Evolving concepts in the pathogenesis of uraemic cardiomyopathy

The term uraemic cardiomyopathy refers to the cardiac abnormalities that are seen in patients with chronic kidney disease (CKD). Historically, this term was used to describe a severe cardiomyopathy that was associated with end-stage renal disease and characterized by severe functional abnormalities that could be reversed following renal transplantation. In a modern context, uraemic cardiomyopathy describes the clinical phenotype of cardiac disease that accompanies CKD and is perhaps best characterized as diastolic dysfunction seen in conjunction with left ventricular hypertrophy and fibrosis. A multitude of factors may contribute to the pathogenesis of uraemic cardiomyopathy, and current treatments only modestly improve outcomes. In this Review, we focus on evolving concepts regarding the roles of fibroblast growth factor 23 (FGF23), inflammation and systemic oxidant stress and their interactions with more established mechanisms such as pressure and volume overload resulting from hypertension and anaemia, respectively, activation of the renin–angiotensin and sympathetic nervous systems, activation of the transforming growth factor-β (TGFβ) pathway, abnormal mineral metabolism and increased levels of endogenous cardiotonic steroids. Uraemic cardiomyopathy is the major phenotype of fatal cardiac disease in patients with end-stage renal disease. This Review focuses on the molecular mechanisms of uraemic cardiomyopathy, crosstalk between these mechanisms and implications for therapy Key points Patients with chronic kidney disease or end-stage renal disease have an increased risk of cardiovascular disease and mortality. Uraemic cardiomyopathy is characterized by diastolic dysfunction and marked left ventricular hypertrophy with profound ventricular fibrosis. Factors that have been implicated in the development and progression of uraemic cardiomyopathy include haemodynamic overload, alterations in mineral metabolism, insulin resistance, circulating uraemic toxins and endogenous cardiotonic steroids. Oxidative stress seems to have a role in all of the putative molecular pathways that are involved in the pathogenesis of uraemic cardiomyopathy. Treatments that are effective in other cardiomyopathic conditions such as antihypertensive drugs improve clinical outcomes in uraemic cardiomyopathy only modestly at best. The available data suggest that targeting oxidative stress might be a beneficial therapeutic strategy for patients with uraemic cardiomyopathy.