Combined Induction Therapy with Rabbit Antithymocyte Globulin and Rituximab in Highly Sensitized Renal Recipients

Abstract

Compared to non-sensitized renal transplant recipients, patients with preformed alloantibodies are at greater risk of cellular and humoral rejection and premature graft failure. We explored the effects of adding B-cell depleting agent (rituximab) to standard rabbit anti-thymocyte globulin (rATG) induction regimen for patients with panel reactive antibody levels >50%. Following induction therapy, 14 recipients were given two doses of rituximab (375 mg/m(2)) within the first month post-transplantation. Their long-term outcomes were compared to a historical control group of 23 recipients who received rATG alone. Graft survival at 5 years was superior with combination therapy compared to induction therapy alone (92.9 versus 48.3%, respectively, p = 0.02). While 30% of the rATG alone group experienced cellular rejection and 26% humoral rejection, none of rituximab plus rATG renal transplant recipients group had rejection. Thus, addition of rituximab to rATG provided superior outcomes to rATG alone. This combination induction therapy should be considered for a high-risk population.

Perspective Chapter: Low Cost Immunosuppressive Strategies in Renal Transplantation

“…When rituximab was combined with ATG for patients with panel reactive antibody levels >50%, no rejections were seen compared to 30% cellular rejection and 26% humoral rejection when rATG was used alone [28]. This suggests a role for combining low dose rituximab with low dose ATG in those with moderate immunologic risk.…”

“…As Rituximab targets B cells and has been used in the management of antibody mediated rejections, there could be a role of combining it with a T cell depleting agent or IL2RA. There are reports on its use as an induction agent in combination with ATG or IL2RA albeit with differing doses and frequency [9,21,28].…”

“…Using rituximab alone as an induction agent along with tacrolimus and mycophenolate mofetil may suffice in those with mild immunologic risk as rejection rates particularly as ACR has declined decreasing the impact of conventional induction therapy [20,35], while AMR has increased [24] where rituximab may have a preventable role [28]. The majority of ACR in the tacrolimus era respond to 3 pulses of methyl prednisolone and only minority who do not respond need ATG [36].…”

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

“…Rabbit antithymocyte (rATG) polyclonal antibody or interleukin-2 receptor monoclonal antibodies are the most common agents used for induction in non-sensitized patients. Sensitized patients with preformed HLA antibodies are at greater risk of cellular and humoral rejection, and outcomes can be optimized by using polyclonal induction agents, such as ATG or alemtuzumab, that are associated with a lower risk of rejection and better graft survival [22][23][24][25]. However, the impact of different induction approaches on sensitized patients has not been fully elucidated and the variability in induction therapy can be largely attributed to transplant center choice and clinician preference rather than patient or donor characteristics [23][24][25][26].…”

“…A cohort of seven sensitized patients (mean PRA class I and II were 31% and 51%, respectively) who received rituximab induction therapy showed a reduced occurrence of postoperative humoral rejection [56]. Furthermore, the combination of rituximab with rATG induction therapy in highly sensitized patients (mean class I PRA > 80%) showed superior graft survival at 5 years compared to rATG induction therapy alone (92.9% vs. 48.3%, p = 0.02) [24]. Intravenous immunoglobulin and rituximab combined induction therapy in highly sensitized patients (mean PRA = 62%, ≥3 HLA-mismatch, positive FXM or positive pretransplant DSA) was also effective in graft survival, graft function, and overall patient survival [57].…”