Focal & Segmental Glomerulosclerosis

Focal & Segmental Glomerulosclerosis Lecture 41

Focal Segmental Glomerulosclerosis

It is a cause of nephrotic syndrome in children and adolescents, as well as an important cause of kidney failure in adults.

• It is also known as "focal glomerular sclerosis"

or "focal nodular glomerulosclerosis”.

• MCD and primary FSGS may have a similar cause.

FSGS• Focal segmental glomerulosclerosis

(FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease

(ESKD). • FSGS is the most common cause of

acquired chronic renal insufficiency in children.

Pathologic variants1. Collapsing variant→ESRD2. Glomerular tip lesion variant3. Cellular variant4. Perihilar variant5. Not otherwise specified (NOS) variant. Most common

Classification by Robbins• 1. In association with other known conditions,

such as HIV infection (HIV Nephropathy) or heroin abuse (Heroin Nephropathy);

• 2. As a secondary event in other forms of GN (e.g., IgA nephropathy);

• 3. As a maladaptation after nephron loss• 4. Congenital forms resulting from mutations affecting cytoskeletal proteins

expressed in podocytes (nephrin);

• 5. Primary or Idiopathic disease

Primary or Idiopathic FSGS• Primary /Idiopathic FSGS accounts for

approximately 20-30 % of

all cases of the NS. It is becoming an increasingly common cause of NS in adults & remains a frequent cause in children.

FSGS vs MCD• 1. Hematuria, Hypertension.• 2. Nonselective proteinuria.• 3. Poor response to corticosteroids.• 4. >50% individuals develop ESRF within 10 y.

• 5. Adults in general fare even less well than children.

Pathogenesis - unknown• MCD may transform to FSGS.• Distinct clinicopathologic entity from the

outset (beginning).• In any case, injury to podocytes is thought

to represent the initiating event of primary FSGS.

• As with MCD, permeability-increasing factors produced by lymphocytes (cytokines) have been proposed.

• The deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops.

• IgM and complement proteins commonly seen in the lesion are also believed to result from nonspecific entrapment in damaged glomeruli.

• The recurrence of proteinuria in some persons with FSGS who receive renal allografts, sometimes within 24 hours of transplantation, supports the idea that

a circulating mediator is the cause of the damage to podocytes.

The most likely candidate representing the responsible circulating factor is soluble urokinase-type plasminogen

activator receptor (suPAR). Another possible circulating

factor is Cardiotrophin-like cytokine 1.

Morphology• The disease first affects only some of the

glomeruli (Focal) & initially only the juxtamedullary glomeruli.

• Eventually all levels of the cortex are affected.

• Lesions occur in some tufts (Segmental) within a glomerulus.

• The affected glomeruli exihibit:

1.Increased mesangial matrix,2.Obliterated capillary lumens3.Deposition of hyaline masses & lipid droplets.

Morphology

Global Sclerosis: Occasionally , glomeruli are

completely sclerosed with or

without interstitial fibrosis.

Morphology• EM shows effacement of foot processes.

Global sclerosis may be found occasionally.• Collapsing glomerulopathy- Collapse of the

entire glomerular tuft & podocyte hyperplasia.CG may be associated with HIV inf drug-

induced toxicities. It has a poor prognosis.

Morphology• Immunofluorescence microscopy:• It reveals nonspecific trapping of

immunoglobulins, usually IgM & complement in the areas of hyalinosis.