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 Black patients. However, no age group is exempt.
Rather than being a single disease, FSGS is a histologic pattern of characteristic sclerotic lesions in parts (hence, focal) of some (hence, segmental) glomeruli. These lesions result from diverse clinicopathological entities that have different mechanisms of injury, but all involve podocytes as the principal target.[2] Kidney Disease: Improving Global Ooutcomes (KDIGO) guidelines classify adult FSGS into four types, based on clinical and pathologic findings: primary, genetic, secondary, and of undetermined cause.[3] Conditions associated with secondary FSGS include the following:
See Etiology for more detail.
FSGS causes asymptomatic proteinuria or nephrotic syndrome with or without kidney insufficiency. Generally, FSGS results in progressive kidney injury; it accounts for 2.3% of all cases of end-stage kidney disease (ESKD), and is the leading glomerular cause of ESKD.
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. However, some patients may be asymptomatic.
Examination of patients with FSGS may include the following findings:
See Presentation for more detail.
Although clinical features are suggestive, a diagnosis of FSGS is established only by histopathology findings.[5] Detailed medical history and pertinent laboratory tests are essential to distnguish between the different types of FSGS. In massively obese patients, FSGS mostly is a diagnosis of exclusion.
Laboratory testing
In patients with suspected secondary FSGS, the search for an underlying etiology may include testing for conditions such as the following:
Genetic testing may be helpful in select patients, such as those with a strong family history and/or clinical features that suggest a syndromal disease.
Imaging studies
On ultrasonography, kidney findings in FSGS include the following:
Procedures
Kidney biopsy is the most definitive way to confirm the diagnosis. Findings are as follows:
See Workup for more detail.
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 or calcineurin inhibitors).
Nonspecific general management
Specific management
For primary FSGS, current evidence favors corticosteroid therapy: high-doses for 4 to 16 weeks, to induce remission, followed by tapering, for a total of 6 months of treatment.
The following medications are used in the management of FSGS:
Precautions in managing primary FSGS include the following:
Management of secondary FSGS is also directed toward the etiology or associated disorder, such as the following:
Some patients with FSGS continue to deteriorate and progress to ESKD. Treatment options include the following:
See Treatment and Medication for more detail.
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 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.[5, 9] Whether these diverse lesions reflect different pathogenesis or account for the differences in the prognoses in patients with FSGS is unclear.
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[10] :
These histologic variants may predict response to immunomodulating agents but do not provide insights into the pathogenesis of FSGS.[11]
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.[12, 13, 14] 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.[15]
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.[16] 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).[17] Wei et al have shown that elevated levels of suPAR were present in the plasma of two-thirds of patients with FSGS.[18] Furthermore, high levels of suPAR were predictive of FSGS recurrence, and lowering suPAR levels by plasmapheresis led to disease remission.
In some cases of primary 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.[19]
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 kidney 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.[20] 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. [21]
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, the protozoan parasite that causes trypanosomiasis (sleeping sickness), which would explain why variants of APOL1 have been preserved in Africans over several generations.
FSGS can be classified as primary, genetic, secondary, or of undetermined cause. The 2021 KDIGO guidelines note that the terms primary FSGS and idiopathic FSGS had been used interchangeably but recommended abandoning the latter term.[3]
Primary FSGS is defined by the following:
Pathologic variants of primary FSGS include the following:
Genetic FSGS may be familial or sporadic. These cases 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.[5]
Secondary FSGS is diagnosed when an FSGS lesion, with or without diffuse podocyte foot process effacement, is found on kidney biopsy in a patient with an established pathophysiologic process known to cause FSGS.[3] 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[22] :
Viruses associated with FSGS include the following[27, 28] :
Hemodynamic factors in patients with reduced renal mass include the following:
Hemodynamic causes in patients without reduced renal mass include the following:
Lymphomas and other malignancies have been associated with FSGS. Scarring may lead to FSGS subsequent to postinfectious glomerulonephritis. Miscellaneous other conditions associated with FSGS include sarcoidosis and radiation nephritis.
