The glomerular filtration barrier (GFB) separates the blood from the urinary space. It consists of two cell types: glomerular visceral epithelial cells, also known as podocytes, and glycocalyx-coated, fenestrated endothelial cells (ECs) that form the glomerular capillary system. They are separated by a glomerular basement membrane (GBM), which is produced by both cell types (Figures 68.1 and 68.2) and consists of laminins, collagens, and heparan sulfate–containing moieties such as perlecan and agrin. In humans, each kidney contains approximately 600,000 to 1 million individual glomeruli that produce 180 L of filtrate per day. Mesangial cells sit between the capillary loops; they provide support and produce the extracellular matrix (ECM) molecules and growth factors required for proper formation of the developing capillary system. The structure of the GFB was first appreciated in electron micrographic (EM) studies that were performed during the 1970s (1–3). Using EM, it was possible to visualize fenestrations in glomerular ECs and specialized intercellular junctions between the foot processes of podocytes known as slit diaphragms (SDs), which are electron-dense structures resembling the teeth of a zipper. Until very recently, it was believed that the major function of the SD was to form the ultimate structural barrier to the blood to prevent loss of critical proteins into the urine.

The identification of human nephrin (NPHS1; nephrosis 1) by Karl Trygvasson's group in 1998 (4) led to an explosion in our understanding of the molecular basis of the SD and the biology of the podocyte (5,6). Nephrin molecules from adjacent foot processes span the SD space and, through homophilic interactions, make up a major structural component of the SD.