Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs.
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 alpha1-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 platinum(2+) 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.
Haschke
Manuel
M
Division of Clinical Pharmacology & Toxicology and Department of Biomedicine, University Hospital, Switzerland.
Vitins
Tanja
T
Lüde
Saskia
S
Todesco
Liliane
L
Novakova
Katerina
K
Herrmann
Richard
R
Krähenbühl
Stephan
S
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000652:urine*; D016190:Carboplatin / Q000627:therapeutic use*; D002331:Carnitine / Q000652:urine*; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D000074058:Solute Carrier Family 22 Member 5
D000970:Antineoplastic Agents; D015415:Biomarkers; D027701:Organic Cation Transport Proteins; D009944:Organoplatinum Compounds; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin; D002331:Carnitine