Vascular calcification and atherosclerosis

This research, conducted at the New York Institute of Technology College of Osteopathic Medicine, examined the relationship between chronic kidney disease (CKD), vascular calcification, and atherosclerosis using an adenine-induced mouse model combined with diet-induced hypercholesterolemia. Motivated by the clinical observation that CKD patients face elevated risk of atherosclerotic cardiovascular disease and often present with vascular calcification, the team sought to test whether calcification associated with CKD could exacerbate atherosclerosis. Recognizing limitations of the commonly used 5/6 nephrectomy model, including surgical variability and irreversibility, the investigators employed a non-surgical adenine-induced model of CKD that has been used in vascular calcification studies and is purportedly reversible upon adenine discontinuation.

Two experimental approaches were used. In the first, mice carrying a mutation in the low-density lipoprotein receptor gene were co-treated with 0.2% adenine in a western diet for eight weeks to induce CKD and atherosclerosis concurrently. In the second, mice were pre-treated with adenine in a regular diet for eight weeks to establish CKD and then switched to a western diet for an additional eight weeks to induce atherosclerosis. Across both study designs, adenine treatment produced a clear CKD phenotype characterized by renal tubulointerstitial damage and polyuria, and in the two-step model these renal abnormalities persisted after adenine discontinuation.

Contrary to the original hypothesis, simultaneous adenine exposure and western diet reduced plasma triglycerides and cholesterol, liver lipid content, and aortic root atherosclerosis relative to mice fed the western diet alone, despite the presence of CKD. In the two-step model, after adenine pre-treatment and subsequent western diet feeding, mice exhibited similar plasma triglycerides, cholesterol, liver lipids, and aortic root atherosclerosis compared with control mice that had not been pre-treated with adenine. An unexpected behavioral and metabolic observation was that adenine pre-treated mice consumed approximately twice the calories from the diet as controls without a corresponding increase in body weight.

These findings led the authors to conclude that the adenine-induced CKD model does not reproduce the anticipated acceleration of atherosclerosis and therefore has limitations for use in preclinical studies aimed at modeling CKD-associated atherosclerotic cardiovascular disease. The paradoxical reduction in plasma lipids and atherosclerosis suggests that excessive adenine intake itself affects lipid metabolism, confounding interpretation when using this model to study the interaction between CKD, vascular calcification, and atherosclerosis. The study highlights the importance of carefully selecting and validating animal models when investigating complex clinical interrelationships, as model-specific effects—such as adenine’s impact on lipid handling—can produce results that diverge from clinical expectations and obscure underlying mechanisms. The researchers call for caution in applying the adenine-induced CKD model to studies of atherosclerosis and suggests a need for alternative or complementary models to investigate how CKD-associated calcification may influence atherogenesis.