Chronic Kidney Disease Increases Cerebral Microbleeds in Mouse and Man

Abstract

Brain microbleeds are increased in chronic kidney disease (CKD) and their presence increases risk of cognitive decline and stroke. We examined the interaction between CKD and brain microhemorrhages (the neuropathological substrate of microbleeds) in mouse and cell culture models and studied progression of microbleed burden on serial brain imaging from humans. Mouse studies: Two CKD models were investigated: adenine-induced tubulointerstitial nephritis and surgical 5/6 nephrectomy. Cell culture studies: bEnd.3 mouse brain endothelial cells were grown to confluence, and monolayer integrity was measured after exposure to 5-15% human uremic serum or increasing concentrations of urea. Human studies: Progression of brain microbleeds was evaluated on serial MRI from control, pre-dialysis CKD, and dialysis patients. Microhemorrhages were increased 2-2.5-fold in mice with CKD independent of higher blood pressure in the 5/6 nephrectomy model. IgG staining was increased in CKD animals, consistent with increased blood-brain barrier permeability. Incubation of bEnd.3 cells with uremic serum or elevated urea produced a dose-dependent drop in trans-endothelial electrical resistance. Elevated urea induced actin cytoskeleton derangements and decreased claudin-5 expression. In human subjects, prevalence of microbleeds was 50% in both CKD cohorts compared with 10% in agematched controls. More patients in the dialysis cohort had increased microbleeds on follow-up MRI after 1.5 years. CKD disrupts the blood-brain barrier and increases brain microhemorrhages in mice and microbleeds in humans. Elevated urea alters the actin cytoskeleton and tight junction proteins in cultured endothelial cells, suggesting that these mechanisms explain (at least in part) the microhemorrhages and microbleeds observed in the animal and human studies.

Critical illness-associated cerebral microbleeds for patients with severe COVID-19: etiologic hypotheses

“…It is known that chronic kidney disease and hemodialysis are associated with a high incidence of microbleeds [21,22]. The underlying physiological mechanisms including increased permeability of the blood-brain barrier secondary to a high concentration of uremic toxins [21]. Indeed, the group of patients with COVID-19 diagnosed with CIAM have shown a more severe kidney failure in agreement with this new assumption.…”

“…The third new hypothesis was formulated based on our results: the role of kidney failure, which was more severe in the group with CIAM. It is known that chronic kidney disease and hemodialysis are associated with a high incidence of microbleeds [21,22]. The underlying physiological mechanisms including increased permeability of the blood-brain barrier secondary to a high concentration of uremic toxins [21].…”

Behavioral Changes During Development of Chronic Kidney Disease in Rats

“…It has been shown that mild CKD may lead to activation of limbic system, central sympathetic, stress-and pain-related brain areas (31). Some CKD-related neurological complications have been attributed to impaired permeability of the blood-brain barrier (22,32,33), neuroinflammation, and oxidative stress (21)(22)(23). Neurotoxicity induced by numerous substances, such as urea, accumulated in blood during kidney disease (34)(35)(36) might also play a role (33).…”

Anticoagulation in Patients with End-Stage Renal Disease and Atrial Fibrillation: Confusion, Concerns and Consequences

“…19 Mechanism for CMB includes uremia induced alteration in actin cytoskeleton and claudin-5 expression, a tight junction protein in endothelial cells. 20 Impaired renal function, age, and hypertension were all found to be associated with CMB in patients with ischemic stroke. 21 In a meta-analysis of studies involving recent ischemic stroke, documented AF and long term anti-coagulation therapy, future odds of ICH were noted to be associated with the presence of CMB at baseline (odds ratio [OR], 2.68; 95% CI, 1.19 to 6.01; P=0.017) and the number of CMB (OR for ICH, 5.5; 95% CI, 2.07 to 14.66; P=0.001 with CMB ≥5).…”

“…Cerebral microbleed (CMB), focal deposits of hemosiderin, is another pathophysiological aspect, which is associated with an increased risk of intracerebral hemorrhage (ICH), ischemic and hemorrhagic stroke, and is quite common among HD patients (54%) [ 19 ]. Mechanism for CMB includes uremia induced alteration in actin cytoskeleton and claudin-5 expression, a tight junction protein in endothelial cells [ 20 ]. Impaired renal function, age, and hypertension were all found to be associated with CMB in patients with ischemic stroke [ 21 ].…”