The many novel immunosuppressive agents introduced in the 1990s have been utilised in regimens intensifying immunosuppression and which are associated with a marked reduction in acute rejection rates, improvement in one-year graft survival and a more modest prolongation of graft half-life.
The following immunosuppressive agents were used:
- A microemulsion preparation of ciclosporin
- A second calcineurin inhibitor (CNI): tacrolimus
- Two new potent antiproliferative agents: mycophenolate mofetil (MMF and EC-MPA [enteric-coated mycophenolic acid; Myfortic]) and sirolimus
- Two anti-interleukin-2 (IL-2) receptor monoclonal antibodies: daclizumab and basiliximab
- A new polyclonal agent, Thymoglobulin, approved in the USA.
The availability of all these new immunosuppressive agents has encouraged transplant physicians to individualise immunosuppression and select immunosuppressive regimens based on a number of factors, including the immunological and nonimmunological risks of the recipients and the quality of the renal allograft. Intensification of the immunosuppressive regimens while decreasing the incidence of acute rejection has been associated with a modest increase in long-term graft survival (i.e. graft half-life). A large number of grafts are lost because of premature death of the transplant recipient from cardiovascular disease or from progressive CNI nephrotoxicity. This problem has lead to experimentation with protocols that spare corticosteroids or CNIs.
Corticosteroid-sparing regimens
The corticosteroid-sparing regimens that are currently used are different from those that were utilised in the late 1980s and early 1990s. Previous corticosteroid-sparing regimens consisted of gradual decrease of the dose of steroids, with eventual withdrawal after three to six months after transplantation.
This approach, however, was not totally satisfactory as it exposed the patient to several weeks or months of corticosteroids, thus decreasing the benefits of ultimate withdrawal and resulting in dependence of the immune system to corticosteroids, which could be associated with a rebound rejection following late withdrawal.
In addition, withdrawal of steroids occurred at the time after transplantation when the patients’ follow-up was less intense and, thus, recognition, diagnosis and therapy of any rebound rejection were delayed. The corticosteroid-sparing regimens that have been introduced in the past five years utilise more rapid withdrawal of corticosteroids, or even complete elimination. Steroids are generally used for up to seven days after transplantation and then discontinued. In some regimens, corticosteroids are completely eliminated.
The advantage of these aggressive corticosteroid-sparing regimens is that the patient will experience minimal exposure or no exposure to corticosteroids and, therefore, suffer minimal side-effects; steroid dependency is avoided, and any rebound rejection usually occurs early in the course of transplantation at the time when the patient is followed in the outpatient transplant clinic more frequently and more intensively.
In addition, current corticosteroid-sparing regimens are characterised by the use of induction therapy consisting of either the anti-IL-2 receptor antibodies (daclizumab or basiliximab), a polyclonal depleting agent, Thymoglobulin, or, less frequently, alemtuzumab, a monoclonal antibody to CD52 antigen on the surface of lymphocytes that causes profound and long-lasting depletion.
The concomitant maintenance immunosuppression associated with corticosteroid-sparing regimens is variable and consists of ciclosporin and MMF, tacrolimus and MMF, ciclosporin and sirolimus, or tacrolimus and sirolimus.
No head-to-head studies with these various combinations have been utilised, so it is unclear which concomitant immunosuppressive regimen is best suited for corticosteroid sparing. However, a review of recent files shows that the acute rejection rate and overall outcome of the various concomitant immunosuppressive regimens appear to be comparable and, thus, the choice of the specific concomitant drugs should be based on the transplant physicians experience and knowledge of that combination.
Table 1 lists the trials, induction therapy, steroid regimen, concomitant immunosuppression regimen and rejection rates of studies that utilise aggressive corticosteroid sparing with withdrawal within seven days.(1–5) Experience with complete steroid elimination is more limited.
