title: Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study.
abstract: BACKGROUND
  Reducing side effects of immunosuppressive regimens has become a priority in transplantation medicine because of the large number of patients and grafts that succumb to infection in the short term and cardiovascular disease in the long term. The Symphony study was a 12-month prospective, randomized, open-label, multi-centre, four parallel arm study that aimed to evaluate the safety and efficacy of low-dose immunosuppressive regimens compared with a standard-dose regimen in renal transplant recipients. This sub-analysis focuses on specific toxicities observed with the low-dose regimens.
  
  
  METHODS
  Adult patients (n = 1645) scheduled to undergo renal transplantation received low-dose cyclosporine (CsA), tacrolimus (Tac) or sirolimus (SRL) in addition to daclizumab induction or standard-dose cyclosporine without induction. All patients received mycophenolate mofetil and corticosteroids. We evaluated the incidence of adverse events (AEs), tested specific group differences and assessed the relationship of selected AEs with drug levels.
  
  
  RESULTS
  The four arms had similar incidences of AEs, but serious AEs were more common with low-dose SRL and led to more discontinuations. Infections were the most common AEs, with the highest incidence in the standard-dose CsA group, in particular, cytomegalovirus (CMV) infections. Low-dose Tac had the most reports of new-onset diabetes, leucopenia and diarrhoea. Low-dose SRL negatively influenced triglycerides, wound healing, lymphocele and anaemia. We found only weak relationships between specific AEs and drug levels.
  
  
  CONCLUSIONS
  Despite the low doses, CsA, Tac and SRL retained distinct and different toxicity profiles. These findings may be of relevance for tailoring specific immunosuppressive regimens to patients with particular needs.
authors.affiliation: Department of Nephrology and Transplantation, Lund University, University Hospital, Malmö, Sweden. henrik.ekberg@med.lu.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Corrado
authors.initials: C
authors.lastname: Bernasconi
authors.forename: Jana
authors.initials: J
authors.lastname: Nöldeke
authors.forename: Alexander
authors.initials: A
authors.lastname: Yussim
authors.forename: Lars
authors.initials: L
authors.lastname: Mjörnstedt
authors.forename: Uģur
authors.initials: U
authors.lastname: Erken
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Pavel
authors.initials: P
authors.lastname: Navrátil
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D000077561:Daclizumab; D051799:Delayed Graft Function / Q000209:etiology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007239:Infections / Q000209:etiology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects*; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000077561:Daclizumab; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus