Focal Segmental Glomerulosclerosis

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 all lead to scarring (glomerulosclerosis). ^{[6, 7]}

Proposed mechanisms of podocyte injury include viral- or toxin-mediated damage and intrarenal hemodynamic changes such as glomerular hyperperfusion and high intraglomerular capillary pressure. FSGS initially involves 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 progresses. 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. ^{[3, 7]} Whether these diverse lesions reflect different pathogenesis or account for the differences in the prognoses in patients with FSGS is unclear.

Columbia classification

A pathologic classification, developed by an international group of renal pathologists that met at Columbia University, New York, NY, and hence known as the Columbia classification, recognizes five histologic variants of primary FSGS, as follows ^[8] :

• FSGS not otherwise specified
• Perihilar FSGS - At least one glomerulus with perihilar hyalinosis, with or without sclerotic lesions at the glomerular vascular pole (perihilar) in more than 50% of glomeruli with segmental lesions.
• Cellular FSGS - At least 1 glomerulus with endocapillary hypercellularity involving at least 25% of the tuft and causing occlusion of the capillary lumen/lumina
• Tip FSGS - Localized sclerotic lesions limited to the proximal tubular pole of the glomerulus
• Collapsingf FSGS- At least one glomerulus displays segmental or global obliteration of the glomerular capillary lumina by wrinkling and collapse of the glomerular basement membranes, associated with podocyte hypertrophy and hyperplasia

These histologic variants may predict response to immunomodulating agents but do not provide insights into the pathogenesis of FSGS. ^[9]

Protein mutations and circulating factors

Understanding of the pathophysiology of FSGS has been advanced by 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 features, such as steroid responsiveness. ^{[10, 11, 12]} For example, FSGS involving mutations in TRPC6 or NPHS2 does not respond well to immunosuppressive therapy; however, when these patients receive kidney transplants, the disease does not usually recur. Apolipoprotein L1 (APOL1) G1/G2 variants, which are more frequently found in patients of African or French West Indies ancestry, have been associated with steroid-resistant nephrotic syndrome/FSGS and a poor renal prognosis. ^[13]

Consistent with these findings, Mele et al found that mutations in MYO1E, which encodes a non-muscle class I myosin, correlate with childhood-onset, steroid-resistant FSGS. ^[14] The observation that in some cases FSGS can occur de novo in transplanted kidneys 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. Proposed candidate molecules include hemopexin, vascular endothelial growth factor, and cardiotrophinlike cytokine-1. One candidate that has been studied the most is the soluble form of urokinase receptor (suPAR). ^[15]

Wei et al have shown that elevated levels of suPAR were present in the plasma of two-thirds of patients with FSGS. ^[16] 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. The same group has analyzed circulating suPAR levels in North American and European cohorts of patients with biopsy-proven FSGS, compared with age- and sex-matched control subjects. They found strong associations between change in circulating suPAR levels with different therapeutic regimens and with remission of proteinuria. ^[17]

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, genetic variations in different races, mutations of many proteins involved in podocyte function (eg,  podocin) is the focus of ongoing research efforts. Genetic variation in circulating apolipoprotein Apol1 predisposes to FSGS in African Americans, although the putative mechanisms are unknown. ^[18] Mutations of podocyte proteins are more often associated with familial forms of FSGS.

Tao et al reported that JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with FSGS. These authors found increased staining for components of the JAK-STAT system in FSGS by microscopy, along with activated peripheral immune cells and increased activated proteins in the kidney.  ^[19]

APOL1-associated FSGS

Investigators had long speculated that genetic susceptibility might explain the much higher incidence of FSGS, hypertensive nephrosclerosis, and diabetic glomerulosclerosis in African Americans. Heroin and HIV-associated FSGS is seen almost exclusively in blacks. Transgenic mice experiments and clinical observations in various studies initially pointed to variants of MYH9 gene on chromosome 22, but subsequently the APOL1 gene emerged as the likely candidate. Apolipoprotein 1 (APOL1) confers protection against Trypanosoma brucei, which is the causative agent of trypanosomiasis (sleeping sickness); this would explain why variants of APOL1 have been preserved in Africans over several generations. 

Based on these findings of the role of genetics, Rosenberg and Kopp have suggested clustering FSGS into six clinical forms. ^[1]  Their classification consists of two common entities (Idiopathic and adaptive FSGS), three less common varieties (genetics, viral infection, and medication associated), and APOL1-associated FSGS (Ref xx).

FSGS can be classified as primary (idiopathic), genetic, or secondary.

