Focal Segmental Glomerulosclerosis

Updated: Jun 06, 2016
  • 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 diseases in adults. The condition causes asymptomatic proteinuria or nephrotic syndrome with or without renal insufficiency. Generally, FSGS is a progressive form of kidney disease, accounting for 2.3% of patients with end-stage renal disease (ESRD).

Signs and symptoms

The most common clinical presenting feature of FSGS (>70% of patients) is nephrotic syndrome, characterized by generalized edema, massive proteinuria, hypoalbuminemia, and hyperlipidemia. However, the natural history of FSGS is variable and can range from edema that is difficult to manage, to proteinuria that is refractory to corticosteroids [1] and other immunosuppressive agents, to worsening hypertension and a progressive loss of renal function.

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. In human immunodeficiency virus (HIV)–associated FSGS, the renal functional deterioration is rapid, leading to ESRD within a few weeks to 1 year.

See Clinical Presentation for more detail.

Diagnosis

Although clinical features are suggestive, a diagnosis of FSGS is established only by histopathology findings. [2] In massively obese patients, FSGS is a diagnosis of exclusion.

Examination of patients with FSGS may include the following findings:

  • Pleural effusion
  • Ascites
  • Abdominal pain: Common in children; may be sign of peritonitis
  • Ulcerations and infections in dependent regions
  • Severe hypertension (diastolic blood pressure of ≥120 mm Hg): Commonly seen in black patients, especially those with renal insufficiency [3]

Laboratory testing

  • Urinalysis: Large amounts of protein; hyaline and broad waxy casts
  • Serum creatinine concentration or creatinine clearance: Usually within reference range
  • 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 infection, or vasculitis (antineutrophil cytoplasmic antibody titers, serum protein electrophoresis)—are generally negative.

In patients with suspected secondary FSGS, obtain HIV antibody, CD4, and viral load studies; serology for hepatitis B and C; and parvovirus testing.

Imaging studies

Ultrasonographic findings of the kidneys include the following in FSGS:

  • 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

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. The specific treatment approach is still empirical; no consensus has evolved due to a lack of prospective controlled trials.

The general consensus is for an aggressive approach in persistently nephritic patients to induce remission (eg, use of corticosteroids and immunosuppressive agents). Precautions in managing patients with 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 renal insufficiency who have refractory FSGS

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

  • HIV-associated FSGS: Highly active antiretroviral therapy (HAART); corticosteroids and/or discontinuation of dialysis in selected patients
  • Heroin-associated FSGS: Discontinuation of the drug

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 renal transplantation

Pharmacotherapy

The following medications are used in the management of FSGS:

  • Immunosuppressants (eg, prednisone, cyclophosphamide)
  • 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

See Treatment and Medication for more detail.

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Background

Focal segmental glomerulosclerosis (FSGS), first described in 1957, is currently recognized as one of the most common causes of primary glomerular diseases in adults, and the incidence of FSGS has been increasing in recent years. [6, 7] FSGS causes asymptomatic proteinuria or nephrotic syndrome (NS) with or without renal insufficiency. In adults undergoing renal biopsy for evaluation of proteinuria, FSGS accounts for 35% of all cases and up to 80% of cases in African-American patients. Generally, FSGS is a progressive form of kidney disease, accounting for 2.3% of patients with end-stage renal disease (ESRD).

Although clinical features are suggestive, a diagnosis of FSGS is confirmed only by histopathology findings. [2] The disease represents several patterns of glomerular injury, and biopsy findings provide no insights into the pathogenesis. FSGS arises through idiopathic (primary) or secondary causes.

Therapy for FSGS includes nonspecific measures (eg, nutrition) and symptomatic treatment. Current evidence, mostly derived from retrospective analyses, favors prolonged corticosteroid therapy to induce remission in patients with idiopathic FSGS.

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Pathophysiology

Etiologic agents or mechanisms that initiate glomerular injury which 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 all lead to scarring (glomerulosclerosis). [8, 9]

Proposed mechanisms include viral- or toxin-mediated damage or intrarenal hemodynamic changes such as glomerular 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 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. [2, 9] 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 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

Drugs associated with FSGS include the following [10] :

  • Intravenous heroin [11, 12, 13, 14]
  • Analgesics
  • Pamidronate
  • Lithium
  • Anabolic steroids

Viruses associated with FSGS include the following:

  • Hepatitis B
  • HIV [10, 15, 16, 17, 4, 5]
  • Parvovirus

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

  • Solitary kidney
  • Renal allograft
  • Renal dysplasia
  • Renal agenesis
  • Oligomeganephronia
  • Segmental hypoplasia
  • Vesicoureteric reflux

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

  • Massive obesity [18]
  • 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

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

Pathogenic classification

A pathogenic classification of FSGS has also been proposed, as follows:

  • Primary alteration of epithelial cells - Includes FSGS from idiopathic, viral-associated, drug-induced, and genetic disorders
  • Secondary to reduction in nephron mass or hemodynamic adaptation - Includes FSGS seen in patients who are obese and those with a single kidney, renal dysplasia/agenesis, reflux nephropathy, sickle cell disease, hereditary nephropathies, and other primary glomerular diseases

This classification also does not contribute much to the understanding of the pathogenesis of FSGS.

Columbia classification

Another classification, often referred to as Columbia classification, recognizes five histologic variants of primary FSGS, as follows:

  • FSGS not otherwise specified
  • Perihilar FSGS
  • Cellular FSGS
  • Tip FSGS
  • Collapsing forms of FSGS

These histologic variants may predict response to immunomodulating agents but do not provide insights into the pathogenesis of FSGS. [19]

Protein mutations and circulating factors

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. [20, 21, 22] 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. [23] The observation that in some cases FSGS can occur de novo in renal 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. 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). [24]

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. [25] 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. Recently, the same group has analyzed circulating suPAR levels in 2 cohorts of patients with biopsy proven FSGS. This included 70 patients from a North America–based FSGS clinical trial and 94 patients from Europebased, steroid-resistant nephrotic syndrome, 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. [26]

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, as podocin and others) 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. [27] Mutations of podocyte proteins are more often associated with familial forms of FSGS.

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Epidemiology

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. [1] 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. [3]

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. This increased incidence is partly explained by variants of 2 important podocyte function proteins; nonmuscle myosin heavy chain-9 and apolipoprotein Apol1 is found in about 60% of African American patients compared with 5% in whites. [28, 29]

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), [11, 12, 3] 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. [3]

The incidence of HIV-associated FSGS in children has practically disappeared because of serologic screening of all transfused products, screening of pregnant mothers, 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%) 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.

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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 [1] 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. [30]

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. [3] 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, the lesion 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 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. [1]

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