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

Abstract

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.

Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

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Calcium polystyrene sulfonate associated colonic mucosal injury—innocent bystander or pathogenic culprit?: a case report and literature review

“…The latest in vitro study explained the pathogenesis of CERs associated mucosal necrosis by diminishing the metabolic activity, forming a neutrophil and monocyte extracellular trap leading to cell death, and causing barrier dysfunction of intestinal epithelial cells. The crystals may further contribute to the auto-amplification of a preexisting barrier dysfunction and necroinflammation [14]. Gastrointestinal complications in the patients who had multiple problems, especially CKD/ESRD, were not uncommon.…”

Kalimate (calcium polystyrene sulfonate) and bowel perforation – a cause not to be ignored

“…Several theories tried to explain the pathogenesis of CERs associated gastrointestinal effects and accordingly to a recent in vitro study, the presence of these crystals can decrease the metabolic activity in situ, which is associated with a neutrophil and monocyte infiltrate, leading to mucosal necrosis. Its presence can also work as a self-amplifier of a preexisting barrier dysfunction and inflammation [12] .…”