title: Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure.
abstract: BACKGROUND
  Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated.
  
  
  METHODS
  Since 2004, 63 HTx-patients (0.5-18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39+/-15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8-14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5-4 microg/mL).
  
  
  RESULTS
  Patients demographics and survival (mean follow-up time: 16.7+/-9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53+/-24 mg/dL [group 1] vs. 38+/-20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively.
  
  
  CONCLUSIONS
  Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.
authors.affiliation: Department of Cardiac Surgery, Ludwig-Maximilians-University Grosshadern, Munich, Germany. j.groetzner@clemenshospital.de
authors.forename: Jan
authors.initials: J
authors.lastname: Groetzner
authors.forename: Ingo
authors.initials: I
authors.lastname: Kaczmarek
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulz
authors.forename: Emilia
authors.initials: E
authors.lastname: Stegemann
authors.forename: Kristina
authors.initials: K
authors.lastname: Kaiser
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wittwer
authors.forename: Johannes
authors.initials: J
authors.lastname: Schirmer
authors.forename: Meinolf
authors.initials: M
authors.lastname: Voss
authors.forename: Justus
authors.initials: J
authors.lastname: Strauch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wahlers
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Sohn
authors.forename: Florian
authors.initials: F
authors.lastname: Wagner
authors.forename: Gero
authors.initials: G
authors.lastname: Tenderich
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Stempfle
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller-Ehmsen
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Michael
authors.initials: M
authors.lastname: Vogeser
authors.forename: Karrl Christian
authors.initials: KC
authors.lastname: Koch
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: Sabine
authors.initials: S
authors.lastname: Daebritz
authors.forename: Bruno
authors.initials: B
authors.lastname: Meiser
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
mesh_terms: D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000276:immunology*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018579:Patient Selection; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D020123:Sirolimus