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


METHODS
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.
Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, and Klinik und Poliklinik für Urologie, Universitätsklinikum Münster, Münster, Germany.
Giuliano
G
Ciarimboli
Cynthia S
CS
Lancaster
Eberhard
E
Schlatter
Ryan M
RM
Franke
Jason A
JA
Sprowl
Hermann
H
Pavenstädt
Vivian
V
Massmann
Denise
D
Guckel
Ron H J
RH
Mathijssen
Wenjian
W
Yang
Ching-Hon
CH
Pui
Mary V
MV
Relling
Edwin
E
Herrmann
Alex
A
Sparreboom
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001692:Biological Transport; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D003404:Creatinine; D002945:Cisplatin