Figure 3. Mechanisms and consequences of lipid nephrotoxicity.

The direct effects of dyslipidaemia on decreased kidney function are referred to as ‘lipid nephrotoxicity’, although the role of altered lipid metabolism in the molecular pathophysiology of nephrotic syndrome is not well understood. During dyslipidaemia, triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) as well as oxidized LDL, are taken up by mesangial cells, leading to the production of cytotoxic agents, cytokines and reactive oxygen species, which further damage the glomerular epithelial and endothelial cells, resulting in sclerosis. Furthermore, levels of free fatty acids are increased in patients with nephrotic syndrome, which have been reported to have toxic effects in the kidney, especially in glomeruli and podocytes, but also in the tubulointerstitium. Free fatty acids bound to albumin cause podocyte damage by enhancing macropinocytosis and activating G protein-coupled receptor (GPCR) signalling, leading to disruption of the podocyte actin cytoskeleton and podocyte morphology. In addition, these albumin bound free fatty acids cause loss of podocyte viability and increased production of several cytokines. Moreover, free cholesterol-mediated injury is another pathway of cellular injury in podocytes, and involves the ATP binding cassette sub family A member 1 (ABCA1) cholesterol transporter. Furthermore, the role of free fatty acids, and saturated fatty acids in particular, is well documented in causing damage to proximal tubule cells and tubulointerstitial injury.