Compared to minimal change glomerulopathy and membranous glomerulopathy, FSGS is a difficult category of glomerular disease to diagnose pathologically. It is probably the most difficult category for a renal pathologist and nephrologist to deal with. There is great confusion about how to define FSGS pathologically. There is disagreement about how many categories of glomerular disease to put into this rather descriptive sounding category of glomerular disease. I break the disease down into a number of categories shown in slide 24.
In the diagram in slide 25 are my conceptions of the major distinctions between the three major categories of FSGS. There is a perihilar predominance of sclerosis in one variant of FSGS, a glomerular tip location for a distinctive injury in the tip lesion variant of FSGS, and a particular type of collapsing pattern of destruction of capillaries and matrix expansion in the collapsing glomerulopathy variant of FSGS.
The diagram in slide 26 depicts perihilar segmental sclerosis, which is continuous with the afferent arteriole where the blood is coming into the glomerulus. A leading theory for the pathogenesis of this variant is single nephron hypertension, hyperperfusion, hyperfiltration. This is possibly analogous to a small local area of arteriosclerosis (arteriolosclerosis) where plasma constituents are exuding into the glomerular tuft much as plasma proteins exude into the walls of arterioles causing the hyaline arteriolosclerosis of hypertension. The PAS-stained section in slide 27 shows the perihilar location of sclerosis with hyalinosis and lipids vacuolation and an adhesion to Bowman's capsule. These are very distinctive and characteristic features of focal segmental glomerulosclerosis, but they are not specific. These features should be present in the absence of any other cause of focal glomerular scarring in order to diagnose FSGS.
The electron micrograph in slide 28 shows a relatively normal capillary wall to the left with effacement of foot processes; and, to the right, a zone of sclerosis with some electron dense material (that would corresponds to hyalinosis by light microscopy) and lipid vacuolation. Immunohistology (slide 29) demonstrates entrapment of IgM and C3 in zones of sclerosis. Sometimes there will be a small amount of IgM and C3 in the mesangium, as is sometimes the case in normal individuals and patients with minimal change glomerulopathy.
Another feature of perihilar FSGS that probably results from single nephron hypertension is increased glomerular size (glomerular hypertrophy). Slide 30 compares an hypertrophied glomerulus from an FSGS patient to a glomerulus from an age matched individual who died secondary to trauma. By morphometric analysis, many but not all specimens of FSGS have a mean glomerular size that is substantially larger the normal range. This differs from minimal change glomerulopathy and glomerular tip lesion, which suggests that tip lesion is pathogenetically different from perihilar FSGS.
As with all other glomerular diseases, there are primary and secondary variants of FSGS. The primary variants are just the ones where we don't know what the underlying cause is (i.e., they probably should be called idiopathic). The secondary variants of the perihilar focal segmental glomerulosclerosis very often have glomerular enlargement (hypertrophy) and very often have associated conditions that would cause overwork of the glomeruli. For example, if you have normally sized kidneys but your body is tremendously big, you are going to overwork the nephrons. Thus, the most common cause for nephrosis in a morbidly obese patient is FSGS with big glomeruli. If you have a normally sized body but you markedly reduce the amount of renal parenchyma you have, you stress the available nephrons and develop secondary focal segmental glomerulosclerosis. For example, FSGS can be secondary to reflux nephropathy with pyelonephritis knocking out most of your functioning parenchyma. The little bit that is left is stressed and develops FSGS. Also, for reasons that are poorly understood, conditions of poor oxygenation will lead to glomerular enlargement and predisposition to FSGS. For example, the most common cause for nephrosis in sickle cell disease is FSGS.
The histologic lesion of the glomerular tip lesion variant of FSGS affects the pole of the glomerulus adjacent to the origin of the proximal tubule (Slide 31). Other variants of FSGS, however, can involve the tip, but they have lesions in other segments of glomeruli as well. Glomerular tip lesion has histologic injury exclusively in the glomerular tip. For example, if there is injury in the tip plus in the perihilar zone, it is not tip lesion. Early in the disease, the glomerular tip lesion variant of FSGS often is more cellular than sclerosing, and it often involves not only the visceral but also the parietal epithelial cells at the origin of the proximal tubule and even some of the most proximal tubular epithelial cells.
