Division of Nephrology
Organ Transplant Center
Akdeniz University Medical School
Immunosuppressive drugs are used to prevent or treat rejection and maintain graft function in organ transplant recipients. They are necessary over long periods; thus, balancing the possible benefits against the risks for each individual patient is important. Reducing side-effects while maintaining long-term graft function is the primary goal of transplantation teams.
Inhibitors of purine synthesis
Mycophenolic acid (MPA), a potent inhibitor of cellular proliferation, acts by selectively inhibiting the inosine monophosphate dehydrogenase and by blocking de-novo purine synthesis (which interferes directly with the proliferation of T- and B-cells).
Mycophenolate mofetil (MMF) is superior to azathioprine or placebo in preventing acute rejection after renal transplantation.(1,2) The preventive effect of MMF has also been confirmed in liver, heart and pancreas transplantations. MMF has also been used successfully in combination with tacrolimus(3) and sirolimus.(4) MMF significantly improves long-term graft survival rates in kidney transplantation,(5) and also reduces the relative risk for developing chronic allograft failure by 27%, this beneficial effect being independent of acute rejection.(6)
MMF has relatively few side-effects (mainly haematological or gastrointestinal); nephrotoxicity, hepatotoxicity or metabolic effects such as diabetes, hyperlipidaemia and bone loss do not occur. Table 1 presents the side-effects linked to MMF usage in renal transplant recipients. These adverse effects are generally successfully overcome with temporary dose reduction; complete withdrawal of MMF is rarely required.
Although many transplant teams do not routinely monitor MPA levels, a consensus panel recommended an MPA area-under-the-curve (AUC) of 30–60mg/h/ml or more in the early post-transplant period.(7) MPA AUC and trough levels are lowered by ciclosporin(8) and increased by tacrolimus.(9) In our team, we use MMF (2g/day) in combination with ciclosporin or sirolimus, and MMF (1–2g/day) in combination with tacrolimus.
Inhibitors of rapamycin
Sirolimus (a macrocyclic lactone) and tacrolimus target the same binding protein, the FK binding protein. However, the mode of action of this drug is distinctively different: it inhibits kinase cascade and interferes with the second phase of T-cell activation, thus inhibiting the response to cytokines, whereas ciclosporin and tacrolimus block their production.
Two forms of sirolimus are available: an oil-based solution and a solid formulation. Switching from the oil-based solution to the solid formulation results in similar AUC(0–12) values.
Acute rejection rates with sirolimus in combination with ciclosporin are superior to those found with azathioprine used in combination with ciclosporin.(10) Sirolimus acts synergistically with calcineurin inhibitors (CNIs), suggesting its potential to allow marked dose reduction of nephrotoxic CNIs in the early post-transplant period.(11) Many authors believe that sirolimus should be used in combination with ciclosporin and steroids for the first three months. Then ciclosporin should be progressively discontinued. The usual dose is a 6mg loading dose, followed by a maintenance dose of 2mg once daily. In the first three months, target whole-blood trough levels are 4–12ng/ml. After withdrawal of CNI, a target whole-blood trough range of 12–24ng/ml is recommended.(12) Other sirolimus-based combinations with tacrolimus or MMF are under evaluation.
CNIs and sirolimus are metabolised in the liver by the cytochrome P450 3A4 (CYP3A4) isoenzyme. Drugs and compounds that inhibit or induce CYP3A4 may increase or decrease their blood levels (see Table 2). Side-effects associated with sirolimus are detailed in Table 3.
Everolimus has a greater polarity than sirolimus. Everolimus was developed in an attempt to improve the oral bioavailability of sirolimus. The usual dosage regimen of everolimus is 1.5–3mg/day.(13) The target trough concentration of everolimus should range from 3 to 15g/l in combination with ciclosporin and steroids.(14)
Anti-interleukin-2-receptor (CD25) antibodies
Recently, two anti-interleukin 2 receptor (CD25) antibodies, daclizumab and basiliximab, have been approved for induction therapy. They do not cause the cytokine release syndrome that is characteristic of the monoclonal antibody OKT3. Both agents reduce acute rejection rates significantly over the first 12 months after transplantation.(15,16) Acute rejection rates with this therapy vary from 10 to 20% without any increase in the rates of infection and malignancy. Anti-interleukin-2-receptor antibodies have become standard in induction therapy, except in highly sensitised patients.
The use of anti-interleukin-2-receptor antibodies has allowed the development of steroid-free regimens that allow marked reduction of CNI doses.(17,18) Basiliximab is administered once before transplantation and on postoperative day 4. In early studies, daclizumab was given for a total of five doses in two-week periods, but recent studies have shown that the same success can be achieved with a two-dose daclizumab regimen.(19)
FTY720 is a new drug that acts through a completely different mechanism: it induces peripheral lymphodepletion of both T- and B-cells by altering lymphocyte recirculation and homing to lymph nodes and Peyer’s patches.(20) It also inhibits cell migration from the thymus.(21) FTY720 shows synergistic effects with ciclosporin. In animal studies, exciting and promising results have been obtained regarding allograft survival. In humans, FTY720 is currently being used in several clinical trials for the prevention of allograft rejection.
Alemtuzumab is a specific CD52 monoclonal antibody. It depletes T-lymphocytes and, to a lesser degree, reduces levels of B-cells and monocytes.(22) It is the most exciting agent in steroid-free regimens aimed at inducing some degree of tolerance. Following early clinical studies,(23,24) hopes of generating and sustaining full tolerance have been tempered by a relatively high rate of rejection in many studies. Alemtuzumab may play a major role in minimising steroid-free immunosuppression. Alemtuzumab is given intravenously preoperatively (a single 30mg dose) followed by either tacrolimus(25) or MMF.(26) It can also be given twice, once at a dose of 20mg six hours after surgery and again 24 hours postoperatively, in combination with ciclosporin.(27)
These studies have shown that alemtuzumab allows the development of steroid-free monotherapy regimens (tacrolimus, ciclosporin or MMF) in the maintenance phase.
- Lancet 1995;60:225-32.
- Transplantation 1996;61:1029-37.
- Transplantation 2000;69:875-80.
- Transplantation 2000;69:1252-60.
- Transplant Proc 2002;34:2087-8.
- Transplantation 2000;69:2405-9.
- Clin Biochem 1998;31:317-22.
- Transplantation 1999;68:1603-6.
- Transplant Proc 1998;30:1299-302.
- Lancet 2000;356:194-202.
- Transplantation 1999;68:1526-32.
- Transplant Proc 2003;35 Suppl 3:S157-61.
- Clin Pharmacokinet 2004;43:83-95.
- Transplantation 2002;73:920-5.
- Progr Transplant 2001;11:33-9.
- Transpl Int 2000;13:151-9.
- N Engl J Med 2000;343:230-8.
- Transplantation 2001;71:1320-8.
- Transplant Proc 2001;33:1692-3.
- Immuno-pharmacology 1999;41:199-207.
- Eur J Immunol 2000;30:1435-44.
- BioDrugs 2003;17:147-54.
- Lancet 1998;351:1701-2.
- Transplantation 1999;68:1613-6.
- Am J Transplant 2004; 4Suppl 9:38-53.
- Ann Surg 2003;238:520-5.
- McCauley J. In: Kidney transplantation. Basel: Karger; 2005:146:43-53.