Daily Caffeine Consumption May Increase the Risk of Acute Kidney Injury Related to Platinum-Salt Chemotherapy in Thoracic Cancer Patients: A Translational Study

Abstract

Although their efficacy has been well-established in Oncology, the use of platinum salts remains limited due to the occurrence of acute kidney injury (AKI). Caffeine has been suggested as a potential pathophysiological actor of platinum-salt-induced AKI, through its hemodynamic effects. This work aims to study the association between caffeine consumption and the risk of platinum-salt-induced AKI, based on both clinical and experimental data. The clinical study involved a single-center prospective cohort study including all consecutive thoracic cancer patients receiving a first-line platinum-salt (cisplatin or carboplatin) chemotherapy between January 2017 and December 2018. The association between daily caffeine consumption (assessed by a validated auto-questionnaire) and the risk of platinum-salt induced AKI or death was estimated by cause-specific Cox proportional hazards models adjusted for several known confounders. Cellular viability, relative renal NGAL expression and/or BUN levels were assessed in models of renal tubular cells and mice co-exposed to cisplatin and increasing doses of caffeine. Overall, 108 patients were included (mean age 61.7 years, 65% men, 80% tobacco users), among whom 34 (31.5%) experienced a platinum-salt-induced AKI (67% Grade 1) over a 6-month median follow-up. The group of high-caffeine consumption (≥386 mg/day) had a two-fold higher hazard of AKI (adjusted HR [95% CI], 2.19 [1.05; 4.57]), without any significant association with mortality. These results are consistent with experimental data confirming enhanced cisplatin-related nephrotoxicity in the presence of increasing doses of caffeine, in both in vitro and in vivo models. Overall, this study suggests a potentially deleterious effect of high doses of daily caffeine consumption on the risk of platinum-salt-related AKI, in both clinical and experimental settings.

Keywords: AKI; acute kidney injury; caffeine; carboplatin; chemotherapy; cisplatin; nephrotoxicity; thoracic cancer.

Figure 1

Repartition of the caffeine daily consumption within the study population.

Figure 2

Cumulative incidences of the competitive risks of AKI and death according to the level of daily caffeine consumption.

Figure 3

Caffeine affects cisplatin-induced toxicity in a dose-dependent manner. (A) Bar charts showing the effects of increasing doses of caffeine on the viability of RPTEC/hTERT cells exposed to cisplatin at a fixed concentration (12.5 μmol/L or 25 μmol/L). (B) Bar charts showing the dose-dependent effect of caffeine on NGAL mRNA level measured in RPTEC/hTERT cells exposed to cisplatin at a concentration of 12.5 μmol/L. n = 2–3 independent experiments. Data are shown as the mean +/− SEM. *: p < 0.05; **: p < 0.01; ***: p < 0.001. (C,D) Bar charts showing the (C) NGAL relative renal expression and (D) plasmatic level of BUN in mice that received a single dose of cisplatin (10 mg/kg) and exposed to increasing doses of caffeine for two weeks before cisplatin administration and one week after. n  =  6–16 mice per group. Data are shown as the mean +/− SEM. *: p < 0.05; **: p < 0.01; ***: p < 0.001 versus vehicle; #: p < 0.05; ### p < 0.001 versus cisplatin (10 mg/kg) without caffeine exposure. NGAL: neutrophil gelatinase-associated lipocalin; BUN: blood urea nitrogen.