Evolving concepts in the pathogenesis of uraemic cardiomyopathy

Abstract

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.

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.

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Fig. 1: Molecular mechanisms of haemodynamic overload in uraemic cardiomyopathy.
Fig. 2: The role of mineral and bone disorder in uraemic cardiomyopathy.
Fig. 3: The role of insulin resistance in uraemic cardiomyopathy.
Fig. 4: Endogenous cardiotonic steroids and the Na+/K+-ATPase–Src–ROS amplification loop in uraemic cardiomyopathy.
Fig. 5: Crosstalk between signalling pathways involved in uraemic cardiomyopathy.

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Acknowledgements

The authors’ work was supported by US National Institutes of Health grants HL109015, HL071556 and HL105649; by the Brickstreet Foundation; and by the Huntington Foundation, Inc.

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Nature Reviews Nephrology thanks C. Faul, J. Jankowski and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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Glossary

Endogenous cardiotonic steroids

A class of steroid hormones with important roles in health and disease. Endogenous cardiotonic steroids such as cardenolide and bufadienolide signal through the Na+/K+-ATPase.

Pressure overload

Refers to the pathological state of cardiac muscle in which it has to contract against excessive pressure.

Volume overload

Refers to the pathological state of the heart in which an abnormally large volume of blood must be pumped.

Hypervolaemia

Also known as fluid overload, hypervolaemia is a pathological condition in which there is too much fluid in the blood. Hypervolaemia is common in the setting of renal failure.

Aortocaval fistula

A surgically created arteriovenous fistula between the abdominal aorta and inferior vena cava, distal to the origin of the renal arteries. Aortocaval fistula is used as an experimental model of volume overload.

Secondary hyperparathyroidism

Refers to excessive secretion of parathyroid hormone by the parathyroid gland in response to low serum calcium level and high phosphorus level in the setting of renal failure.

Inflammasomes

A multiprotein intracellular complex that detects pathogenic microorganisms and activates inflammatory responses via the activation of pro-inflammatory cytokines such as IL-1β and IL-18.

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Wang, X., Shapiro, J.I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy. Nat Rev Nephrol 15, 159–175 (2019). https://doi.org/10.1038/s41581-018-0101-8

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