Chapter 9 - The Pathophysiology of Proteinuria

Abstract

The presence of albumin in the urine has clinically long been recognized as a hallmark of dysfunction of the glomerular filtration barrier. Albuminuria suggests the presence of structural glomerular injury. The glomerular barrier is an unique biological sieve. The glomerular filtration barrier allows for high filtration rates of water and solutes, while completely restricting filtration of albumin and larger proteins. The glomerular filtration barrier is structurally comprised of glomerular endothelial cells, the glomerular basement membrane and specialized epithelial cells – podocytes – that cover the basement membrane on the side facing the urinary space. Podocytes and specifically their intercellular junction, the slit diaphragm, have become the major focus of investigation in diseases presenting with albuminuria. This focus has been driven by the discovery of gene mutations of proteins expressed at the slit diaphragm, which are responsible for development of nephrotic syndrome in both human diseases and animal gene knockout models. These insights into podocyte biology have advanced our understanding of albuminuria in the setting of inherited nephrotic syndrome and immune-mediated and autoimmune diseases, where the immune system can target the podocyte microenvironment. However, in the setting of systemic diseases such as hypertension and diabetes mellitus, the development of albuminuria is probably a multistep process where initially, loss of the endothelial barrier function may play a role. Endothelial activation and subsequent shedding of the glycocalyx surface allows albumin to penetrate the sub-podocyte space. Podocytes may then take up albumin through scavenger receptors and display actin skeleton rearrangements and injury. Compensatory tubular reabsorption and the accompanying inflammatory responses may then further contribute to the structural interstitial damage that has been associated with albuminuria. Although there has been substantial progress in understanding the way by which the glomerular filtration barrier prevents albumin filtration, there continues to be a lack of therapies that specifically target dysregulated components of the glomerular filtration barrier.