Hydration with 15 mEq Magnesium Is Effective at Reducingthe Risk for Cisplatin-induced Nephrotoxicity in Patients Receiving Cisplatin (≥50 mg/m²) Combination Chemotherapy

Patients and Methods

Study participants. This study was a single-center, prospective, open-label, non-randomized, historically-controlled study conducted at Aichi Medical University School of Medicine. We targeted an experimental cohort (Mg-hydration group) and a retrospective control group (non-Mg-hydration group). Patients were selected for this study according to the following criteria: (i) diagnosis of gynecological cancer; (ii) Eastern Cooperative Oncology Group performance status of 0-2; (iii) chemotherapy regimens that included 50 mg/m² or more of cisplatin; (iv) receiving treatment as an inpatient at our Institution between January 2010 and December 2014. The following variables were recorded for each patient: age, body surface area, body mass index, performance status according to the Eastern Cooperative Oncology Group scale, tumor type, disease stage, cisplatin dosage, number of chemotherapy cycles and baseline renal function. We began to measure serum magnesium levels before the administration of cisplatin when the magnesium hydration protocol was started in 2012.

We defined patients receiving cisplatin-containing regimens between January 2010 and June 2012 as the non-Mg-hydration group and between July 2012 and December 2014 as the Mg-hydration group. We compared nephrotoxicity between these two groups.

The Institutional Review Board decided to exempt this study from the usual review process. Study approval was obtained from the president of the Aichi Medical University Hospital, Aichi, Japan (approval number: 13-102).

Administration of pre-hydration. A program of forced diuresis of 2,500 ml of fluids (lactate Ringer's solution) infused with cisplatin dissolved in 500 ml of normal saline was administered as pre-hydration. Urine flow was established at rates of at least 100 ml/h for 2 days following cisplatin administration. If urine flow rate dropped below 100 ml/h, an additional infusion solution was administered. If the additional solution failed to increase urine flow rate, 20 mg furosemide was administered. Mannitol was not administered.

After chemotherapy treatment, 500 ml, 1,000 ml and 1,000 ml of intravenous infusion fluid (lactate Ringer's solution) were administered as post-hydration on days 1, 2, and 3, respectively. Beginning in July 2012, a modified hydration protocol including magnesium sulfate was used. Fifteen mEq of magnesium sulfate was used as pre-hydration and a daily dose of 5 mEq of magnesium sulfate was used as post-hydration on days 2 and 3.

Nephrotoxicity evaluation. In line with a previous report (6), we used serum creatinine (Scr) and creatinine clearance (Ccr) to divide patients into categories based on the Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) criteria. RIFLE criteria are used widely in cases involving acute nephrotoxicity (13). Scr was measured enzymatically, while Ccr was calculated using the Cockroft-Gault formula. The Common Terminology Criteria for Adverse Events classify renal dysfunction only as an elevation of Scr and do not refer to Ccr values. However, we chose to use the RIFLE criteria, which define nephrotoxicity according to Ccr and Scr values. RIFLE criteria define “risk” (Class R) as a proportional increase in Scr of more than 50% or a decrease in Ccr of less than 25% relative to baseline after cisplatin administration. In addition, “injury” (Class I) is defined as a proportional increase in Scr of more than 100% or a decrease in Ccr of less than 50% relative to baseline after cisplatin administration. We also used the difference between the baseline values of Scr and the maximum increment of Scr (ΔScr), as well as the difference between baseline value of Ccr and maximum decrement of Ccr (ΔCcr) to evaluate cisplatin-induced nephrotoxicity. When there was no change over a particular time period, we recorded this as 0.

Statistical analyses. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. Tumor type, disease stage, pathological stage, chemotherapy regimen, number of chemotherapy cycles and RIFLE criteria were compared using Fisher's exact test. Other patient demographic data, ΔScr and ΔCcr were compared using the Mann–Whitney U-test. A comparison of serum magnesium levels before and after treatment was performed using a one-way ANOVA. All reported p-values are two-sided, with a value of p<0.05 considered statistically significant.