Department of Nephrology
University Medical Centre
Rejection episodes, especially early graft rejections, appear to be an important determinant of graft outcome,(1) although the minor grades of rejection with no vascular changes that respond to treatment do not appear to be associated with poorer graft survival.
In the more recent multicentre trials of new immunosuppressive drugs, reduced incidence of acute rejections has not been reflected by improved graft survival;(2) however, in addition to influencing graft survival, rejection treatment also increases the expected side-effects of immunosuppressive drugs.
A decade ago, a limited number of immunosuppressive agents were used: muromonab-CD3 (OKT3), antilymphocyte globulin (ATG), ciclosporin, tacrolimus, mycophenolate mofetil (MMF), azathioprine and corticosteroids. For maintenance immunosuppression, these drugs were used as a “triple therapy” consisting of corticosteroids, a calcineurin inhibitor and an antiproliferative agent.
In recent years, a number of new immunosuppressive drugs have been introduced in clinical transplantation. Including monoclonal antibodies, there are at least eight immunosuppressive agents for tailoring immunosuppressive therapy. With modern immunosuppression, a number of new regimens have come into use. Examples include steroid minimisation and steroid withdrawal regimens for avoidance of side-effects,(3–7) while other regimens reduce or eliminate calcineurin inhibitors to try to avoid nephrotoxicity by using MMF and sirolimus-based regimens.(8–11) More aggressive experimental protocols have used lymphodepleting antibodies such as alemtuzumab(12) and antithymocyte globulin(13) in an attempt to induce the state of immune tolerance. In such protocols, leucopenia persisting for months increases the risk of haematological and infectious complications. Special immune desensitisation protocols using rituximab, plasmapheresis and intravenous immunoglobulin facilitate removal of donor-specific antibodies and allow transplantation that would otherwise not be possible due to a positive crossmatch.(14)
Induction immunosuppression for kidney transplantation
Antibody induction has become frequent in modern immunosuppression protocols. Currently, 72% of kidney transplant recipients are receiving induction immunosuppression.(15) Several studies and meta-analyses have found that induction therapy with antibodies may be superior to nonantibody-based regimens.(16) A meta analysis showed that interleukin-2 (IL2) receptor antagonists compared with placebo reduced acute rejection rates at six months and one year, but the incidence of graft loss was the same.(17)
Basiliximab is a chimeric anti-IL2 receptor monoclonal antibody. Compared with a placebo, it lowered the incidence of acute rejection without increasing adverse effects.(18,19) Compared with another antithymocyte globulin (ATG), basiliximab was associated with similar acute rejection rates but a lower incidence of adverse events at one year, when either ciclosporin or MMF was added to corticosteroids.(20)
Daclizumab is a humanised anti-IL2 receptor monoclonal antibody. In a study comparing daclizumab with OKT3 as induction therapy, acute rejection and the risk of infections requiring hospitalisation were lower in the daclizumab group.(21)
Alemtuzumab (Campath-1H) is a humanised anti-CD52 panlymphocytic monoclonal antibody. It drastically reduces lymphocyte numbers, and lymphocyte depletion is maintained for several weeks. It has not fulfilled the expectations of being a tolerance-inducing agent but, regardless, it is increasingly being used for induction therapy.(22) The main advantage of this drug is the possibility of a low-dose nonsteroidal maintenance regimen. In a trial where three different induction agents (alemtuzumab, rabbit antithymocyte globulin or daclizumab) in combination with partial withdrawal of maintenance therapy were compared, the group with alemtuzumab received steroids only on days 0 and 4 to prevent reaction to alemtuzumab administration. There was no significant difference in acute rejection or graft survival between groups at 12 months.(23) However, the drug should probably not be used in patients with potential severe chronic viral infections such as hepatitis C.(12)
Corticosteroids have been a mainstay of immunosuppression in kidney transplantation for more than 40 years. The well-recognised adverse effects of long-term steroid therapy have led to the need to develop steroid-sparing and steroid-free immunosuppressive regimens. Early experiences with steroid avoidance in patients receiving ciclosporin monotherapy or azathioprine/ciclosporin combination showed high acute rejection rates and long-term graft failure.(6) To date, several studies have demonstrated that steroid-free maintenance immunosuppression can be safe with regard to graft survival, but it is recommended that risk factors such as the presence of anti-HLA antibodies, previous rejection episodes, African-American ethnicity, delayed graft function, HLA DR mismatch and female gender are taken into account when steroid discontinuation is planned.(5) Steroid-free immunosuppression in tacrolimus- and daclizumab-based protocols has been shown to be safe with regard to acute rejection rates and short-term graft survival.(24) Withdrawing steroids from ciclosporin/MMF immunosuppression has been associated with an increased acute rejection rate at the end of the first year. However, most episodes were of Banff grade I, and renal function remained similar in both groups.(7,25) A recent meta-analysis of prednisone withdrawal in patients on triple therapy with ciclosporin and MMF has demonstrated that corticosteroid withdrawal carries a risk for acute rejection. However, corticosteroid withdrawal was not associated with worse graft survival in short- to medium-term follow-up.(4) The European Collaborative Transplant Study has demonstrated that steroids can be successfully withdrawn in a group of low-risk renal transplant patients without increasing the risk of acute rejection or having a deleterious impact on renal function in recipients on ciclosporin-based immunosuppression.(3)
