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Pathobiology of focal segmental glomerulosclerosis: new developments

D’Agati, Vivette D.

Current Opinion in Nephrology and Hypertension: May 2012 - Volume 21 - Issue 3 - p 243–250
doi: 10.1097/MNH.0b013e32835200df

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.

Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

Correspondence to Vivette D. D’Agati, MD, Renal Pathology Laboratory, Department of Pathology, Columbia University Medical Center, Room VC14-224, 630 W. 168th St, New York, NY 10032, USA. Tel: +1 212 305 7460; fax: +1 212 342 5380; e-mail:

© 2012 Lippincott Williams & Wilkins, Inc.