Plasma ghrelin levels as a predictor of adverse renal events due to cisplatin-based chemotherapy in patients with esophageal cancer

Abstract

Objective: Although combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil demonstrates high response rates in esophageal squamous cell carcinoma, patients treated with docetaxel, cisplatin and 5-fluorouracil frequently experience acute kidney injury. Ghrelin has shown renal protective effects in an experimental acute kidney injury model by reducing tubular apoptosis. In this prospective observational study, we evaluated the association between plasma ghrelin concentrations and docetaxel, cisplatin and 5-fluorouracil-related acute kidney injury. Methods: Forty consecutive patients with esophageal squamous cell carcinoma who received docetaxel, cisplatin and 5-fluorouracil from October 2013 to July 2014 were enrolled in this study. Serum creatinine and urinary α-1 microglobulin, a marker of renal tubular damage, were measured six times during chemotherapy. Results: The increases of creatinine level which is defined in Common Terminology Criteria for Adverse Event were observed less frequently in patients with acyl ghrelin concentrations of ≥9.6 fmol/ml (HAG group) than in those with concentrations <9.6 fmol/ml on Day 2 (LAG group) (P = 0.024). Serum creatinine was significantly lower in the HAG group than in the LAG group (Day 8: 0.79 ± 0.16 vs. 0.97 ± 0.26, P = 0.024; Day 11: 0.85 ± 0.19 vs. 1.08 ± 0.34 mg/dl, P = 0.049). Urinary α-1 microglobulin levels were significantly lower in the HAG group than in the LAG group (Day 4: 2.48 ± 1.83 vs. 3.33 ± 1.41, P = 0.011; Day 8: 4.67 ± 5.50 vs. 5.09 ± 2.54, P = 0.011; Day 11: 11.55 ± 13.78 vs. 16.43 ± 17.84 mg/l, P = 0.020). Conclusions: Plasma acyl ghrelin concentrations on Day 2 of chemotherapy may be a potential predictor of docetaxel, cisplatin and 5-fluorouracil-induced acute kidney injury.

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

“…In this study, DOX significantly decreased the circulating plasma levels of AG, increased those of DAG and reduced the overall ratio of AG/DAG. A similar picture was also seen in patients with renal failure or cancer patients after chemotherapy with cisplatin 37,40,42 . Some authors have attributed such an increase in DAG to the concurrent decrease in its clearance due to the associated renal damage 40 .…”

“…Of note, levels of AG and DAG are significantly increased during AKI and renal failure 28,40 . However, serum AG levels are significantly decreased in patients (by 60%) after cisplatin and DOX‐based chemotherapy and were strongly correlated with the degree of renal dysfunction 37,41,42 . However, in a randomized phase II trial of cisplatin‐treated cancer patients, continuous administration of AG attenuated renal dysfunction, thus suggesting that AG is an interesting option to prevent chemotherapy‐induced renal damage 37 …”

Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial

“…These results suggest the molecular mechanisms underlying the renal protective effect of ghrelin against cisplatin-induced nephrotoxicity. In fact, our previous study showed that blood ghrelin concentrations are decreased to ∼60% of pre-chemotherapy levels early in the course of cisplatin-based chemotherapy, and that lower plasma acyl ghrelin levels are associated with renal dysfunction during cisplatin-based chemotherapy ( Yamamoto et al , 2013 ; Yanagimoto et al , 2016 ). Thus, we conducted this prospective interventional trial of ghrelin to test the hypothesis that it decreases the renal dysfunction induced by cisplatin nephrotoxicity.…”

“…On the basis of our previous study, we estimated that the mean serum creatinine in the placebo group would be 1.1±0.3 mg dl −1 ( Yanagimoto et al , 2016 ). The sample size calculation was based on a 20% improvement by ghrelin administration, power of 80% and alpha of 10%.…”

“…Our previous study showed that serum ghrelin concentrations decrease to ∼60% during cisplatin-based chemotherapy as compared with pre-chemotherapy levels ( Yamamoto et al , 2013 ; Yanagimoto et al , 2016 ). In addition, plasma acyl ghrelin is a predictor of renal dysfunction associated with cisplatin-based chemotherapy, and decreased levels of plasma ghrelin are correlated with renal dysfunction during chemotherapy ( Yanagimoto et al , 2016 ). These results suggest that ghrelin may act as a protective factor for the kidney via promoting the release of IGF-1 during cisplatin-based chemotherapy.…”