title: Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal dysfunction in heart transplant recipients--the IMPROVED multi-centre study.
abstract: OBJECTIVE
  This comparative prospective multi-centre study evaluated efficacy and safety of cyclosporine A downtitration in heart transplant recipients with chronic renal dysfunction potentially attributable to cyclosporine (n=161).
  
  
  METHODS
  In the intervention arm (n=109, recruited from 9 centres), mycophenolate mofetil was introduced de novo or substituting azathioprine, followed by cyclosporine reduction (target trough levels 2-4 microg/ml and 50 ng/ml, respectively). In controls (n=52, recruited from 1 centre), immunosuppression remained unchanged. Renal function was recorded twelve, six, and three months before, and throughout the eight-month study period.
  
  
  RESULTS
  At study entry, cyclosporine trough levels and renal function parameters were comparable. At study end, mean+/-SD cyclosporine in the intervention arm was 57+/-24 vs. 116+/-36 ng/ml in controls. During the study, creatinine decreased by 23.3+/-50.7 micromol/l (P<0.0001) in the intervention arm but increased by 7.3+/-46.9 micromol/l (P=0.992) in controls (P=0.0001 for comparison between groups). A creatinine reduction of at least 20% was found in 35% of subjects of the intervention arm but only in 4% in the control arm (P<0.0001 for comparison between groups). Improvement in renal function was not weakened after adjustment for baseline characteristics in multiple regression analysis. Renal function improved in strata of creatinine entry values from 150 to 310 micromol/l, regardless of the presence of diabetes. Myocardial biopsies at target levels for cyclosporine and mycophenolate mofetil showed three reversible subclinical rejection episodes.
  
  
  CONCLUSIONS
  Cyclosporine downtitration improved renal dysfunction in diabetic and non-diabetic heart transplant recipients across a wide range of creatinine levels. The long-term benefit of this strategy deserves further study.
authors.affiliation: Kardiologie--Medizinische Poliklinik, Julius-Maximilians Universität Würzburg, Klinikstrasse 6-8, 97070 Wurzburg, Germany. angermann_c@klinik.uni-wuerzburg.de
authors.forename: Christiane E
authors.initials: CE
authors.lastname: Angermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Störk
authors.forename: Angelika
authors.initials: A
authors.lastname: Costard-Jäckle
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dengler
authors.forename: Uwe
authors.initials: U
authors.lastname: Siebert
authors.forename: Gero
authors.initials: G
authors.lastname: Tenderich
authors.forename: Axel
authors.initials: A
authors.lastname: Rahmel
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Schwarz
authors.forename: Herbert
authors.initials: H
authors.lastname: Nägele
authors.forename: Florian M
authors.initials: FM
authors.lastname: Wagner
authors.forename: Bernd
authors.initials: B
authors.lastname: Haaff
authors.forename: Klaus
authors.initials: K
authors.lastname: Pethig
mesh_terms: D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006331:Heart Diseases / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid