University Hospital Valdecilla
University of Cantabria
After kidney transplantation, recipients receive immunosuppressive drugs in order to reduce or eliminate the appearance of acute rejection, contributing to improve long-term graft survival and renal function, which is related to mortality and morbidity of patients.(1) The modern era of clinical transplantation began when the combination of azathioprine with glucocorticoids made kidney transplant a realistic option for the treatment of endstage renal disease.(2) The introduction of the calcineurin inhibitor (CNI) ciclosporin (CsA) into clinical practice in the 1980s improved survival rates at one year from approximately 60% to 85%, although the incidence of acute rejection remained relatively high. In the 1990s, the progressive introduction of various newer immunosuppressive agents, such as the new CNI tacrolimus and the antiproliferative drugs mycophenolate mofetil (MMF) and sirolimus, resulted in a decrease in the incidence of acute rejection, although long-term allograft survival had only marginally improved.(3-5) Today, the two most common causes of late loss of kidney transplant are chronic allograft nephropathy (CAN) and death of the patients with a functioning graft, mainly due to cardiovascular causes.(3) Both immunological and nonimmunological risk factors, such as CNI toxicity and atherosclerotic risk factors (eg, hypertension, dyslipidaemia or new-onset diabetes mellitus), play a role in the development of CAN; this, in turn, contributes to cardiovascular morbidity and mortality.(3)
Glucocorticoids and CNI drugs increase cardiovascular risk and exert other secondary adverse events. There is a pressing need for more selective, more specific and less toxic immunosuppressive agents that may prevent early and late allograft loss, improve long-term outcomes and decrease the appearance of adverse events such as infections, cancer and cardiovascular diseases.(2,3) This brief review attempts to summarise the knowledge about immunoï¿½suppressive agents recently approved or in trials in kidney transplantation (see Table 1).
In addition to CsA and tacrolimus, other CNIs are under development. Tacrolimus is administered in two divided doses per day in order to maintain target blood trough concentrations. A modified-release oral dosage form of tacrolimus (MR-4) is being developed for once-daily administration, with the purpose of improving patient compliance. In stable kidney transplant recipients, the steady-state pharmacoâ€‘kinetics of MR-4 and tacrolimus are equivalent after a milligram-for-milligram conversion.(6) Phase III clinical trials are underway in de-novo kidney transplant recipients.(7)
CsA toxicity may be attributable to factors not related to inhibition of calcineurin, such as induction of transforming growth factor Î² or inhibition of mitochondrial high-energy phosphate metabolism. Thus, it may be possible to develop CNI drugs that are less toxic but equally effective. ISA247 is a CsA analogue that has shown more immunosuppressive power than CsA in in-vitro and animal models.(8)
Inhibitors of purine or pirimidine synthesis
MMF (CellCept) inhibits inosine monophosphate dehydrogenase, a key enzyme in purine synthesis. In large trials, MMF was superior to azathioprine in improving patient and graft survival and reducing early and late allograft rejection. Its principal toxic effects are gastrointestinal and haematological. The drug also possess antipneumocystis activity in vitro. Recently, an enteric-coated mycophenolic acid (Myfortic) has been introduced as an alternative in order to reduce gastrointestinal effects.(9)
Mizoribine inhibits inosine monophosphate dehydrogenase in the same way as MMF, but its clinical dosage is much lower than that of MMF. It has been registered for the prevention of rejection after renal transplantation in Japan. In preliminary studies, higher doses of mizoribine were effective for the prevention of rejection in AB0-incompatible recipients and as rescue therapy for ongoing acute humoral rejection.(10)
FK778, a synthetic malononitrilamide, is derived from an active metabolite of leflunomide, and it has both immunosuppressive and antiproliferative activities. FK778 inhibits T- and C-cell function by blocking de-novo pyrimidine synthesis through blockade of the mitochondrial enzyme dihydroorotate dehydrogenase and the inhibition of tyrosine kinase activity. The main advantages of FK778 are antiviral activity (the drug blocks the replication of herpes and polyomavirus) and prevention of vascular remodelling. Clinical studies are underway to evaluate the efficacy and safety of FK778. A higher incidence of anaemia and lower cholesterol level have been observed in FK778-treated patients.(7)
Target of rapamycin (TOR) inhibitors
Sirolimus and the recently introduced everolimus inhibit target of rapamycin (TOR), blocking signal 3 by preventing cytokine receptors from activating the T-cell proliferation. Combined with a CNI, TOR inhibitors showed low acute rejection rate but potentiated CNI nephrotoxicity. By contrast, sirolimus allows CNI withdrawal, with increased risk of acute rejection, significant improvement in renal function and similar one-year graft survival.(11) Despite reported adverse effects (hyperlipidaemia, impaired wound healing or pneumonitis), TOR inhibitors have three major advantages. Firstly, they reduce cytomegalovirus disease. Secondly, both TOR inhibitors are associated with a reduction in the risk of developing any post-transplant de-novo malignancy. Thirdly, they have arterial protective effects, inhibiting coronary stent restenosis and diminishing the incidence of coronary artery disease in heart transplant patients.(9)
Inhibitors of lymphocyte trafficking
