Induction therapy in renal transplant recipients: how convincing is the current evidence?

The goal of organ transplantation is to provide durable organ function while minimizing risks such as infection and cancer. Induction therapy in renal transplantation provides improved short- and long-term graft outcomes compared with placebo. Three agents are currently available and widely used in the US; rabbit anti-thymocyte globulin (rATG), basiliximab and alemtuzumab. These agents are all clinically effective in transplantation. In patients at high risk of rejection, graft outcomes are improved with the use of depleting agents, such as rATG or alemtuzumab, rather than basiliximab. Depleting agents are associated with more complications, such as infection and malignancy. The risk-benefit analysis for low-risk patients indicates that basiliximab may be the preferred agent in this population. Use of induction therapy, particularly with rATG, may not only allow for but also mandate reduction of maintenance immunosuppression. The mechanisms by which induction agents lead to improved clinical outcomes have not been elucidated. rATG and alemtuzumab lead to prompt and durable lymphocyte depletion, but many other mechanisms contribute to their suppression of alloimmunity. For instance, rATG contains antibodies specific for multiple adhesion molecules and even human leukocyte antigen, while CD52 (the target of alemtuzumab) is present on many antigen-presenting cells as well as lymphocytes. The manner in which the immune system recovers after induction may also aid in establishment of immune tolerance, with proliferation of suppressor T lymphocytes seen with rATG use. The various contributions of these mechanisms in achieving the goal of allograft tolerance are currently being investigated. The currently available data are of generally low quality, based on many small and often retrospective studies. Definitions of 'high risk' vary between studies, as do induction and maintenance dosing regimens. Standardization of definitions and establishment of large, prospective, multicentre trials would lead to a better understanding of the currently available agents and their best use in renal transplantation induction therapy.