Focal Segmental Glomerulosclerosis 

Focal segmental glomerulosclerosis (FSGS) was first described in 1957. The condition causes asymptomatic proteinuria or nephrotic syndrome (NS) with or without renal insufficiency. A diagnosis of FSGS is confirmed only by histopathology findings, but it can be suggested clinically.^[1] FSGS arises through idiopathic or secondary causes.

Etiologic agents or mechanisms that initiate glomerular injury and lead to glomerulosclerosis are largely unknown, except in certain animal models of viral-induced renal disease. The primary pathophysiologic process in FSGS is an injury inherent within or directed to podocytes; foot process effacement; proliferation of mesangial, endothelial, and epithelial cells in the early stages, followed by shrinkage/collapse of glomerular capillaries; and ultimately, scarring (glomerulosclerosis).^{[2, 3]}

Proposed mechanisms include viral- or toxin-mediated damage or intrarenal hemodynamic changes such as hyperperfusion and high intraglomerular capillary pressure. FSGS initially begins in the deeper juxtamedullary glomeruli and subsequently extends to the superficial nephrons. The characteristic lesion is a segmental solidification of the glomerular tuft, usually in the perihilar region and sometimes in the peripheral areas, including the tubular pole. The extent of lesions varies in different portions of the kidney, ranging from normal unaffected glomerulus to segmental sclerosis and, eventually, global glomerulosclerosis as the disease evolves. Diffuse foot process fusion occurs, predominantly in the sclerotic segments, although partial effacement may be observed in normal-appearing lobules.

Many morphologic subsets, such as a cellular variant (endocapillary and extracapillary hypercellularity), a collapsing variant (FSGS with mesangial hypercellularity), and FSGS with tip lesions, have been described.^{[1, 3]} Whether these diverse lesions reflect different pathogenesis or account for the differences in the prognoses in patients with FSGS is unclear. To better comprehend some aspects of pathogenesis, FSGS can be classified as follows:

• Primary (idiopathic) FSGS

  • FSGS with hyalinosis
  • Progression from minimal-change disease
  • Progression from immunoglobulin M (IgM) nephropathy
  • Progression from mesangial proliferative glomerulonephritis
  • Superimposed on other primary glomerulonephritis conditions (eg, membranous glomerulonephritis, immunoglobulin A [IgA] nephropathy)
  • Variants of primary FSGS
    • Collapsing form
    • Cellular variant (endocapillary and extracapillary hypercellularity)
    • FSGS with mesangial hypercellularity
    • FSGS with glomerular tip lesions
• Secondary FSGS

  • Drugs^[4]
    • Intravenous heroin^{[5, 6, 7, 8]}
    • Analgesics
  • Viruses
    • Hepatitis B
    • HIV^{[4, 9, 10, 11, 12, 13]}
    • Parvovirus
  • Hemodynamic factors - With reduced renal mass
    • Solitary kidney
    • Renal allograft
    • Renal dysplasia
    • Renal agenesis
    • Oligomeganephronia
    • Segmental hypoplasia
    • Vesicoureteric reflux
  • Hemodynamic causes - Without reduced renal mass
    • Massive obesity^[14]
    • Sickle cell nephropathy
    • Congenital cyanotic heart disease
  • Malignancies
    • Lymphomas
    • Other malignancies
  • Scarring - Postinflammatory in postinfectious glomerulonephritis
  • Miscellaneous
    • Hypertensive nephrosclerosis
    • Alport syndrome
    • Sarcoidosis
    • Radiation nephritis

In other words, factors as diverse as infections, inflammations, toxins, and intrarenal hemodynamic alterations can initiate injury and lead to glomerulosclerosis.

The discovery that mutations in several proteins that play critical roles in podocyte structure, function, or both not only cause FSGS but can predict disease phenotype such as steroid responsiveness has advanced the understanding of the pathophysiology of FSGS.^{[15, 16, 17]} For example, people with causal mutations in TRPC6 or NPHS2 do not respond well to immunosuppressive therapy; however, when they receive kidney transplants, the disease does not usually recur.

