Focal segmental glomerulosclerosis: Treatment and prognosis

INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a morphologic pattern of glomerular injury primarily directed at the glomerular visceral epithelial cell (the podocyte) and defined by the presence of sclerosis in parts (segmental) of some (focal) glomeruli by light microscopy of a kidney biopsy specimen. The lesion of FSGS can be classified into primary, secondary, genetic, and undetermined forms using a clinicopathologic approach. This classification step is crucial for determining appropriate therapy; identification of an FSGS lesion solely by light microscopy is never sufficient for management decisions. The lesion of FSGS is distinct from focal and global glomerulosclerosis, which has a different prognosis and treatment.

This topic will review the treatment and prognosis of the FSGS lesion in adults in all of its forms but will focus on patients with presumed primary FSGS. Other aspects of the FSGS lesion, including the treatment of children with FSGS lesions, the treatment of collapsing glomerulopathy, and the treatment of recurrent FSGS in the transplanted kidney, are discussed separately:

●(See "Focal segmental glomerulosclerosis: Pathogenesis".)

●(See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)

●(See "Focal segmental glomerulosclerosis: Genetic causes".)

●(See "Treatment of idiopathic nephrotic syndrome in children".)

●(See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)

●(See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

GENERAL PRINCIPLES

Goals of therapy — A primary goal of therapy in FSGS is remission of proteinuria, preferably a complete remission, with the long-term goal of preventing progression to end-stage kidney disease (ESKD). For patients with primary FSGS, remission of proteinuria is primarily achieved with the use of a variety of agents having both immunosuppressive properties as well as direct actions on glomerular podocytes (most commonly glucocorticoids or calcineurin inhibitors [CNIs]), as well as with supportive measures (such as renin-angiotensin inhibition). For patients with secondary FSGS, cessation of the offending drug or effective treatment of the underlying condition, combined with supportive measures, is the therapy of choice. Adults with proven genetic forms of FSGS usually do not respond to immunosuppressive therapy and should also be primarily treated with supportive measures. (See 'Treatment of primary FSGS' below and 'Treatment of secondary FSGS or FSGS of undetermined cause' below and 'Treatment of genetic FSGS' below.)

Definitions of response — The following are commonly used definitions of treatment response for adults with nephrotic syndrome due to primary FSGS [1]. These definitions are not necessarily evidence based and may need to be modified on a case-by-case basis by other factors, such as duration of therapy before switching or adding treatment.

●Complete remission – A complete remission is reduction of proteinuria to <300 mg/day (or <300 mg/g of creatinine), stable serum creatinine, and serum albumin >3.5 g/dL.

●Partial remission – A partial remission is a reduction in proteinuria to between 300 mg and 3.5 g/day and a decrease of >50 percent from baseline, with or without a return of serum albumin levels to normal.

●Relapse – A relapse is a return of proteinuria to >3.5 g/day in patients who had previously undergone a complete remission or an increase in proteinuria of >50 percent in patients who had previously undergone a partial remission.

●Glucocorticoid-resistant primary FSGS – Glucocorticoid resistance refers to the persistence of proteinuria >3.5 g/day with ≤50 percent reduction from baseline after 16 weeks of high-dose oral glucocorticoid therapy (ie, oral prednisone 1 mg/kg/day or 2 mg/kg every other day).

●Glucocorticoid-dependent primary FSGS – Glucocorticoid dependence refers to relapse occurring during, or within two weeks of completing, glucocorticoid therapy.

●Calcineurin inhibitor-resistant primary FSGS – CNI resistance refers to the persistence of proteinuria >3.5 g/day with ≤50 percent reduction from baseline despite cyclosporine treatment at trough levels of 100 to 175 ng/mL or tacrolimus treatment at trough levels of 5 to 10 ng/mL for four to six months.

●Calcineurin inhibitor-dependent primary FSGS – CNI dependence refers to relapse occurring during, or within two weeks of completing, cyclosporine or tacrolimus therapy for >12 months.

