Steroid Avoidance: Is It Ready for Prime Time?

Le résumé fourni par la source

One mark of success in organ transplantation is the attempt to reduce maintenance immunosuppression. This change in direction from maximizing therapy to exploring alternatives of minimizing drug treatment to prevent rejection is predicated on the success of current regimens to reduce rejection. This accomplishment allows investigators to focus on alternative immunosuppression to lessen undesirable side effects, some of which may be life threatening. Prime examples are the corticosteroid withdrawal trials in conventional renal transplantation. The drive behind these studies is the reduction of debilitating side effects of corticosteroids including cataract formation, osteoporosis or osteonecrosis, cosmetic changes and importantly the cardiovascular risks of hypertension, dyslipidemia, and diabetes mellitus. Some efforts of steroid withdrawal were fraught with an increased risk of rejection and graft loss (1). However, use of currently available induction drugs and maintenance therapy in addition to withdrawing corticosteroids in the first 2 weeks posttransplant has produced results with graft survival equal to those recipients using chronic corticosteroids. In this issue, Galliford et al. (2) described their experience with a rapid steroid withdrawal protocol in ABO incompatible kidney transplantation, a group at high risk for antibody-mediated rejection and early graft loss. In the past, ABO incompatibility was a contraindication to kidney transplantation. Through trial and error, investigators developed regimens to successfully remove blood group antibody and lower the risk of antibody rebound posttransplantation, permitting kidney transplantation. These regimens required significant immunosuppression, relying on combinations of plasmapheresis, double-filtration plasmapheresis, antigen-specific immunoadsorption, splenectomy, intravenous immunoglobulin, or rituxamab (anti-CD20a monoclonal antibody) in addition to various induction agents and triple maintenance immunosuppression to generate results equal to ABO compatible kidney transplantation. As noted by the authors, “ABO incompatible renal transplantation is now an accepted therapy for end-stage renal failure.” Thus, it is not surprising that this group pursued minimization of immunosuppression to reduce the detrimental side effects of corticosteroids that conventional kidney transplant candidates similarly face. In the study of Galliford et al. (2), blood group antibodies were removed by pheresis with intravenous immunoglobulin replacement pre- and posttransplant. Rituxamab and daclizumab were administered along with maintenance therapy using tacrolimus and mycophenolate mofetil. A 7-day steroid taper was given. Ten patients received living donor kidney transplantation with 100% patient and graft survival at a median follow-up of 21.6 months. Graft function was excellent early and at 12 months as measured by creatinine and estimated clearance. Three patients experienced biopsy-proven antibody-mediated rejection successfully responding to treatment. All three patients required chronic corticosteroid treatment. Of these three patients, two developed diabetes mellitus associated with significant weight gain. Hypertension and dyslipidemia were not reported. This is a pilot study designed to look at the safety of corticosteroid withdrawal in this high-risk group and does not address the question if there is a metabolic benefit to this change. The favorable short-term graft and patient survival call for larger randomized studies to confirm this data. These future trials should carefully document changes in weight, bone disease, blood pressure, dyslipidemia, and diabetes mellitus during long-term follow-up of the steroid maintenance and steroid withdrawal groups. Hopefully, a clearer picture of the benefits of steroid withdrawal will form. A review of the ABO compatible kidney transplant literature examining steroid avoidance or withdrawal is inconclusive with respect to metabolic advantages. A decrease in the incidence of weight gain, bone disease, hypertension, dyslipidemia, and diabetes mellitus was not apparent in all studies. One report describes a reversal of diabetes mellitus with steroid withdrawal only to see the majority of these patients develop diabetes later without steroids on board. Although total cholesterol drops after steroid withdrawal, in one study it is accompanied by a fall in high density lipoprotein which may not produce the desired cardiovascular benefit. One large randomized study still underway reported no differences at 1 year in weight, blood pressure, dyslipidemia, or diabetes between the corticosteroid versus steroid withdrawal arms. It is not certain that steroids need to be completely withdrawn to attain these benefits. Some investigators report no gain in weight, blood pressure, or diabetic control when reducing corticosteroids below 5 to 10 mg/day. Although most recent reports note equal graft survival despite an increased risk of biopsy proven rejection, the follow-up is often short and it may be premature to draw firm conclusions. Preliminary results of a randomized, double-blinded trial show that the steroid withdrawal arm enjoys cardiovascular risk or metabolic benefits but has a statistically higher rate of chronic allograft nephropathy at 5 years compared with the steroid control group (3). Is complete withdrawal of corticosteroids necessary to achieve metabolic gains? Is there a protective effect of corticosteroids in reducing chronic allograft nephropathy or calcineurin inhibitor toxicity? The answers to these questions are unknown, yet the clinical use of steroid avoidance or withdrawal by the transplant community has markedly increased in the past 10 years as depicted in Figure 1 (4). Certainly patients desire this change, but are steroid avoidance or withdrawal immunosuppression regimens really ready for prime time?FIGURE 1.: Steroid use at discharge in kidney recipients.

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