Calcineurin inhibitors (CNIs), such as ciclosporin and tacrolimus, are another cornerstone of immunosuppressive therapy following kidney transplantation. US data show that, in the year 2004, 93% of kidney transplant patients received them as a part of their discharge regimen.(15) Tacrolimus was shown to be superior to ciclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but it increased post-transplant diabetes, neurological and gastrointestinal side-effects.(26) One year after transplantation, 51% of patients in the USA were receiving tacrolimus/MMF and 17% ciclosporin/MMF.(15) Early trials with ciclosporin showed a significant reduction in acute rejection episodes and an increase in short-term graft survival,(27) but concerns about acute and chronic nephrotoxicity quickly emerged.(28) Therefore, CNI withdrawal is used as a strategy to improve renal allograft function; however, it also carries a risk of acute rejection. A variety of MMF-based CNI-sparing regimens have demonstrated benefits in preserving or restoring renal function with acceptable levels of risk for mild acute rejection episodes, but long-term follow-up is still lacking.(29) CNI withdrawal from sirolimus-based therapy was associated with an increased risk of acute rejection but a higher creatinine clearance and improvement in hypertension at one year compared with continued CNI and sirolimus therapy.(30) In another study comparing sirolimus and ciclosporin, renal biopsy at two years post-transplant showed a higher percentage of patients with normal biopsies in the MMF/sirolimus group than in the MMF/ciclosporin group (67% vs 21%, respectively).(11)
MMF has become a mainstay of therapy in renal transplantation and has largely replaced another antiproliferative drug, azathioprine. Three multicentre studies have demonstrated significant reductions in the incidence of acute rejections in patients receiving MMF.(31–33) Initially, MMF was used in combination with ciclosporin A and steroids, but subsequent trials have evaluated MMF in combination with newer induction and maintenance agents. In a trial comparing MMF versus sirolimus in combination with tacrolimus, the incidence of acute rejections after six months was similar, but patients receiving MMF had better renal function with lower serum creatinine levels. Cardiovascular parameters were improved in the MMF group.(34) The use of MMF with sirolimus has the potential to reduce the need for CNIs without increasing the acute rejection rate and with significantly better renal function one year after transplantation.(10)
Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation of mycophenolic acid, developed with the objective of reducing upper gastrointestinal tract side-effects. Administration of 720mg of EC-MPS and 1,000mg of MMF resulted in a similar maximal plasma concentration and mycophenolic acid exposure, but results of several clinical studies showed that the incidence of gastrointestinal disorders was similar in patients receiving either MMF or EC-MPS.(35–37)
Sirolimus and its derivative everolimus are mammalian targets of rapamycin inhibitors (TOR-I). They have been evaluated in four different primary immunosuppressive regimens: as replacement for CNI and antimetabolites; in combination with CNI at low and high doses; and with variable doses of CNI.(38) TOR-I enhances ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled TOR-I should be used with a reduced dosage of ciclosporin when these two drugs are used in combination.
Sirolimus reduces the incidence of acute rejection episodes in new transplants and appears to be more effective when given in combination with a CNI than alone.(39,40)
When evaluating after renal transplantation as a part of triple therapy with ciclosporin and corticosteroids, everolimus in a dose of 1.5mg/day showed equivalent patient and graft survival and rejection rate compared with MMF,(41,42) although the discontinuation of everolimus for adverse events was more common.(41)
There are some new drugs under investigation in the field of immunosuppression. FTY 720 is a sphingosine-1 phosphate receptor agonist. In animal models, it demonstrated synergistic effects with CNIs and TOR-I (everolimus, sirolimus) in the prevention of allograft rejection. FTY720 produces a dose-dependent, reversible decrease in the peripheral blood lymphocyte count by as much as 80%.(43) In a phase II study, FTY720 was found to be as effective as MMF in combination with ciclosporin for the prevention of acute rejection after renal transplantation. It was well tolerated and not associated with the side-effects commonly observed with immunosuppressive therapies.(44) FK778 reversibly blocks de-novo pathways of pyrimidine synthesis. It efficiently suppresses T-cell-mediated immune reactions and directly affects B-cell responsiveness as well as IgM and IgG antibody production. It shows synergistic or additive effects with CNIs. In a phase II multicentre study, the drug was shown to be effective, well tolerated and safe.(45)
Modern immunosuppression enables a very low acute kidney graft rejection rate. Because it is not expected that a further reduction of acute rejections would improve long-term graft survival, the most important role of new immunosuppressive protocols is to diminish the side-effects of immunosuppression, which reduce long-term patient and graft survival, and to make immune tolerance possible. This is becoming a reality with antibody induction, steroid avoidance and CNI-reduced protocols. New immunosuppressive drugs, the clinical use of which still has to be evaluated in future clinical trials, are also in the horizon.
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