Focal Segmental Glomerulosclerosis

Updated: Dec 07, 2020
  • Author: Sreepada TK Rao, MD, FACP; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Practice Essentials

Focal segmental glomerulosclerosis (FSGS) is one of the most common causes of primary glomerular disease in adults. [1] In adults undergoing kidney biopsy for evaluation of proteinuria, FSGS accounts for 35% of all cases and up to 80% of cases in African-American patients. However, no age group is exempt from the disease.

FSGS causes asymptomatic proteinuria or nephrotic syndrome with or without renal insufficiency. Generally, FSGS results in progressive kidney injury; it accounts for 2.3% of all cases of end-stage renal disease (ESRD), and is the leading glomerular cause of ESRD.

FSGS can be broadly classified as primary (unknown cause) or secondary. Conditions associated with secondary FSGS include the following:

  • Infections (eg, human immunodeficiency virus [HIV] infection)
  • Drugs (eg, heroin, sirolimus, doxorubicin)
  • Hemodynamic adaptations in the kidney (morbid obesity, reduced nephron mass)
  • Genetics (eg, APOL1 gene variants, TRPC6, NPHS2)

See Etiology for more detail.

Signs and symptoms

The most common clinical presenting feature of FSGS (> 70% of patients) is nephrotic syndrome, characterized by generalized or dependent edema, along with fatigue and loss of appetite.

Examination of patients with FSGS may include the following findings:

  • Leg edema
  • Ascites
  • Pleural effusion
  • Abdominal pain: Common in children; may be a symptom of peritonitis
  • Ulcerations and infections in dependent regions
  • Hypertension (may be severe, with diastolic blood pressure ≥120 mm Hg; this is common in Black patients, especially those with kidney insufficiency [2] )

However, some patients may be asymptomatic.

See Presentation for more detail.

Diagnosis

Although clinical features are suggestive, a diagnosis of FSGS is established only by histopathology findings. [3] Detailed medical history and pertnent laboratory tests are essential to distnguish between primary (idiopathic) and secondary forms of FSGS.  In massively obese patients, FSGS, mostly is a diagnosis of exclusion.

Examination of patients with FSGS may include the following findings:

  • Leg edema
  • Ascites
  • Pleural effusion
  • Abdominal pain: Common in children; may be symptom of peritonitis
  • Ulcerations and infections in dependent regions
  • Severe hypertension (diastolic blood pressure ≥120 mm Hg): Commonly seen in Black patients, especially those with kidney insufficiency [2]

Laboratory testing

  • Urinalysis: Large amounts of protein; hyaline and broad waxy casts, generally no RBC casts
  • Serum creatinine (Scr) concentration or creatinine clearance (Ccr): Usually within reference range; in later stages, varying degrees of elevated Scr or decreased Ccr
  • Albumin levels: Generally low
  • Lipid studies: Hyperlipidemia

In patients with idiopathic FSGS, investigational findings for an underlying etiology—such as systemic lupus erythematosus (serum complement C4/C3 levels, antinuclear antibody/anti-DNA titers), hepatitis B or C or HIV infection, vasculitis (antineutrophil cytoplasmic antibody titers, serum protein electrophoresis)—are generally negative.

In patients with suspected secondary FSGS, viral studies for HIV, parvovirus, and hepatitis B and C are indicated. In some patients, genetic testing may also be helpful.

Imaging studies

On ultrasonography, kidney findings in FSGS include the following:

  • Early stages: Normal or large kidneys with increased echogenicity, suggesting diffuse intrinsic medical renal disease
  • Advanced renal failure: Small and shrunken kidneys, indicating severe glomerular scarring and interstitial fibrosis
  • HIV-associated disease: Generally, large echogenic kidneys

Procedures

Kidney biopsy is the most definitive way to confirm the diagnosis. Findings are as follows:

  • Segmental solidification of the glomerular tuft: Characteristic lesion
  • Segmental obliteration of glomerular capillaries by accumulation of acellular matrix and hyaline deposits, along with adhesion to the Bowman capsule
  • Fusion of diffuse foot process, predominantly in the sclerotic segments; morphologic subsets may occur
  • HIV-associated FSGS: Collapsing glomerular lesions with microcystic dilatation of renal tubules and tubuloreticular inclusions in endothelial and mesangial cells [4, 5]

See Workup for more detail.

Management

Therapy for FSGS includes nonspecific measures (eg, nutrition) and symptomatic treatment. In patients with persistent nephrosis, the general consensus is to use aggressive measures to induce remission (eg, use of corticosteroids and immunosuppressive agents such as cyclophosphamide, calcineurin inhibitors).

Nonspecific, general management

  • Control hypertension, including pharmacotherapy (eg, diuretics, antihypertensives)
  • Reduce lipid levels
  • Reduce daily salt and protein intake
  • Nephrotic syndrome: Maintain adequate nutrition, minimize/eliminate proteinuria, prevent complications from edema

Specific management

Idiopathic FSGS is difficult to treat due to its highly variable clinical course. Current evidence, mostly derived from retrospective analyses, favors prolonged corticosteroid therapy to induce remission.

The following medications are used in the management of FSGS:

  • Immunosuppressants (eg, prednisone, ACTH, cyclophosphamide, cyclosporine)
  • Loop diuretics (eg, furosemide)
  • Potassium-sparing diuretics (eg, spironolactone, triamterene)
  • Other diuretics (eg, metolazone)
  • Volume expanders (eg, albumin)
  • Osmotic agents (eg, mannitol)
  • Angiotensin-converting enzyme inhibitors
  • Angiotensin receptor blockers

Precautions in managing idiopathic FSGS include the following:

  • Patient counseling and close monitoring for adverse effects of long-term steroid therapy
  • Monitoring for bone marrow suppression; encourage adequate fluid intake to prevent hemorrhagic cystitis
  • Avoiding prolonged use of cyclophosphamide, particularly in nonresponsive cases
  • Early patient and family counseling about treatment choices for ESRD
  • Avoiding cyclosporine in patients with kidney insufficiency who have refractory FSGS

Management of secondary FSGS is also directed toward the etiology or associated disorder, such as the following:

  • HIV-associated FSGS: Highly active antiretroviral therapy (HAART); corticosteroids
  • Heroin- or other drug–associated FSGS: Discontinuation of the offending agent

Some patients with FSGS continue to deteriorate and progress to ESRD. Treatment options include the following:

  • Maintenance hemodialysis
  • Continuous ambulatory peritoneal dialysis
  • Cadaver or living donor kidney transplantation

See Treatment and Medication for more detail.

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Pathophysiology

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).

   

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Etiology

FSGS can be classified as primary (idiopathic) 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

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] :

  • Hepatitis B and C
  • HIV [20, 26, 27, 28, 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 [29] (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
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Epidemiology

Rates of FSGS seem to be incresing worldwide. 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. [30] 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. [31] 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. [32, 33]

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. [34]  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. [31] In Black and white patients in the United States, idiopathic FSGS is now the commonest cause of ESRD resulting from primary glomerular disease.

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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 [35] 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. [36]

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. [35]

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