title: Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study.
abstract: OBJECTIVE
  The nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity.
  
  
  METHODS
  We analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury.
  
  
  RESULTS
  The rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan-Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033).
  
  
  CONCLUSIONS
  These findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikemura
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Enokiya
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Oda
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishinaga
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Muraki
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Katayama
authors.affiliation: Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. okudam@clin.medic.mie-u.ac.jp.
authors.forename: Masahiro
authors.identifier: http://orcid.org/0000-0002-5517-0918
authors.initials: M
authors.lastname: Okuda
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000150:complications / Q000188:drug therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000150:complications / Q000188:drug therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D007674:Kidney Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D054328:Proton Pump Inhibitors; D002945:Cisplatin; D005472:Fluorouracil
keywords: Cisplatin; Nephrotoxicity; Organic cation transporter 2; Proton pump inhibitor