Chronic Kidney Disease Increases Cerebral Microbleeds in Mouse and Man

Wei Ling Lau,David Floriolli,Long Lertpanit,Annlia Paganini-Hill,Ane C F Nunes,Vitaly Vasilevko,Sameen Naqvi,Zhihui Yao,David H Cribbs,Maria Bangash,Krunal Shah,Mark Fisher,Nosratola D Vaziri,Javad Savoj

doi:10.1007/s12975-019-00698-8

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 age-matched 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.

Highlights

One of the most significant stroke neurology discoveries in recent years is the emergence of chronic kidney disease (CKD) as an independent risk factor for early cognitive decline and cerebrovascular disease, especially cerebral microbleeds and stroke [2,3,4,5,6,7,8,9]
Brain magnetic resonance imaging (MRI) with T2*-weighted and susceptibility-weighted imaging (SWI) and FLAIR images were performed on 1.5T and 3T MRI scanners
We report an increased prevalence of cerebral microhemorrhages in CKD mice and of microbleeds in CKD patients

Summary

Introduction

One of the most significant stroke neurology discoveries in recent years is the emergence of chronic kidney disease (CKD) as an independent risk factor for early cognitive decline and cerebrovascular disease (reviewed in [1]), especially cerebral microbleeds and stroke [2,3,4,5,6,7,8,9]. Cerebral microbleeds are small foci of hemosiderin–iron demonstrable on magnetic resonance imaging (MRI), believed to reflect underlying cerebral microhemorrhages [12, 13], and indicative of heightened risk for stroke, both hemorrhagic and ischemic [9, 14]. Hypertension and cerebral amyloid angiopathy are the best described risk factors for development of microbleeds [13, 17]. In late-stage CKD, microbleeds are present in up to 50% of the population [2,3,4]

Methods

Results

Conclusion