Microvascular Injury in Ketamine-Induced Bladder Dysfunction

Abstract

The pathogenesis of ketamine-induced cystitis (KC) remains unclear. In this study, bladder microvascular injury was investigated as a possible contributing mechanism. A total of 36 KC patients with exposure to ketamine for more than 6 months, and 9 control subjects, were prospectively recruited. All participants completed questionnaires, including the O’Leary–Sant interstitial cystitis symptom index (ICSI) and the interstitial cystitis problem index (ICPI). All KC patients received a urodynamic study and radiological exams. Bladder tissues were obtained from cystoscopic biopsies in the control group and after hydrodistention in the KC group. Double-immunofluorescence staining of N-methyl-d-aspartate receptor subunit 1 (NMDAR1) and the endothelial marker, cluster of differentiation 31 (CD31), was performed to reveal the existence of NMDAR1 on the endothelium. Electron microscopy (EM) was applied to assess the microvascular change in the urinary bladder and to measure the thickening of the basement membrane (BM). A proximity ligation assay (PLA) was used to quantify the co-localization of the endothelial CD31 receptor and the mesenchymal marker [fibroblast-specific protein 1 (FSP-1)]. The Mann–Whitney U test and Spearman’s correlation coefficient were used for statistical analysis. The mean ICSI [14.38 (± 4.16)] and ICPI [12.67 (± 3.54)] scores of the KC group were significantly higher than those (0 and 0, respectively) of the control group (both p < 0.001). The KC patients had decreasing cystometric bladder capacity (CBC) with a mean volume of 65.38 (± 48.67) mL. NMDAR1 was expressed on endothelial cells in both groups under immunofluorescence staining. Moreover, KC patients had significant BM duplication of microvessels in the mucosa of the urinary bladder under EM. The co-expression of the endothelial marker CD31 and mesenchymal marker FSP1 was significantly stained and calculated under PLA. In conclusion, microvascular injury and mesenchymal phenotypic alteration of endothelial cells can potentially contribute to KC-induced bladder dysfunction.

Vascular fibrinoid necrosis in the urinary bladder of ketamine abusers: A new finding that may provide a clue to the pathogenesis of ketamine‐induced vesicopathy

“…The pathological mechanism of KIV is not well understood . Previous studies have suggested that a direct toxic effect, bladder barrier dysfunction, neurogenic inflammation, IgE‐mediated inflammation, or microvascular injury may be involved in the pathogenesis of KIV …”

“…The mechanism of ketamine‐induced microvascular changes in the urinary bladder is a result of endothelial cell injury through ketamine‐mediated activation of NMDA receptors on the endothelial cells, contributing to thickening of the basement membrane by multilayer duplication with tortuous and angular changes to the vascular lumen, chronic inflammation, and subsequent interstitial fibrosis over the submucosal layer. These microvascular changes may give rise compromised microcirculation or decrease the density of microvessels …”

“…Previous reports of nerve bundle hyperplasia on pathological examination and neovascularization on cystoscopic findings provide evidence for postischemic changes with repair, and support this pathological mechanism for the disease. Furthermore, the observed suprapubic pain may be the result of bladder ischemia caused by fibrinoid necrosis.…”

“…The former is caused by deposition of antigen–antibody immune complexes in the arterial walls with subsequent induction of inflammation and presents characteristic pathological morphology with an amorphous, circumferentially bright pink appearance along the vascular wall after hematoxylin and eosin staining . The latter is caused by endothelial cell injury through ketamine‐mediated activation of NMDA receptors on the endothelial cells, with subsequent thickening of the basement membrane and chronic inflammation, and presents with vascular wall thickening without any amorphous pinkish deposition under microscopic examination . Another vascular finding, autoimmune‐mediated vascular congestion, has also been proposed in the pathogenesis of KIV, which is triggered by ketamine or it metabolites giving rise to an autoimmune reaction in the bladder urothelium and submucosa, resulting in pathological presentation with vascular congestion, submucosal edema, and scarring …”

What urologists need to know about ketamine‐induced uropathy: A systematic review

“…Lin et al showed in human bladder biopsy that microvessels had tortuous and multiple angular shapes, and the basal membrane beneath the endothelial cells was thicker with multilayer compared to healthy controls 38 . They also demonstrated the presence of N ‐methyl‐ d ‐aspartate receptors on the endothelium of vessels and postulated that the chronic receptor activation might be the cause of vessel impairment and subsequent chronic inflammation 38 . Damage of microvessels in the bladder may lead to compromised microcirculation and ischemia in the urothelium, which could explain dysuria and pelvic pain.…”