Chronic kidney disease promotes cerebral microhemorrhage formation

Abstract

Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood–brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). Conclusions CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Development and validation of a nomogram predictive model for cerebral small vessel disease: a comprehensive retrospective analysis

“…Elevated creatinine, indicative of impaired kidney function, has been increasingly recognized as a contributing factor to cerebrovascular pathologies. This relationship is supported by the study of Fang et al, which demonstrated that chronic kidney disease (CKD) promotes the formation of cerebral microhemorrhages, a key feature of CSVD ( 21 ). Furthermore, the systematic review and meta-analysis by Tang et al reinforce the association between kidney function and brain health, providing additional validation for our model's emphasis on creatinine levels ( 22 ).…”

Cerebrovascular damage caused by the gut microbe/host co-metabolitep-cresol sulfate is prevented by blockade of the EGF receptor

“…Together, these data strongly implicate pCS as a major contributory factor to the links between kidney failure and impaired brain function. Interactions of pCS with the peripheral vasculature have previously been reported, with evidence of arterial leakage in patients with CKD 46 and in animal 28 and in vitro models of uraemia 47 . Mechanistically, pCS at concentrations found in uraemia can cause interendothelial adherens junction disruption 46 , potentially underlying uraemia-associated endothelial leakage.…”

Chronic kidney disease prevalence and clinical outcomes in anterior circulation acute ischemic stroke patients with reperfusion therapy: A meta‐analysis

“…37 In the case of IVT, the hyperinflammatory state and disruption of the blood-brain barrier in CKD patients could impede the brain's capacity for effective tissue remodelling and neural repair, particularly impacting clot dissolution and reperfusion. 38 EVT's mechanical nature may pose unique challenges for CKD patients in comparison to IVT. The procedure's reliance on iodinated contrast agents, administered intravenously as opposed to intra-arterial administration, can worsen kidney dysfunction, potentially leading to contrast-induced nephropathy.…”

“…The biochemical buildup and inflammatory mediators stemming from CKD intensify the inflammatory response after a stroke, exacerbating endothelial dysfunction 37 . In the case of IVT, the hyperinflammatory state and disruption of the blood‐brain barrier in CKD patients could impede the brain's capacity for effective tissue remodelling and neural repair, particularly impacting clot dissolution and reperfusion 38 . EVT's mechanical nature may pose unique challenges for CKD patients in comparison to IVT.…”