Service de Néphrologie
University Hospital of Bicêtre
Tacrolimus was used first in Pittsburgh (USA) in early 1989 as a last resort in patients who were rejecting liver grafts despite the use of all drugs available at the time. Soon after this initial success as a rescue medication, the clinical development of tacrolimus was started. In this article, key results of randomised, prospective, multicentre trials will be summarised.
Two early large studies compared tacrolimus with the cyclosporine standard formulation, with one study being conducted in the USA and the other in Europe.(1,2) Both studies resulted in significantly lower rates of acute rejection, a risk factor for late graft loss,(3) with tacrolimus. Moreover, the incidence of vascular rejection, which is associated with the development of chronic rejection,(4) was also lower with tacrolimus than with cyclosporine.(5) The main differences in the safety profiles of the two regimens were higher incidences of tremor, post-transplant diabetes mellitus (PTDM) and pruritus in the tacrolimus group, whereas hypercholesterolaemia, acne, gingival hyperplasia, arrhythmia and hirsutism occurred more often with cyclosporine. Long-term follow-ups confirmed reduced incidences of both acute and chronic rejection with tacrolimus.(6)
In 1996, microemulsified (ME) cyclosporine was introduced; however, the superiority of tacrolimus was maintained compared with this new formulation (see Table 1).(1,2,7–9) A large European study compared tacrolimus and cyclosporine-ME in combination with azathioprine and corticosteroids.(9) At six months post-transplant, there were significantly lower rates of biopsy-proven acute rejection (19.6% vs 37.3%, p<0.0001) and biopsy-proven corticosteroid-resistant rejection (9.4% vs 21.0%, p<0.0001) in favour of tacrolimus. At two years post-transplant (International Congress of the Transplantation Society 2002), tacrolimus-treated patients required lower doses of concomitant corticosteroids, had lower serum cholesterol levels and better renal function. Tacrolimus was also more efficacious than cyclosporine-ME in a paediatric setting,(10) and two-year graft survival rates were higher with tacrolimus.(11)
Tacrolimus can also be used as a “rescue” agent for patients suffering from refractory rejection or to reverse cyclosporine- related side-effects. Patients who experienced a first biopsy-confirmed rejection while on cyclosporine-ME- based therapy benefited from conversion to tacrolimus.(12) The initial rejection responded to steroid treatment in 86.4% of patients switched to tacrolimus and in 63.8% of patients who continued cyclosporine-ME (p=0.001), and less of the switched patients had recurrent rejection (8.8% versus 34.1%; p=0.002). Moreover, cyclosporine-ME-associated hypertrichosis, gingival hyperplasia, treatment-resistant hyperlipidaemia and arterial hypertension were either resolved or improved within six months after cyclosporine-ME was replaced by tacrolimus (American Transplant Congress 2002; Abs 1060).
Tacrolimus has been investigated in various combination regimens. Induction with antithymocyte globulin (ATG) achieved low rates of acute rejection, but at the price of increased rates of viral infection, leukopenia, thrombocytopenia, fever and serum sickness. Antibody induction was significantly more effective in a tacrolimus- based regimen than with cyclosporine-ME.(13)
The addition of azathioprine to a tacrolimus–corticosteroid dual regimen did not improve efficacy, but only increased the incidences of leukopenia and anaemia (International Congress of the Transplantation Society 2002; Abs 2107).(14) In contrast, mycophenolate mofetil (MMF; 1 or 2g/day) significantly improved the efficacy of a dual tacrolimus– corticosteroid regimen. The 2g/day dose of MMF only showed more MMF-related leukopenia and leukopenia gastrointestinal adverse events, but was not more effective than the 1g/day dose in a European study,(15) whereas in a similar US study the 2g/day dose was more effective than 1g/day.(16) The difference in results may be attributed to the different ethnic composition of the European and US study populations.
Combinations of tacrolimus and sirolimus (doses of 0.5g, 1g and 2g/day) have been investigated (American Transplant Congress 2002; Abs 1314).(17) The incidence of acute rejection decreased in patients who received sirolimus, but the incidence of hyper-cholesterolaemia, a known side-effect of sirolimus, increased.(18,19)
Minimising the immunosuppressive load
Routine immunosuppressive regimens almost always include corticosteroids. However, the long-term administration of corticosteroids may increase cardiovascular comorbidity.(20)
Withdrawal, or even avoidance, of steroids was investigated in recent trials. A large three-arm study showed that, with a standard initial triple therapy of tacrolimus, MMF and corticosteroids, withdrawal of either corticosteroids or MMF at three months did not increase the incidence of acute rejection.(21) The benefits were the reduced incidence of leukopenia in the MMF withdrawal group and a substantial reduction in cholesterol levels in patients who stopped the steroids.
The risk for acute rejection generally decreases after the first months post-transplant, but how can patients who are suitable for complete steroid withdrawal be identified? A six-month study showed that freedom from steroid-resistant rejection and serum creatinine concentrations <160µmol/l provide a reliable indication for safe corticosteroid withdrawal.(22)
Immunosuppressive monotherapy is still in its early stages. Although the four-year results of a preliminary tacrolimus monotherapy study in 30 patients were positive, and despite the fact that 70% of patients remained on tacrolimus monotherapy, that patient and graft survival rates were 93% and 77%, respectively, and that serum creatinine levels were below 200µmol/l in all but one patient,(23) larger studies are required to confirm these results.
Improving long-term survival
Cardiovascular complications are responsible for at least 50% of mortality in renal transplant patients;(24) therefore, risk factors receive particular attention. Lipid neutrality under tacrolimus has been demonstrated in nearly every study, both in short- and long-term follow-ups.(1,2,25) A reduction in lipid levels can be achieved by switching the regimen from cyclosporine to tacrolimus.(26) Studies repeatedly showed lower incidences of hypertension with tacrolimus than with cyclosporine, despite a lower use of antihypertensive medication in tacrolimus patients.(1,2) The reported lower use of concomitant corticosteroids with tacrolimus than with cyclosporine also suggests long-term advantages.(1,2)
Post-transplant diabetes mellitus (PTDM) was a side-effect associated with high tacrolimus blood levels in early studies. Experience in the use of tacrolimus has reduced the initial high rates of PTDM, and recent trials reported incidences similar to that seen with cyclosporine-ME (ATC 2001, Abs 1070).(7–9)
Long-term follow-up of various studies has shown a tendency towards better kidney function under tacrolimus, compared with cyclosporine.(6–10) Serum creatinine tends to remain at the level reached during the first year post-transplantation (see Table 2).
While new immunosuppressive approaches are constantly being developed, tacrolimus remains a cornerstone medication in renal transplantation. Today, progressive decline of kidney function and death with a functioning graft are the main reasons for graft loss after renal transplantation. Tacrolimus-based regimens achieve low rejection rates, and the favourable cardiovascular risk profile and maintenance of kidney function offer good prospects for a long patient and graft survival.
- Transplantation 1997;63:977-83.
- Transplantation 1997;64:436-43.
- Transplantation 1993;56:307-15.
- Transplantation 1995;59:1280-5.
- Transplant Proc 1999;31:86S-87S.
- Transplant Proc 2002;34:1491-2.
- Transplant Proc 1999;31:64S-66S.
- Transplantation 2001;72:245-50.
- Lancet 2002;359:741-6.
- Pediatr Nephrol 2002;17:141-9.
- Transplant Proc 2002;34:1935-8.
- Transplant Proc 2001;33:1034-5.
- Transplant Proc 2002;34:1625-6.
- Transplant Int 2000;13 Suppl 1: S336-40.
- Transplantation 2001;72:63-9.
- Transplant Proc 1998;30:1287-9.
- Transplantation 2003;75:1934-9.
- Transplantation 2001;72:1181-93.
- Transplantation 2001;71:271-80.
- Am J Kidney Dis 1999;33:829-39.
- Transplant Proc 2002;34:1584-6.
- Ann Transplant 2002;7:28-31.
- Transplant Proc 2002;34:1612-3.
- J Am Soc Nephrol 1996;7:158-65.
- Transplantation 2002;73:775-82.
- Transplantation 1998;65:87-92.