Is Rituximab Useful or Harmful in Blood Group Incompatible (ABOi) Renal Transplantation?

Abstract

Purpose: Rituximab has been proven to suppress anti-ABO titer rebound in ABOi renal transplantation. However, an increased risk of severe infectious disease and of acute antibody-mediated rejection (AMR) has been described after ABOi renal transplantation. We performed a prospective renal transplant study up to 5 years posttransplant to detect long-term immunological effects of rituximab administration. Methods: Mononuclear cell subsets in peripheral blood, regional lymph nodes and protocol biopsies, and in-vitro T and B cell responses were assessed in 85 renal transplant recipients (living donation: n=25 ABOi, n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible). IgG anti-HLA antibodies were assessed by single antigen assay. Results: The frequency of severe infectious diseases was doubled in ABOi versus ABOc recipients (P=0.042 within 2 years). In ABOi recipients, peripheral blood B cell subsets were profoundly downregulated for at least 3 years, together with impaired in-vitro B cell responses (P=0.010, T-dependent; P=0.053, T-independent), but increased CD4 helper activity for 2 years (P=0.019). CD4+ T cell counts were significantly lower up to 6 months (P=0.046), without an impact on Tregs. In regional lymph nodes of ABOi patients, we found a significant downregulation of naive B cells (P=0.031) and short lived plasma cells (P<0.0005) at the time of transplantation. ABOi patients showed an increased frequency of biopsy-proven acute rejection (3-12 months posttransplant, P=0.003) and of AMR (P=0.008 within 5 years). In protocol graft biopsies, we found rituximab-induced B cell depletion at 3 months (P<0.001), but even enhanced counts of T cells (P=0.041), macrophages (P=0.021) and plasma cells (P=0.033) at 1 year. IgG anti-HLA antibody formation was not significantly different between ABOi and ABOc patients. Conclusions: An increased frequency of severe infectious diseases in rituximab treated ABOi renal transplant recipients may be explained by the rituximab-induced long-term immunological effects on CD4+ T cell counts and the prolonged depletion of B cell subsets together with compromised B cell responses. In protocol graft biopsies, rituximab induced early B cell depletion but counter-regulatory proinflammatory effects, coinciding with an increased acute rejection frequency. IgG anti-HLA antibody formation was not suppressed.