Treatment of First Acute Rejection Episode: Systematic Review of Level I Evidence

The primary objective of this review was to clarify the efficacy of commercially available and tested agents for the treatment of first acute rejection episode (ARE) and particularly a steroid-resistant rejection (SRR) seeking to provide generalizable level I evidence for clinical practice. The inclusion criteria were restricted to prospective randomized trials (PRT) that (1) reported outcomes of first, biopsy-proven ARE based on Banff 97 diagnostic criteria; (2) excluded borderline changes that were not considered to be acute rejection; (3) included protocol biopsies confirming reversal or recurrence of rejection; (4) utilized calcineurin inhibitor-based double or triple baseline immunosuppression prior to and after the reversal of ARE and possessed Jadad scores at least 3 upon final assessment by both reviewers. Two PRTs compared rabbit-anti-thymocyte globulin (ATG) to low-dose corticosteroids or OKT3, following a first rejection episode in renal transplantation patients. The analysis of pooled data revealed 25% and 31% absolute risk reduction (ARR), in regard to initial treatment failure and recurrence of ARE, respectively, in favor of ATG treatment. Treatment morbidity showed similar long-term graft and patient survival rates in both arms. Three optimal trials compared the efficacy of various polyclonal or polyclonal versus monoclonal (OKT3) antibodies for the treatment of SRR. The estimated efficacy potential of rabbit-ATG appeared to be 11,4% greater than horse-ATG with particularly Banff grade II but also grade III patients demonstrating the greatest benefit. Among two PRTs comparing ATG to OKT3, ATG tended to show better graft function, fewer recurrent rejections (9% ARR), fewer graft losses due to immunologic failure (7% ARR), and better tolerance. The incidence of malignant tumors was similar in both treatment arms. In conclusion, thymoglobulins, especially those of rabbit origin, displayed greater efficacy for the treatment of ARE and SRR. Application of CD3 monitoring using flow-cytometry provided a reliable guid to prevented excessive immunosuppressive administration.