Magnesium supplementation and high volume hydration reduce the renal toxicity caused by cisplatin-based chemotherapy in patients with lung cancer: a toxicity study

The mortality rate associated with lung cancer is increasing worldwide. In fact, lung cancer (along with tracheal and bronchial cancers) was responsible for 1.5 million (2.7%) deaths in 2011, compared with 1.2 million (2.2%) deaths in 2000, according to the World Health Organization. In more than 60% of patients with lung cancer, particularly those with non-small cell lung cancer (NSCLC), the cancer is inoperable at the time of diagnosis and requires chemotherapy [1].

Cisplatin is one of the most important components of standard therapies for lung cancer and is also an effective adjuvant for chemotherapy and chemoradiotherapy [2]. Renal toxicity is a well-known adverse effect of cisplatin treatment, which limits its use. Despite intensive prophylactic measures, renal toxicity still affects a large proportion of patients treated with cisplatin, and a significant decrease in glomerular filtration rate is commonly observed during treatment [3]. In 1977, Cvitkovic et al. reported that cisplatin-induced renal toxicity could be avoided with substantial hydration and mannitol-induced diuresis [4]. Subsequently, clinical trials were initiated in several types of cancers, including epidermoid carcinoma, ovarian adenocarcinoma, germ cell tumors of the testis, and metastatic melanoma [5, 6]. Hayes et al. reported about patients who had been pre-hydrated intravenously with 2,000 ml of 5% glucose in one-half normal saline over 12 h, and post-hydrated with 1,200 ml of one-half normal saline over 6 h. Mannitol was infused (50 ml of 25% mannitol) as an intravenous bolus just before the administration of cisplatin, and was continuously infused (300 ml of 20% mannitol) for 6 h after the administration of cisplatin [6]. Even if cisplatin was approved in 1984 for use in Europe and the United States, nephrotoxic damage still affects 28 − 42% of patients treated with cisplatin [7].

To date, a number of studies have investigated strategies for prevention of cisplatin-induced renal toxicity. As free cisplatin causes renal toxicity, shortening the free cisplatin and renal tubular contact time is important to reduce its nephrotoxicity [8]. As more than 90% of free cisplatin binds to plasma proteins within 4 h, hydration within that time after initiating treatment is a critical factor in reducing toxicity [8]. In addition, previous reports have demonstrated that cisplatin-induced Mg depletion may occur in some patients [9]. Willox et al. revealed that supplementation with 16 mEq Mg was beneficial in reducing renal tubular damage in patients with testicular cancer receiving cisplatin [10], while Bodnar et al. demonstrated that 40 mEq Mg supplementation had nephroprotective effects during chemotherapy with cisplatin in patients with epithelial ovarian cancer [7]. Muraki et al. showed that hydration with 8 mEq Mg and mannitol without furosemide prevents the nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced NSCLC [11]. Hirai, et al. also showed that 20 mEq Mg supplementation may be beneficial in preventing cisplatin-induced nephrotoxicity in patients with esophageal or hypopharyngeal cancer [12]. Yoshida et al. reported that 8 mEq Mg preloading before cisplatin administration significantly reduced cisplatin-induced nephrotoxicity in 496 patients with thoracic malignancies [13]. Therefore, Mg supplementation, in addition to hydration, may also reduce the renal toxicity induced by cisplatin. Therefore, Mg supplementation is being considered an option for cisplatin-based chemotherapy. Prospective studies since 2007 have examined the use of low-volume hydration in combination with Mg supplementation. Tiseo, et al. demonstrated that low-volume hydration with 16 mEq Mg supplementation in cisplatin-based chemotherapy led to no increase in creatinine in only 35.3% of patients [14]. Hotta et al. reported that low-volume hydration (2,500 ml) with 4 mEq Mg supplementation before and after cisplatin administration was associated with slightly worse renal toxicity during all cycles of chemotherapy, without significance [15]. Horinouchi et al. examined the safety of low-volume hydration (1,550 − 2,050 ml) with 8 mEq Mg supplementation; however, renal function during all courses of cisplatin administration was slightly worse [2]. However, few studies have compared the renal toxicities associated with treatment using high-volume hydration with Mg supplementation to those associated with treatment using low-volume hydration with Mg supplementation. We hypothesized that Mg infusion may not be sufficient to overcome the renal toxicity caused by cisplatin during low-volume hydration. Therefore, we performed a historical prospective cohort study wherein patients were classified into three groups: high-volume hydration without Mg infusion, high-volume hydration with Mg infusion, and low-volume hydration with Mg infusion.

We found that renal function was significantly worse after cisplatin treatment in the high-volume Mg- group, and it also tended to worsen in the low-volume Mg+ group. Only the high-volume Mg+ group showed no significant alterations in renal function after cisplatin treatment. Multivariate analysis indicated that both the absence of Mg infusion and low-volume hydration were independent predictors for decreased renal function.

