Learning objectives Discuss the experimental and clinical data on the pathophysiology of FSGS Review the alterations in glomerular structure and function associated with FSGS To identify potential mechanisms responsible for disease progression in FSGS Distinguish some targets for the future therapy of FSGS 1 2 3 2 1 4 5 1 6 2 7 1 6 Fig. 1 A B 9  1 1 1 7 8 7 9 10 5 6 6 9 6 9 7 7 7 9 10 6 9 11 NEPH-1 6 10 9 10 6 10 9 10 12 10 13 14 10 10 15 17 18 19 20 20 20 21 22 23 23 1 5 2 8 24 7 24 24 24 25 Fig. 2 Factors involved in the progression of FSGS to end-stage kidney disease (ESKD): initial loss or injury to podocytes (related to defects in membrane proteins or cytoskeleton instability) leads to cytokine release, mechanical stress, hyperfiltration, and glomerular hypertrophy. These factors lead to upregulation of an inflammatory response mediated by monocytes, macrophages, and T-cells. The end result is collagen matrix deposition and fibrosis, and progression to ESKD  9 26 9 1 27 28 9 29 24 24 24 24 24 9 29 30 Questions FSGS may result from immune-complex-mediated damage to endothelial cells Alterations in components of the slit diaphragm may play a role in the pathogenesis of FSGS Proliferation of podocytes leads to cytokine release and mechanical stress, resulting in scarring and sclerosis of the glomeruli Mutations in a chloride channel have been associated with FSGS and may be pathogenic Sodium channel mutation Alpha-actinin-4 Nephrin Podocin Downregulation of transforming growth factor β (TGFβ) Decreased glomerular filtration Tubulointerstitial injury Blockade of the renin-angiotensin system Has no effect on clinical course May be decreased by treatment with angiotensin-converting enzyme (ACE) inhibitors Results from an increased number of glomerular foot processes Leads to the loss of mesangial matrix A circulating factor may play a role in the pathogenesis of FSGS Proliferation of parietal epithelial cells has been identified in collapsing FSGS Podocyte loss due to necrosis appears to play a role in the pathogenesis of FSGS CD2-associated protein, FAT, nephrin, and podocin are examples of slit diaphragm proteins