Drug Crystal-Related Gastrointestinal Complications Involve Crystal-Induced Release of Neutrophil and Monocyte Extracellular Traps

Cells

MarionJulia Pollheimer¹  Kathrin Eller²  Tehyung Kim³  Qiuyue Ma³  Hans-Joachim Anders³  Stefanie Steiger³  CelsoVataru Nakamura⁴  Sueli de Oliveira Silva Lautenschlager⁴  Danielle Lazarin-Bidóia⁴ 

[1] Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria;Division of Nephrology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria;Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, 80336 Munich, Germany;Postgraduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná 5790, Brazil;

关键词: sevelamer;    polystyrene sulfonate;    cholestyramine;    patiromer;    exchange resin;    extracellular traps;   

DOI  :  10.3390/cells9112481

来源: DOAJ

【 摘 要 】

Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy.

【 授权许可】

Unknown