GROUP-2 PATHOGENESIS OF GLOMERUSCLEROSIS

MOHAMMED SANWAR HUSSAIN

Etiopathogenesis
(cause &development of disese)
Thought to be MCD with intensifying of epithelial tissue damage in the form of hyalinosis & sclerosis Currently divided into three groups:
1.Idiopathic type 2.Superimposed primary globular disease 3.Sceondary type

Idiopathic-differs from MCD with non-selective proteinuria,

steroid-resistant.Immunofluroscence microscopy reveals deposits of IgM & C3 in the sclerotic segment. Mostly in children & Adults with nephrotic syndrome

Etiopathogenesis
(cause &development of disese)
Thought to be MCD with intensifying of epithelial tissue damage in the form of hyalinosis & sclerosis Currently divided into three groups:
1.Idiopathic type 2.Superimposed primary globular disease 3.Sceondary type

Idiopathic-differs from MCD with non-selective proteinuria,

steroid-resistant.Immunofluroscence microscopy reveals deposits of IgM & C3 in the sclerotic segment. Mostly in children & Adults with nephrotic syndrome

Superimposed primary globular disease-FSGS with

superimposed MCD or IgA nephropathy.associated with MCD show good response to steroid therapy & might progress to chronic renal failure after long time

Secondary type-FSGS as a secondary manifestations of other

disease like HIV,Diabetes Melitus.In blacks with HIV infection variant of FSGS is characterized by collapsing sclerosis

Hallmark of FSGS Pathogenesis is disruption of epithelial cells & resultant nephron loss

Pathologic changes
Light Microscopy Glomeruli affected focally & segmentally Affected glomeruli show solidification or sclerosis of lobules of the tuft hyalinosis(collection of eosinophilic,homogenous,P AS-positive,hyaline material present on sclerotic peripheral capillary loop) Mesangial Hypercellularity present HIV associated nephropathy have collapsed capillaries in the tuft.interestitial fibrosis & infiltration by mononuclear leucocytes & tubular epithelial cell atrophy & degeneration

Electron Microscopy
Diffuse loss of foot process like MCD Electron dense deposits in the region of hyalinosis & sclerosis

Immunofluroscence Microscopy
Deposits in the lesion containing IgM & C3

Glomerular hypertrophy with haemodynamic changes.Increase in glomerular blood flow ,filtration and transcapillary pressure(capillary hypertension & often with systemic hypertension

Histologic variants of FSGS

According to the location of the lesion in the tuft, to the cellularity degree, and the aspect of the capillary tuft, five morphologic variants of FSGS have been proposed . Morphologic features are non-specific and superimposed on other glomerular processes Five main light microscophic patters of Histologic variants of FSGS are :

 This morphologic classifications include cases of primary and secondary diseases, but it excludes any glomerular change that it is consequence of another glomerulopathy All share common feature of podocyte alterations at the ultrastructure level At present its unclear whether morphologic variants reflect pathologic differences or consequence of different severities of podocyte or histopathologic evolution Future studies are needed to clearly explain these varities

FSGS not otherwise specified (NOS)

commonest. this variant have segmental sclerosing lesions that can compromise any part of tuft, but, this category requires that all other categories (perihiliar, cellular, tip, and collapsing) be excluded. It is defined by focal and segmental consolidation of the tuft by increased extracellular matrix, obliterating the glomerular capillary lumen. There may be segmental glomerular capillary wall collapse without overlying podocyte hyperplasia. Lesions of sclerosis are typically discrete and can affect perihiliar and/or peripheral segments. Lesions can be sclerosing or hyaline. There can be mesangial hypercellularity, podocyte hypertrophy-hyperplasia, or glomerulomegaly. All the other variants can evolve to this category of FSGS.

FSGS perihiliar variant

exclude the hypercellular variant and the collapsing variant. In other words, if there are many glomeruli with perihiliar lesions, but at least one with hypercellular or collapsing lesion, we do not diagnose the perihiliar variant, but like these last ones respectively. If there are a glomerulus with tip lesion it does not exclude this category. Defining criteria include both of the following: a) there must be at least 1 glomerulus with perihiliar hyalinosis, with or without sclerosis; and b) more than 50% of glomeruli with segmental lesions must have perihiliar sclerosis and/or hyalinosis. Other glomeruli may show lesions as described in FSGS NOS. In some cases there is some degree of mesangial proliferation, and lipid vacuoles and hypertrophy or hyperplasia of podocytes may be identified, although this last finding is less frequent than in other variants. This type of lesion is common in patients with secondary forms of FSGS mediated by an adaptive response to nephron loss or glomerular hypertension: in association with obesity, cyanotic congenital heart disease, reflux nephropathy, renal agenesis, or any renal disease with reduced number of functioning nephrons.