Mg supplementation and high-volume hydration may protect against the renal toxicity induced by cisplatin [7, 10, 11]. Although the detailed mechanism underlying this effect is not clear, recent reports have shown that the human organic cation transporter 2 (OCT2) is predominantly expressed in the human kidney at the basolateral membrane of renal proximal tubules [17]. In mice, Oct2 has been implicated in the cellular uptake of cisplatin, and Oct1/Oct2-deficient mice are protected from severe cisplatin-induced renal tubular damage [17]. In rats, Mg depletion may cause dehydration and up-regulation of rat Oct2, which enhances renal accumulation of cisplatin and subsequent acute kidney injury [18]. In humans, a single nucleotide polymorphism in the OCT2 gene SLC22A2 (rs316019) has been associated with reduced cisplatin-induced nephrotoxicity and decreased gene expression [17]. In renal proximal tubule cells, the accumulation of cisplatin from the basolateral side is significantly greater than that from the apical side [19]. Thus, Mg supplementation was subsequently proposed to prevent Mg depletion and renal toxicity.

The volume of fluid for hydration is also an important factor that affects cisplatin-induced renal toxicity [4, 20, 21]. To our knowledge, no previous reports have compared renal toxicity between patients receiving high-volume Mg+ and low-volume Mg+ regimens. In the present multivariate analysis, both the volume of hydration and Mg infusion contributed to increased renal protection. These protocols were based on previous reports. Recent prospective studies have investigated low-volume hydration with Mg supplementation using hydration volumes of 1,500 − 2,500 ml [2, 14, 15]. In our study, the volumes of pre-hydration fluid administered were 1,800 ml in the high- and 900 ml in the low-volume Mg+ groups. However, the volumes of post-hydration fluid administered within 4 h were almost similar between the high- and low-volume Mg+ regimens. The difference in volume may thus be an important factor related to the observed differences in renal toxicity. Hydration volume is related to osmolality and both serum and urinary concentrations of cisplatin. The extent of cisplatin induced nephrotoxic injury is dependent on both dose and cumulative cisplatin levels. Since high-volume hydration reduces the concentration of cisplatin compared to low-volume hydration, low plasma levels of cisplatin should reduce renal accumulation and decrease nephrotoxicity. In addition, high volume hydration decreases osmolality of blood resulting in decreased secretion of antidiuretic hormone, decreased water reabsorption, more diluted urine, and increased urine output. It can thus be hypothesized that low urinary levels of cisplatin reduce renal accumulation of cisplatin and decrease nephrotoxicity. Therefore, the differences in osmolality in these two protocols may be related to the observed differences in nephrotoxicity.

One remaining question is whether Mg supplementation will also reduce the cytotoxic effects of cisplatin on tumor cells. Laboratory and clinical findings of Mg depletion have been observed in patients treated with high-dose cisplatin. Under low Mg conditions, tumor suppressors such as p21 and p27 are up-regulated, while oncogenes such as cyclins D and E are down-regulated [22]. It has also been suggested that there may be a correlation between the availability of Mg and vascular endothelial growth factor [23], and in particular that Mg depletion may suppress tumor cell proliferation and neoangiogenesis. Therefore, there could be some concern that Mg supplementation might promote tumor cell proliferation. However, previous prospective clinical trials and retrospective studies have indicated that Mg supplementation does not affect tumor response to cisplatin-based chemotherapy [7, 10, 11]. At any rate, the relationship between Mg depletion and tumor response to chemotherapy will require further investigation.

The present study has some limitations. First, this was a historical prospective cohort study and included a relatively small number of patients. Second, while some patients had consumed 2,000 ml of water on day 1 and 1,000 ml of water on days 2 and 3, the optimal amount of fluid intake was not evaluated. Indeed, many previous examinations of low-volume hydration involved oral hydration on days 2 and 3 rather than infusion; however, the effect of oral hydration has not yet been examined. Third, no data on the levels of serum Mg levels was available. It is known that serum hypomagnesemia reflects Mg depletion, but serum Mg is only 1% of the total Mg present in the body [24]. In some cases, levels of serum Mg may not be decreased even in the presence of Mg depletion. Cisplatin treatment is one such case, and Mg supplementation is needed even in the absence of serum hypomagnesemia. This renders it difficult to know the optimal amount of Mg supplementation. Nonetheless, our study revealed that even 8 mEq of Mg sulfate reduced renal toxicity. Fourth, renal function in cisplatin chemotherapy was assessed only after the first or last cycle. The renal damage by cisplatin may be cumulative. The knowledge of sCr in the following cycles would be important. In our study, in the high-volume Mg- group, the median value of sCr after the last cycle was significantly higher than after the first cycle (p = 0.004) (data not shown). This result suggests that the renal damage by cisplatin was cumulative with every cycle in Mg- group. Thus, Mg supplementation with high-volume hydration may have a much greater impact on renal damage caused by cisplatin.

High-volume hydration and Mg supplementation can reduce the renal toxicity induced by cisplatin. Our data also suggest that a low-volume Mg+ regimen can be considered for patients with adequate renal function. Further prospective clinical studies in a larger patient population, including association with total body Mg levels and optimization of Mg intake, along with correlations between Mg depletion and tumor response to chemotherapy should be performed.