Primary (idiopathic) FSGS

Primary (idiopathic) FSGS includes the following:

• 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 include the following:

• Collapsing form
• Cellular variant (endocapillary and extracapillary hypercellularity)
• FSGS with mesangial hypercellularity
• FSGS with glomerular tip lesions

Genetic FSGS

Genetic FSGS may be a direct result of mutations in genes that code for slit diaphragm or podocyte proteins, or may be the indirect result of polymorphisms that make podocytes more vulnerable to damage. Examples of the former include NPHS1 and NHPS2 mutations that result in the absence of essential slit diaphragm components, which leads to severe congenital nephrotic syndrome. An example of the latter is polymorphisms in the APOL1 gene, which are usually found in individuals of African descent and that markedly increase risk for FSGS. ^[3]

Secondary FSGS

A range of different factors, including drugs, infections, inflammations, toxins, and intrarenal hemodynamic alterations, can initiate injury to podocytes and lead to glomerulosclerosis.

Drugs associated with FSGS include the following ^[20] :

• Intravenous heroin ^{[21, 22, 23, 24]}
• Analgesics
• Pamidronate
• Lithium
• Anabolic steroids
• Doxorubicin, daunomycin

Viruses associated with FSGS include the following ^{[25, 26]} :

• Hepatitis B and C
• HIV ^{[20, 27, 28, 29, 4, 5]}
• Parvovirus B19
• Cytomegalovirus

Hemodynamic factors in patients with reduced renal mass include the following:

• Solitary kidney
• Kidney allograft
• Renal dysplasia
• Renal agenesis
• Oligomeganephronia
• Segmental hypoplasia
• Vesicoureteral reflux

Hemodynamic causes in patients without reduced renal mass include the following:

• Obesity ^[30] (especially morbid obesity)
• Sickle cell nephropathy
• Congenital cyanotic heart disease

Lymphomas and other malignancies have been associated with FSGS. Genetic cases may be familial or sporadic. Scarring may lead to FSGS subsequent to postinfectious glomerulonephritis. Miscellaneous other conditions associated with FSGS include the following:

• Hypertensive nephrosclerosis
• Alport syndrome
• Sarcoidosis
• Radiation nephritis

Rates of FSGS seem to be increasing worldwide. ^[31]  FSGS lesions are observed in about 10% of kidney biopsies performed for the evaluation of proteinuria. Australia has reported one of the highest incidence of FSGS, attributable to an increased recognition of disease from a liberal kidney biopsy policy.

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with nephrotic syndrome, FSGS is found in 7-10% of kidney biopsies; the incidence is much greater in those whose condition is resistant to steroid and cyclophosphamide therapy. In adults, FSGS is more common in men and is observed in 20-30% of patients with nephrotic syndrome. The incidence of FSGS is 3-7 times higher in young black men than in whites. ^[2]

In one review of the international literature, the annual incidence of FSGS ranged from 0.2 to 1.8/100,000 population. ^[32] The reported annual incidence rates for FSGS is 5 cases per million population in whites, compared with 24 cases per million population in Blacks. In the US, ESRD attributable to FSGS reported as patients per million population was 1.9 in whites and 6.8 in Blacks. ^[33] This increased incidence is partly explained by variants of 2 important podocyte function proteins; non-muscle myosin heavy chain-9 and apolipoprotein Apol1 is found in about 60% of African American patients compared with 5% in whites. ^{[34, 35]}

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), ^{[21, 22, 2]} 50% are intravenous drug abusers, and the remaining are either homosexual or bisexual men, or heterosexual contacts of infected persons. HIV-associated FSGS is distinctly rare in whites. In the United States and elsewhere, more than 95% of patients are black. ^[2]

With the introduction of screening of pregnant women and institution of early HAART therapy, no cases of HIV-associated nephropathy have been reported in children for more than a decade. ^[36]  HIV-associated FSGS in children has practically disappeared, because of serologic screening of all transfused products, screening of pregnant women, and effective use of antiretroviral drugs during pregnancy and childbirth.

The annual incidence of ESRD attributed to idiopathic FSGS increased 11-fold (from 0.2% to 2.3%) from 1980 to 2000. ^[33] In Black and White patients in the United States, idiopathic FSGS is now the commonest cause of ESRD resulting from primary glomerular disease.

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 ^[37] 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. ^[38]

In patients who are unresponsive to therapy and who continue to have massive proteinuria of greater than 10 g/d, most develop ESRD within 5 years. The prognosis is much worse in black patients compared with white patients. 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. ^[2] 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 seven 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.

The reported annual incidence rates for FSGS is 5 cases per million population in whites, compared with 24 cases per million population in African Americans. In recent years, the incidence of heroin-associated FSGS has drastically decreased.

Sex- and age-related variance

In adults, FSGS is three to four times more common in men than women.

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with nephrotic syndrome, FSGS is found in 7-10% of kidney biopsy specimens; incidence is much greater in patients who are resistant to steroid and cyclophosphamide therapy. ^[37]