Figure . In this microphotography, we see a glomerular arteriole (blue arrows), in the tuft there are hyaline segments in its vascular pole (green arrows). The perihiliar variant characterize by al least one glomerulus with perihiliar hyalinosis (as seen in this image), accompanied or not by sclerosis, and more than 50% of glomeruli with segmental lesions must have sclerosis and/or perihiliar hyalinosis. There must not be glomeruli with collapsing or hypercellular lesions. (Masons trichrome, X400).

FSGS cellular variant

must exclude the tip and the collapsing variants; if there is at least one glomerulus with tip lesion or collapsing lesion this variant is excluded. It is defined by the presence of at least one glomerulus with endocapillary hypercellularity involving at least 25% of the tuft and causing occlusion of the capillary lumen/lumina. Any segment may be affected. The endocapillary cells include endothelial cells, macrophages and foam cells. Also lymphocytes and polymorphous can be identified. The cells occasionally manifest apoptosis, producing pyknotic or karyorrhectic debris. Endocapillary fibrin occasionally is identified, but without associated rupture of the glomerular basement membrane (in these cases we must suspecting a necrotizing glomerulonephritis). Podocyte Exclusion of cases wit tip lesion is based on the observation that in many cases this lesion is cellular.

Figure . The arrows indicate a segment with increase of the cellularity and diminution or loss of the capillary lumina; the hypercellularity is due to proliferation of intrinsic glomerular cells and inflammatory cells that have migrated to the tuft, in this case mononuclear (lymphocytes and monocytes). Sometimes we can find polymorphous. In the case of the microphotography we found segmental and focal sclerosing lesions, NOS type, in 4 of 18 glomeruli, and only one (the one of the photo) with features of hypercellular variant. (H&E, X400)..

FSGS tip variant

The tip domain is the glomerular tuft zone adjacent to the proximal tubule: outer 25% of tuft next to origin of proximal tubule. must exclude the collapsing variant, if there is at least one glomerulus with the characteristics collapsing lesion the tip variant is excluded. In addition, as was expressed in the perihiliar variant, if there are lesions in perihiliar segments the tip variant is excluded, having in consideration the peripheral nature of the lesions in the tip variant. It is defined by the presence of at least 1 segmental lesion involving the tip domain with either adhesion between the tuft and Bowmans capsule at the tubular lumen or neck, or confluence of podocytes with parietal or tubular epithelial cells at the tubular lumen or neck. The proximal tubular pole must be identified in the defining glomerulus. In some cases, the affected segment appears herniated into the tubular lumen. Segmental lesions may be characterized by endocapillary hypercellularity or sclerosis. Foam cells are common. Hyalinosis is variable. There often is podocyte hypertrophy/hyperplasia overlying the involved segment. In other glomeruli there can be sclerosing lesions or hypercellularity in sites diverse to the tip domain, nevertheless, they must not compromise perihiliar segments.

Figure a . In this glomerulus we can appreciate the characteristic location of the tip lesion. We can see adhesion to Bowmans capsule and sclerosis. In other cases we can see hyaline segments or endocapillary hypercellularity in this portion of the tuft. (Masson trichrome, X400).

Figure 11. In this glomerulus the tip lesion is characterized by adhesion of the tuft to Bowmans capsule near to the tubular neck. (Methenamine-silver, X400).

This variant has been associated, in different works, with a better prognosis (smaller risk of terminal renal failure) (Howie AJ, et al. Glomerular tip changes in childhood minimal change nephropathy. Pediatr Nephrol. 2008 Aug;23(8):1281-6. [PubMed link]). In our series of Hispanic patients we do not found a favorable prognosis for this variant and clinical outcome was similar to FSGS NOS (manuscript in preparation).

FSGS collapsing variant

This category excludes all the other variants. It is defined by at least 1 glomerulus with collapse and overlying podocyte hypertrophy and hyperplasia. The capillary walls present retraction and collapse. The lesion may be segmental or global and may involve peripheral or perihiliar segments. The number of affected glomeruli is very variable. It is unusual adhesions to the Bowmans capsule and hyaline lesions. In other glomeruli may be lesions of any category: sclerosis, hypercellularity, tip lesion or global sclerosis.

Figure . See the glomerular tuft collapse, without conserved capillary lumina, with an irregular aspect and wrinkling of the capillary walls and with marked hypertrophy and hyperplasia of podocytes. This case corresponds to a 37-years-old male patient with NS, HIV negative, and without other predisponent factors: primary collapsing FSGS (idiopathic). (Methenamine-silver, X400).

Figure 13. Collapsing lesions can not be global and involve only some segments of the tuft. Although in this case the lesion is global, see greater collapse and podocyte hypertrophy and hyperplasia in the segments indicated with arrows (Silver, X.400).