Risk Factors for Cisplatin-Induced Nephrotoxicity and Potential of Magnesium Supplementation for Renal Protection

<div><p>Background</p><p>Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity.</p><p>Patients and Methods</p><p>We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m²) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%).</p><p>Results</p><p>Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012).</p><p>Conclusions</p><p>A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.</p></div

Comparison of clinicopathologic characteristics as risk factors for cisplatin-induced nephrotoxicity.

<p>Drug administration variables refer to the first course of cisplatin chemotherapy. Abbreviations: PS, performance status. TPN, total parenteral nutrition; NK1, neurokinin 1; NSAIDs, nonselective nonsteroidal anti-inflammatory drugs.</p><p>*<i>P</i> value for heterogeneity for the occurrence of nephrotoxicity among tumor types. <i>P</i> values of <0.05 are shown in bold.</p

Risk ratio in multivariable analysis of potential predisposing factors for cisplatin-induced nephrotoxicity (<i>n</i> = 401).

<p>Drug administration variables refer to the first course of cisplatin chemotherapy. Abbreviations: CI, confidence interval; PS, performance status; TPN, total parenteral nutrition; NK1, neurokinin 1; NSAIDs, nonselective nonsteroidal anti-inflammatory drugs.</p>a<p>These risk factors were compared with lung cancer.</p

Baseline characteristics of the 401 study patients.

<p>Drug administration variables refer to the first course of cisplatin chemotherapy. Abbreviations: PS, performance status; Cr, serum creatinine concentration; BSA, body surface area; BMI, body mass index; TPN, total parenteral nutrition; NK1, neurokinin 1; NSAIDs, nonselective nonsteroidal anti-inflammatory drugs.</p

Box-and-whisker plot for the relation between the development of hypomagnesemia and the mean change in serum creatinine concentration during the first course of cisplatin chemotherapy.

<p>The difference between the two groups was analyzed with the unpaired Student's <i>t</i> test.</p

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (&gt;90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting