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Review
. 2014 Sep;21(5):408-16.
doi: 10.1053/j.ackd.2014.05.009.

The pathogenesis of focal segmental glomerulosclerosis

J Ashley Jefferson  1 , Stuart J Shankland  2
Affiliations
Review

The pathogenesis of focal segmental glomerulosclerosis

J Ashley Jefferson et al. Adv Chronic Kidney Dis. 2014 Sep.

Abstract

Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury on kidney biopsy that can arise from a diverse range of causes and mechanisms. Although primary and secondary forms are described based on the underlying cause, there are many common factors that underlie the development of this segmental injury. In this review, we will describe the currently accepted model for the pathogenesis of classic FSGS and review the data supporting this model. Although the podocyte is considered the major target of injury in FSGS, we will also highlight the contributions of other resident glomerular cells in the development of FSGS.

Keywords: Focal segmental glomerulosclerosis; Glomerular disease; Parietal epithelial cell; Podocyte; Proteinuria.

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Figures

Figure 1
Figure 1. Pathogenesis of FSGS
Panel A: Normal capillary loop (segment) within a glomerulus showing glomerular basement membrane (GBM) lined by the fenestrated endothelium (GEN) and covered by a podocyte (P) with intact foot processes. Mesangial cells (MC) support capillary loop. Bowman's capsule basement membrane (BCBM) is covered with parietal epithelial cells (PECs). Panel B: Podocyte injury with foot process effacement (FPE) leads to loss of podocyte coverage (cell death or detachment) and an area of uncovered GBM. A tuft adhesion (TA) forms between PECs and the uncovered GBM. Panel C: PECs deposit matrix leading to a broad fibrous tuft attachment (TA). Some PECs migrate onto the glomerular tuft via the attachment and deposit matrix on the glomerular segment on the outside of the GBM. Deposition of fibrillar collagen leads to mesangial expansion reducing capillary lumen. Hyalinosis (trapped plasma proteins) and foam cells (F) obliterate capillary lumen. Panel D: Fully formed segmental sclerosis (fibrosis) with collapse of capillary lumen and areas of trapped hyaline.
Figure 2
Figure 2. Formation of FSGS lesion
Light microscopy (Trichrome stain). Panel A: Normal glomerulus showing multiple open capillary loops (compare with single loop in Figure 1). Panel B: A cellular tuft adhesion (TA) forms between parietal epithelial cells (PECs) and capillary loop(s) with early matrix deposition. Panel C: Further deposition of matrix by PECs leads to formation of fibrous tuft adhesion, with underlying insudates of trapped hyaline. Panel D: Area of segmental sclerosis (SS) within glomerulus, with adherence to Bowman's capsule.
Figure 3a
Figure 3a. FSGS lesion
Electron micrograph. Unaffected open capillary loop containing red blood cell (dotted arrow). Tuft adhesion of glomerular basement membrane to Bowman's capsule (long arrow) with collapse and obliteration of capillary loop (short arrow).
Figure 3b
Figure 3b. FSGS lesion
Higher power electron micrograph shows evidence of hyaline (trapped plasma proteins) and fibrillar collagen within collapsed loops associated with obliteration of capillary lumen.
Figure 4
Figure 4. Persistent podocyte depletion results in FSGS
Multiple etiologies may cause podocyte injury resulting in podocyte depletion. Alterations in the glomerular filtration barrier lead to proteinuria which can further podocyte injury. Reconstitution of podocyte number may lead to recovery of glomerular architecture and function, whereas persistent podocyte depletion produces a cascade of steps leading to an FSGS lesion (see Figure 1).
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