Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study.

Monica Grafals,Naoka Murakami,Elizabeth A Pomfret,Leonardo V Riella,Agnes Trabucco,Jamil Azzi,Katherine Hamill,Brian Smith,Erick Marangos,Nader Najafian,James J Pomposelli,Hannah Gilligan,Mary A Simpson,Aric Gregson

doi:10.1371/journal.pone.0104408

Abstract

Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings.Trial RegistrationClinicalTrials.gov NCT00548405

Highlights

Most kidney transplant centers in the United States utilize induction agents as part of their immunosupression protocols as it is believed that these agents prevent early acute rejection episodes and possibly improve graft survival [1,2,3]
The two arms were well balanced with no major differences in terms of living versus deceased donor transplant, recipient’s gender, age, ethnicity, re-transplant, diabetes, CKD etiology, dialysis time prior to transplant, panel reactive antibody (PRA), donor age and kidney weight (Table 1), with the exception of a slightly higher prevalence of coronary artery disease in the lowATG group compared with sATG (n = 9 vs 4, p = 0.06)
antithymocyte globulin (ATG) is a potent immune-depleting induction therapy that has significantly reduced the rate of acute rejection in solid organ transplantation

Summary

Introduction

Most kidney transplant centers in the United States utilize induction agents as part of their immunosupression protocols as it is believed that these agents prevent early acute rejection episodes and possibly improve graft survival [1,2,3]. Rabbit antithymocyte globulin (ATG or Thymoglobulin) is the most common induction agent used in renal transplantation and is used in more than 55% of kidney transplants in the USA, despite not being FDA-approved for this use [2]. ATG causes T-cell depletion by inducing complement-dependent cell lysis. It modulates cell surface and adhesion molecules that regulate T-cell function and leukocyte endothelial interactions, respectively [1,4,5]. An ATG dosage of 6–10 mg/kg has traditionally been the standard of care in most transplant centers in the USA [5,9,10,11,12]. ATG has been widely studied in the cyclosporine and low-dose steroid maintenance era, the optimal dosage of ATG in the setting of tacrolimus use and steroid withdrawal has not been determined

Methods

Results

Conclusion