Low- to moderate-risk kidney transplant patients treated with corticosteroids as part of immunosuppressive protocols show no significant reductions in the risk of allograft failure or patient death compared with those not receiving corticosteroids, in a 15-year follow-up of a randomized trial.
“Long-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low to moderate immune risk kidney transplant recipients,” the authors conclude in research published online February 3 in JAMA Surgery.
In an accompanying editorial, Arthur J. Matas, MD, agrees that the findings add to important evidence of acceptable outcomes when low-risk transplant patients withdraw from corticosteroids.
“The study provides convincing long-term data showing that recipients of transplants are not penalized by early steroid cessation,” writes Matas, of the Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis.
“Going forward, in contrast with justifying early steroid cessation, transplant centers using steroids should justify why they are using steroids for their recipients or recipient subpopulations, given that there is no evidence of improved outcomes and steroids have adverse effects,” he asserts.
Most Rigorous Randomized Trial of Steroid Withdrawal in Kidney Transplant
The results come from a long-term follow-up of a 2008 study that is described as the most rigorous randomized trial of corticosteroid withdrawal in kidney transplant patients to date.
In the prospective, placebo-controlled, double-blind trial, first author E. Steve Woodle, MD, of the University of Cincinnati, Ohio, and colleagues enrolled 386 low to moderate immune risk adult kidney transplant recipients who received deceased or living donor transplants at 28 kidney transplant centers in the United States.
Patients were randomized to withdrawal from corticosteroids 7 days after transplant (n = 191) or to continue maintenance with corticosteroids (n = 195) at a dose of 5 mg/day.
The original trial results, with a follow-up of 5 years, showed no differences between groups in the composite primary endpoint of death, allograft loss censored for patient death, or moderate to severe short-term rejection.
However, the original study did show a higher rate of biopsy-confirmed rejection among patients withdrawn from corticosteroids (34 of 191 patients; 17.8%) compared with patients who continued them (21 of 195 patients; 10.8%).
Although kidney function was similar between groups, patients withdrawn from corticosteroids had lower rates of some of the effects associated with steroid use, including weight gain, serum triglyceride levels, and insulin-requiring diabetes.
However, there were no differences in blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol levels, or new-onset diabetes between groups.
New Findings From Longer-Term Follow-Up
With ongoing concerns about longer-term outcomes, Woodle and colleagues revisited the trial using data available through the mandatory Organ Procurement and Transplant Network (OPTN) registry.
With a median follow-up of 15.8 years post-transplant, after adjustment, no significant differences were observed between those treated with steroids and no steroids in terms of allograft failure from any cause including death (hazard ratio [HR], 0.83; P = .19) and allograft failure censored for patient death (HR, 0.78; P = .25).
Furthermore, the results were consistent with those of a per-protocol analysis of 223 contemporary-matched patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years following transplant.
“The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs,” the authors note.
“Long-term corticosteroids may not be necessary as part of a…multiple drug immunosuppressive regimen in low to moderate immune risk kidney transplant recipients,” they conclude.
Corticosteroid Withdrawal Rates Still Low; Short-Term Rejection a Concern
In addition to Woodle’s research, several single-center studies have also reported acceptable outcomes with corticosteroid withdrawal after follow-up ranging from 10 to 15 years, and studies have further suggested a patient preference for withdrawal of this drug class.
Yet despite the evidence, recent reports suggest only about 30% of kidney transplant patients with characteristics similar to those in the studies have their corticosteroids discontinued.
“This is particularly concerning because the characteristics of trial participants are similar to those among the majority (approximately 65%) of kidney transplant recipients in the United States today,” say Woodle and coauthors.
Among likely reasons for hesitancy around early steroid withdrawal are the higher rates of early short-term rejection that have been seen, which can be a concern as short-term rejection is linked to increased risk of graft loss.
However, Woodle and colleagues point out that in their original trial, the 7% higher incidence of short-term rejection in the steroid withdrawal group involved histologically low-grade rejection events, and there were no increases in moderate or severe short-term rejection events.
Further analyses also showed an increased risk of long-term histological changes associated with corticosteroid withdrawal, but evolving evidence suggests such events may be treated with short courses of high-dose steroids.
Notably, the current study was limited to relatively low risk patients. However, as noted by Matas in his editorial, single-center and other studies have shown favorable outcomes with steroid withdrawal in higher-risk groups, including pediatric patients, African Americans, highly sensitized patients, those with potentially recurring disease, and patients with retransplants.
“The authors question why early steroid cessation is not used more widely,” he writes. “I agree.”
Woodle has reported receiving grants from Astellas Pharma and grants and personal fees from Sanofi during the conduct of the study. Disclosures for the other authors are listed in the article. Matas has reported no relevant financial relationships.