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Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

Abstract

Chronic kidney disease (CKD) induces modifications in lipid and lipoprotein metabolism and homeostasis. These modifications can promote, modulate and/or accelerate CKD and secondary cardiovascular disease (CVD). Lipid and lipoprotein abnormalities — involving triglyceride-rich lipoproteins, LDL and/or HDL — not only involve changes in concentration but also changes in molecular structure, including protein composition, incorporation of small molecules and post-translational modifications. These alterations modify the function of lipoproteins and can trigger pro-inflammatory and pro-atherogenic processes, as well as oxidative stress. Serum fatty acid levels are also often altered in patients with CKD and lead to changes in fatty acid metabolism — a key process in intracellular energy production — that induce mitochondrial dysfunction and cellular damage. These fatty acid changes might not only have a negative impact on the heart, but also contribute to the progression of kidney damage. The presence of these lipoprotein alterations within a biological environment characterized by increased inflammation and oxidative stress, as well as the competing risk of non-atherosclerotic cardiovascular death as kidney function declines, has important therapeutic implications. Additional research is needed to clarify the pathophysiological link between lipid and lipoprotein modifications, and kidney dysfunction, as well as the genesis and/or progression of CVD in patients with kidney disease.

Key points

  • HDL and LDL modifications in chronic kidney disease (CKD) increase cardiovascular risk; targeting these modifications might lead to the development of novel therapeutic strategies.

  • In CKD, alterations in proteome content, metabolic solute accumulation and post-translational modifications convert HDL from an anti-inflammatory to a pro-inflammatory molecule and enhance the pro-inflammatory character of LDL.

  • HDL modifications, and the altered correlation between HDL levels and cardiovascular risk in patients with CKD compared with the general population, support the concept that HDL function, rather than HDL cholesterol levels, influences cardiovascular risk.

  • The contribution of non-atherosclerotic cardiovascular disease to cardiovascular risk in patients with CKD increases with declining kidney function, which further contributes to an altered correlation between lipoprotein levels and overall cardiovascular risk in these patients.

  • Deregulated fatty acid metabolism and mitochondrial dysfunction not only negatively affect the heart but also contribute to kidney pathology by promoting inflammation and fibrosis; autophagy has protective effects.

  • Accumulation of saturated fatty acids triggers mitochondrial and cell damage in the kidney, whereas the polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid are renoprotective.

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Fig. 1: Lipoprotein structure, classification and metabolism.
Fig. 2: Dyslipidaemia in CKD.
Fig. 3: Effects of changes in HDL and LDL composition in CKD.
Fig. 4: Impaired fatty acid metabolism and mitochondrial overload contribute to inflammation, fibrosis and cellular damage in kidney.

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Acknowledgements

This work was supported by the German Research Foundation (DFG) SFB/TRR219 Project-ID 322900939 (S-03, C-04, M-03, M-05), SFB 1382 Project-ID 403224013 (A-04), by the CORONA foundation and by the Interreg V-A EMR program (EURLIPIDS, EMR23). This project also received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn).

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Glossary

Uraemic retention solutes

Substances that accumulate in blood of patients with chronic kidney disease owing to reduced kidney clearance.

Mitochondrial overload

A condition in which mitochondria are presented with an excess of substrate, which overwhelms the mitochondrial capacity for fatty acid β-oxidation, reduces free CoA levels and induces the accumulation of excess acetyl-CoA.

Cholesterol efflux capacity

The capacity of HDL to extract cholesterol from macrophages.

Pulse wave velocity

Velocity at which a blood pressure pulse travels through the vessels; used as a clinical measure of arterial stiffness.

Acute phase protein

A component of the acute phase response, which is the initial systemic response of an organism to inflammation and is characterized by an increase or decrease in acute phase proteins in blood.

Residence time

The length of time present in the circulation.

Malnutrition–inflammation–cachexia syndrome

A condition characterized by malnutrition (protein-energy wasting, defined as loss of body protein mass and energy reserves (fat mass)), inflammation and/or oxidative stress; common in chronic diseases such as chronic kidney disease.

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Noels, H., Lehrke, M., Vanholder, R. et al. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations. Nat Rev Nephrol 17, 528–542 (2021). https://doi.org/10.1038/s41581-021-00423-5

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