Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology

Abstract

The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.

Keywords: animal; biomarker; cardiorenal; uremic cardiomyopathy.

Figure 1:

Human biomarkers of increased cardiovascular risk in patients with CKD. Parameters of kidney injury, cardiac injury, inflammation and mineral bone disorder, as well as uremic toxins have been associated with increased cardiovascular risk in patients with CKD. For more information, see text.

Figure 2:

Pathophysiological mechanisms studied in animal models of CKD-induced cardiomyopathy. CKD triggers pathophysiological effects like hemodynamic alterations through the RAAS, the SNS and MR signaling, inflammation and oxidative stress, disturbances in mineral metabolism and the accumulation of uremic toxins. In red, molecular mediators are indicated that have been identified to contribute to uremic cardiomyopathy. In green, treatments or conditions that were effective in reducing or attenuating uremic cardiomyopathy, are highlighted. For more information, see text. β1-AR, beta-1 adrenergic receptor; LCZ696, combination of sacubitril and valsartan; TAK-242, TLR4 inhibitor.