Chronic kidney disease induces a distinct lipidomic signature and accelerates atherosclerosis progression in a novel minipig model

Chronic kidney disease (CKD) markedly accelerates atherosclerosis, driving the excess cardiovascular morbidity and mortality in these patients. While rodent models have been indispensable for mechanistic studies, their small vessel size limits the use of non-invasive vascular imaging to monitor disease progression. Therefore, large-animal models are needed to bridge experimental insights with clinical applicability. We aimed to establish a novel minipig model of CKD to characterize the temporal changes of CKD-driven atherosclerosis. Six female Yucatan minipigs overexpressing a human gain-of-function PCSK9 mutant were randomized to CKD (n = 3) or control (n = 3) groups. CKD was induced by selective clamping of the left renal artery branches combined with contralateral nephrectomy using a minimally invasive laparoscopic approach. All animals were fed with a high-fat, high-cholesterol diet and followed for 15 months. Longitudinal assessments included vascular and renal ultrasound, computed tomography, plasma iohexol clearance for glomerular filtration rate (GFR) determination, and biochemical profiling of ions, cytokines, chemokines, and lipids, including advanced lipoprotein, lipidomic and fatty acid analyses. Between-groups differences were evaluated using effect sizes with 95% confidence intervals. CKD pigs exhibited a significant reduction in GFR and increased blood creatinine. They exhibited accelerated atherogenesis, reflected by enhanced progressive adventitial vasa vasorum neovascularization in both carotid and iliac arteries, a higher burden of arterial calcifications in abdominal aorta and iliac arteries and postmortem larger atherosclerotic plaques and calcified areas in coronary arteries. CKD also altered the systemic inflammation profile (elevated IL-1ra, IL-2, IL-4, IL-8, and IL-10), promoted a proatherogenic lipoprotein phenotype with triglyceride-enriched VLDL, LDL, and IDL particles, increased VLDL particle number, and reduced LDL particle size. Lipidomic analyses revealed increased circulating and renal palmitic acid and distinct lesion-specific fatty acid signatures. Fatty streaks were enriched in palmitic acid and 10,16-dihydroxy-palmitic acid, and mature carotid plaques accumulated polyunsaturated fatty acids. This minimally invasive CKD model in gentically modified minipigs accelerates atherosclerosis and induces a unique lipidomic remodelling, providing a valuable translational platform to study kidney-vascular interactions and to test therapeutic interventions targeting CKD-driven atherosclerosis.