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Cardiac metabolic remodelling in chronic kidney disease

Abstract

Chronic kidney disease (CKD) affects millions of people globally and, for most patients, the risk of developing cardiovascular disease is higher than that of progression to kidney failure. Moreover, mortality owing to cardiovascular complications in patients with CKD is markedly higher than in matched individuals from the general population. This mortality was traditionally thought to be driven by coronary heart disease but >75% of patients with CKD have left ventricular hypertrophy, which contributes to mortality, particularly sudden cardiac death. The aetiology of cardiac complications in CKD is multifactorial. In addition to haemodynamic overload, uraemic toxin accumulation and altered ion homeostasis, which are known to underlie left ventricular hypertrophy in CKD and drive cardiac dysfunction, we examine the role of myocardial metabolic remodelling in CKD. Uraemic cardiomyopathy is characterized by myriad cardiac metabolic maladaptations, including altered mitochondrial function, changes in myocardial substrate utilization, altered metabolic transporter function and expression, and impaired insulin response and phosphoinositide-3 kinase–AKT signalling, which collectively lead to impaired cardiac energetics. Interestingly, none of the standard treatments used to treat CKD target the metabolism of the uraemic heart directly. An improved understanding of the cardiac metabolic perturbations that occur in CKD might allow the development of novel treatments for uraemic cardiomyopathy.

Key points

  • Uraemic cardiomyopathy observed in patients with chronic kidney disease (CKD) is characterized by the presence of diastolic dysfunction, left ventricular hypertrophy and fibrosis. Some of the main mechanisms underlying this cardiomyopathy are unique to CKD, whereas others are also observed in other conditions, such as hypertension and volume overload.

  • Left ventricular hypertrophy is a hallmark of CKD and the main factors underlying its development include insulin resistance, accumulation of endogenous cardiotonic steroids and uraemic toxins, vitamin D deficiency, hyperphosphataemia and haemodynamic overload, which induces mechanical stress.

  • Uraemic cardiomyopathy is characterized by extensive metabolic remodelling, including secondary carnitine deficiency, reduced fatty acid use, enhanced glucose utilization, mitochondrial dysfunction and altered expression of metabolic regulatory genes, which collectively result in impaired energetics.

  • The prevalence of CKD and its associated cardiovascular complications is rising globally, therefore increasing the demand for novel therapeutic approaches. Cardiac metabolic remodelling in uraemia represents a potential therapeutic target for addressing cardiovascular mortality in CKD.

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Fig. 1: Mechanisms involved in the progression to HFpEF in CKD.
Fig. 2: Left ventricular hypertrophy mechanisms in CKD.
Fig. 3: Altered cardiac metabolism in CKD.
Fig. 4: Mechanism of myocardial insulin resistance in CKD.

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Acknowledgements

N.P. has received a British Heart Foundation MRes/PhD Studentship. [FS/4YPhD/P/20/34016]. D.A. has received funding from the Wellcome Trust (221604/Z/20/Z) and Barts Charity Grants (MRC0215, G-002145). M.M.Y. acknowledges a Barts Charity programme grant for the Diabetic Kidney Care research centre.

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Correspondence to Dunja Aksentijevic.

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Glossary

Pressure overload

Pathological state in which the heart has to contract with excessive afterload owing to an increase in arterial pressure.

Volume overload

Expansion of extracellular fluid volume, which is common in patients with CKD and is associated with anaemia, hypertension, proteinuria, arterial stiffness and inflammation.

Concentric hypertrophy

Increased cardiac muscle wall thickness resulting in diminished capacity or volume.

Positive inotropic responses

Increased strength of muscular contraction and cardiac output.

Rapid cooling contractures

Muscle damage and impaired recovery caused by rapid myocardial cooling.

Randle cycle

Metabolic process also known as the glucose–fatty acid cycle, which describes metabolic fuel flux and selection in tissues.

Anaplerosis

Replenishment of Krebs cycle intermediates that have been extracted for biosynthetic pathways.

Dobutamine stress

Administration of strongly inotropic catecholamine dobutamine to increase cardiac output.

Late Na+ current

The residual Na+ current flowing after the large peak Na+ current during an action potential or voltage clamp.

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Patel, N., Yaqoob, M.M. & Aksentijevic, D. Cardiac metabolic remodelling in chronic kidney disease. Nat Rev Nephrol 18, 524–537 (2022). https://doi.org/10.1038/s41581-022-00576-x

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