Rates of FSGS seem to be increasing worldwide.[33] 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, primary 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.[4]
In one review of the international literature, the annual incidence of FSGS ranged from 0.2 to 1.8/100,000 population.[34] 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, ESKD attributable to FSGS reported as patients per million population was 1.9 in Whites and 6.8 in Blacks.[35] 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.[36, 37]
In selected urban centers in the United States, heroin-associated FSGS, which occurred mostly in young men of African descent, accounted for 11.4% of ESKD patients in the 1970s and 1980s. Heroin-associated FSGS gradually disappeared in the 1990s. Lan et al propose that heroin or contaminants may have been a “second hit” that caused kidney disease in individuals who were susceptible because they carried APOL1 variants, and that HIV replaced or masked heroin as that second hit.[38]
Most patients with HIV-associated FSGS are young Black men (mean age, 33 y; male-to-female ratio, 10:1),[23, 24, 4] 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.[4]
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.[39] 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 ESKD attributed to primary FSGS increased 11-fold (from 0.2% to 2.3%) from 1980 to 2000.[35] In Black and White patients in the United States, idiopathic FSGS is now the commonest cause of ESKD 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[40] and other immunosuppressive agents, to worsening hypertension and progressive loss of kidney function. In patients who do not respond to therapy, the average time from the onset of gross proteinuria to ESKD 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.[41]
In patients who are unresponsive to therapy and who continue to have massive proteinuria of greater than 10 g/d, most develop ESKD 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 ESKD.
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 decades, the incidence of heroin-associated FSGS has drastically decreased.
The prevalence rate is much higher in Blacks than in Whites.[4] 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. As previously noted, most subjects with HIV-associated FSGS are young Black men.
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.[40]
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 end-stage kidney disease (ESKD). A typical course runs from edema that is difficult to manage, to proteinuria that is refractory to corticosteroids[40] and other immunosuppressive agents, to worsening hypertension and a progressive loss of kidney function. In nonresponders, the average time from the onset of proteinuria to ESKD 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 ESKD in 10 years. More than 50% of patients with persistent nephritic syndrome develop ESKD in 10 years. In those with massive proteinuria greater than 10-15 g/day, kidney function deteriorates even more rapidly (over 2-3 years).
The Post-Transplant Glomerular Disease (TANGO) project, which included 176 adults with FSGS, reported that FSGS recurred after kidney transplantation in 32% of patients, with subsequent allograft loss in 39% of those. Risk factors for recurrence were older age at primary disease onset, native kidney nephrectomy, White race, and lower body mass index at the time of transplantation.[42]
In the early 1980s, before the introduction of antiretroviral drugs, patients with HIV-associated FSGS typically developed ESKD 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 kidney 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 Kidney Disease: Causes, Symptoms, and Treatment.
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[43] :
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 kidney insufficiency.[4] Rarely, patients experience severe kidney 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 kidney 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 suspected secondary FSGS, investigational findings for an underlying etiology may include tests for the following:
Genetic testing may be helpful in select patients, such as those with a strong family history and/or clinical features that suggest a syndromal disease. Genetic testing may later be considered in patients whose condition does not respond to immunosuppressive treatment.
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.[6, 7]
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 kidney 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 therapy.
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.[45] 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.[45]
In patients with secondary FSGS and nephrotic-range proteinuria, the mainstay of therapy remains BP control with ACEIs and ARBs, along with disease-specific treatment if available (eg, antiretroviral therapy in HIV-associated nephropathy).
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 kidney 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 kidney 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 primary FSGS develop hypertension, which further contributes to kidney function 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.
Primary 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 limited to persistently nephritic patients. Ultimately, prognosis in nephritic FSGS patients is determined by their response to prednisone and other immunosuppressive agents.
Current evidence favors prolonged corticosteroid therapy (approximately 6 months) to induce remission in patients with idiopathic FSGS. Evidence for use of steroids in adults with FSGS has been extracted from observational studies in adults and extrapolated from randomized controlled trials of pediatric patients with nephrotic syndrome, which included some children with primary FSGS.[3]
Since long-term steroid therapy may lead to serious toxicity, patient counseling is essential before embarking on such a protracted regimen, as is close monitoring for adverse effects during the regimen. In adults, the current approach calls for initiating therapy with prednisone in a dose of 1 mg/kg daily (maximum 80 mg) or 2 mg/kg on alternate days. This dosage is continued for at least 4 weeks and until complete remission is reached, or to a maximum of 16 weeks.[3] Patient response is assessed by the following:
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 kidney function in 31%, decline in the glomerular filtration rate in 23%, and development of end-stage kidney disease (ESKD) 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 unresponsive to treatment and progress to kidney failure.[46]
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.
Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend reducing the prednisone dose by 5 mg every 1-2 weeks, to complete a total treatment duration of 6 months.
