Steroid avoidance or withdrawal after kidney transplantation: a balancing act.

S teroids have been a mainstay of immunosuppressive therapy for kidney transplant recipients (KTR) for 50 years. However, as a consequence of the multiple side effects associated with long-term steroid usage, there has been a growing interest in steroid avoidance or withdrawal (SAW) after kidney transplantation. In the recent Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for the care of KTR, it is suggested that “. in patients who are at low immunologic risk and who receive induction therapy, corticosteroids could be discontinued during the first week after transplantation” and “If prednisone is being used beyond the first week after transplantation, we suggest prednisone be continued rather than withdrawn” (1). Two recent systematic reviews and meta-analyses published in this journal suggest that these guidelines require some modification. The first by Knight and Morris (2) examines four groups of recipients, namely those in whom steroids are avoided, those in whom steroids were used for 7 days or less, those in whom steroids were withdrawn between 7 days and 12 months, and finally those in whom withdrawal took place after 12 months. The incidence of acute rejection (AR) was increased in the first three groups but not in the fourth. However, graft and patient survival was not altered, and there was a marked reduction in cardiovascular risk factors. The second review in this edition by Pascual et al. (3) examined steroid withdrawal between 3 and 6 months after renal transplantation and found an increased incidence of AR in patients on cyclosporine but not tacrolimus, but with no impact on graft and patient survival. No difference between cyclosporine and tacrolimus was noted in the first review, but this examined withdrawal between 7 days and 12 months and so the two analyses are not strictly comparable. So where do we go from here? As far as the safety of early withdrawal of steroids (before day 7 posttransplant) is concerned, we would like to highlight some of the findings of two recently published randomized prospective trials (4, 5). Woodle et al. (4) randomized 386 KTR on antibody induction, tacrolimus, and mycophenolate mofetil (MMF) to rapid discontinuation or long-term steroids. A significantly higher rate of AR in patients on steroid-free immunosuppression was observed. Although this increased rate of AR was not associated with inferior graft or patient survival at 5-year follow-up, there was a doubling of the incidence of chronic allograft nephropathy in patients on steroid-free immunosuppression (4). In the second study, KTR treated with basiliximab, cyclosporine, and enteric-coated MMF were randomized to no steroids, rapid discontinuation of steroids (posttransplant day 7), or maintenance steroids (5). At 12 months, the incidence of biopsy-proven AR was significantly increased in the groups with steroid minimization. Moreover, allograft function was also lower in these groups when recipients with graft loss or death were taken into account (5). Therefore, in addition to the well-known increased rate of AR, these two trials raise substantial concerns regarding long-term renal function and chronic allograft nephropathy after steroid avoidance. A recent analysis of data from the U. S. Scientific Registry of Transplant Recipients was performed to determine the intermediate outcome in KTR with or without corticosteroids at the time of discharge from the hospital (6). KTR discharged without corticosteroids exhibited significant better patient and (death-censored) allograft survival (6). Because this type of retrospective analysis based on discharge therapy is inevitably flawed by multiple biases, these data can hardly be used to prove long-term safety of steroid minimization. Taken together, in our opinion, the KDIGO guideline that early steroid discontinuation can be safely performed in patients treated with induction therapy who are at low immunological risk is based on few studies, and more long-term follow-up data regarding allograft function and survival are required. More data are available regarding withdrawal of steroids at 3 to 6 months after kidney transplantation. The impact of the concomitant immunosuppressive regimen on the results obtained in SAW trials has been increasingly recognized. Based on early studies and meta-analyses of steroid withdrawal trials using cyclosporine (7–9), the interest in steroid-free immunosuppression was initially dampened in the transplant community. However, since the introduction of newer, more potent immunosuppressants, several clinical trials have shown a lower rate of AR compared with cyclosporinecontaining regimens (10 –12). In a prospective trial from the Collaborative Transplantation Study, Opelz et al. (13) reported that the 7-year patient, graft, and death-censored graft 1 Department of Medicine, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium. 2 Address correspondence to: Yves Vanrenterghem, M.D., Ph.D., Division of Nephrology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: yves.vanrenterghem@uzleuven.be Received 29 April 2010. Accepted 29 April 2010. Copyright © 2010 by Lippincott Williams & Wilkins ISSN 0041-1337/10/9004-350 DOI: 10.1097/TP.0b013e3181e5927a