Introduction 

Chronic kidney disease (CKD) affects 10–15% of the population globally ^[1]. Reduced kidney function can lead to CKD-associated cardiomyopathy, characterized by increased left ventricular mass, diastolic and systolic dysfunction, arrhythmias, and cardiac fibrosis. Our research shows that even individuals with moderate renal impairment exhibit cardiac structural changes ^[2] and are at risk of arrhythmias. Despite its high morbidity and mortality, CKD-associated cardiomyopathy remains poorly understood. This study explores the early mechanistic drivers of CKD-associated cardiomyopathy using a murine model induced by an adenine-rich diet. 

Methods 

8–12-week-old C57BL/6 mice were fed normal chow (male n=9, female n=9) or a 0.15% adenine diet (male n=16, female n=9) for up to 7 weeks. Blood plasma creatinine and urea were measured at sacrifice to assess kidney dysfunction. Kidney and cardiac tissue weights were recorded, and fibrosis was evaluated using histology and collagen 1 western blots. An O-link Target 48 proteomic cytokine panel assessed changes in serum levels of 45 cytokines. 

Results 

Adenine diet at 7 weeks significantly increased urea (p < 0.0001) in both males (adenine 27.91±5.385 mmol/L vs. control 8.84±0.786 mmol/L) and females (adenine 25.80±2.480 mmol/L vs. control 8.39±0.318 mmol/L). Creatinine also saw a significant increase (p < 0.0001) in both adenine males (adenine 48.89±3.434 umol/L vs. control 10.43±2.159 umol/L) and females (adenine 53.00±5.279 umol/L vs. control 14.86±1.184 umol/L). Kidney weight significantly decreased (p<0.001) in adenine-fed males (104.2 ± 4.600 mg) and females (190.2 ± 11.20 mg) compared to controls (155.8 ± 6.565 mg and 260.9 ± 8.957 mg, respectively). No significant changes in heart-to-body weight ratio were observed in adenine-fed mice (5.489 ± 0.3302 mg/g) compared to controls (5.307 ± 0.1096 mg/g).  Histological evidence of fibrosis was observed in the right atrium (4.869 ± 0.5893% vs. 2.158 ± 0.3725%, p < 0.0001), left ventricle (2.866 ± 0.8118% vs. 0.8257 ± 0.1084%, p < 0.01), and left atrium (2.038 ± 0.2326% vs. 1.258 ± 0.1475%, p < 0.05) compared to controls. Western blots also detected an increased collagen 1 protein expression (p<0.05) in adenine fed mice. 39 of 45 proinflammatory cytokines were elevated in adenine fed mice, including biomarkers associated with cardiomyopathy, such as Ccl5, Ccl11, and Ffgf21. 

Conclusion 

The adenine diet induced early CKD-associated cardiomyopathy, characterized by cardiac fibrosis and systemic inflammation, without significant changes in heart weight ^[3]. Our ongoing work is examining the haemodynamic changes, in vivo ECG and electrical changes in the heart.