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]

Patients with focal segmental glomerulosclerosis (FSGS) typically present with signs and symptoms of nephrotic syndrome. In children, this usually begins with facial swelling, followed by swelling of the entire body. Adults can present with dependent edema. Typically, edema develops over a few weeks, but the onset may be abrupt, with weight gain of 15-20 lb or more. Frequently, the onset of edema follows a recent upper respiratory tract infection. Foamy urine may be noted. Fatigue and loss of appetite are common.

To identify causes of secondary FSGS, details about the following should be elicited[39] :

• Birth history (eg, low birth weight/premature birth)
• Congenital urinary tract malformations (eg,  vesicoureteral reflux)
• Medical comorbidities
• Pre-existing kidney disease
• Exposure to drugs/toxins
• Recent viral illnesses
• Family history

The most common clinical presenting feature, found in more than 70% of patients, is nephrotic syndrome, which is characterized by generalized or dependent edema, massive proteinuria, hypoalbuminemia, and hyperlipidemia.  In patients with primary (essential) hypertension and analgesic abuse, nephrotic syndrome is not a common manifestation (although hypertension may be observed in patients with nephrotic syndrome from all causes).

Occasionally, routine urinalysis may reveal proteinuria, prompting referral to a nephrologist. Less than a third of patients with FSGS present with nonnephrotic proteinuria along with microscopic hematuria and hypertension. Typically, edema develops over a few weeks, but the onset may be abrupt, with weight gain of 15-20 lb or more. Frequently, the onset of edema follows a recent upper respiratory tract infection.

Pleural effusion and ascites may be present; pericardial effusions are rare. Gross edema may predispose patients to ulcerations and infections in dependent areas (eg, lower extremities). Abdominal pain, a common finding in children, may be a sign of peritonitis. Rarely, xanthomas may be evident in association with severe hyperlipidemia. In many patients, physical examination findings are normal except for generalized or dependent edema.

Severe hypertension (ie, diastolic blood pressure of 120 mm Hg or more) is not uncommon, especially in black patients with renal insufficiency.[2] Rarely, patients experience severe renal failure with signs and symptoms of advanced uremia (eg, nausea, vomiting, bleeding, seizures) or altered mental status.

Patients with FSGS secondary to diseases such as massive obesity, reflux nephropathy, and renal dysplasia/agenesis may present with non-nephritic proteinuria. These patients often experience worsening renal function over a course of months to years.

In patients with focal segmental glomerulosclerosis (FSGS), urinalysis reveals large amounts of protein, along with hyaline and broad waxy casts, whereas red blood cell (RBC) casts are generally absent. Broad casts may be observed in patients with advanced cases. Serum creatinine (SCr) concentration or creatinine clearance (CrCl) is usually within reference ranges in early stages.

In patients with idiopathic FSGS, investigational findings for an underlying etiology are generally negative. Such conditions may include the following:

• Systemic lupus erythematosus (serum complement C4/C3 levels, antinuclear antibody/anti-DNA titers)
• Hepatitis B or C infection
• Vasculitis (antineutrophil cytoplasmic antibody titers, serum protein electrophoresis)

In patients thought to have secondary FSGS, obtain HIV antibody, CD4, and viral load studies; serology for hepatitis B and C; and parvovirus testing. Diagnosis of FSGS in morbidly obese patients is by excluding other causes. FSGS can be considered in patients with proteinuria on the basis of nephrotic syndrome; however, in young patients with an absence of RBC casts and negative serologic study findings, definitive diagnosis rests on a kidney biopsy.

Kidney biopsy is the most definitive way to establish the diagnosis. The characteristic lesion in FSGS is segmental solidification of the glomerular tuft, usually in the perihilar region and sometimes in the peripheral areas, including the tubular pole. In the affected glomeruli, capillaries are segmentally obliterated by accumulation of acellular matrix and hyaline deposits, along with adhesion to the Bowman capsule. Coarsely granular deposits of IgM and C3 are often found in these areas.

Diffuse foot process fusion occurs, predominantly in the sclerotic segments, although partial effacement may be observed overlying 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 (localized sclerotic lesions limited to the proximal tubular pole of the glomerulus) have been described (see Overview/Pathophysiology). Whether these diverse lesions reflect different pathogeneses or can account for the differences in the prognosis in patients with FSGS is unclear.

In HIV-associated FSGS, in addition to collapsing glomerular lesions with microcystic dilatation of renal tubules, electron microscopy of the kidney reveals tubuloreticular inclusions in endothelial and mesangial cells, an indirect marker of viral disease.[4, 5]

In the early stages of FSGS, ultrasound examination reveals normal or large kidneys with increased echogenicity, suggesting diffuse intrinsic medical renal disease. In patients with advanced renal failure, kidneys are small and shrunken, indicating severe glomerular scarring and interstitial fibrosis. In HIV-associated FSGS, ultrasound generally reveals large echogenic kidneys.

Treatment of focal segmental glomerulosclerosis (FSGS) can be divided into nonspecific and specific treatment.

In patients with primary or secondary FSGS (non-nephrotic or nephrotic) and proteinuria, the initial approach consists of optimal blood pressure (BP) control and the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). For patients who remain non-nephrotic or become non-nephrotic after 6 months of therapy, this remains the primary therapeutic approach.[41]

In patients with secondary FSGS and nephrotic-range proteinuria, the mainstay of therapy remains BP control and ACEIs and ARBs, along with disease-specific treatment if available (eg, antiretroviral therapy in HIV-associated nephropathy). Patients who are persistently nephrotic after a course of conservative therapy or who present with complications from nephrotic syndrome require more aggressive treatment with prednisone or immunosuppressive agents.[41]

Nonspecific treatment goals in patients with nephrotic syndrome include maintenance of adequate nutrition, minimization or elimination of proteinuria, and prevention of complications resulting from edema. Control of hypertension is one of the most important aspects of overall management. Lowering of lipid levels is necessary to reduce cardiovascular risk and to possibly delay the progression of renal disease.

The mainstay of treatment is reduction in daily salt intake to 2 g of sodium (6 g of salt) and the use of diuretics in varying doses and combinations. Because a high level of protein intake may further aggravate proteinuria, adversely affecting renal function, current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight. A reduction of dietary fat intake may help with dyslipidemia.

In most patients, loop diuretics (eg, furosemide) are needed to promote diuresis. Patients with massive edema with impaired oral absorption may require intravenous administration. In patients with refractory conditions, addition of other diuretics (eg, metolazone) and potassium-sparing agents (eg, spironolactone, triamterene) facilitates diuresis and prevents hypokalemia.

Rarely, some patients (especially children) with intractable edema may need intravenous albumin and mannitol in a hospital setting to initiate diuresis. Protracted use of intravenous albumin should be discouraged; the regimen is expensive and ineffective, because most of the infused albumin is lost in the urine.

ACEIs and ARBs are nonspecific agents that reduce proteinuria because of their antihypertensive and intrarenal hemodynamic effects of reducing glomerular capillary pressure and resistance. ACEIs and ARBs are effective in reducing protein loss even in normotensive patients. These agents do not eliminate proteinuria completely or reverse the primary glomerular disease process.

Since most patients with idiopathic FSGS develop hypertension, which further contributes to renal functional deterioration, meticulous attention must be paid to maintain BP in the reference range. In addition to lowering BP, all classes of antihypertensive agents have a beneficial effect in reducing proteinuria. In many patients, combination antihypertensive therapy may be needed to maintain normal blood pressure.

Another nonspecific therapy is the use of lipid-lowering agents to control hyperlipidemia. Statins are better tolerated than some of the older agents.

Idiopathic FSGS is a difficult disease to treat because of its highly variable clinical course. Because of a lack of prospective controlled trials, the specific treatment approach is still empirical, and no consensus has evolved. Spontaneous remissions are very rare, probably occurring in less than 5% of patients.

In patients with non-nephritic proteinuria, many physicians use only the nonspecific measures outlined above, and the general consensus is that aggressive approaches should be used in persistently nephritic patients. Ultimately, prognosis in nephritic FSGS patients is determined by their response to prednisone and other immunosuppressive agents.

Steroid therapy

Current evidence, mostly derived from retrospective analyses, favors prolonged corticosteroid therapy (6 mo or longer) to induce remission in patients with idiopathic FSGS.

