Copyright © 2004 by the European Society of Cardiology.
Clinical research
Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal dysfunction in heart transplant recipients — The IMPROVED multi-centre study
a Kardiologie — Medizinische Poliklinik, Julius-Maximilians Universität Würzburg, Klinikstrasse 6—8, 97070 Wurzburg, Germany
b Herz- und Gefäßchirurgie, Christian-Albrechts Universität Kiel, Germany
c Kardiologie der Universität Heidelberg, Germany
d MGH Institute for Technology Assessment, Harvard Medical School, Boston, MA, USA
e Herz-Thorax Chirurgie, Ruhr-Universität Bochum-Bad Oeynhausen, Germany
f Herzzentrum der Universität Leipzig, Germany
g Medizinische Klinik I, Rheinisch-Westfälische Technische Hochschule Aachen, Germany
h Division of Cardiology, The University of Texas Medical Branch Galveston, Texas, USA
i Herzchirurgie am Universitätsklinikum Hamburg-Eppendorf, Germany
j Herz-Kreislaufzentrum der Universität Dresden, Germany
k Westpfalz-Klinikum Kaiserslautern, Germany
l Klinik für Thorax-, Herz-, Gefäßchirurgie, Medizinische Hochschule Hannover, Germany
Received December 11, 2003; revised June 3, 2004; accepted June 17, 2004 * Corresponding author. Tel.: +49-931-20170450; fax: +49-931-20171240 (E-mail: angermann_c{at}klinik.uni-wuerzburg.de).
AIMS: 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 μg/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 μmol/l (P<0.0001) in the intervention arm but increased by 7.3±46.9 μmol/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 μmol/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.
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