Causes proteinuria or nephrotic syndrome with or without renal insufficiency.
Proteinuria occurs due to the dysfunction of the glomerular filtration barrier.
The glomerular filtration barrier is tripartite with a fenestrated endothelium, glomerular basement membrane, and podocytes, the latter are epithelial cells with interdigitated foot processes interconnected by multi-protein slit diaphragms (Manchuca E et al).
Histologic pattern of injury that characterizes broad spectrum of diseases with different underlying pathophysiologies.
Accounts for approximately 20% of cases of nephrotic syndrome in children and 40% of such cases in adults.
Majority of cases are secondary, not primary.
And estimated incidence of 7 per million (Kititakara C et al).
Incidence increasing in adults for past few decades.
The most common problem of glomerular disorder resulting in end-stage renal disease in the US.
Prevalence of 4%.
Diagnosis confirmed by histopathologic testing.
Cardinal abnormality glomerular scarring.
Focal refers to involvement of a subgroup of glomeruli and segmental refers to involvement of a portion of the glomerular tuft.
Primary injury is to the podocytes, with proliferation of mesangial, endothelial and epithelial cells in early stages.
Primary focal segmental glomerulosclerosis presumed to be a circulating permeability factor diffusely toxic to podocytes.
Mutations in podocyte genes are associated with genetic focal segmental glomerulosclerosis.
Genetic forms are usually resistant to steroid therapy and often progress to end-stage renal disease.
Familial forms are associated with mutations in genes that encode podocyte proteins.
MYO1E mutations are associated with childhood onset, corticosteroid resistant focal segmental glomerulosclerosis (Mele C et al).
Early disease is focal with involvement of a minority of glomeruli, and segmental with involvement affecting a portion of the glomerular globe.
As the disease progresses more widespread and globular glomerulosclerosis develops.
In later stages there is shrinkage and or collapse of the glomerular capillaries and eventually sclerosis.
Proposed mechanisms for the process include: viral, toxins and high intraglomerular capillary pressure.
Usually starts in the deeper juxtamedullary glomeruli and extends to the superficial nephrons.
Characteristic lesion: segmental solidification of the glomerular tuft in the perihilar region and sometimes in the peripheral areas.
Eventually global glomerulosclerosis develops.
Diffuse foot process fusion occurs mainly in the sclerotic segments. In
Defining feature is proteinuria, which is typically associated with hypoalbuminemia, hypercholesterolemia and peripheral edema.
Nephrotic syndrome in children is defined as proteinuria of greater than 1 g of urine protein per square meter of body surface area per day, albumin level of less than 2.5 g, cholesterol total of greater than 200 mg/dL and edema.
Nephrotic syndrome in adults defined is a urine protein level of more than 3.5 g per day, albumin level less than 3.5 g/dL.
Approximately 75-90% of children and 50-60% of adults have associated nephrotic syndrome at presentation of focal segmental glomerulosclerosis.
There are many subsets of disease including a cellular variant, a collapsing variant, and tip lesions.
Classification includes primary (idiopathic ) and secondary forms.
May be a primary process, or a secondary process associated with drugs, viral infections, and diseases that affect the renal mass and glomerular hemodynamics (Barisoni L et al).
Primary forms include: focal segmental glomerulosclerosis, progression from minimal change disease, progression from immunoglobulin M nephropathy, progression from mesangial proliferate glomerulonephritis, superimposed on other primary glomerulonephritis conditions and variant of primary focal segmental glomerulosclerosis.
Secondary forms include: familial, virus associated, drug-induced and adaptive.
Secondary FSGS is a response to reduction in the number of functioning nephrons from or am abnormal stress on initially normal nephrons.
Approximately 80% of cases are primary and idiopathic.
Focal segmental glomerulosclerosis and the related disorder minimal change disease are podocyte diseases.
Podocyte foot process injuries correlate with nephrotic proteinuria.
Alterations in podocyte shape causes rearrangement of the actin cytoskeleton, a process which is a reversible with glucocorticoids therapy in minimal change disease but it is lrreversible and progressive in focal segmental glomerulonephritis.
Primary FSGS may respond to immunosuppressive treatment.
Secondary FSGS treatment is centered around unloading the pressure on glomeruli using renin-angiotensin-aldosterone inhibition.