Since long-term steroid therapy may lead to serious toxicity, patient counseling and close monitoring for adverse effects are essential before embarking on such a protracted regimen. The current approach calls for initiating therapy with prednisone in a dose of 1 mg/kg (60-80 mg/d) for 2-6 months or longer, depending on patient response as assessed by the following:

• Presence or absence of edema
• 24-hour urine protein excretion
• Creatinine clearance
• Serum creatinine, albumin, and lipid levels

Studies indicate that 30-60% of patients may undergo complete or partial remission with such a regimen, and relapses are frequent when steroids are discontinued. Complete remission is protein excretion of less than 200-300 mg/d, and partial response is excretion of 200-3500 mg/d, or a greater than 50% reduction in baseline proteinuria. In children, results from several studies show a remission of proteinuria in 11% of patients, persistence of nephrotic syndrome with preservation of renal function in 31%, decline in the glomerular filtration rate in 23%, and development of end-stage renal disease (ESRD) in 21%. In adults, 10-year renal survival in nephrotic patients ranges from 25-55%, compared with 85-90% in patients with mild proteinuria.

In general, patients with tip lesions on histology are more responsive to corticosteroids, with excellent renal preservation compared with those with other forms of FSGS. Blacks and patients with collapsing FSGS are generally refractory to treatment and progress to renal failure.[42]

In responding patients, the goal is to titrate prednisone to the lowest dose that will stop or reduce proteinuria and prevent relapses. Use of steroids on alternate days can also reduce toxicity. Some have used a combination of prednisone and a cytotoxic agent such as cyclophosphamide as initial therapy to reduce the dose and duration of corticosteroids.

The optimal treatment duration is uncertain. Some authorities recommend continuing steroids indefinitely.

Other therapies

In patients whose FSGS is refractory to 2-3 months of prednisone therapy, the recommendation is to reduce the steroid dose and to add cyclophosphamide (2.5 mg/kg [150-200 mg/d]). Monitor patients for bone marrow suppression, and encourage them to drink adequate fluids to prevent hemorrhagic cystitis. Prolonged use of cyclophosphamide may lead to gonadal toxicity. Therefore, persisting with cyclophosphamide beyond 3 months in patients who do not respond is unwise.

Guidelines from Kidney Disease/Improving Global Outcomes (KDIGO) suggest considering calcineurin inhibitors (cyclosporine or tacrolimus) as first-line therapy for patients with relative contraindications or intolerance to high-dose corticosteroids (eg, uncontrolled diabetes, psychiatric conditions, severe osteoporosis).[43]

Randomized controlled trials and uncontrolled studies indicate that cyclosporine in a dose of 5-10 mg/kg/d may be beneficial in patients unresponsive to prednisone and cyclophosphamide. Few limited studies have employed tacrolimus. Since both of these calcineurin inhibitors can cause nephrotoxicity, the recommendation is to avoid them in patients with renal insufficiency.

Because of favorable results in other glomerular diseases, mycophenolate mofetil (MMF) has also been evaluated in FSGS. Although the experience is limited, the suggested dose is 750-1000 mg twice daily in patients who are refractory to corticosteroids and in whom calcineurin inhibitors may not be appropriate.

To assess whether treatment with MMF and oral pulses of dexamethasone was more effective than treatment with cyclosporine alone for steroid-resistant FSGS, a National Institutes of Health–sponsored multicenter randomized controlled trial, the largest study to date, was conducted in 138 patients aged 2-40 years. At the end of the 52-week treatment period, the incidence of complete and partial remissions was 33% in the MMF and dexamethasone group compared with 46% in the cyclosporine group, which was not significantly different. A critical analysis of this study highlights the limitations of current practices in the treatment of the individual patient with FSGS.[36]

Isolated reports have suggested that in patients with FSGS refractory to steroids and cyclophosphamide, treatment with other immunosuppressive agents, such as tacrolimus and sirolimus, may be beneficial in inducing remissions. In a prospective study of 44 patients with steroid-resistant nephrotic syndrome due to FSGS, 48 weeks of treatment with oral tacrolimus given in combination with prednisolone resulted in complete remission in 17 patients (38.6%) and partial remission in 6 patients (13.6%). Resistance to tacrolimus was observed in 21 patients (47.7%). Mean time to remission was 15.2 ± 6 weeks.[44]

Among the patients who achieved complete remission, relapse occurred in five (21.7%) after the tacrolimus dose was tapered and in 7 (30.4%) after tacrolimus was stopped. Reversible and irreversible nephrotoxicity occurred in 7 (15.9%) and 4 patients (9%), respectively. Tacrolimus-related diarrhea was observed in 10 patients (22.7%), infections in 19 patients (43.1%), and impaired fasting glucose and diabetes mellitus in 10 patients (22.7%).[44]

