Induction in Sensitized Kidney Transplant Recipients Without Preexisting Donor-specific antiboDies: a Randomized Multicentre Trial Between a Lymphocyte Depleting and Basiliximab.

Kidney transplantation is the first-line treatment of end stage renal disease, improving life expectancy and quality of life in comparison to dialysis. The success of transplantation is a consequence of major advances, especially the development of efficient immunosuppressive drugs. However, thousands of kidney transplants fail yearly around the world, and kidney allograft failure is known as an important case of end-stage renal disease, leading to increased morbidity, mortality and costs. To improve graft survival is therefore a priority, especially in a context of organ shortage.

Many risk factors of kidney graft loss have been identified but alloimmune response remains the first determinant of graft loss. This powerful donor specific immune response involves numerous effectors that may be harmful to the graft, such as T and B lymphocytes and antibodies. Those antibodies are mainly directed against human leucocyte antigens (HLA) and DSAs can be detected and identified in serum of sensitized KTRs. Alloreactivity T-cells and antibodies may induce distinct categories of acute and chronic graft damages. Lesions of rejection, recognized on tissue fragments sampling by percutaneous ultrasound-guided core needle graft biopsy, are classified and graded according to international Banff classification that is regularly updated. Two categories of biopsy-proven acute rejections (BPAR) are thus distinguished: T-cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR). TCMR is a well-known risk factor of graft loss and also associated with subsequent de novo DSAs appearance. ABMR is considered as the first cause of kidney graft loss. In contrast to TCMR, that is usually sensitive to steroids, no treatment is able to completely block the production of DSA and reverse the process of ABMR, especially chronic ABMR. Prevent appearance of DSA and subsequent ABMR is therefore a major concern to improve kidney transplant outcome.

Appearance of DSA after transplantation (de novo DSA) depends mainly on number of HLA mismatches between donor and recipient and level of immunosuppression. Regarding immunosuppression, two clinical trials have reported an increased incidence of de novo DSA in patients receiving a calcineurin inhibitor-free maintenance treatment. In addition, some retrospective studies have suggested that mycophenolic acid would be more efficient to prevent de novo DSA formation. Standard-of-care for maintenance immunosuppression is therefore a combination of anticalcineurin (tacrolimus has widely replaced cyclosporin over last two decades), mycophenolic acid (mycophenolate mofetil or enteric-coated mycophenolate sodium) and steroids. Data about induction therapy (i.e. initial immunosuppressive treatment given during the first post-transplantation week) and risk of de novo DSA and ABMR are scarce.

Induction therapy is a pivotal component of the immunosuppressive treatment. It has decreased the rate of acute allograft rejection in KTRs and is strongly recommended. Polyclonal lymphocyte-depleting antibodies and interleukin-2 receptor (IL2R) antagonists are thus widely used around the world, with a leading position for rabbit anti-thymocyte globulin (rATG, Thymoglobulin®) and basiliximab (Simulect®), respectively. Today, these two induction treatments are used in common practice in kidney transplantation (rATG since 1984 and basiliximab since 2003). According to international KDIGO recommendations, IL2R antagonists are the first-line induction therapy in low-immunological risk no sensitized recipients (level 1, grade A), while immunosuppressive intensification using lymphocyte depletive agents is warranted in high-immunological KTRs (level 2, grade A). This intensification is supported by two randomized clinical trials that found rATG as more efficient to prevent acute rejection in recipients with a high immunological risk.

The current concern is that the definition of "immunological risk" used in those studies and international recommendations is no longer in line with current clinical practices. Indeed, immunological risk was estimated by the number of previous transplantations, recipient age, donor age, ethnicity, number of HLA mismatches and level of sensitization (calculated panel-reactive antibodies (cPRA) > 30%), based on cytotoxicity and ELISA techniques. Nowadays, highly sensitive single HLA-antigen flow bead (SAB) assays have replaced cytotoxicity and ELISA techniques in all French histocompatibility laboratories to detect low amounts of anti-HLA antibodies and accurately determine their specificity. It is therefore possible to characterize with a great precision whether a KTR is sensitized (i.e. presence of any anti-HLA antibody, irrespective of its specificity) and has anti-HLA antibody specific for DSA. Hence, the broad use of SAB assays has split sensitized KTRs in two distinct groups: those with at least one pre-transplant DSA, who have undoubtedly a high risk of BPAR and graft loss, and those without DSA. The actual immunological risk of the sensitized KTRs without DSA is still debated. Some studies have suggested that the presence of non-donor specific anti-HLA antibodies would represent an intermediate risk for graft loss and antibody mediated rejection and others that these antibodies did not affect graft outcome and risk of BPAR. A prospective study that compared rATG and basiliximab has recently confirmed that rATG should be used in sensitized KTRs with low amount of DSA detectable using SAB assay. Finally, the benefit-risk equation of lymphocyte depleting antibodies (versus IL2R antagonists) remains unknown only in sensitized KTRs without DSA.