Nephrotoxicity Associated with Low-dose Methotrexate and Outpatient Parenteral Microbial Therapy: A Case Report, Review of the Literature and Pathophysiologic Insights

Abstract

Methotrexate (MTX) toxicity can affect multiple organ systems, manifesting as nephrotoxicity, myelosuppression, hepatotoxicity, mucositis, and gastrointestinal upset. Serious adverse events are rare in patients prescribed low-dose methotrexate. We present a case of an 86-year-old female on a weekly dose of oral MTX 12.5 mg for rheumatoid arthritis presenting with painful gingiva and oral bleeding during outpatient antimicrobial therapy (OPAT) for osteomyelitis with vancomycin and piperacillin-tazobactam. She had acute kidney injury (AKI), elevated serum MTX levels, thrombocytopenia, neutropenia, and a vancomycin level three times therapeutic concentration. MTX toxicity was suspected to have been triggered by vancomycin and piperacillin-tazobactam causing AKI and impaired renal clearance of MTX which itself is nephrotoxic. The patient was managed with leucovorin, alkalinized intravenous fluids, and filgrastim injections over a 2-week period. Her renal function continued to be reduced at 5-week outpatient follow-up, far after other markers of toxicity normalized. This case demonstrates the importance of considering potential drug-drug interactions and the need for robust monitoring for OPAT in select groups.

The Nephrotoxicity of Drugs Used in Causal Oncological Therapies

“…Additionally, disturbances in the vascular resistance of the supplying glomerular arteries (reduced perfusion) and direct damage to the glomeruli and renal tubules are assumed as factors increasing the nephrotoxicity of methotrexate. Methotrexate is actively filtered and secreted by the renal tubular cells [ 47 , 48 ]. Thus, prior renal dysfunction is a serious risk factor for nephrotoxic complications.…”

“…The pathophysiology of nephrotoxicity takes into account the increase in the activity of myeloperoxidase, antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and malondialdehydes, which leads to cell damage caused by free oxygen radicals. At the same time, an increased response from neutrophils (tissue infiltrations) occurs, which ultimately leads to kidney damage [ 47 , 49 ]. Due to the development of molecular biology, searches for mutations in genes responsible for the occurrence of nephrotoxicity have been recently conducted.…”

Platelet Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Mitigate Methotrexate-Induced Nephrotoxicity in Rat via Nrf2/Pparγ/HO-1 and NF-Κb/Keap1/Caspase-3 Signaling Pathways: Oxidative Stress and Apoptosis Interplay

“…Even with the low-dose therapy in such diseases, serious adverse effects have been attributed to MTX therapy, for example, myelosuppression, infection, hepatotoxicity, and lung diseases [ 3 , 4 , 5 ]. Recent studies determined that the risk of nephrotoxicity with low-dose MTX is higher than previously thought and should be put under consideration [ 6 , 7 ].…”

The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview

“…Within MTX therapy, preclinical and clinical studies reported long-term side effects and toxicity effects on multiple organs and a promising therapeutic strategy aimed at restoring the toxicity of MTX is currently needed. The negative effects of MTX treatment are reflected on multiple organs, including hepatic fibrosis, acute lung injury, dysregulation of gut microbiota and nephrotoxicity [ 24 , 25 , 26 , 27 ]. There are a wide range of short- and long-term side effects, ranging from nausea, drowsiness, liver enzymes elevation, to renal insufficiency, hepatic fibrosis/cirrhosis, pulmonary fibrosis and life-threatening blood disorders, i.e., pancytopenia and aplastic anemia [ 5 ].…”