Chronic kidney disease in the pathogenesis of acute ischemic stroke

Abstract

Chronic kidney disease has a graded and independent inverse impact on cerebrovascular health. Both thrombotic and hemorrhagic complications are highly prevalent in chronic kidney disease patients. Growing evidence suggests that in chronic kidney disease patients, ischemic strokes are more common than hemorrhagic strokes. Chronic kidney disease is asymptomatic until an advanced stage, but mild to moderate chronic kidney disease incites various pathogenic mechanisms such as inflammation, oxidative stress, neurohormonal imbalance, formation of uremic toxins and vascular calcification which damage the endothelium and blood vessels. Cognitive dysfunction, dementia, transient infarcts, and white matter lesions are widespread in mild to moderate chronic kidney disease patients. Uremic toxins produced after chronic kidney disease can pass through the blood-brain barrier and mediate cognitive dysfunction and neurodegeneration. Furthermore, chronic kidney disease precipitates vascular risk factors that can lead to atherosclerosis, hypertension, atrial fibrillation, and diabetes. Chronic kidney disease also exacerbates stroke pathogenesis, worsens recovery outcomes, and limits the eligibility of stroke patients to receive available stroke therapeutics. This review highlights the mechanisms involved in the advancement of chronic kidney disease and its possible association with stroke.

Keywords: Thrombolysis; brain damage; inflammation; peripheral organ disease; vascular fibrosis.

Figure 1.

CKD induces pre- and post-stroke complications. Abnormal changes in endogenous tPA/PAI-1, MMP-9, uremic toxins such as indoxyl sulfate, p-cresyl sulfate and guanidino substances and profibrotics like TGF-β1, Tenascin-C, PAI, ANG-II, and comorbid conditions like hypertension and diabetes lead to the progression of CKD from stage 1 to stage 5. Advancement of CKD also leads to progressive endothelial dysfunction, vascular stiffness, BBB disruption, and peripheral/central inflammation. These have severe consequences in the brain during both pre-stroke and post-stroke stages. tPA: tissue plasminogen activator; PAI-1: plasminogen activator inhibitor-1; MMP-9: matrix metalloproteinase-9; ESRD: end-stage renal disease; BBB: blood–brain barrier; rtPA: recombinant tissue plasminogen activator.

Figure 2.

Possible mechanism of hemorrhagic transformations after thrombolysis. Cumulative endogenous tPA in circulation due to abnormalities in tPA/PAI ratio and exogenous administration affects the influx of excess circulatory tPA into the ischemic tissue. Excess accumulation of extracellular matrix components, uremic toxins, energy failure, oxidative stress, and excitotoxicity influences the effects of cellular as well as circulatory tPA. In stroke–CKD cases, bleeding complications are mediated by MMP-9, synergistically with cytokine activity of tPA, uremic toxins, and altered ECM leading to hemorrhagic transformation. CKD: chronic kidney disease; MMP-9: matrix metalloproteinase-9; tPA: tissue plasminogen activator; ECM: extracellular matrix.