Abstract Body (Do not enter title and authors here): The anatomical and physiological congruence of cynomolgus macaques (Macaca fascicularis) to humans make them valuable models for translational research into heart failure (HF), renal disease (RD), and cardio-renal syndrome (CRS).

In this study, we characterized aged cynomolgus monkeys with atherogenic diet-induced heart failure with reduced ejection fraction (HFrEF), including those with albuminuric RD—with or without changes in glomerular filtration rate (GFR)—to determine CRS progression and to compare findings with age-matched healthy controls.

Sixty cynomolgus monkeys with HFrEF (mean ejection fraction [EF] 55.3% ± 0.7%) were studied. Animals were stratified into two groups based on baseline albuminuria status: microalbuminuric (HFrEF+RD; n=30) and normoalbuminuric (HFrEF-only, n=30). Multimodal diagnostics included cardiac 2D echocardiography, renal ultrasound, and biochemical analyses of urine and blood samples. Parameters assessed were 24-hour urine albumin-creatinine ratio (UACR), blood urea nitrogen, serum creatinine, and estimated GFR. Renal hemodynamics were evaluated by renal artery volume flow, peak systolic velocity, resistive index (RI), and pulsatility index (PI).

HFrEF+RD animals exhibited a significant 2.8-fold increase in UACR over 25 weeks from 47.9±16.6 mg/g to 134.6±50.6 mg/g (p<0.001) while the UACR of the HFrEF-only animals remained stable. Baseline renal ultrasound revealed significantly lower renal artery volume flow (p<0.01) and peak systolic velocity (p<0.0001) in both HFrEF+RD and HFrEF-only groups compared to controls. GFR was moderately reduced in both groups implying mild to moderate renal functional impairment. Notably, RI and PI values remained within normal limits, consistent with early or less severe renal vascular injury. These findings reflected evolving CRS primarily characterized by progressive proteinuria and declining renal hemodynamics essentially in the HFrEF+RD cohort.

These findings demonstrate that aged cynomolgus macaques with HFrEF develop CRS phenotypes closely resembling human disease, with HF contributing to progressive renal impairment through hemodynamic and molecular mechanisms. This NHP model offers significant translational potential to elucidate bidirectional heart-kidney interactions, and to enable the preclinical evaluation of novel therapeutic strategies targeting CRS.