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Tramadol-attributed toxicity may involve opioid-like, serotoninergic, and noradrenergic mechanisms. We investigated the mechanisms of toxicity in a massive tramadol ingestion case by examining serial clinical, imaging, electroencephalography, pharmacokinetics, and genotyping data. A 32-year-old female who presumably ingested 9000 mg sustained-release tramadol was found comatose without hypoglycemia, bradypnea, hypotension, marked hypoxemia or seizures. She developed eyelid myoclonus and non-reactive mydriasis. Electroencephalogram showed non-reactive encephalopathy. MRI showed extensive brain injury. Despite supportive care and ventricular derivation, brain death occurred on day 12. Plasma concentrations of tramadol and metabolites were measured using a liquid chromatography–tandem mass spectrometry assay. Genotyping for the presence of metabolizing cytochrome P450 (CYP) gene polymorphisms was performed. Plasma concentrations of tramadol and metabolites were extremely high (∼70-fold the therapeutic concentrations) and slowly decreased during the first ∼146 h post-admission, possibly due to prolonged gastrointestinal absorption. Elimination half-lives were 2–3-fold longer than usual values. The patient was an intermediate CYP2D6 metabolizer with decreased CYP3A4 and CYP2B6 activities. Clinical and electroencephalographic data did not support the hypotheses of opioid or serotoninergic toxicity nor prolonged/repeated seizures. Based on serial imaging showing progressive extension of ischemic edema in the context of prolonged high plasma concentrations, we hypothesized a cerebral vasospasm as mechanism of injury. Massive tramadol ingestion with prolonged high plasma concentrations can result in severe brain injury, possibly involving vasospasm.

Autophagy is a highly conserved process that degrades cellular long-lived proteins and organelles. Accumulating evidence indicates that autophagy plays a critical role in kidney maintenance, diseases and aging. Ischemic, toxic, immunological, and oxidative insults can cause an induction of autophagy in renal epithelial cells modifying the course of various kidney diseases. This review summarizes recent insights on the role of autophagy in kidney physiology and diseases alluding to possible novel intervention strategies for treating specific kidney disorders by modifying autophagy.

A major side effect of the powerful immunosuppressive drug cyclosporine (CsA) is the development of a chronic nephrotoxicity whose mechanisms are not fully understood. Recent data suggest that tubular cells play a central role in the pathogenesis of chronic nephropathies. We have shown that CsA is responsible for endoplasmic reticulum (ER) stress in tubular cells. Autophagy has recently been described to be induced by ER stress and to alleviate its deleterious effects. In this study, we demonstrate that CsA induces autophagy in primary cultured human renal tubular cells through LC3II expression and autophagosomes visualization by electron microscopy. Autophagy is dependant on ER stress because various ER stress inducers activate autophagy, and salubrinal, an inhibitor of eIF2alpha dephosphorylation that protects cells against ER stress, inhibited LC3II expression. Furthermore, autophagy inhibition during CsA treatment with beclin1 siRNA significantly increases tubular cell death. Finally, immunohistochemical analysis of rat kidneys demonstrates a positive LC3 staining on injured tubular cells, suggesting that CsA induces autophagy in vivo. Taken together, these results demonstrate that CsA, through ER stress induction, activates autophagy as a protection against cell death.

Kikuchi-Fujimoto disease is characterized by painful cervical lymphadenopathy and constitutional symptoms. Microscopical study of lymph nodes shows focal areas of non-suppurative necrosis with histiocytic and plasmacytoid cell infiltrates. The course is usually benign. Often primitive, necrotising histiocytic lymphadenopathy may be associated with autoimmune disorders. We describe the case of a 30-year-old female patient with two 15-day courses of Kikuchi-Fujimoto disease flares within a period of 3 months, occurring in association with mixed connective tissue disease.