Causes and pathogenesis of focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies.

Figure 1

FSGS lesions have varying morphologic appearances. a | Not otherwise specified type with obliteration of segmental areas of the glomerular capillary tuft by increased matrix. b | Collapsing type, with proliferation of visceral epithelial cells and collapse of the tuft. c | Tip lesion with adhesion and/or sclerosis at the proximal tubular pole (right). d | Cellular, with increased endocapillary cells. e | Hilar, with sclerosis with or without hyalinosis at the vascular pole. Stains: part a, periodic acid Schiff; parts b–e, Jones’ silver. Abbreviation: FSGS, focal segmental glomerulosclerosis.

Figure 2

Possible pathways for regeneration of podocytes from PEC migration to the glomerular tuft and for the development of sclerosis. a | During embryonic development, or after severe acute injury in young mice, PEC migration to the tuft from the vascular pole (1) or via early adhesions (2) may replenish injured podocytes and prevent further podocyte loss and sclerosis. b | In older mice, or after secondary injury due to nephron loss, PEC migration does not result in restoration of podocytes, but rather progressive sclerosis (3). Further, segmental podocyte injury may spread to initially spared podocytes (4), especially if ongoing filtration is occurring. Manipulation of other potential stem cells or the microenvironment may modulate these responses. Abbreviation: PEC, parietal epithelial cell.