In patients with advanced lung adenocarcinoma, the results of phase III trials show that pemetrexed maintenance therapy allows longer survival [
1,
2]. Given pemetrexed safety and simple intravenous administration every 3 weeks, this strategy seems to be of important clinical value. However, not all patients need or benefit from maintenance therapy. Events associated with decreased renal function were reported [
3‐
5,
11]. In phase III trials, all grades of renal failure and grade 4 requiring dialysis were reported in 2.4 and 0.6% of patients, respectively [
5]. Our case report describes renal insufficiency as a leading cause of maintenance pemetrexed discontinuation for toxicity to advanced non-small cell lung cancer in routine practice. Cr Cl decreased from 85 to 25 ml/minute per 1.73 m
2 following the third pemetrexed infusion. This observed nephrotoxicity seems to be related to the mechanism of action of pemetrexed and its pharmacokinetics. Pemetrexed was eliminated as unchanged drug primarily from the kidney, by both tubular secretion and glomerular filtration with the former being the predominant mechanism for patients with normal renal function [
12,
13]. Only a few patients were submitted to renal biopsy. Our patient experienced acute tubular necrosis and interstitial fibrosis following sequential treatment with pemetrexed. Our data are in agreement with other reports where renal injury has been reported after three, four, or six cycles of pemetrexed [
6‐
10,
14,
15]. After discontinuation of pemetrexed, our patient’s renal function stabilized, but did not return to pre-treatment baseline. Although many acute kidney injury (AKI) risk factors were present (dehydration, NSAIDs, radiocontrast agents), none of them seemed to be responsible for kidney injury. The lapse of time between the administration of radiocontrast agents and AKI development excludes radiocontrast agent-induced nephropathy. Interstitial fibrosis was attributed to pemetrexed. However, we cannot exclude the contribution of these factors. Thus, pemetrexed must be considered an important cause of renal failure in patients with cancer. However, it is difficult to identify patients at higher risk of discontinuation based only on changes in laboratory values. Oncologists have to be vigilant in assessing their patient’s renal function for treatment.