RESUMO
BACKGROUND: Immunosuppression is effective in treating a number of diseases, but adverse effects such as bone marrow suppression, infection, and oncogenesis are of concern. Methotrexate is a key immunosuppressant used to treat rheumatoid arthritis. Although it is effective for many patients, various side effects have been reported, one of the most serious being methotrexate-related lymphoproliferative disorder. While this may occur in various organs, liver involvement is rare. Information on these liver lesions, including clinical characteristics, course, and imaging studies, has not been summarized to date. CASE SUMMARY: We present a case of 70-year-old woman presented with a 2-wk history of fever and abdominal pain. She had had rheumatoid arthritis for 5 years and was being treated with medication including methotrexate. Contrast-enhanced computed tomography revealed multiple low density tumors in the liver and the histological analyses showed significant proliferation of lymphocytes in masses that were positive on immunohistochemical staining for CD3, CD4, CD8, and CD79a but negative for CD20 and CD56. Staining for Epstein-Barr virus-encoded RNA was negative. And based on these findings, the liver tumors were diagnosed as Methotrexate-related lymphoproliferative disorders. A time-dependent disappearance of the liver tumors after stopping methotrexate supported the diagnoses. CONCLUSION: The information obtained from our case and a review of 9 additional cases reported thus far assist physicians who may face the challenge of diagnosing and managing this disorder.
RESUMO
Nephrotoxicity induced by antimicrobial or anticancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the apical membranes of proximal tubules, mediates the nephrotoxicity of aminoglycosides and colistin, key antimicrobials for multidrug-resistant organisms. The mechanisms underlying the nephrotoxicity induced by vancomycin, an antimicrobial for methicillin-resistant Staphylococcus aureus, and cisplatin, an important anticancer drug, are unknown, although the nephrotoxicity of these drugs and gentamicin, an aminoglycoside, is suppressed experimentally with cilastatin. In the clinical setting, cilastatin has been used safely to suppress dehydropeptidase-I-mediated renal metabolism of imipenem, a carbapenem antimicrobial, and thereby limit tubular injury. Here, we tested the hypothesis that cilastatin also blocks megalin-mediated uptake of vancomycin, cisplatin, colistin, and aminoglycosides, thereby limiting the nephrotoxicity of these drugs. Quartz crystal microbalance analysis showed that megalin also binds vancomycin and cisplatin and that cilastatin competes with megalin for binding to gentamicin, colistin, vancomycin, and cisplatin. In kidney-specific mosaic megalin knockout mice treated with colistin, vancomycin, or cisplatin, the megalin-replete proximal tubule epithelial cells exhibited signs of injury, whereas the megalin-deficient cells did not. Furthermore, concomitant cilastatin administration suppressed colistin-induced nephrotoxicity in C57BL/6J mice. Notably, cilastatin did not inhibit the antibacterial activity of gentamicin, colistin, or vancomycin in vitro, just as cilastatin did not affect the anticancer activity of cisplatin in previous studies. In conclusion, megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by gentamicin, colistin, vancomycin, or cisplatin. Cilastatin may be a promising agent for inhibiting various forms of drug-induced nephrotoxicity mediated via megalin in the clinical setting.
