Efficacy and Safety of Antibody Induction Therapy in the Current Era of Kidney Transplantation

Gerhard Opelz; Christian Unterrainer; Caner Süsal; Bernd Döhler

Disclosures

Nephrol Dial Transplant. 2016;31(10):1730-1738. 

In This Article

Abstract and Introduction

Abstract

Background. Antibody induction with polyclonal rabbit-antithymocyte globulin (rATG) or an interleukin-2 receptor antagonist (IL−2RA) is widely used in kidney transplantation.

Methods. Collaborative Transplant Study data from 38 311 first deceased-donor kidney transplants (2004–13) were analysed. Transplants were classified as 'normal risk' or 'increased risk' according to current guidelines. Cox regression analysis was applied to subpopulations of propensity score–matched recipients.

Results. rATG or IL–2RA induction was given to 64% of increased-risk and 53% of normal-risk patients, respectively. rATG and IL–2RA induction were each associated with reduced risk for graft loss versus no induction in increased-risk patients [hazard ratio (HR) 0.85, P = 0.046 and HR 0.89, P = 0.011, respectively]. The HR values for incidence of treated rejection in increased-risk patients for rATG and IL−2RA versus no induction were 0.75 (P = 0.037) and 0.77 (P < 0.001), respectively. In the normal risk subpopulation, neither induction therapy significantly affected the risk of graft loss or treated rejection. Hospitalization for infection was increased by rATG (P < 0.001) and IL−2RA (P < 0.001) induction. In contrast to patients transplanted during 1994–2003, among patients transplanted during 2004–13, rATG did not significantly affect the risk of non-Hodgkin's lymphoma versus no induction (P = 0.68).

Conclusion. Induction therapy following kidney transplantation should be targeted to increased-risk transplants. In this analysis, a beneficial effect of antibody induction in normal-risk transplants could not be demonstrated.

Introduction

Induction therapy with lymphocyte-depleting polyclonal antibodies or lymphocyte non-depleting monoclonal antibodies that inhibit the T-cell response is widely used in kidney transplantation. In the USA, 90% of all kidney transplant recipients receive induction therapy, with 65% given T-cell-depleting agents and approximately 25% given a non-depleting interleukin-2 receptor antagonist (IL−2RA).[1] A recent review of the literature concluded that antibody induction improves both short- and long-term outcomes following kidney transplantation.[2] Antibody induction, however, is not without risk. Notably, increased rates of infection have been reported with lymphocyte-depleting induction.[3] These arise from complex immunomodulatory effects on the host,[4] which also increased the risk of malignancy in the early era of its use.[5] The benefit of lymphocyte-depleting induction has been reported to apply particularly to patients at high immunological risk.[6,7] Therefore, depleting agents are typically used preferentially in higher-risk transplants,[2] as recommended by current guidelines.[8,9] The present analysis was restricted to the most widely prescribed depleting induction agents: Thymoglobulin, a rabbit-derived polyclonal antithymocyte antibody (rATG; Genzyme Corporation, Cambridge MA, USA), and the monoclonal IL−2RA agents daclizumab (Zenapax, Roche, Basel, Switzerland) and basiliximab (Simulect, Novartis, Basel, Switzerland).

A previous analysis of data from the Collaborative Transplant Study (CTS), based on kidney transplants performed during 1985−2004, showed significantly different effects for lymphocyte-depleting and non-depleting antibody induction in terms of the occurrence of non-Hodgkin's lymphoma (NHL).[10] The depleting agent rATG was associated with improved graft survival compared with no induction, but also with a strongly increased risk for NHL. In contrast, induction with IL−2RA also resulted in improved graft survival versus no induction, but with no associated increase in NHL.[10] Since that time, kidney graft survival rates have improved,[11] maintenance therapies have evolved and doses of rATG have decreased.[5] It was therefore deemed appropriate to analyse CTS data obtained during the last decade to provide a more up-to-date assessment of the efficacy and adverse consequences of antibody induction therapy in kidney transplant recipients.

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