follow-up), safety, and renal function were evaluated at 6, 12, and 36 months. A protocol amendment allowed further reduction of CsA exposure after 12 months. Efficacy failure was significantly higher in FDN than in the RDN group at 6 (15.1% vs. 3.4%; P=0.046), 12 (28.3% vs. 8.6%; P=0.012), and 36 (35.8% vs. 17.2%; P=0.032) months. Mean creatinine clearance was higher in the RDN group at 6 (59.7 mL/min vs. 51.1 mL/min; P=0.009), 12 (60.9 mL/min vs. 53.5 mL/min; P=0.007), and 36 (56.6 mL/min vs. 51.7 mL/min; P=0.436) months. Discontinuations and serious adverse events were more frequent in the FDN group. Reduction of CsA exposure for 6 months during the amendment improved renal function in the FDN group. In de novo renal-transplant recipients, the regimen of everolimus plus RDN was well tolerated, with low efficacy failure and better renal function in comparison with everolimus plus FDN.

The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.

The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.

It has been demonstrated that total parenteral nutrition (TPN) modulates the function of the hepatic reticuloendothelial system (RES). The objective of this study was to evaluate the impact of two different TPN lipid emulsions on the recovery of allograft RES function after orthotopic liver transplantation (OLTx). In a prospective, double-blind study, OLTx patients were randomly assigned to two treatment groups. Group I ( n=13) received a TPN regimen that included long-chain triglycerides (LCT). Group II ( n=9) received a TPN regimen that included a fat emulsion consisting of both medium-chain triglycerides (MCT) and LCT. At baseline, i.e., on days 2 or 3 after OLTx ( t1), before lipids for TPN were started, hepatic RES function was determined using the human serum albumin millimicrosphere technique (K-value, 1/min). A second measurement ( t2) was obtained after 7 days of TPN, including one of the study's two fat emulsions. The mean (+/- SD) K-value (1/min) was 0.48+/-0.16 in the LCT group and 0.55+/-0.28 in the MCT/LCT group at t1, and it improved to 0.62+/-0.21 in the LCT group and to 0.86+/-0.32 in the MCT/LCT group at t2. RES function recovery was significantly better in the MCT/LCT group ( P< or = 0.05). MCT/LCT emulsion appears to be the TPN fat emulsion of choice after OLTx as it seems to have less impact on hepatic RES recovery.

In the past decade liver transplantation has become the standard therapy for terminal liver failure. An increasing organ shortage, specific regional allocation systems within the Eurotransplant area and the lack of an efficient system to identify donors have resulted in decreasing numbers of liver transplants. Approximately 20% of patients are dying on the waiting list, a list that has exploded in numbers and waiting time in the past 3 years. In particular children and small adults are put at a disadvantage since standard donors have standard size livers. Two options to solve this dilemma are the expanded use of split-liver and living-donor liver transplantation. The specific experiences applying these techniques at the Medizinische Hochschule Hannover are discussed and compared with the results given in the European Liver Transplant Registry. The retrospective analysis demonstrates a shift in the use of resources, with decreasing numbers of full-size cadaver liver transplants and an increase in split- and living-donor liver transplantation. Both techniques are limited to specific patient populations, a notion that has to be considered in the comparison of results and outcome. According to our experience the full-size cadaver liver is still the standard option, while other techniques require careful attention to the chosen recipient population, advanced surgical skills and, for living donors, as a sine qua non the prerequisite of nihil nocere.