BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

Central and Northern Adelaide Renal and Transplantation Services Royal Adelaide Hospital Adelaide Australia

Department of Microbiology and Immunology University of Leuven Leuven Belgium

Department of Nephrology and Hypertension Inselspital Bern Bern Switzerland

Department of Nephrology and Renal Transplantation CHRU de Tours Hôpital Bretonneau Tours France

Department of Nephrology and Renal Transplantation Gasthuisberg University Hospital University of Leuven Leuven Belgium

Department of Nephrology and Renal Transplantation Hôpital Pasteur Nice France

Department of Nephrology Arterial Hypertension Dialysis and Transplantation University Hospital Centre Zagreb School of Medicine University of Zagreb Zagreb Croatia

Department of Nephrology Heidelberg University Hospital Heidelberg Germany

Department of Nephrology Hospital del Mar Barcelona Spain

Department of Nephrology Hospital Universitari de Bellvitge Barcelona Spain

Department of Nephrology Transplant Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Renal Medicine Royal Prince Alfred Hospital University of Sydney Sydney Australia

Department of Renal Transplantation Santa Casa de Misericórdia de Porto Alegre Porto Alegre Brazil

Department of Transplantation Surgery Severance Hospital Yonsei University Health System Seoul Republic of Korea

Division of Nephrology Hospital do Rim Universidade Federal de São Paulo São Paulo Brazil

Division of Transplant and Hepatobiliary Surgery Henry Ford Hospital Detroit MI

Mansoura Urology and Nephrology Center Mansoura Egypt

Policlinico Foundation A Gemelli University IRCCS Catholic University of the Sacred Heart Rome Italy

Research and Development Novartis Pharma AG Basel Switzerland

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