TREATMENT MEASURES FOR ALL FORMS OF FSGS — General treatment measures in all patients with FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, treatment of dyslipidemia, and in selected patients, anticoagulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit, although data specifically in patients with FSGS are limited [2]. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. This approach is consistent with the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases [1]. These issues are discussed in greater detail elsewhere:

●Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

●Antihypertensive therapy (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults")

●Renin-angiotensin system inhibition (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors')

●SGLT2 inhibitors (see "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria')

●Lipid lowering (see "Lipid abnormalities in nephrotic syndrome", section on 'Management')

●Anticoagulation (see "Hypercoagulability in nephrotic syndrome", section on 'Patients with other causes of nephrotic syndrome')

●Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload')

TREATMENT OF PRIMARY FSGS

Initial therapy

General approach — Our approach to initial therapy in patients with a clinicopathologic diagnosis of presumed primary (permeability factor-related) FSGS is as follows:

●For patients with presumed primary FSGS who present with nephrotic syndrome (ie, proteinuria >3.5 g/day and serum albumin <3.5 g/dL), we suggest initial treatment with glucocorticoids, rather than a calcineurin inhibitor (CNI). Such patients have a poor prognosis without this therapy. In patients who have a high risk for glucocorticoid-induced toxicity (eg, patients with obesity, diabetes, severe osteoporosis, or age >70 years), a CNI (cyclosporine or tacrolimus), with or without low-dose glucocorticoids, is an alternative option for initial therapy. However, we avoid using CNIs in patients with significantly reduced kidney function (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) because of the potential nephrotoxicity of these drugs. All patients receiving glucocorticoids or a CNI should also be treated with general supportive measures. (See 'Dosing and duration of initial therapy' below and 'Treatment measures for all forms of FSGS' above.)

Patients who are pregnant can generally be safely treated with glucocorticoids or a CNI. (See 'Patients who are pregnant' below.)

Patients who cannot be treated with either glucocorticoids or a CNI are rare. In such cases, alternative options might include mycophenolate mofetil (MMF)/enteric-coated mycophenolate sodium (EC-MPS), rituximab, and adrenocorticotropic hormone (ACTH) gel, although there is no evidence to support the use of these agents as initial therapy.

●By contrast, we typically do not administer glucocorticoids or CNI therapy in patients who have the following clinical features:

•Patients without nephrotic syndrome – Patients without nephrotic syndrome (ie, patients with nephrotic-range proteinuria and normal serum albumin or those with subnephrotic proteinuria) who have normal kidney function typically have more indolent disease that either spontaneously remits or remains stable for years [3-5]. Patients without nephrotic syndrome who have decreased eGFR may have secondary FSGS, previously severe primary FSGS that progressed and went undiagnosed, or primary FSGS that was inadequately treated or resistant to standard therapies; such patients are less likely to respond to therapy.

•Patients with histologic evidence of extensive glomerulosclerosis and interstitial fibrosis – These findings are manifestations of irreversible damage, particularly in patients with substantially reduced kidney function. Glucocorticoids or CNIs are unlikely to be beneficial in this setting.

•Most patients with secondary, genetic, or unknown forms of the FSGS lesion. (See 'Treatment of secondary FSGS or FSGS of undetermined cause' below and 'Treatment of genetic FSGS' below.)

Patients with these clinical features are generally treated with supportive measures only. (See 'Treatment measures for all forms of FSGS' above.)

The recommendations for initial therapy with glucocorticoids are based primarily upon observational studies and the authors' clinical experience [3,4,6-13]. There are no randomized trials comparing prednisone or other agents with placebo for initial therapy of primary FSGS, using a modern definition of primary FSGS. Prednisone induces complete or partial remission in 40 to 80 percent of such patients with relatively preserved kidney function, and as discussed below, responders have better long-term outcomes (see 'Prognosis' below). The following studies illustrate the range of findings:

●In one report that evaluated the course of 55 adults (mean creatinine clearance of 90 mL/min) over a mean of 11 years, 18 were treated with prednisone, 7 also received cyclophosphamide, and the remainder were not treated [9]. Among the 18 treated patients, 8 (44 percent) achieved complete remission, compared with 4 of 37 (11 percent) untreated patients (2 of whom were never nephrotic). End-stage kidney disease (ESKD) occurred less frequently in treated nephrotic patients (29 versus 53 percent in untreated nephrotic patients).

●In another study of 60 nephrotic and 21 non-nephrotic patients with FSGS, in which one-half of the nephrotic patients were treated with prednisone, the 5- and 10-year kidney survival in the non-nephrotic patients was 92 percent, compared with 76 and 57 percent among the treated and non-treated nephrotic patients [8]. Among the treated nephrotic patients, one-half responded. The 5- and 10-year kidney survival among responders was 100 percent, compared with 65 and 40 percent among nonresponders, respectively.

