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Clin Cancer Res. 2012 Feb 15;18(4):1101-8. doi: 10.1158/1078-0432.CCR-11-2503. Epub 2012 Jan 5.

Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients.

Author information

1
Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, and Klinik und Poliklinik für Urologie, Universitätsklinikum Münster, Münster, Germany.

Abstract

PURPOSE:

Knowledge of transporters responsible for the renal secretion of creatinine is key to a proper interpretation of serum creatinine and/or creatinine clearance as markers of renal function in cancer patients receiving chemotherapeutic agents.

EXPERIMENTAL DESIGN:

Creatinine transport was studied in transfected HEK293 cells in vitro and in wild-type mice and age-matched organic cation transporter 1 and 2-deficient [Oct1/2(-/-)] mice ex vivo and in vivo. Clinical pharmacogenetic and transport inhibition studies were done in two separate cohorts of cancer patients.

RESULTS:

Compared with wild-type mice, creatinine clearance was significantly impaired in Oct1/2(-/-) mice. Furthermore, creatinine inhibited organic cation transport in freshly isolated proximal tubules from wild-type mice and humans, but not in those from Oct1/2(-/-) mice. In a genetic association analysis (n = 590), several polymorphisms around the OCT2/SLC22A2 gene locus, including rs2504954 (P = 0.000873), were significantly associated with age-adjusted creatinine levels. Furthermore, in cancer patients (n = 68), the OCT2 substrate cisplatin caused an acute elevation of serum creatinine (P = 0.0083), consistent with inhibition of an elimination pathway.

CONCLUSIONS:

Collectively, this study shows that OCT2 plays a decisive role in the renal secretion of creatinine. This process can be inhibited by OCT2 substrates, which impair the usefulness of creatinine as a marker of renal function.

PMID:
22223530
PMCID:
PMC3288323
DOI:
10.1158/1078-0432.CCR-11-2503
[Indexed for MEDLINE]
Free PMC Article

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