Perioperative Minimal Induction Therapy: A Further Step toward More Effective Immunosuppression in Transplantation

Abstract

Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens.

In Kidney Transplant Patients, Alemtuzumab but Not Basiliximab/Low-Dose Rabbit Anti-Thymocyte Globulin Induces B Cell Depletion and Regeneration, Which Associates with a High Incidence of De Novo Donor-Specific Anti-HLA Antibody Development

“…Since the day of transplant, reference patients received five consecutive rATG (thymoglobulin) infusions at a daily dose of 0.5 mg/ kg (12,13). The dose of rATG was reduced or temporary withdrawn when WBC or platelet counts decreased to ,2,000/ml or ,50,000/ml, respectively.…”

“…Induction therapy with very low-dose rATG combined with the mAb anti-IL-2R basiliximab (Bas), given with the aim of inhibiting the activity of T cells surviving the lymphocytolytic effect of rATG, prevented acute graft rejection in kidney transplant patients as effectively as did full-dose rATG monotherapy but with remarkably fewer side effects (12,13) and negligible risk for acute humoral rejection.…”

Low-Dose RATG with or without Basiliximab in Renal Transplantation: A Matched-Cohort Observational Study

“…The first infusion was started in the Nephrology Unit as soon as the graft was definitely allocated and was continued during and after the surgical procedure. Reference-patients also received a fixed dose of 20 mg of basiliximab (Simulect®, Novartis, Italy) the day of transplant and 4 days apart[17]. Steroids were withdrawn on day 6 post-transplant.…”

“…However, steroids were continued up to month 1 in patients with postponed cyclosporine therapy because of DGF and were reintroduced in the immunosuppression regimen after any intercurrent allograft rejection. All participants were maintained on cyclosporine (Sandimmune®, Novartis, Italy) [17,21] plus either MMF (750 mg twice daily; Cell Cept®, Roche, Italy) or AZA (125 or 75 mg/day if body weight > or ≤75 kg, respectively; Imuran®, GlaxoSmithKline, Italy), administered from post-transplant day 1, and were followed according to standardized guidelines [17,21]. Circulating B, T and NK cells were counted by fluorescence-assisted cell-sorter analysis.…”

“…The efficacy of dual induction has been further improved by starting the induction protocol before transplantation, in order to achieve T-cell depletion and inhibition already at the time of engraftment [15,16]. Indeed, compared to post-surgery combined therapy, perioperative induction further reduced the rates of acute allograft rejections and even of delayed graft function (DGF) episodes, with similar tolerability [17]. To assess the specific antirejection activity of basiliximab in this context and whether and to what extent this could affect post-transplant renal function recovery, in the present matched-cohort observational study we compared the incidence of acute allograft rejections and directly measured GFR [18] in deceased-donor renal transplant recipients induced with low-dose RATG monotherapy or in combination with basiliximab.…”