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NDT Advance Access published online on September 7, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp456
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs

Manuel Haschke1,*, Tanja Vitins1,*, Saskia Lüde1, Liliane Todesco1, Katerina Novakova1, Richard Herrmann2 and Stephan Krähenbühl1

1 Division of Clinical Pharmacology & Toxicology and Department of Biomedicine 2 Division of Oncology, University Hospital, Switzerland

Correspondence and offprint requests to: Stephan Krähenbühl; E-mail: kraehenbuehl{at}uhbs.ch



  Abstract

Background. Patients treated with cisplatin or carboplatin show increased renal excretion of carnitine. It is currently unclear whether this is also the case for oxaliplatin and which are the responsible mechanisms.

Methods. We investigated 22 patients treated either with a single dose of cisplatin, carboplatin or oxaliplatin. Carnitine and kidney function parameters were determined in plasma and urine. Inhibition and mRNA expression of OCTN2, the principle carnitine transporter, were assessed in L6 cells overexpressing OCTN2 and in 293-EBNA cells, respectively.

Results. Renal excretion of free and short-chain acylcarnitine increased already at the day of administration was maximal the day after and had normalized 1 week after administration of cisplatin, carboplatin or oxaliplatin. The renal excretion fractions for free carnitine and acylcarnitines increased 4–10 times during treatment with platin derivatives. Renal excretions of {alpha}1-microglobulin and other proximal tubular markers were also increased, compatible with a proximal tubular defect. Direct inhibition of OCTN2 expressed in L6 cells by cisplatin, oxaliplatin or platinum2+ could not be demonstrated, and experiments using urine from patients treated with cisplatin inhibited OCTN2 activity no more than expected from the carnitine content in the respective urine sample. Cisplatin was associated with a time- and concentration-dependent decrease of OCTN2 mRNA and protein expression in 293-EBNA cells.

Conclusions. All platin derivatives investigated are associated with renal tubular damage in humans without significantly affecting glomerular function. The rapid onset and complete reversibility of this effect favour a functional mechanism such as impaired expression of OCTN2 in proximal tubular cells.

Keywords: carboplatin; carnitine; cisplatin; OCTN2; oxaliplatin

*These authors contributed equally to this work.

Received for publication: 18. 6.09
Accepted in revised form: 12. 8.09


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