Both hyperglycemia and hyperuricemia aggravate acute kidney injury during cholesterol embolism syndrome despite opposite effects on kidney infarct size

Abstract

Kidney cholesterol crystal embolism (CCE) occurs in advanced atherosclerosis and induces a thrombotic (micro)angiopathy, a drop in the glomerular filtration rate (GFR), and an ischemic kidney infarction with necroinflammation. We speculated that common metabolic comorbidities such as diabetes or hyperuricemia would independently modulate each of these distinct pathophysiological processes. To test this, experimental CCE was induced by injecting cholesterol crystals into the left kidney artery of mice and thrombotic angiopathy, GFR drop, and infarct size were analyzed after 24 hours in the presence of hyperglycemia (about 500 mg/dL) or hyperuricemia (about 8 mg/dL) or their absence. In healthy mice, unilateral CCE caused diffuse thrombotic angiopathy in interlobar, arcuate and interlobular arteries, followed by a 50% or less drop in GFR compared to baseline and a variable degree of ischemic kidney necrosis. Hyperglycemia but not hyperuricemia aggravated thrombotic angiopathy although both caused a GFR decline, albeit via different mechanisms. Hyperglycemia aggravated GFR loss by increasing necroinflammation and infarct size, while the antioxidative effects of hyperuricemia reasonably attenuated necroinflammation and infarct size but induced a diffuse vasoconstriction in affected and unaffected kidney tissue. Thus, both hyperglycemia or hyperuricemia aggravate CCE-induced acute kidney failure despite having opposite effects on ischemic necroinflammation and infarction.

Keywords: acute kidney injury; diabetes; infarct; necroinflammation; thrombosis.