Consistent with these findings, Mele et al found that mutations in MYO1E, which encodes a nonmuscle class I myosin, are correlated with childhood-onset, glucocorticoid-resistant FSGS.^[18] The finding in some cases that FSGS can occur de novo in transplants and may occur immediately after transplantation, has led to speculation that circulating factors in plasma may engender podocytopathy. The nature of these circulating factors linked to the development of FSGS is being constantly clarified as findings continue to come to light.

Wei et al have shown that elevated levels of soluble form of urokinase receptor (suPAR) was present in the plasma of two-thirds of patients with FSGS.^[19] Furthermore, high levels of suPAR were predictive of FSGS recurrence, and lowering suPAR levels by plasmapheresis led to disease remission. In some cases of idiopathic FSGS, other yet-to-be identified circulating factors may be involved. Not all patients with FSGS have elevated suPAR levels, a fact consistent with the suggestion that FSGS is not a disease but a pattern of renal injury that may follow many forms of primary podocyte insults.

The search for other permeability factors is the focus of ongoing research efforts. Genetic variation in the circulating apolipoprotein Apol1 predisposes to FSGS in African Americans, although the putative mechanisms are unknown.^[20]

Frequency

United States

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with NS, FSGS is found in 7-10% of renal biopsies; incidence is much greater in those who are resistant to steroid and cyclophosphamide therapy.^[21] In adults, the lesion is more common in men and is observed in 20-30% of patients with NS. Incidence of FSGS is 3-7 times higher in young black men as compared with whites.^[22]

The annual incidence of secondary FSGS in patients who are addicted to intravenous heroin is 30 times higher (611 cases per million population). In selected urban centers in the United States, heroin-associated FSGS accounted for 11.4% of end-stage renal disease (ESRD) patients in the 1970s and 1980s, although the disease gradually disappeared in the 1990s. Most patients with HIV-associated FSGS are young black men (mean age, 33 y; male-to-female ratio, 10:1),^{[5, 6, 22]} 50% are intravenous drug abusers, and the remaining are either gay or bisexual men, heterosexual contacts of infected persons, or children with HIV infection. HIV-associated FSGS is distinctly rare in whites. In the United States and elsewhere, more than 95% of patients are black.^[22]

The annual incidence of ESRD attributed to idiopathic FSGS increased 11 fold (from 0.2% to 2.3%) between 1980 and 2000. In black and white patients in the United States, idiopathic FSGS is now the commonest cause of ESRD resulting from primary glomerular disease.

International

FSGS lesions are observed in about 10% of renal biopsies performed for the evaluation of proteinuria.

Mortality/Morbidity

The natural history of FSGS varies a great deal. A typical course runs from edema that is difficult to manage to proteinuria refractory to corticosteroids^[21] and other immunosuppressive agents to worsening hypertension and progressive loss of renal function. In patients who do not respond to therapy, the average time from the onset of gross proteinuria to ESRD is 6-8 years, although wide variations in the time course occur. One of the key factors that determines renal survival is the persistence and degree of proteinuria. Achievement of a remission, whether spontaneous or induced by immunosuppressive therapy, is associated with a good renal outcome.^[23]

In patients with unresponsive massive proteinuria of greater than 10 g/d, most will develop ESRD within 5 years. The prognosis is much worse in blacks compared to whites. In the collapsing form of FSGS, the disease is marked by severe hypertension, more massive proteinuria, a very poor response to corticosteroids, and a much faster rate of progression to ESRD.

Race

The prevalence rate is much higher in blacks than in whites.^[22] In one large epidemiologic study, the annual incidence of FSGS in patients aged 18-45 years was 20 cases per million population in blacks, a rate 7 times higher than that of individuals who are not black. On the other hand, the annual incidence of secondary FSGS in patients addicted to intravenous heroin is 30 times higher (611 cases per million population). As previously noted, most subjects with HIV-associated FSGS are young black men.

Sex

In adults, the lesion is 3-4 times more common in men than women.

Age

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with NS, FSGS is found in 7-10% of renal biopsy specimens; incidence is much greater in those who are resistant to steroid and cyclophosphamide therapy.^[21]