Rapid Steroid Withdrawal after Renal Transplantation Reduces Mortality: Five Year Follow-Up of a Randomized Controlled Trial (Harmony Study) Confirms Long Term Efficacy and Safety

Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled one year “Harmony” trial, in which 587 predominantly deceased-donor kidney transplant recipients were randomized either to basiliximab or rabbit ATG induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. Methods: Following the end of the original one-year study period, patients were asked to participate in the observational follow-up (FU) study examining most of the end points of the original study. Hereby, de novo incidences between year one and three as well as year three and five were assessed at the three-/five-year visits, respectively. Findings: Biopsy-proven acute rejection and death-censored graft survival rates remained low and independent of RSWD. RSWD was an independent positive factor for patient survival (adjusted hazard ratio 0·554, 95% confidence interval 0·314 to 0·976; p=0·041). Survival rate was increased with 89·4 % or 90·4 % in RSWD patients (basiliximab or rabbit ATG) compared to 84·7 % in control patients (p = 0·064). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original one-year study period was not compensated by later incidences during FU. Also, incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during FU period. Unexpectedly, patient incidences of bacterial infections requiring hospitalization was reduced in the rabbit ATG group. Interpretation: The Harmony FU trial confirms excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy. This is the first randomized study demonstrating increased patient survival in RSWD patients. The results shown here support that RSWD should become the new gold standard approach in an immunologically low-risk, elderly, and severely diseased population of Caucasian kidney transplant recipients. Trial Registration: Follow-up study DRK5786; Original trial NCT 00724022). Funding: The FU trial was designed and run by the first and last author who received financial support from Astellas Pharma GmbH and Sanofi (Investigator Initiated Trial (NCT 00724022, follow up study DRK5786). Neither of the funders had any role in data collection, data analysis, data interpretation, or writing of the manuscript. An independent contract research organization (Coordination Center for Clinical Studies of the Technical University of Dresden, Dresden, Germany) was responsible for data collection, monitoring and statistical analyses. Declaration of Interest: CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. CK received consulting fees and lecture fees from Astellas, Chiesi, Novartis, Sanofi-Genzyme. JWM received grant support, consulting fees, and lecture fees from Vifor, GSK, Novartis, Astra-Zeneca and Boehringer Ingelheim. OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Kohler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. BB received grant support, consulting fees and lecture fees from Astellas, Bayer, Chiesi and Novartis. All other authors declare no competing interests. Ethical Approval: The study was approved by the institutional review boards of all sites participating in the follow-up period.