1.2 Focal segmental glomerulosclerosis and variants

Definition: segmental obsolescence of individual glomerular lobules (segments).

By light microscopy, the segmental lesions are primarily found in the juxtamedullary glomeruli and spread later throughout the cortex. Within the glomerulus, the lesions may be present at any site close to or remote from the vascular pole. Primarily only one lobule is affected, later more and more lobules are involved and finally the glomerulus becomes completely obsolescent.

The hallmark is often hyalinosis (large protein thrombi) sometimes with lipid inclusions or foam cells. The basement membranes are thickened and often wrinkled, i.e. collapsed. The involved lobules often become attached to Bowman’s capsular basement membrane (i.e. synechia formation). Activated podocytes covering the affected lobule form a new basement membrane.

Electron microscopy confirms the microscopic findings. In addition complete foot process fusion is present, even in glomeruli showing no segmental sclerosis. However, as in MCD, more often electron dense deposits are present in the mesangium, especially along the mesangial basement membrane.

Immunohistochemical findings often go in parallel with the light microscopic damage seen. In the loop periphery, as well as in the mesangium, segmental and focal deposits of IgM and complement components (C1q, C3, C4, C5-9) may be present. The protein thrombi (hyalinosis) consist of IgM and complement components.

The lesions in the tubulo-interstitial space parallel the extent of the glomerular damage. In some cases however, the tubular lesions may be much more severe than expected from the extent of glomerular involvement. Tubular atrophy, interstitial fibrosis, lympho-histiocytic infiltrates, foam cells in tubules and in the interstitial space as well as protein resorption (hyaline) droplets in the tubular epithelium may be found. In advanced cases, especially when hypertension is also present, the arterioles may exhibit arteriolar hyalinosis.

Several variants of FSGS can be differentiated. Their clinical significance is, however, still unclear.

1. Unspecific form (not otherwise specified), as described above, is the most common form of FSGS.
2. Cellular variant: The involved lobules show hypercellularity due to proliferation of endothelial cells, monocytes and neutrophilic granulocytes. In addition hyaline material and/or fibrin may be present. The whole picture is highly suggestive of a focal segmental proliferative glomerulonephritis.
3. Diffuse mesangial hypercellularity: the glomeruli not affected by FSGS show mesangial matrix and cell increase.
4. Collapsing variant: prominent segmental or global collapse of glomerular loops accompanied by a prominent hypertrophy and hyperplasia of podocytes.
5. Glomerular tip-lesion: the segmental lesion is situated just at the urinary pole of the glomerulus. Individual glomerular loops have prolapsed into the urinary pole and adhesions between the glomerular basement membrane and the basement membrane of proximal tubules have formed.
6. C1q nephropathy: diffuse and global deposits of C1q in the mesangium accompanied by FSGS not otherwise specified.