In an analysis of 485 patients with biopsy-proven primary FSGS who were enrolled in Glomerular Disease Collaborative Network (GDCN), use of immunosuppressive therapy with calcineurin inhibitors and/or glucocorticoids as part of early regimen was associated with improved renal outcome, but there was no superiority of calcineurin inhibitors over glucocorticoids alone.[45, 46]

Rituximab has proved effective for maintenance of remission in frequently relapsing FSGS and for treatment of remission, including in kidney transplant recipients.[47, 48] Kronbichler and colleagues, in a systematic review of 14 studies involving 86 adult patients with either steroid-dependent or frequently relapsing minimal change disease or FSGS, found that rituximab treatment significantly reduced the number of relapses per year from a mean of 1.3 before treatment to none after treatment. Rituximab treatment decreased proteinuria from 2.43 g/day to 0 g/day (P< 0.001), increased serum albumin from 2.9 to 4.0 g/dL, and decreased the need for immunosuppression.[49]

Despite all attempts, some patients continue to deteriorate and progress to ESRD. Counsel patients and their families early regarding treatment choices for ESRD. A well-informed patient can choose among maintenance hemodialysis, continuous ambulatory peritoneal dialysis, or cadaver or living donor transplantation. FSGS recurs in 30%-50% of patients who undergo kidney transplantation for the disease. However, most nephrologists do not consider this a contraindication for kidney transplantation.[50, 51] Recurrence of FSGS in the kidney allograft is much more common in patients with primary FSGS than in those with FSGS due to genetics or to hyperfiltration and other maladaptive or secondary forms of FSGS.[3]

In a study of recurrent FSGS in kidney transplant recipients whose initial treatment consisted of plasma exchanges, high doses of calcineurin inhibitors, and steroids, Garrouste et al reported that treatment with rituximab led to remission in 12 of 19 patients (nine complete remissions and three partial remissions). Four patients required a further course of rituximab for FSGS relapse, with good results.[52]

A multicenter retrospective case series on the use of long-term apheresis (with plasmapheresis, immunoadsorption, or both) in adult patients with recurrent FSGS after kidney transplantation reported that 23 of 27 patients (85%) had achieved partial or complete remission at one point after treatment. Median frequency of apheresis was twice monthly, and median time on apheresis was 23 months. In , and rituximab was administered in 78% of the cases (21 patients). Other treatments administered were rituximab, in 21 patients, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, in 23 patients.[53]

In 2013, the FDA approved the Liposorber LA-15 System to treat children with primary FSGS before kidney transplantation or recurrent FSGS after kidney transplantation.[54] This product is an extracorporeal blood processing system that removes certain lipoproteins from the blood; it was previously approved to lower low-density lipoprotein cholesterol (LDL-C) in selected patients with familial hypercholesterolemia.[54]

Approval was based on two studies in children with FSGS. One study showed normal or near-normal renal function in most children who had had a high risk for progression to ESRD but who achieved remission of FSGS following treatment with the system.[54] The second study reported that posttransplant children who were treated with the Liposorber LA-15 System had less proteinuria relative to children not treated with the system.[54]

Small studies have found benefit with use of galactose, abatacept, and adalimumab.[55, 56]

Subcutaneously injected adrenocorticotropic hormone (ACTH) gel may have some efficacy for treatment of FSGS, especially in treatment-resistant or relapsing cases.[57] In a study of 24 patients with nephrotic syndrome from idiopathic FSGS, Hogan et al reported that treatment with ACTH gel resulted in full remission in two patients and partial remission in five patients. However, two responders relapsed during follow-up and 21 patients experienced adverse events, including one episode of new-onset diabetes, which resolved after stopping ACTH, and two episodes of acute kidney injury.[58]

Alhanad et al reported complete or partial remission with the use of ACTH gel in 10 of 20 cases of posttransplant recurrent and de novo FSGS resistant to therapy with therapeutic plasma exchange and rituximab. Urine protein-to-creatinine ratio improved from a mean of 8.6 g/g before ACTH gel to 3.3 afterward (P=0.004).[59]

