Nephrotic Syndrome Complications - New and Old. Part 2

Abstract

The nephrotic syndrome consists of heavy proteinuria with hypoalbuminemia. These are the clinical manifestations of several rare kidney disease. Although the population incidence is low (an estimated incidence of three cases per 100 000 patient-years), nephrotic syndrome has been associated with a range of complications including cardiovascular and thromboembolic events, acute kidney injury or systemic infections. These complications are generated by a combination of increased protein urinary losses and greater liver protein synthesis. The current paper aims to present pathophysiological mechanisms and current therapeutic recommendations for hyperlipidemia, acute kidney injury and other complications associated with nephrotic syndrome.

FIGURE 1.

Pathogenesis of hyperlipidemia in the nephrotic syndrome. ACAT-2=acyl-CoA cholesterol acyltransferase-2; CETP=cholesteryl ester transfer protein; CM=chylomicrons; LCAT=lecithin cholesterol acyltransferase; LDLr=LDL receptor; SR-B1=class B scavenger receptor type 1; TG=triglyceride. The main mechanisms of hypercholesterolemia include the increase in hepatic cholesterol synthesis and impaired reverse cholesterol transport, and for hypertriglyceridemia, impaired triglycerides uptake. (i) Increased hepatic cholesterol synthesis is stimulated by the low intracellular level of free cholesterol induced by the increased expression of PCSK9 and INDOL (which reduces LDL hepatic uptake by degrading the LDLr) and by the increase in cholesterol acylation by activated ACAT2. (ii) The reverse cholesterol transport to the liver is altered as a result of reduced HDL-mediated extraction of cholesterol from lipid-laden cells by heavy urinary loss of LCAT and increased ACAT-1 expression. Moreover, the marked increase in serum CETP impairs HDL maturation, and the marked reduction of SR-B1, an HDL docking receptor, limits HDL uptake by the hepatocyte. The altered reverse cholesterol transport promotes atheroma plaque organization. (iii) The reduced activity of hepatic lipoprotein lipase affects chylomicron (CM) clearance and contributes to the development of hypertriglyceridemia.

FIGURE 2.

Potential effects of hyperlipemia on kidney (18-23). AMPK=AMP activated protein kinase; CTGF=conective tissue growth factor; ER=endoplasmic reticulum; ERK=extracelular signal-regulated kinase; JNK=c-jun-NH2 terminal kinase; PPARá=peroxisome proliferator-activated receptor alpha; ROS=reactive oxygen species. Ox-LDL are taken over by “scavenger” receptors (SR-A, CD 36, CXCL-16) resulting in foam cells. Scavenger receptor CXCL-16 mediates podocytes uptake of ox-LDL, which induces loss of nephrin expression, contributing to proteinuria and glomerulosclerosis. Nephrin loss also affects insulin-stimulated glucose uptake in podocytes, which will exacerbate the endoplasmic reticulum stress initiated by podocyte lipid accumulation. Unlike other glomerular structures, the mesangial cells, being not covered by the basement membrane, will more easily meet Ox-LDL, which are taken by special “scavenger” receptors like TLR 4 (toll-like receptors) or LOX-1 (lectin-like oxidized LDL receptor). Thereafter, TGF-â/Smad signaling and PAI-1 transcription (plasminogen activator inhibitor-1) are activated, leading to progression of kidney failure. Overexpression of SREBP-1 and fatty acid synthase leads to increase in renal triglyceride contents. These alterations increase TGFâ1 and vascular endothelial growth factor expression, which contribute to increased mesangial matrix expression, glomerulosclerosis and proteinuria. Tubule-interstitial involvement is mainly due to albumin transported fatty acids and, to a lesser extent, to direct action of both native and oxidized LDL forms. Following high lipid exposure, tubular epithelial cells change their phenotype to a pro-inflammatory one, with increased permeability, chemotactic stimulation and leukocyte adherence. Cellular permeability is affected by reduced E-cadherin expression and FAK overexpression. Tubular cells exhibit ICAM-1, whose expression is MAPK-dependent, which promotes neutrophiles trafficking along the peritubular capillaries. These alterations in tubular cells may play a crucial role in the development and progression of tubular dysfunction.

TABLE 1.

LDL-C goals according to cardiovascular risk. Adapted after (26, 27)

TABLE 2.

Benefits and limitations of different lipid-lowering therapies used in the treatment of hypercholesterolemia associated with nephrotic syndrome. Adapted after (33)