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

G Ciarimboli; CS Lancaster; E Schlatter; RM Franke; JA Sprowl; H Pavenstadt; V Massmann; D Guckel; RHJ Mathijssen; WJ Yang; CH Pui; MV Relling; E Herrmann; A Sparreboom

doi:10.1158/1078-0432.CCR-11-2503

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

G Ciarimboli, CS Lancaster, E Schlatter, RM Franke, JA Sprowl, H Pavenstadt, V Massmann, D Guckel, RHJ Mathijssen, WJ Yang, CH Pui, MV Relling, E Herrmann, A Sparreboom^*

^*Corresponding author for this work

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

135 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1101-1108
Number of pages	8
Journal	Clinical Cancer Research
Volume	18
Issue number	4
DOIs	https://doi.org/10.1158/1078-0432.CCR-11-2503
Publication status	Published - 15 Feb 2012

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10.1158/1078-0432.CCR-11-2503

http://hdl.handle.net/1765/70232

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Ciarimboli, G., Lancaster, CS., Schlatter, E., Franke, RM., Sprowl, JA., Pavenstadt, H., Massmann, V., Guckel, D., Mathijssen, RHJ., Yang, WJ., Pui, CH., Relling, MV., Herrmann, E., & Sparreboom, A. (2012). Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clinical Cancer Research, 18(4), 1101-1108. https://doi.org/10.1158/1078-0432.CCR-11-2503

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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.",

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Ciarimboli, G, Lancaster, CS, Schlatter, E, Franke, RM, Sprowl, JA, Pavenstadt, H, Massmann, V, Guckel, D, Mathijssen, RHJ, Yang, WJ, Pui, CH, Relling, MV, Herrmann, E & Sparreboom, A 2012, 'Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients', Clinical Cancer Research, vol. 18, no. 4, pp. 1101-1108. https://doi.org/10.1158/1078-0432.CCR-11-2503

TY - JOUR

T1 - Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients

AU - Ciarimboli, G

AU - Lancaster, CS

AU - Schlatter, E

AU - Franke, RM

AU - Sprowl, JA

AU - Pavenstadt, H

AU - Massmann, V

AU - Guckel, D

AU - Mathijssen, RHJ

AU - Yang, WJ

AU - Pui, CH

AU - Relling, MV

AU - Herrmann, E

AU - Sparreboom, A

PY - 2012/2/15

Y1 - 2012/2/15

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-11-2503

DO - 10.1158/1078-0432.CCR-11-2503

M3 - Article

C2 - 22223530

SN - 1078-0432

VL - 18

SP - 1101

EP - 1108

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 4

ER -

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

Abstract

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