Efficacy of Rabbit Anti-Thymocyte Globulin Therapy for Severe Acute Rejection in Kidney Transplant Patients using Calcineurin Inhibitor and Mycophenolate Mofetil based Immunosuppressive Therapy

Abstract

Background T-cell depleting antibody therapy is the treatment of choice for glucocorticoid-resistant kidney allograft rejection and is used as first-line therapy in severe T-cell mediated rejection (TCMR). Most studies investigating the effectiveness of this treatment were conducted when cyclosporine and azathioprine combinatiwere therapy. However, there is little evidence for its effectiveness in combination with current standard maintenance immunosuppressive therapy consisting of tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids (CS) with or without induction therapy. Here, the long-term outcome of rATG therapy for AR in patients using the current standard immunosuppressive therapy (i.e. tacrolimus and mycophenolate mofetil), is described. Methods Between 2002 to 2012, we identified 108 patients, treated with rabbit anti-thymocyte globulin (rATG) for biopsy-proven severe (Banff TCMR grade IIA or more) or glucocorticoid-resistant acute rejection; 78 patients had TAC/MMF and/or CS therapy at time of rejection. Patients were treated with high dose methylprednisolone, followed by rATG when kidney function showed further deterioration or a biopsy showed TCMR grade II. Results Overall survival after rATG was comparable to overall survival of all kidney transplant patients (p = 0.10). Allograft survival 5 years after rATG was 55.6%. Serum creatinine 1 year after rATG was 179 μmol/L (interquartile range (IQR) 136-234 μmol/L) and was comparable to baseline serum creatinine (p = 0.22). Early AR showed better allograft survival than late AR (p = 0.0007). Remarkably, allograft survival was worse in patients with acute T cell mediated rejection (aTCMR) grade I versus aTCMR grade II+III (p = 0.03). This was associated with a longer interval between pulse glucocorticoids and rATG (31 days (IQR 23-92) versus 8 days (IQR 3-15; p < 0.05). After rATG (mean follow-up 1948 days) 212 infections requiring hospitalization, 12 solid tumors and 2 lymphomas occurred. Conclusion rATG is an effective anti-rejection therapy in patients using current standard immunosuppressive therapy, even in patients with poor allograft function. Treatment with rATG for AR in this study seems not to be associated with increased mortality compared to patients without rATG treatment. The timing of rATG therapy is important. Early recognition of severe and /or glucocorticoid-resistant AR followed by aggressive treatment leads to better allograft function and allograft survival. When this window of opportunity is used, the benefits may outweigh the risks of adverse events.