A New Model of Chronic Kidney Disease, Metabolic Derangements, and Heart Failure with Preserved Ejection Fraction in Aging Swine.

INTRODUCTION

Chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF) are more prevalent in the elderly. There is a lack of large animal models that allow the study of the impact of age on CKD and HFpEF in a translational fashion. This manuscript reports the first large preclinical model of CKD-HFpEF and metabolic derangements in naturally aged swine.

METHODS

CKD-HFpEF was induced in naturally aged (6-9 years old) and young (3 months old) pigs, followed for 14 weeks, and compared to normal young and old controls (n = 5/group). Renal and cardiac hemodynamics were quantified in vivo by multidetector-CT, echocardiography, and pressure-volume relationship studies. Renal and cardiac microvascular (MV) architecture (3D-micro-CT) and morphometric analysis (staining) were investigated ex vivo.

RESULTS

Both young and old pigs developed CKD-HFpEF, but the renal, cardiac, and metabolic phenotype was accentuated in aging animals. Aging and CKD-HFpEF influenced fasting insulin levels and insulin resistance, glomerular filtration rate, cortical MV density, glomerulosclerosis, perivascular fibrosis, and tubular injury. Tubule-interstitial fibrosis and peritubular capillary density were influenced by aging, CKD-HFpEF, and their interaction (2-way ANOVA). Similarly, cardiac MV density, perivascular fibrosis, and myocardial remodeling were influenced by aging and CKD-HFpEF, and E/A by their interaction. Notably, renal and cardiac MV density correlated with renal and cardiac functional and structural changes.

CONCLUSION

Our study establishes the first large animal model of aging CKD-HFpEF, allowing the investigation of age as a biological variable in cardiorenal and metabolic diseases. This new platform could foster new age-related research toward developing therapeutic interventions in CKD-HFpEF.