Heart dysfunction in a rat model with autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) is a congenital hepatorenal fibrocystic pathology and is one of the most significant childhood nephropathies leading to chronic kidney disease (CKD). While kidney damage has been well studied in this pathology, only a few studies have investigated specific cardiac damage during ARPKD. This study aimed to conduct a large analysis of heart dysfunction during the progression of CKD. ARPKD rats with the Pkhd1 gene mutation (IVS35-2A>T) were monitored for CKD progression and heart dysfunction via echocardiography. Heart fibrosis was assessed using Sirius red staining, and cardiokines mRNA expressions in heart tissue were analysed. ARPKD rats exhibited increased blood pressure, cardiac hypertrophy and thickening of the left ventricular posterior wall, correlated with elevated plasma creatinine levels. Diastolic dysfunction was evident, shown by altered E/A and E/e' ratios, which worsened with CKD severity. Heart fibrosis correlated with renal dysfunction, and fibrosis signalling pathways were activated, marked by increased galectin-3, collagen-1, fibroblast growth factor 23, suppressor of tumorigenicity 2 (ST2) and soluble ST2 expression. Growth differentiation factor 15 levels rose with CKD progression, while Irisin levels decreased, negatively correlating with the E/e' ratio. This study highlights diastolic dysfunction, heart fibrosis, and hypertrophy in ARPKD rats with severe CKD. These cardiac changes are linked to dysregulation in cardiokine signalling, providing new insights into uraemia-induced heart failure in ARPKD KEY POINTS: Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder with a reduced life expectancy and a broad clinical spectrum including systemic hypertension, renal failure, portal hypertension, and renal and hepatic fibrosis. PCK rats have a spontaneous mutation in the Pkhd1 gene, the same gene affected in human ARPKD. PCK rats develop renal and hepatic cysts and other manifestations of human ARPKD. Changes in heart tissue (fibrosis, hypertrophy) and diastolic dysfunction (decreasing E/A and increasing E/e' ratios) worsen with renal dysfunction in PCK rats. Heart dysfunctions are associated with a dysregulation of cardiokine signalling such as Irisin, in PCK rats. Irisin could be a new marker of diastolic function in ARPKD and chronic kidney disease patients.