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Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

Nature Reviews Nephrology volume 14, pages 57–70 (2018)Cite this article

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A Corrigendum to this article was published on 13 December 2017

This article has been updated

Key Points

  • Prolonged hyperlipidaemia in nephrotic syndrome is a major risk factor for multiple disease complications, including accelerated atherosclerosis, myocardial infarction, stroke, chronic kidney disease and thrombosis

  • Direct lipid-induced cellular injury to podocytes, mesangial cells and, potentially, renal tubular cells as a result of dyslipidaemia increasingly seems to have a role in the pathogenesis of nephrotic syndrome

  • Given the available evidence, we suggest that statins should be the first-line treatment for prolonged hyperlipidaemia in patients with nephrotic syndrome, given their efficacy in the treatment of other diseases and the fact that they are well tolerated

  • Alternative, less supported treatments include LDL apheresis, cholesterol absorption inhibitors, nicotinic acid and bile acid sequestrants; targeting proprotein convertase subtilisin/kexin type 9 is another potential treatment for hyperlipidaemia in patients with nephrotic syndrome

  • Treatment recommendations in children are limited by a lack of data for both the efficacy and the risk of pharmacological interventions

Abstract

Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.

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Figure 1: The major pathways of lipid metabolism.
Figure 2: Pathophysiology of dyslipidaemia in nephrotic syndrome.
Figure 3: Mechanisms and consequences of lipid nephrotoxicity.

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Change history

  • 13 December 2017

    In the version of this article originally published online, the affiliations of the authors were incorrect. This error has now been corrected in the print and online versions.

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Acknowledgements

The authors acknowledge the expert assistance of L. Feurer (Center for Clinical and Translational Research, The Research Institute at Nationwide Childrens Hospital, Columbus, Ohio,USA) in creating initial drafts of the figures in this manuscript.

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Authors and Affiliations

  1. and Department of Pediatrics, Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, W303, Columbus, 43205, Ohio, USA

    Shipra Agrawal & William E. Smoyer

  2. Division of Pediatric Nephrology, Department of Pediatrics Nemours/Alfred I. duPont Hospital for Children, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19803, Delaware, USA

    Joshua J. Zaritsky

  3. Katz Family Division of Nephrology and Hypertension, Peggy and Harold Katz Drug Discovery Center, University of Miami Miller School of Medicine, 1580 NW 10th Avenue, Miami, 33133, Florida, USA

    Alessia Fornoni

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Glossary

Sialylation

Addition of sialic acid groups onto molecules such as oligosaccharides and carbohydrates.

Glycocalyx

Layer of glycoproteins and sugar moieties surrounding the outer surface of the cell membrane of some bacteria, epithelia and other cells.

Tangier disease

A rare inherited disorder characterized by significantly reduced levels of HDL in the blood.

Lipid raft

A subdomain of the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids.

Lipid apheresis

A non-surgical therapy and a form of apheresis that removes LDL from a patient's blood.

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Agrawal, S., Zaritsky, J., Fornoni, A. et al. Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. Nat Rev Nephrol 14, 57–70 (2018). https://doi.org/10.1038/nrneph.2017.155

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