Yoshitaka Saito

Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity

PurposeMagnesium supplementation is an effective protective method against cisplatin-induced nephrotoxicity (CIN); however, there are few reports regarding the mechanism of its nephroprotective effect. The aim of this study was to determine whether premedication with intravenous magnesium prevents CIN and to determine the relationship between its nephroprotective effect and serum magnesium level.MethodsFifty-eight patients with head and neck cancer who received cisplatin, docetaxel, and 5-fluorouracil (DCF) were retrospectively investigated. Grade 2 or more serum creatinine elevation was defined as CIN. The incidence of CIN was compared between a magnesium sulfate (20xa0mEq, 2.46xa0g) premedication group and a non-magnesium group during the first cycle and in all cycles.ResultsCIN did not occur in any patients receiving magnesium premedication but did occur in 5 of 29 patients during the first cycle and in 6 patients during all subsequent cycles in patients who did not receive magnesium premedication. Furthermore, the variation of creatinine clearance was significantly worse in the non-magnesium group than in the magnesium premedication group from baseline. There was no difference in adverse effects or response rate between the two groups. Univariate analysis suggested that magnesium premedication significantly reduced the risk of CIN. On the other hand, serum magnesium depletion was seen in both groups to equal degrees despite supplementation.ConclusionIntravenous magnesium premedication has a protective effect on cisplatin-induced nephrotoxicity without the influence on the serum magnesium level. Magnesium premedication is a simple nephroprotective method that does not influence other adverse effects or rate of response to chemotherapy.

Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters

Cisplatin (CDDP)-induced nephrotoxicity (CIN) is one of the most serious toxicities caused by this potent antitumor agent. It has been reported that Mg premedication attenuates CIN in clinical trials; however, the mechanism underlying its nephroprotection is not fully understood. Therefore, the aim of this study was to determine whether Mg administration affects CDDP accumulation by regulating the expression level of renal transporters. Rats were divided into control, Mg (40mg/kg) alone, 2.5mg/kg CDDP with (20 and 40mg/kg) and without Mg, 5mg/kg CDDP groups. These substances were administered on the same day and 7 days later their kidneys were removed. The expression levels of renal transporters and platinum (Pt) accumulation were analyzed. The serum creatinine level was significantly increased by CDDP administration and treatment with Mg significantly ameliorated such elevation. The expressions of the renal organic cation transporter 2 (rOct2) and renal multidrug and toxin extrusion protein 1 (rMate1) were downregulated and upregulated, respectively following co-administration with Mg, which significantly reduced the renal Pt accumulation in the 2.5mg/kg CDDP-treated group. Moreover, Mg dose-dependently downregulated rOct2, not affecting rMate expression, resulting in the attenuation of CIN. Mg co-administration protected the downregulation of the transient receptor potential subfamily Melastatin 6 (rTrpm6), but not the epidermal growth factor (rEgf), as a result, Mg co-injection attenuated CDDP-induced hypomagnesemia. In conclusion, Mg co-administration reduced Pt accumulation by regulating the expression of the renal transporters, rOct2 and rMate1 and, thereby, attenuated CIN.

Antiproteinuric effects of renin–angiotensin inhibitors in lung cancer patients receiving bevacizumab

PurposeThe objective of this study was to investigate the effect of renin–angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients.Materials and methodsWe retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment.ResultsA total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (Pu2009=u20090.037) but was not significantly lower than that in the non-user group (Pu2009=u20090.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12–0.86; Pu2009=u20090.024).ConclusionOur study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.

Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration

Purpose: Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)‐induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co‐administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose. Methods: Rats were divided into control, Mg alone, CDDP alone, and CDDP with Mg groups. Rats received CDDP (2.5 mg/kg), MgSO4 (40 mg/kg), or saline once per week for three weeks. Seven days after the third round of treatment, the kidneys were excised, and the expression of renal transporters and renal platinum accumulation were analyzed. Results: CDDP significantly elevated serum creatinine levels, which were significantly reduced by Mg co‐administration. Renal platinum accumulation was significantly lower in the CDDP‐Mg group than in the CDDP group. Expression of renal organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1), which are involved in CDDP transport, did not differ between the groups. However, the expression of copper transporter 1 (rCtr1) was significantly downregulated after Mg co‐administration. Conclusion: Mg co‐administration significantly attenuated CIN by reducing renal platinum accumulation even after multiple rounds of treatment with CDDP as effectively as in a model of a single CDDP administration. However, the specific underlying mechanism was different between single and multiple administrations, further studies will be needed to identify what contributes to this difference and to elucidate how Mg regulates the expression of renal transporters.