Studies on cyclosporine are restricted to glucocorticoid-resistant or glucocorticoid-dependent primary FSGS; there is only one uncontrolled study of initial therapy with tacrolimus. In this report, tacrolimus was administered to six patients with a mean protein excretion of 11 g/day who were being treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) but no immunosuppression [14]. All patients entered a partial remission with >75 percent reduction in proteinuria (to a mean of 2.8 g/day) within a mean of six months. eGFR declined initially in two patients from >90 to 50 mL/min/1.73 m² but subsequently stabilized. (See 'Calcineurin inhibitors as preferred second-line therapy' below.)

Dosing and duration of initial therapy

Glucocorticoids — In patients initiating glucocorticoid therapy for primary FSGS, we administer treatment as follows:

●Initial dose – We administer prednisone 1 mg/kg per day (maximum dose 60 to 80 mg/day) with subsequent tapering of the dose. An alternative is to use 2 mg/kg every other day (maximum dose 120 mg every other day). The full dose should be given once daily around 9 or 10 AM, to minimize suppression of the hypophyseal-adrenal axis.

Some prefer daily dosing for initial therapy in patients with no contraindications since failure to respond to alternate-day dosing would necessitate conversion to daily dosing and result in prolongation of the glucocorticoid course. However, alternate-day dosing may be a better option in patients at higher risk of complications due to glucocorticoids, including older adult patients and those who are obese.

There is no high-quality evidence to guide the optimal dose and regimen (ie, daily or every other day) of prednisone therapy, and these dosing recommendations are extrapolated from doses used with success in observational studies and trials of other kidney diseases [3,4,8-13].

●Duration and tapering – In general, the duration of therapy varies according to the degree and rapidity of response (eg, faster taper for patients who achieve a quick remission), whether complete or partial remission is achieved, and the degree of glucocorticoid toxicity (see 'Definitions of response' above):

•If a complete remission is achieved within 8 to 12 weeks, we continue the initial dose of prednisone for one to two more weeks and then taper the dose over two to three months. One strategy is to switch to alternate-day prednisone (double the daily dose but to a maximum of 80 to 120 mg), and then decrease the dose by approximately one-third every two to three weeks.

•If a partial remission is achieved by 8 to 12 weeks, we taper prednisone slowly over three to nine months. We initially switch to alternate-day dosing and decrease the dose by one-third approximately every six weeks.

•For patients who have had a substantial reduction (>50 percent from baseline) in proteinuria by 8 to 12 weeks but do not meet criteria for partial remission (ie, proteinuria remains >3.5 g/day), the decision to continue high-dose prednisone or modify therapy is based upon the severity of glucocorticoid toxicity, the risk of continued therapy, and whether protein excretion is continuing to fall. Prednisone can be continued, for example, in patients whose proteinuria continues to decline, provided they are not experiencing severe side effects from therapy.

•If, at any time after a complete or partial remission is attained, proteinuria increases while the prednisone is being tapered, we stop the taper and temporarily maintain the current prednisone dose while adding a CNI or, if the eGFR is <30 mL/min/1.73 m², MMF/EC-MPS. Although the use of MMF/EC-MPS is not supported by evidence, some authors and editors of this topic use it in this setting based on its potential role as a glucocorticoid-sparing agent, its safe use in patients with low eGFR, and its role as maintenance therapy in other glomerular diseases such as minimal change disease and lupus nephritis. (See 'Glucocorticoid-dependent or glucocorticoid-resistant disease' below.)

•Adult patients who have little or no reduction in proteinuria after 16 weeks of daily prednisone are presumed to be glucocorticoid resistant. In such patients, we prefer to add a CNI (or MMF if the eGFR is low) and switch to alternate-day prednisone with a progressive taper in prednisone therapy, reducing the dose by approximately one-third every week. (See 'Glucocorticoid-dependent or glucocorticoid-resistant disease' below.)

●Adverse effects – Side effects associated with use of glucocorticoids are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)

Calcineurin inhibitors as alternative initial therapy — CNIs are an acceptable alternative option for initial therapy in patients who are at increased risk for glucocorticoid-associated toxicity, although supportive evidence is limited [15]. We avoid using CNIs in patients who have significant vascular or interstitial disease on kidney biopsy, or a chronic reduction in kidney function with an eGFR <30 mL/min/1.73 m², because of the potential nephrotoxicity of these drugs.

