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Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease

Nature Reviews Nephrology volume 19, pages 629–645 (2023)Cite this article

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Abstract

Chronic kidney disease (CKD) is a global health problem with rising incidence and prevalence. Among several pathogenetic mechanisms responsible for disease progression, lipid accumulation in the kidney parenchyma might drive inflammation and fibrosis, as has been described in fatty liver diseases. Lipids and their metabolites have several important structural and functional roles, as they are constituents of cell and organelle membranes, serve as signalling molecules and are used for energy production. However, although lipids can be stored in lipid droplets to maintain lipid homeostasis, lipid accumulation can become pathogenic. Understanding the mechanisms linking kidney parenchymal lipid accumulation to CKD of metabolic or non-metabolic origin is challenging, owing to the tremendous variety of lipid species and their functional diversity across different parenchymal cells. Nonetheless, multiple research reports have begun to emphasize the effect of dysregulated kidney lipid metabolism in CKD progression. For example, altered cholesterol and fatty acid metabolism contribute to glomerular and tubular cell injury. Newly developed lipid-targeting agents are being tested in clinical trials in CKD, raising expectations for further therapeutic development in this field.

Key points

  • Lipids and lipid-related enzymes have a major role in modulating the function of glomerular and tubular cells, and can drive chronic kidney disease (CKD) irrespective of circulating lipid levels.

  • The mechanisms that initiate the accumulation of kidney lipids might differ between CKD of different aetiologies. Thus, the accumulation of kidney lipids in diabetic kidney disease is driven by increased glucose and fatty acids levels owing to insulin resistance, whereas in glomerulonephritis, inflammation can disrupt normal kidney lipid metabolism.

  • Several lipid species, such as cholesterol, triglycerides, fatty acids and phospholipids, are dysregulated in podocytes, endothelial and tubular cells, and contribute to CKD progression.

  • Accumulation of kidney parenchymal cholesterol occurs in association with impaired reverse cholesterol transport in diseases of both metabolic and non-metabolic origin, and contributes to CKD progression.

  • Accumulation of fatty acids triggers mitochondrial and kidney cell damage by promoting inflammation, including cellular sterile inflammation, via innate immune system activation and fibrosis; lipophagy has a protective effect.

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Fig. 1: Main mechanisms of fatty acid dysregulation in health and CKD.
Fig. 2: Main mechanism of cholesterol dysregulation in health and CKD.

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Acknowledgements

We give special thanks to the Katz family for their continuous support.

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Authors and Affiliations

  1. Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA

    Alla Mitrofanova, Sandra Merscher & Alessia Fornoni

  2. Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA

    Alla Mitrofanova, Sandra Merscher & Alessia Fornoni

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Contributions

A.M. researched data for the article, made substantial contributions to discussions of the content and wrote the manuscript. S.M. and A.F. reviewed or edited the manuscript before submission.

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Correspondence to Alessia Fornoni.

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Competing interests

A.F. and S.M. are inventors on pending or issued patents (US10.183.038, US10.052.345) aimed at diagnosing or treating proteinuric kidney diseases and therefore stand to gain royalties from their future commercialization. A.F. is Chief Scientific Officer of L&F Health LLC, holds equity interests in L&F Research and is the inventor of assets developed by ZyVersa Therapeutics. ZyVersa has licensed worldwide rights to develop and commercialize hydroxypropyl-β-cyclodextrin for the treatment of kidney disease from L&F Research. A.F. also holds equity in River 3 Renal Corporation. S.M. holds equity interest in L&F Research. A.M. declares no competing interests.

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Mitrofanova, A., Merscher, S. & Fornoni, A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat Rev Nephrol 19, 629–645 (2023). https://doi.org/10.1038/s41581-023-00741-w

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