Novel cisplatin kidney injury biomarkers and transporter interactions
Creators: name: George, Blessy
Publisher: name: No Publisher Supplied
Year: 2018

description: Despite the recent development of new immunotherapies and anticancer drugs, cisplatin remains an important component of chemotherapeutic regimens for the treatment of solid tumors. However, use of cisplatin is limited by nephrotoxicity, which occurs in about one-third of patients and leads to small but permanent changes in kidney function over the long-term. Current clinical markers, such as serum creatinine and estimated glomerular filtration rate, are limited in their ability to detect acute kidney injury (AKI). Additionally, a recent study reported a potential interaction in vivo between concurrently administered antiemetic drug, ondansetron, and cisplatin that may exacerbate cisplatin-induced nephrotoxicity. One mechanism of cisplatin kidney injury is the ability of renal transporters to mediate its urinary secretion. Presently, the degree of interaction between antiemetic drugs and cisplatin renal transporters is unknown. The purposes of this dissertation research were to assess time-dependent changes in urinary protein biomarkers in cisplatin treated oncology patients with subclinical nephrotoxicity, characterize the renal expression and regulation of the novel urinary biomarker calbindin in cisplatin-mediated acute kidney injury, and determine the extent of antiemetic drug inhibition of renal transporters involved in cisplatin secretion. In 57 patients with solid tumors receiving outpatient cisplatin therapy (≥25 mg/m2), mean serum creatinine was unchanged following cisplatin infusion. Compared to baseline values, several novel biomarkers were significantly increased in the urine. B2M was increased 3-fold by day 3, while KIM-1, TFF3, and calbindin were elevated 2-fold, 2-fold, and 8-fold by day 10, respectively. In a subset of 27 patients, time-dependent changes in KIM-1, calbindin, and TFF3 were assessed during early and subsequent cycles of cisplatin-containing chemotherapy. Although significant increases were seen during the early cycle, baseline biomarker levels remained elevated for KIM-1 and TFF3 and for all three biomarkers (KIM-1, TFF3, and calbindin), time-dependent changes were modest during subsequent cycles. Subsequent mechanistic studies were performed to better understand the intrarenal regulation of one biomarker, calbindin, during cisplatin AKI in mice as well as identify potential cisplatin-drug interactions due to alterations in cisplatin transporter activity in vitro. In mice treated with cisplatin, calbindin protein was robustly elevated in urine prior to elevations in serum creatinine and blood urea nitrogen. A time-dependent decrease in renal calbindin protein was observed on day 4 with concurrent up-regulation of calbindin mRNA. Finally, in vitro models revealed that 5-HT3 antagonists used to treat cisplatin-induced emesis dose-dependently inhibited the activity of OCT2 and MATE1, two transporters responsible for cisplatin secretion. Importantly, the most potent inhibitor was ondansetron, which inhibited transport of a probe substrate ASP+ in MATE1 overexpressing HEK293 cells at concentrations that are pharmacologically relevant (IC50: 0.1 μM) and also caused accumulation and inhibition of ASP+ transport in polarized MDCK tubule cells that overexpress OCT2 and MATE1. These data suggest that potent inhibition of MATE1-mediated efflux of cisplatin from human proximal tubules by antiemetic drugs may increase intratubular concentrations of cisplatin. This research demonstrates that novel urinary protein biomarkers are responsive to cisplatin therapy in the absence of clinically detectable AKI during early cycles, but are not reflective of progressive kidney damage during subsequent cycles of cisplatin therapy. Additionally, this research provides new mechanistic understanding of urinary calbindin release as well as the potential for antiemetic drug inhibition of renal cisplatin transporters.