[[HPE22_table1_75]]
CNI-sparing regimens
CNI-based immunosuppressive regimens have been credited with reducing acute rejection and improving one-year graft survival. However, the use of CNIs is frequently associated with nephrotoxicity and, in a recent prospective study of protocol kidney biopsies over a period of 10 years, an inexorable progression of nephrotoxicity was observed. Thus, in an effort to improve long-term renal function and graft outcome, a number of trials have experimented with CNI-sparing regimens that consist of withdrawal of CNIs two to four months after transplantation.
Five large, prospective, multicentre trials have evaluated the safety and efficacy of CNIs withdrawal after renal transplantation. The first study, reported by Smak Gregoor et al, was designed as a prospective randomised study in primary transplant recipients treated with an immunosuppression regimen consisting of ciclosporin, MMF and prednisone.(6)
The objective of this study was to assess the safety of withdrawal of ciclosporin (50% reduction for two weeks before discontinuation) or prednisone at six months after transplantation compared with the continuation of triple therapy.
Some 18 months after drug withdrawal, patients withdrawn from ciclosporin had a significantly higher incidence of biopsy-proven rejection compared with patients withdrawn from prednisone or maintained on triple therapy.
The second study, reported by Abramowicz et al, is a European multicentre trial that enrolled 187 renal transplant recipients treated with triple therapy (ciclosporin/MMF/ prednisone) and randomised at three months to either ciclosporin withdrawal or to continue ciclosporin therapy.(7) Ciclosporin withdrawal was gradual over three months.
The primary endpoint was creatinine clearance six months after complete withdrawal of ciclosporin. In the per-protocol population (the withdrawal group), which excluded patients with acute rejections, there was a statistically significant increase in creatinine clearance (7.5ml/min, p=0.02) and improvement in serum creatinine (–11 versus +4µmol/l, p=0.0003).
Reversible acute rejections, the majority of which were mild, occurred in nine ciclosporin withdrawal patients versus two ciclosporin continuation patients (10.6% versus 2.4% of each group, p=0.03), with no graft loss. The lower rejection rate following CNI withdrawal reported by Abramowicz et al may have been achieved because of the more gradual withdrawal of ciclosporin.
The next two trials were designed to evaluate the efficacy of a maintenance regimen of sirolimus/prednisone following ciclosporin withdrawal. These trials were conceived to minimise the enhanced nephro‑toxicity that was observed when sirolimus was used in combination with full-dose ciclosporin.(8,9)
These two studies (the first conducted in the USA and Europe and the second in Europe, Australia and Canada) have slightly different designs but the same underlying rationale: assessing the safety and the potential benefits of ciclosporin withdrawal from a sirolimus/steroid regimen. In both studies, ciclosporin was withdrawn gradually over a period of one month.
In the US–European trial, ciclosporin was withdrawn at the end of month 2 after transplantation only in patients who had been rejection-free (82% of patients were eligible for ciclosporin elimination). The incidence of acute rejection at one year was not statistically significant (18.6% versus 22.0%, respectively) between patients who continued therapy with ciclosporin versus patients who were withdrawn from ciclosporin.
Patients withdrawn from ciclosporin experienced a significant increase in the calculated graft function (GFR). In the design of the global trial, ciclosporin could be withdrawn in patients who had previously had a rejection episode (provided it was not a Banff grade 3 rejection).
The overall incidence of biopsy-confirmed acute rejection was 13.1% in the first three months before the randomisation period. After randomisation, between months 3 and 12, patients withdrawn from ciclosporin had a significantly higher incidence of acute rejection compared with patients maintained on ciclosporin (9.8% versus 4.2%, p=0.035).
However, the cumulative rejection rate at one and three years in the ciclosporin withdrawal group, although numerically higher, was not statistically significant (20.2% versus 13.5%, and 20.5% versus 14.9%) than in the group maintained on ciclosporin. The ciclosporin withdrawal group experienced a significant and sustained increase in calculated GFR soon after discontinuation of ciclosporin and better three-year graft survival.
