High Dose Methotrexate and Acute Kidney Injury—Is It Predictable?

Introduction

For more than 6 decades the anti-metabolite methotrexate (MTX) is used across a wide range of medical conditions. From 10mg/week to 13 g/day, MTX is given at different schedules and doses. High dose methotrexate (HDMTX), defined as dose above 500 mg/m2 is used in several pediatric and adult hematological malignancies. MTX-induced renal-tubular injury occurs in a significant number of patients. Yet, while acute renal injury is well defined and measures to reduce this risk are routinely administered, risk factors in adult patients who receive HDMTX are not well defined.

The purpose of this study is to define risk factors and setup the cutoffs that will help clinicians predict who is at-risk to develop acute renal toxicity following HDMTX treatment.

Methods

This is a single center, retrospective study. We reviewed the medical records of all consecutive patients who received a MTX dose of 1g or more. For these patients we collected demographic, clinical and outcome data. Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria (an increase in serum creatinine of at least 0.3 mg/dL). We compared patients with or without renal toxicity. For categorical variables, we used the χ2 test. We used a logistic regression model with the exp(β) as an estimator of the odds ratio (OR) and the confidence interval (CI) around it in order to define which baseline variables, predict renal toxicity. We used receiver operator characteristics (ROC) curves and the area under the curve to define the best cutoff for continuous variables. The probability of overall survival (OS) was estimated by the Kaplan-Meier method. The log-rank test was used to compare survival distributions.

Results:

Between January 2012 and February 2017, 160 patients received at least one course of HDMTX in our Institute for a total of 265 courses. Indications for HDMTX included: primary CNS lymphoma (N = 22, 14%), primary CNS prophylaxis for other types of lymphoma (N=110, 69%), acute lymphatic leukemia (N=24, 15%) other (N=4, 2%). The median age at diagnosis was 58 years (range 18 to 84), and 86 patients were males (54%). The vast majority were of good functional status (ECOG=0-1), and 54 (34%) had at least one major comorbidity: vascular (N=23, 14%), diabetes (N=29, 18%) or prior malignancy (N=11, 7%).

The median number of cycles per patient was 1 (range 1-6) and the median dose of MTX was 1941 mg/m² (range: 743 to 5442). The median time to MTX clearance was 5 days (range 3 to 20). During this time AKI developed in 9% of patients (n=24), the vast majority in the first cycle (21 out of 24 patients). In a univariate analysis for prediction of acute nephrotoxicity: age above 40 years [p=0.05, OR =7.6, 95% CI 1-57 ], LDH above 480 units/L [p=0.03, ORR=5.4, 95% CI 1.2-23.5 ], MTX dose adjusted for BSA above 1440 mg/m² [p=0.55, OR=7.3, 95% CI 0.9-55 ], creatinine level above 0.9 mg/dl [p=0.012, OR=3.0, 95% CI 1.3-7.2 ] and albumin levels under 3.6 mg/dl [p=0.017, OR=2.9, 95% CI 1.2-6.8 ] at baseline predicted for MTX associated acute renal toxicity. In a multivariable analysis of these parameters, only creatinine level above 0.9 mg/dl and albumin level under 3.6 mg/dl remained predictive [OR 4.161, 95% CI 1.04-7.55 and OR 5.73, 95% CI 1.27-11.48]. In 80% of cases, the creatinine levels returned to normal within 1 month. Yet, the median survival of patients who developed acute toxicity was only 37 months, while it was not reached in patients who maintained normal kidney function (Log rank= 0.023). The median time for drug clearance was 8 days (range, 4-20) in patients with AKI, while it was only 5 days (range 3-9) in those without toxicity. Only 3 patients with AKI developed also prolonged renal toxicity.

Conclusions

Albumin under 3.6 gr% and creatinine above 0.9gr% are the strongest risk factors which predict AKI in patients receiving HDMTX. While creatinine levels returned to baseline in most patients, AKI was associated with increased mortality rates.

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