Belatacept as a Replacement for CNIs 3 to 12 Months Post-transplantation in Patients With Early Graft Dysfunction

The standard maintenance regimen in renal transplantation combines calcineurin inhibitor (CNI: ciclosporin or tacrolimus) and anti-metabolite drugs (mycophenolate mofetil (MMF) or mycophenolic acid (MPA)). CNI in the 1980s made kidney transplantation possible by drastically reducing acute rejection rates in the first year. Currently the main limitation of kidney transplantation is the occurrence of chronic graft dysfunction. While half of patients die with a functional graft, the other half return to dialysis and require retransplantation. Paradoxically, CNI has been identified as a leading cause of chronic graft dysfunction. Indeed, these molecules are nephrotoxic both : acutely and transitory due to a vasoconstrictor effect that modulates intra-renal hemodynamic and chronically due to extensive fibrosis. In the late 1990s, with the development of a new class of immunosuppressants, mammilian target of rapamycin (mTor) inhibitors (sirolimus and everolimus), CNI-free protocols were developed. The results were disappointing due in part to the undesirable effects of these treatments and secondly to the occurence of chronic rejections related to the appearance of Donor Specific Antibody (DSA) antibodies.

Finally in the mid-2000s belatacept is a fusion protein (CTLA4-Ig) blocking the ligands of the main costimulatory molecule (CD28) emerged. In the Phase III princeps assay (BENEFIT), this molecule was used as a maintenance treatment following transplantation (de novo) in combination with MMF (without CNI). Compared to the control group with CNI, patients receiving belatacept had better renal function from 1 year and after 7 years survival (graft and patient) were better. These benefits were attributed, on the one hand, to the absence of CNI and, on the other hand, to a very good control of the alloimmune response demonstrated by a lower incidence of DSA in the belatacept group.

Despite these excellent results, belatacept has not become the gold standard in renal transplantation for two main reasons. First, when it is used de novo (as in BENEFIT), there is a significant incidence of early rejection, known as "costimulation blockade resistant". The second issue is medico-economic. Indeed, to date and despite the accumulation of favorable data, in France and in most countries, belatacept has marketing authorization but is not supported by social security policy due to benefits regarded as insufficient with respect to the cost (related to the IV administration requiring hospital environment every month).

Consequently, it is important to precise which recipients may benefit more from this molecule. Patients, often elderly, with poor early function of the graft due to the poor quality of a marginal / "extended criteria" donor, are a good indication of belatacept not used de novo but after 3 months instead of CNI. This conversion most often allows to significantly improve the renal function of these patients to a much more acceptable level which remains stable beyond and without cost in terms of rejection (probably because of the time interval with the transplant). In this situation, several series reported success rates ranging from 80 to 100% with a rejection incidence between 0 and 20%. Failures are most often due to patients with non-primary graft function.

Currently after the conversion, belatacept is always maintained indefinitely most often in association with MMF. This usage generates significant costs and in fact, limits the access of belatacept for other patients. This practice is based on the dominant idea that chronic nephrotoxicity of CNI is the cause of chronic graft dysfunction.