Several studies have shown that intravenous Mg supplementation has preventive effects against CDDP-induced nephrotoxicity [13, 15–19, 24]. The dosage of Mg supplementation has varied widely in previous studies, ranging from 8 to 40 mEq [12, 13, 15–19, 24]. The NCCN has developed chemotherapy order templates for CDDP-based regimens, which consist of mannitol and 8 mEq Mg supplementation for the prevention of renal toxicity in cancer care, and this strategy has been adopted worldwide. Although some reports indicate the benefit of Mg supplementation at higher doses such as 20 mEq [18, 19] and 40 mEq [12], the optimal Mg supplementation dose for the prevention of CDDP-induced nephrotoxicity remains unknown because of a lack of comparative studies.
In the present study, we evaluated whether 20 mEq of Mg supplementation was more effective than 8 mEq in preventing CDDP-induced nephrotoxicity. To our knowledge, this is the first report comparing the dose of Mg supplementation for the prevention of CDDP-induced nephrotoxicity. There was no significant difference in the incidence of CDDP-induced nephrotoxicity between the 8 mEq and 20 mEq groups. There was also no significant difference in the severity of nephrotoxicity, elevated SCr levels, and decreased estimated Clcr levels between the two groups. Cardiac disease and albumin level, but not Mg dosage, were identified as independent risk factors for CDDP-induced nephrotoxicity.
The serum Mg store is estimated to account for only 0.3% of the total Mg in the entire body [25]; therefore, it is unclear whether serum Mg levels reflect total body Mg conditions, including the condition of the kidney. Saito et al. [24] reported that the renal protective effect of Mg supplementation could be observed as of the first course of chemotherapy, and the degree of serum Mg depletion remained constant in all subsequent cycles. These findings largely ruled out the mechanism underlying the protective effect of Mg against CDDP-induced nephrotoxicity involving the prevention of serum Mg depletion.
To assess the risk factors for CDDP-induced nephrotoxicity, we performed multivariate analyses. We found that cardiac disease and an albumin level ≤ 3.9 g/dL were associated with an increased risk for CDDP-induced nephrotoxicity. In general, CDDP-induced nephrotoxicity has been associated with reduced levels of plasma proteins that bind to CDDP. Approximately 98% of CDDP binds to plasma proteins such as albumin [26], and nephrotoxicity is associated with peak plasma CDDP levels and/or the area under the plasma CDDP concentration-time curve for unbound CDDP [27, 28]. It is well known that hypoalbuminemia can lead to elevated free platinum concentrations and enhanced nephrotoxicity. Several studies have also indicated an association between CDDP-induced nephrotoxicity and comorbidities such as cardiac disease [22, 23]. In patients with cardiac disease, a reduction in renal perfusion caused by decreased cardiac output may affect the clearance of drugs eliminated by renal excretion. For example, renal clearance of vancomycin is reduced in patients with heart disorders [29]. Thus, decreased renal perfusion associated with cardiac disease can influence the clearance of CDDP. In addition, regular use of non-steroidal anti-inflammatory drugs (NSAIDs), male sex, and poor PS have been reported as risk factors for CDDP-induced nephrotoxicity [15, 18]; however, these factors were not identified to increase the risk of CDDP-induced nephrotoxicity in this study. This is possibly due to the fact that nearly 80% of the patients in our cohort were male, with a majority PS score of 0 or 1. Male sex and poor PS were also not identified as independent risk factors in our previous study [20]. Regular use of NSAIDs could not be considered in this study because of the small number of included patients using NSAIDs. In the previous reports [13, 15–19, 24], forced diuresis was used to prevent CDDP-induced nephrotoxicity, as in this study, while hydration was supplied either through conventional methods or short hydration. The interrelationship between forced diuresis and type of hydration in the prevention of CDDP-induced nephrotoxicity is unknown. The optimal dosage of Mg supplementation under short hydration conditions is a subject for further investigation.
Under conditions of forced diuresis and conventional high-volume hydration, 20 mEq Mg supplementation had no greater preventive effect on CDDP-induced nephrotoxicity than 8 mEq. In Japan, magnesium sulfate products at 20 mEq are conventionally used as electrolyte supplements. Since magnesium sulfate preparations are not expensive, if the cost is acceptable, the use of 20 mEq as a packaging unit might be useful in terms of risk management against preparation errors.
This study has some limitations. First, this was a retrospective observational study and not a randomized or prospective study. Second, individual quantifiable data of heart disease (e.g., cardiac output and ejection fraction) were not available; therefore, we defined heart disorders based only on the medical history of cardiac diseases such as angina or myocardial infarction. Third, we were unable to examine other potential risk factors such as the regular use of NSAIDs. Fourth, the safety profile could not be determined in this pooled analysis because adverse event data were not available in the medical records for this analysis. Fifth, the sample size was relatively small. Finally, the inclusion of only cases with both forced diuresis and conventional high-volume hydration, as a method for preventing nephrotoxicity other than Mg supplementation, limits the generalizability of the study results.
In conclusion, we did not find an advantage of 20 mEq Mg supplementation over 8 mEq in terms of a preventive effect against CDDP-induced nephrotoxicity. The optimal dose of Mg supplementation for the prevention of CDDP-induced nephrotoxicity remains unknown, and further studies, such as randomized clinical trials, are warranted. Careful monitoring of SCr levels during CDDP-based chemotherapy is recommended for patients with heart disease and hypoalbuminemia.