Purpose of review: Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and renal failure. All forms of FSGS share podocyte injury and depletion as central mediators. This review focuses on new insights into pathogenesis from study of extrinsic toxins in experimental models, permeability factors in human disease, and novel genetic causes.
Recent findings: Experimental toxin models have advanced our understanding of the threshold and dynamics of podocyte injury. Following initial podocyte depletion, spreading fields of podocyte injury through secondary mediators appear to be important in generating the segmental pathologic lesions. Proliferating glomerular epithelial cells are common in FSGS, although there are conflicting views about their identity. Evidence suggests potential contributions by mature parietal epithelial cells, facultative stem cells and podocytes. A number of novel candidate permeability factors that affect podocyte function and motility have been discovered in human FSGS and related podocytopathy minimal change disease. Exome capture has identified new monogenic causes of familial FSGS. Apolipoprotein L-1 (APOL1) is expressed in podocytes, and the prevalence of APOL1 risk alleles in patients of African descent with primary FSGS and HIV-associated nephropathy is high, implicating potential podocyte effects.
Summary: FSGS is caused by a complex interplay of inherent genetic susceptibilities and external injurious factors acting on podocytes. Critical levels of podocyte stress eventuate in podocyte depletion, segmental glomerular scarring, and glomerular epithelial cell hyperplasia.