#2920 MAGNESIUM DEFICIENCY ABROGATES THE RENOPROTECTIVE EFFECT OF DPP-4 INHIBITOR ON CISPLATIN-INDUCED KIDNEY INJURY

Abstract

Abstract Background and Aims Cisplatin is an effective chemotherapeutic agent, but often induces acute kidney injury (AKI). Magnesium (Mg) deficiency is often found in cancer patients, and the nephrotoxicity of cisplatin is exacerbated under Mg deficiency [1]. We previously reported the potential of Dipeptidyl peptidase-4 (DPP-4) inhibitor to attenuate cisplatin nephrotoxicity in rats and diabetic cancer patients [2, 3]. However, it remains to be investigated whether DPP-4 inhibitor can preserve its renoprotective effect under Mg deficiency. The purpose of this study was to examine whether DPP-4 inhibitor can prevent cisplatin-induced AKI even under Mg deficiency. Method Sprague Dawley rats received Mg-deficient diet for 7days to induce Mg deficiency. AKI was induced in rats by injecting cisplatin intravenously. Oral administration of a DPP-4 inhibitor, once a day, was started 1day before injecting cisplatin. Mg sulfate was once injected intraperitoneally just before injecting cisplatin to correct Mg deficiency (Fig. 1A). By using our previous cohort data [3], we divided diabetic cancer patients treated with high-dose cisplatin (>50 mg/m2)-containing regimens into 4 groups according to the use/unused of Mg sulfate or DPP-4 inhibitor. The change of estimated glomerular filtration rate (eGFR) within 2 weeks after cisplatin treatment was compared between the groups. Results At the peak of AKI (day 5), Mg sulfate supplementation significantly attenuated the increase of blood urea nitrogen (BUN), and combination of Mg sulfate and DPP-4 inhibitor further suppressed the increase of BUN as compared to rats received only cisplatin. However, DPP-4 inhibitor alone did not attenuate the increase of BUN under Mg deficiency (Fig. 1B). The result of serum creatinine (sCr) was consistent with that of BUN (Fig. 1C). This effect was associated with a reduced renal cell death as evaluated with the terminal uridine nick-end labeling (TUNEL)+ cells (Fig. 1D).The change of eGFR was significantly less in the patients treated with both of DPP-4 inhibitors/Mg supplementation, compared to those without DPP-4 inhibitors/Mg supplementation. The effect was not found in patients with either DPP-4 inhibitor alone or Mg supplementation alone as compared to those without DPP-4 inhibitor/Mg supplementation (Fig. 2). Conclusion Our results suggested that Mg deficiency must be corrected to exert the renoprotective effect of DPP-4 inhibitor on cisplatin nephrotoxicity. The molecular mechanisms underlying this phenomenon remain to be defined.