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.

Increased cardiovascular risk in patients with chronic kidney disease

“…Furthermore, the risk of heart failure, atrial fibrillation, and sudden cardiac death is increased in CKD, with the latter responsible for 28% of cardiovascular deaths in CKD patients compared to only 2% in the general population [ 1 , 4 ]. Underlying causes include uremic cardiomyopathy characterized by left ventricular hypertrophy and cardiac interstitial fibrosis, as well as cardiac electrical dysregulation triggering arrhythmias [ 7 ].…”

“…Chronic kidney disease is associated with a chronic activation of the RAAS as well as of the sympathetic nervous system (SNS), which results in persistently increased blood flow and hypertension. Inhibition of the RAAS system under CKD conditions is cardioprotective as shown in animal models of uremic cardiomyopathy, in which RAAS inhibition prevented or at least alleviated CKD-induced cardiac fibrosis and cardiac inflammation, and this at least partly also through blood pressure-independent effects [ 7 ].…”

“…These neurotransmitters can contribute to hypertension, vascular stiffness, and endothelial dysfunction [ 39 ]. Inhibition of increased SNS activity in a cardiorenal rat model reduced blood pressure, cardiac fibrosis, and cardiac apoptotic pathways [ 7 ].…”

Thrombospondin-1 in Chronic Kidney Disease Driven Cardiac Dysfunction

“…Accordingly, previous studies summarized the use of serum biomarkers (eg, atrial and B-type natriuretic peptide, isoforms of troponins, adiponectin, plasma growth differentiation factor-15, ECM proteins) for cardiovascular disease risk prediction in CKD. 2 , 3 Most cardiovascular diseases (eg, CKD) involve severe remodeling of the ECM, culminating in the formation of fibrotic tissue that is deleterious to organ function and ECM protein may serve as a biomarker for disease progression 4 and targeted therapy for heart failure in CKD. In addition, the accumulation of non-hemodialyzable uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, in the circulation and in tissues serves as a biomarker and is associated with the progression of CKD, and CVD in patients with CKD.…”