A variety of other immunosuppressive agents have been used in patients with contraindications, unacceptable toxicity, or inadequate response to corticosteroids. These have included cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil, and rituximab, among others. However, 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.[47]
Cyclophosphamide
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.
Calcineurin inhibitors
Guidelines from Kidney Disease/Improving Global Outcomes (KDIGO) suggest considering calcineurin inhibitors (cyclosporine or tacrolimus) as first-line therapy for patients who fail to respond to corticosteroids or experience significant adverse effects, as well as for patients with relative contraindications to high-dose corticosteroids (eg, uncontrolled diabetes, psychiatric conditions, severe osteoporosis).[3] Since both of these calcineurin inhibitors can cause nephrotoxicity, the recommendation is to avoid them in patients with kidney insufficiency.
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. A Cochrane review that included four studies of cyclosporine for treatment of FSGS concluded that its use "for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers."[48]
Induction of remission with tacrolimus was demonstrated in a retrospective study of 22 pediatric patients with steroid-resistant FSGS and heavy proteinuria. Tacrolimus was targeted to a trough level of 5-8 ng/mL. Thirteen patients (59%) achieved remission (complete in 7 patients and partial in 6) and 12 patients showed stable or improved kidney function over an average follow-up of 2.9 years (range: 0.5-7 years).[49]
In a prospective study of 44 patients with adult-onset 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.[50]
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%).[50]
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 an early regimen was associated with improved renal outcome, but calcineurin inhibitors showed no superiority over glucocorticoids alone.[51, 52]
Mycophenolate
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 whose FSGS is 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.[39]
Rituximab
Rituximab has proved effective for maintenance of remission in frequently relapsing FSGS and for treatment of remission, including in kidney transplant recipients.[53, 54] 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.[55]
Angeletti et al reported five cases of early FSGS recurrence after kidney transplantation that were resistant to plasma exchange and rituximab treatment but demonstrated a complete response to combined therapy with rituximab and daratumumab.[56]
Small studies have found benefit with use of galactose, abatacept, and adalimumab.[57, 58]
Subcutaneously injected adrenocorticotropic hormone (ACTH) gel may have some efficacy for treatment of FSGS, especially in treatment-resistant or relapsing cases.[59] 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.[60]
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).[61]
Despite all attempts, some patients continue to deteriorate and progress to ESKD. Counsel patients and their families early regarding treatment choices for ESKD. A well-informed patient can choose among maintenance hemodialysis, continuous ambulatory peritoneal dialysis, or deceased 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.[62, 63] 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.[5]
More rapid allograft failure has been reported with deceased-donor kidney transplants from donors that carry an APOL1 high-risk genotype (ie, two copies of the G1 and/or G2 renal-risk variants: G1G1, G2G2, or G1G2). In addition, living kidney donors with APOL1 high-risk genotypes are at higher risk of eventually developing chronic kidney disease. Consequently, Mena-Gutierrez and colleagues advise that transplant physicians should discuss APOL1 genotyping with potential living kidney donors who self-report recent African ancestry (eg, African Americans, Hispanic blacks, Afro-Caribbeans, Africans).[64]
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.[65]
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.[66]
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.[67] 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.[67]
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.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.[67]
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 kidney function.[30] 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 kidney 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.
Complications of prednisone therapy include the following:
Complications of cyclophosphamide therapy include the following:
Complications of cyclosporine therapy include the following:
Note the following:
The goals of pharmacotherapy are to preserve kidney function, to reduce morbidity, and to prevent complications in patients with focal segmental glomerulosclerosis (FSGS). Medications used include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for control of hypertension and diuretics for edema. In primary FSGS, corticosteroids are used for remission of proteinuria, with other immunosuppressive agents such as cyclophosphamide considered in steroid-resistant cases.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Calcineurin inhibitor; suppresses cellular and humoral immunity/ Used off-label in focal segmental glomerulosclerosis.
Clinical Context: Calcineurin inhibitor, used off-label in focal segmental glomerulosclerosis.
Immunosuppressants are used for inducing remission of proteinuria in patients with primary focal segmental glomerulonephritis. Corticosteroids are the first-line choice, with other immunosuppressive agents, such as cyclophosphamide and calcineurin inhibitors, used in patients who have contraindications to high-dose steroids or unacceptable toxicity from them, or whose conditions are refractory to steroid therapy. These powerful immunosuppressive agents need careful monitoring and are best used by specialists in the field.