A systematic review and meta-analysis of efficacy and safety of immunosuppressive therapy in primary FSGS concluded that treatment resulted in reduction of proteinuria, but its effect on kidney survival was uncertain.[60]

Secondary FSGS

Management of secondary FSGS is directed toward the etiology or associated disorder. For example, in HIV-associated FSGS, highly active antiretroviral therapy (HAART) is associated with remission of proteinuria and preservation of renal function.[28] Current guidelines call for initiation of HAART therapy in patients with HIV who have nephropathy irrespective of CD4 count and viral load. In selected patients with HIV infection and FSGS, corticosteroid therapy is associated with a significant improvement and, in some patients, discontinuation of dialysis. In heroin-associated FSGS, discontinuation of the drug may result in remission of proteinuria and improvement in kidney function.

Daily salt intake should be reduced to 2 g of sodium (5 g of salt). Potassium supplementation may be needed in patients treated with diuretics who develop hypokalemia.

As high protein intake may further aggravate proteinuria, adversely affecting renal function, current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight. Reduction of fat intake may help with dyslipidemia. 

The goals of pharmacotherapy are to preserve renal function, to reduce morbidity, and to prevent complications. Medications used include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), diuretics, and corticosteroids, with agents such as cyclophosphamide considered in steroid-resistant cases.

Class Summary

Current approach calls for initiating therapy with prednisone. In patients whose conditions are refractory to 2-3 mo of prednisone therapy, recommendations include reducing the steroid dose and adding cyclophosphamide. A prospective study indicated that 5-10 mg/kg/d of cyclosporine may be beneficial in patients unresponsive to prednisone and cyclophosphamide. Mycophenolate mofetil may be another alternative agent in patients with renal insufficiency in whom cyclosporine cannot be used. These powerful immunosuppressive agents need careful monitoring and are best used by specialists in the field.

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Patients receiving long-term corticosteroid therapy must be monitored for adverse effects (eg, infections, hypertension, hyperglycemia). If cyclophosphamide is used, watch for leukopenia and hemorrhagic cystitis. During cyclosporine therapy, monitor renal function. Adjust diuretic doses according to fluid retention. During mycophenolate mofetil therapy, monitor white blood cell count and liver function. Patients with HIV infection will need periodic determination of viral load to assess the effectiveness of their antiretroviral therapy.[28]

Complications of prednisone therapy include the following:

• Infections
• Hypertension
• Hyperglycemia

Complications of cyclophosphamide therapy include the following:

• Infections
• Leukopenia
• Hemorrhagic cystitis

Complications of cyclosporine therapy include the following:

• Renal insufficiency
• Gingival hyperplasia
• Infections

The natural history of focal segmental glomerulosclerosis (FSGS) varies a great deal. Patients with tip lesions generally respond to therapy. The collapsing form of FSGS is marked by severe hypertension, more massive proteinuria, a very poor response to corticosteroids, and a much faster rate of progression to ESRD. A typical course runs from edema that is difficult to manage, to proteinuria that is refractory to corticosteroids[37]  and other immunosuppressive agents, to worsening hypertension and a progressive loss of renal function. In nonresponders, the average time from the onset of proteinuria to end-stage renal disease (ESRD is 6-8 years, although wide variations in the time course occur. The presence of interstitial fibrosis on an initial kidney biopsy specimen is a uniform predictor of poor renal prognosis. Blacks have a worse prognosis than whites.

Spontaneous remissions are extremely rare, although the literature contains isolated case reports.

The level of proteinuria greatly influences the outcome in FSGS. In patients with non-nephritic proteinuria, kidney function remains stable and fewer than 15% progress to ESRD in 10 years. More than 50% of patients with persistent nephritic syndrome develop ESRD in 10 years. In those with massive proteinuria greater than 10-15 g/day, kidney function deteriorates even more rapidly (over 2-3 years).

In the early 1980s, before the introduction of antiretroviral drugs, patients with HIV-associated FSGS typicallydeveloped ESRD in less than a year. With the introduction of HAART, the natural history is now dramatically different, including both prevention of nephropathy and preservation of renal function in those with established disease.

Educate patients about chronic kidney disease, control of hypertension and lipids, and options for renal replacement therapy, such as peritoneal dialysis, hemodialysis, and kidney transplantation. For further information, see Glomerulosclerosis and the Kidney Disease Directory.