FTY720 is the first of a new drug class, the sphingosine-1-phosphate receptor agonist. It drives T-cells into lymphoid tissues and prevents them from leaving and homing to the graft. In phase II trials, FTY720 at higher doses was superior to MMF in reducing a composite endpoint (acute rejection, graft loss or death). The most severe adverse effect, which could limit its use, was transient bradycardia. Phase III trials will supply more information about its role in transplantation.(12)
Polyclonal antithymocyte globulins, such as Thymoglobulin and ATG-Fresenius, have been successfully used as induction agents or as rescue therapy in corticoid-resistant acute rejection. They produce profound and durable lymphopenia that increases the risk of severe infections and post-transplant lymphoproliferative disorders. Monoclonal antibodies allow us to supply a more specific immunoâ€‘suppressive therapy. Alemtuzumab (Campath-1H), a humanised monoclonal antibody against CD52, massively depletes lymphocyte populations.(9) The first report on the use of alemtuzumab in organ transplantation had the intention of using this agent to produce a near-tolerant state called “proper tolerance”. A five-year study has shown that patients receiving alemtuzumab and half-dose CsA, avoiding steroid therapy, have graft survival and acute rejection rates similar to those of patients treated with CsA, azathioprine and prednisolone. In addition, the drug is cheaper. Further controlled trials are needed to understand the role of alemtuzumab in kidney transplantation.(13)
Costimulatory pathway inhibitors
Belatacept (LEA29Y) binds costimulatory ligands (CD80 and CD86) of antigen-presenting cells, blocking costimulation pathway. In the context of antigen recognition (signal 1), the interaction of CD80 and CD86 with the surface costimulatory receptor CD28 of T-cells (signal 2) is required for full activation of T-cells. Blockade of signal 2 inhibits T-cell activation, promoting anergy and apoptosis. A recently reported phase II trial has shown that periodic infusion of belatacept is as effective as CsA in preventing acute rejection. In addition, belatacept better preserves glomerular filtration rate, reduces the rate of CAN and shows lower lipid and blood pressure values than patients in CsA group.(14)
Janus kinase 3 (JAK3) inhibitors
JAK3 is a tyrosine kinase associated with the cytokine receptor Î³ chain that participates in the signalling of a large number of cytokines from the receptors to the nuclei. JAK3 is expressed at high levels in natural killer cells and thymocytes; it is inducible in T-cells, B-cells and myeloid cells, but it is not expressed in resting T-cells. Thus, theoretically, JAK3 inhibition would only suppress cells actively participating in the rejection process. CP-690,550 is a synthetically developed JAK3 inhibitor that is being studied in vitro and in animal models.(15)
Drugs for the hypersensitised patient
In patients on waiting lists with high anti-HLA antibody levels, intravenous immunoglobulin (IVIG) reduces anti-HLA antibody titres and improves graft survival rate, although the mechanism of action is not completely understood.(16) Rituximab, an anti-CD20 monoclonal antibody, appears to be safe and have some efficacy as a sole agent in eliminating alloantibodies.(17) Both IVIG and rituximab are also used in combination with maintenance immunosuppressive drugs and plasmapheresis to suppress deleterious alloantibody responses after kidney transplantation.(9) Only a few controlled trials are available to decide what is the best strategy to eliminate anti-HLA antibodies in hypersensitised patients.
The development of new immunosuppressive drugs and new regimens will improve kidney transplant outcome, preventing acute rejection, CAN and associated morbidity. In future, “individualised” immunosuppression will become feasible.
- Fellstrom B, Jardine AG, Soveri I, et al. Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation. Am J Transplant 2005;5:1986-91.
- Ingelfinger JR, Schwartz RS. Immunosuppression – the promise of specificity. N Engl J Med 2005;353:836-9.
- Wong W, Venetz J-P, Tolkoff-Rubin N, Pascual M. Immunosuppressive strategies in kidney transplantation: which role for the calcineurin inhibitors? Transplantation 2005;80:289-96.
- Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-83.
- Vincenti F. What’s in the ï¿½pipeline? New immunosuppressive drugs in transplantation. Am J Transplant 2002;2:898-903.
- Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from a twice daily prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc 2005;37:867-70.
- First MR, Fitzsimmons WE. New drugs to improve transplant outcomes. Transplantation 2004;77:S88-92.
- Birsan T, Dambrin C, Freitag DG, et al. The novel calcineurin inhibitor ISA247: a more potent immunoâ€‘ suppressant than cyclosporine in vitro. Transpl Int 2005;17:767-71.
- Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-29.
- Liu DG, Kobayashi T, Nagasaka T, et al. Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection. Transpl Int 2005;18:401-7.
- Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomised trials. Am J Transplant 2005;5:1748-56.
- Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 2005;79:1553-60.
- Knechtle SJ. Commentary on “How does alemtuzumab affect long-term graft and patient outcomes after deceased-donor kidney transplantation?” Nat Clin Pract Nephrol 2005;1:74-5.
- Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770-81.
- Paniagua R, Si M-S, Flores MG, et al. Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation 2005;9:1283-92.
- Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease. J Am Soc Nephrol 2004;15:3256-62.
- Pescovitz MD. Drugs for the hypersensitized patient. Curr Opin Org Transplant 2005;10:279-83.