Clin Res Cardiol 96: Suppl 1 (2007)

P566 - Calcineurin-inhibitor associated nephrotoxicity after orthotopic heart transplantation associated with single nucleotide polymorphisms (SNP)
 
H. Milting1, B. Klauke1, A. Wirth1, G. Tenderich2, B. Bohms1, A. Zittermann2, R. Körfer2
 
1E.& H. Klessmann-Institut f. kardiovask. Forschung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 2Klinik für Thorax- und Kardiovaskularchirurgie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen;
 
Introduction: Survival of heart-transplanted (HTx) patients is limited by nephrotoxicity of calcineurin inhibitors (CNI). Genetic factors appear to be involved in renal dysfunction (RD) under immunosuppression. We genotyped heart-transplanted patients with and without RD, since knowledge of the risk to develop RD might improve clinical management. We analysed single nucleotide polymorphisms (SNP) in target genes, which might be involved in CNI-related nephrotoxicity.
Methods: SNP were screened in: Transforming-growth-factor-beta 1 (TGFb1; L10P, R25P), multi-drug-resistence 1 (MDR1; A893T/S), cytochrome P450 (CYP3A5*1/*3 allele) and exon 9 of calcineurin A (CnA). A case-control study was performed with 52 cardiac allograft recipients matched concerning age, gender and time after HTx (n=26 cases and controls, respectively). Controls had serum creatinine (SC) of less than 1.2 mg/dl, SC above 1.8 mg/d was defined as RD. SC values were determined earliest 1 year post HTx. Genotyping was done by dHPLC, RFLP and DNA sequencing.
Results: No significant relationship was found between the polymorphisms investigated and the prevalence of RD under CNI-immunosuppressive therapy. No sequence variation was found in exon 9 of CnA.
Discussion: The results do not confirm data previously published for polymorphisms in the TGF-ß1 gene in HTx-patients and the MDR1 gene in non-cardiac transplant patients. Although there are differences in the pharmacokinetics of CNI dependent on the CYP3A5 genotype no association to renal dysfunction was found in our cohort. Exon 9 of CnA is not polymorph. For RD-risk assessment genotyping of these SNP appears not to be justified for the immunosuppressive management of HTx-patients.
 

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