Corticosteroids have been the mainstay of immunosuppression for kidney transplantation for the last 50 years, with most transplant recipients still receiving steroids as part of their immunosuppressive regimen today. Despite their effectiveness in reducing incidence of acute rejection, corticosteroids are an important cause of morbidity and mortality.1
Some of the side effects of steroid use, such as osteopenia, weight gain, hypertension, hyperlipidemia, hyperglycemia, and, particularly, an increase in cardiovascular morbidity, make its reduction or elimination from immunosuppressive therapy an attractive goal.2−4
Several investigators have tried to come up with a protocol to minimize steroid exposure without jeopardizing graft and patient survival. Some protocols have prescribed no postoperative steroids (i.e., steroid avoidance), stopped steroids in the first week after transplantation, or tapered and discontinued them after several months (i.e., steroid withdrawal). Steroid minimization is used in this article as a broad term, encompassing both steroid avoidance and withdrawal.
Higher Acute Rejection Rates
Early studies of steroid avoidance or withdrawal in kidney transplant recipients showed inferior outcomes.5,6 In a placebo-controlled trial conducted in Canada around two decades ago, Sinclair et al enrolled 532 stable kidney transplant recipients with well–functioning grafts (serum creatinine below 220 μmol/L) at 90 days posttransplant.5
Patients were randomized to receive either placebo or prednisone. Prednisone was dosed based on weight and tapered down to 0.3 mg/kg; it was given on alternate days. All patients received cyclosporine, but the use of a third drug, azathioprine, was not part of the protocol and not reported.
The study showed significantly inferior five-year graft survival in the steroid-free group. Serum creatinine and creatinine clearance differed six months into the protocol and remained about 10% lower in steroid-free patients over the follow-up period, suggesting a persistent beneficial effect of steroid on renal function.
However, this study is open to criticism, as steroid withdrawal started relatively late (i.e., more than 90 days after transplantation) and increased immunological risk was not part of the exclusion criteria. Nevertheless, the results of this study and other similar studies initially dampened interest in steroid-free protocols.
After the introduction of newer and more potent agents such as tacrolimus and mycophenolate mofetil, some investigators suggested that using these therapies might diminish the effects of steroid on graft survival.
To answer this question, Woodle et al randomized 386 patients who were on antibody induction, tacrolimus, and mycophenolate mofetil to rapid discontinuation of steroid therapy (at seven days posttransplant) or long-term steroid treatment.7
The researchers found a significantly higher rate of acute rejection and a doubling of the incidence of allograft nephropathy but no effects on five-year graft and patient survival with rapid steroid discontinuation.
Interestingly, side effects were similar across the two groups, with the exception of small increases in triglyceride levels and weight in the steroid group. The incidence of new-onset diabetes after transplantation (NODAT) also was similar, but the incidence of insulin–requiring NODAT was slightly higher in the steroid-treated group.
Five-year graft survival in this study was significantly better than the overall three-year outcomes reported to the Organ Procurement and Transplantation Network during the same time period, which suggests inclusion of lower-risk patients. Moreover, the steroid dose used in the treatment group was relatively low and tapered down to 5 mg/day within six months of transplantation. This could explain the low incidence of steroid–related side effects.
Two recent meta-analyses assessed the effects of steroid withdrawal or avoidance after kidney transplantation.
The first meta-analysis, conducted by Knight and Morris, included 5,637 kidney recipients from 34 trials.8 The authors divided these patients into four subgroups based on the time of steroid withdrawal.
The first subgroup, the “avoidance” group, received no steroid for induction or maintenance. Patients who received steroid were divided into three subgroups: those who received steroid for seven days or less, those in whom steroid was withdrawn from eight days to 12 months after transplantation, and those with steroid withdrawal any time after 12 months posttransplant.
The incidence of acute rejection was increased in the group that had steroid withdrawal before 12 months, but graft and patient survival, as well as steroid–resistant acute rejection, were not different. Additionally, there was a marked reduction in cardiovascular risk factors, including incidence of hypertension, new-onset diabetes, and hypercholesterolemia, with steroid avoidance or withdrawal.
The second meta-analysis, by Pascual et al, examined nine randomized controlled trials of steroid withdrawal between three and six months posttransplant.9
The authors found higher incidence of acute rejection in patients on cyclosporine but not in patients on tacrolimus. Graft function and survival remained stable up to three years after transplantation, the longest follow-up reported.
The difference in rates of acute rejection between cyclosporine and tacrolimus that was observed in this study should be interpreted with caution, as only two of nine studies used tacrolimus for immunosuppressive treatment. Moreover, a large cyclosporine-based trial included high-risk patients and had to be terminated due to increased rejection in the steroid withdrawal arm.
The Next Generation
Using newer and more potent agents has allowed clinicians to lower steroid dose in the majority of low-risk kidney recipients, changing the side-effect profile in this group of patients. In one of the trials discussed earlier,7 kidney transplant recipients treated with low-dose steroid showed almost similar side effects to the steroid-free group at five years of follow-up.
Considering the higher risk of rejection and chronic allograft nephropathy reported with steroid withdrawal, some question whether this minimal difference in side effects is sufficient to justify the approach. Conversely, others believe that, with longer follow-up, even small doses of steroids can show significant detrimental effects.
Overall, complete steroid avoidance has been associated with inferior outcomes. As evident in the majority of studies discussed in this article, there has been a higher rate of acute rejection with steroid withdrawal even in low-risk kidney recipients.
Although this increase in rejection rate did not affect five-year graft and patient survival, long-term data beyond five years of follow-up are unavailable. Moreover, maintaining low-dose steroid therapy can give us the benefit of decreasing calcineurin inhibitor dose and reducing overall side effects.
The next generation of immunosuppressive medications with fewer side effects might help us safely withdraw steroids in the future. Larger studies with longer duration of follow-up are required before steroid withdrawal/avoidance can be used as standard practice in the treatment of kidney transplant recipients.
Opelz G, Döhler B, Laux G, for the Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplantation 2005;5:720–728.
Citterio F. Steroid side effects and their impact on transplantation outcome. Transplantation 2001;72[suppl 12]:S75-S80.
Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis
Hjelmesaeth J, Hartmann A, Kofstad J, Egeland T, Stenstrøm J, Fauchald P. Tapering off prednisolone and cyclosporin the first year after renal transplantation: the effect on glucose tolerance. Nephrol Dial Transplantation 2001;16:829–835.
Sinclair NR, for the Canadian Multicentre Transplant Study Group. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. CMAJ
Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol
Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P, for the Astellas Corticosteroid Withdrawal Study Group. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248:564–577.
Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis. Transplantation
Pascual J, Galeano C, Royuela A, Zamora J. A systematic review on steroid withdrawal between three and six months after kidney transplantation. Transplantation