In the H&E stained section in slide 32, the hilum is to the left. There are enlarged (hypertrophy), vacuolated cells at the origin of the proximal tubule. Slide 33 shows a PAS-stained section with the hilum to the left. There is a little adhesion at the glomerular tip, and there is disturbance in matrix and cells at the origin of the proximal tubule. The trichrome stained section in slide 34 shows numerous foam cells, some increase in matrix, a tiny spot of hyalinosis and an adhesion in the glomerular tip. In the silver-stained section in slide 35, there is an arteriole to the left, and to the right there is an epithelial response bulging into the origin of the proximal tubule with some foam cells and a little bit of matrix disturbance. Glomerular tip lesion FSGS seems to be different from the perihilar FSGS pathophysiologically because it does not have glomerular enlargement and demographically it is very different with respect to age and racial predilections. The greatest risk for developing this pattern of FSGS is in older patients and whites rather than blacks, which is the reverse of the age and racial predilection for other variants of FSGS.
The collapsing variant of FSGS has the greatest predilection for blacks vs whites (approximately 80% of our collapsing glomerulopathy FSGS patients are African-American). This collapsing glomerulopathy variant of FSGS can be divided into primary (i.e., idiopathic) variants and secondary variants. The secondary variants were recognized first in association with intravenous drug abuse and HIV infection. Only later was the occurrence of this pattern of glomerular injury observed in the absence of drug abuse or HIV infection.
The collapsing variant of FSGS does not have a predilection for any particular glomerular segments. Unlike tip lesion and perihilar FSGS, which often have adhesion between Bowman's capsule and the sclerotic segment, collapsing FSGS usually does not develop adhesions until the sclerosis is very advanced. The epithelial cells adjacent to collapsed segments are very hypertrophied(and sometimes hypertrophied) and often contain very conspicuous hyaline droplets shown in the diagram in slide 36. These are resorption droplets similar to but larger and more numerous than those seen in visceral epithelial cells with any cause for nephrotic syndrome. Slide 37 shows a silver-stained section with collapsing variant of FSGS. There is segmental increase in matrix with obliteration of capillary lumens. Capillary loops have collapsed into the increased matrix. There are hypertrophied, somewhat hyperplastic, epithelial cells with conspicuous resorption droplets. The epithelial hypertrophy and hyperplasia in some of these cases could be called crescent formation; however, the convention has been that this kind of visceral (rather than parietal) epithelial response in collapsing FSGS is not called crescent formation.
Often the collapsing glomerulopathy variant of FSGS is a more focal global process than a focal segmental process, especially in patients with HIV nephropathy, who tend to have more severe disease. Slide 38 shows a glomerulus from a patient with HIV nephropathy. Note the absence of capillary loops, the collapse of matrix with no adhesions (even though there is global sclerosis), and very conspicuous hypertrophied epithelial cells. Especially with HIV nephropathy, as shown in the trichrome stained section in slide 39, there is microscystic dilation of tubules. In fact, in most cases of collapsing FSGS, there is substantial disturbance in the tubulointerstitial compartment. This raises the possibility that collapsing FSGS actually affects not only glomerular epithelial cells but also tubular epithelial cells.
In a patient with collapsing FSGS, the electron microscopic marker that indicates HIV nephropathy is the presence in the endothelial cells of tubuloreticular inclusions (slide 40). These tubuloreticular inclusions (TRI) appear to arise as a result of high levels of alpha interferon in the circulation. The three settings in which tubuloreticular inclusions are frequent are 1) HIV associated nephropathy, 2) lupus nephritis, and 3) patients treated with alpha interferon (e.g. hepatitis C patients). Anybody with HIV infection has TRI whether or not they have nephrosis. Likewise, patients with lupus erythematosus have TRI whether or not they have glomerulonephritis. Over 90% of patients with HIV nephropathy have TRI, and lots of them. Around 80% of lupus nephritis patients have TRI. Less than 5% of everybody else has TRI.
Collapsing FSGS has an extreme black predilection, even when other risk factors are controlled. The collapsing variant of FSGS has a very poor prognosis. After two years of follow-up, about half the patients with idiopathic collapsing FSGS reach end-stage renal disease. HIV associated collapsing glomerulopathy does even worse. Therefore, collapsing FSGS is a very fulminate disease compared to the perihilar and glomerular tip lesion variants of FSGS, which are relatively indolent.