The fifth trial of CNI withdrawal, the CAESAR (Cyclosporine Avoidance Eliminates Serious Adverse Reactions) trial, has enrolled 525 patients in three treatment groups. The purpose of this study is to evaluate whether a very low dose of ciclosporin (with and without late ciclosporin withdrawal) in combination with daclizumab and MMF is safe and provides effective immunosuppression.
Among the important endpoints of this study are acute rejection, measured GFR and histological analysis of protocol biopsy at one year. The results of this trial will be reported in 2006.
The more ambitious and experimental approach to CNI-sparing is complete elimination from the regimen. The use of the combination of MMF and sirolimus with corticosteroids in a CNI-free regimen has been reported from single-centre and multicentre trials.(10,11)
This regimen appears to be more successful when used in conjunction with induction therapy with either an IL-2 receptor monoclonal antibody or Thymoglobulin. However, the efficacy and safety of these regimens remain to be determined.
The emergence of novel protein therapies
Novel protein therapies are emerging in renal transplantation in an attempt to eliminate or spare CNIs and/or corticosteroids.(12) In addition, these protein therapies have been utilised or developed in tolerance-inducing regimens.
Two of the most novel protein therapies are alemtuzumab (Campath 1H) and belatacept (a second-generation CTLA4Ig). Alemtuzumab is a humanised monoclonal antibody against CD52, which is expressed on lymphocytes, monocytes and macrophages. Alemtuzumab causes profound and prolonged T-cell depletion via complement-dependent lysis.
A study in recipients of living donor kidneys who received alemtuzumab perioperatively as monotherapy with no maintenance immunosuppression exhibited profound lymphocyte depletion in the periphery and secondary lymphoid tissue.(13)
However, all seven patients treated with alemtuzumab monotherapy developed acute rejection episodes within the first month; these episodes were responsive to steroid therapy and/or sirolimus immunosuppression. Knechtle et al reported a second study with alemtuzumab.
Some 29 primary renal transplant patients were treated with two doses of alemtuzumab (30mg), 14 days of corticosteroid therapy and maintenance sirolimus.(14) A total of 12 of the 29 patients developed acute rejection, and half of these rejections were vascular.
A recent modification of these regimens utilises tacrolimus for two to three months, followed by discontinuation and maintenance of monotherapy with sirolimus.
Belatacept
Another exciting protein therapy is belatacept, a second-generation CTLA4Ig developed as a single agent to inhibit competitively both CD80 and CD86 molecules from interacting with CD28. Blockade of this costimulatory pipe by belatacept results in inhibition of allogeneic-driven T-cell activation.
Preclinical studies demonstrated that CTL4AIg and belatacept resulted in prolongation of transplanted organs. However, belatacept was shown to be more effective in prolonging graft survival in primates than CTL4AIg, and was selected for clinical development in renal transplantation.(15)
Belatacept is a modified version of CTLA4Ig that was rationally designed to provide more potent immunosuppression, suitable for transplantation. Belatacept differs by two amino acid residues in the region that binds to CD80 and CD86, resulting in binding affinities for CD86 and CD80 being four times and twice higher, respectively, than those of CTLA4Ig.
The clinical development of belatacept offers a new paradigm in immunosuppression: chronic intermittent protein therapy in a CNI-free regimen. A phase II, multicentre trial was carried out to compare the safety and efficacy of belatacept versus ciclosporin as part of a quadruple immunosuppressive drug regimen in 217 patients who had undergone renal transplantation with diseased or living donor kidneys.(16)
Patients received two different regimens (less and more intensive) of belatacept (versus ciclosporin). All patients were treated with MMF, corticosteroids and two doses of basiliximab.
At six months, there was no significant difference in the incidence of clinically suspected, biopsy-proven acute rejection between the different treatment groups. In addition, this study demonstrated that patients treated with belatacept had better renal function and better cardiovascular and metabolic endpoints than those treated with ciclosporin.
Belatacept will be tested in two phase III trials and in a pilot study to determine whether it can induce tolerance in recipients of living donor kidneys.
Author
Flavio Vincenti MD
Kidney Transplant Service, University of California, San Francisco, CA, USA
E:[email protected]
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