●Initial dose – If a CNI is used, either cyclosporine or tacrolimus is a reasonable choice. Cyclosporine has been studied more extensively than tacrolimus in patients with FSGS. However, there are advantages to tacrolimus, which is used extensively in kidney transplantation and has been studied in other glomerular diseases such as minimal change disease (see "Minimal change disease: Treatment in adults"). As an example, tacrolimus is associated with a lower risk of cosmetic side effects (eg, hirsutism, gingival hyperplasia); thus, many clinicians prefer tacrolimus over cyclosporine as the CNI of choice, especially in females.

•If cyclosporine is used, initial dosing is 3 to 5 mg/kg per day in two divided doses, with dose adjustments as necessary to target a trough level between 100 and 175 ng/mL. Some authors use a starting dose of 200 mg twice daily in males and 100 to 150 mg twice daily in females and titrate up the dose as needed to achieve target levels.

•If tacrolimus is used, initial dosing is 0.05 to 0.1 mg/kg per day in two divided doses, with dose adjustments as necessary to target a trough level between 5 and 10 ng/mL. Some authors use a starting dose of 1 mg twice daily in smaller-sized females (weight <60 kg) or 2 mg twice daily in males and larger-sized females and titrate up the dose as needed to achieve target levels.

Dose adjustments are typically made in small increments with subsequent drug concentration monitoring. Certain foods (eg, grapefruit or grapefruit juice) and drugs (eg, those metabolized by, or that affect metabolism by, cytochrome P-450 3A4/5 enzymes) can interact with CNIs and affect drug concentrations. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Food and drug interactions'.)

Some experts use low-dose glucocorticoid therapy in combination with CNIs, but supportive evidence for such a combination is weak. If prednisone is used, we give 0.15 mg/kg per day (maximum 15 mg/day) or 0.4 mg/kg (approximately 30 mg) every other day. After six months, we taper prednisone to 5 mg/day (or 10 mg on alternate days) and maintain it along with the CNI for an additional 6 to 12 months after attaining a remission. In patients with significant glucocorticoid toxicity, we taper prednisone earlier with the goal of discontinuation.

●Duration – We continue cyclosporine or tacrolimus for at least six months following attainment of a complete remission and for at least 12 months following attainment of a partial remission but at the lowest dose required to maintain remission. The dose can then be slowly tapered over 6 to 12 months as tolerated.

●Adverse effects – Side effects associated with use of cyclosporine or tacrolimus are discussed separately. (See "Pharmacology of cyclosporine and tacrolimus".)

Patients are unlikely to respond if there is little or no reduction in protein excretion after four to six months; the CNI should be discontinued in such patients with CNI resistance, and an alternative therapy should be attempted. (See 'Glucocorticoid-dependent or glucocorticoid-resistant disease' below.)

Monitoring the response to therapy — All patients who are receiving treatment for primary FSGS should be closely monitored for their clinical response to therapy. Definitions of clinical response are presented elsewhere in this topic. (See 'Definitions of response' above.)

●Patients receiving glucocorticoid or CNI therapy – In all patients receiving glucocorticoid or CNI therapy, we obtain a serum creatinine concentration, electrolytes, and a urine protein-to-creatinine ratio (UPCR) every two to four weeks during the initial two to three months of therapy. Prior to tapering immunosuppression, some authors confirm the level of proteinuria with a 24-hour urine collection. Once drug therapy is stabilized and/or is being tapered, we monitor laboratory studies every one to two months.

In patients who are being treated with a CNI, we measure the serum creatinine and electrolytes and a whole blood trough level of cyclosporine or tacrolimus approximately one week (7 to 10 days) after initiating therapy to monitor for acute nephrotoxicity and hyperkalemia.

●Patients receiving supportive measures only – In patients who are receiving supportive measures only, we obtain a serum creatinine, electrolytes, and a UPCR every three to four months until these parameters stabilize and then every three to six months thereafter.

We generally do not repeat a kidney biopsy in patients with primary FSGS unless there are signs of disease progression and it is uncertain if another factor may be responsible. A biopsy may also be indicated in a patient who develops an unexpected or severe relapse and there is concern for transformation to the collapsing form of FSGS, which may require more aggressive therapy. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)

Relapsing disease — Relapse occurs in approximately 25 to 35 percent of patients after a complete remission and in more than 50 percent of patients with a partial remission [3,9,12]. The timing of first relapse may range from 4 to 23 months following a complete remission [16]. (See 'Definitions of response' above.)

Patients who achieve a remission and then develop a relapse at least several months after discontinuation of therapy are considered to have a late relapse. By contrast, patients who previously had a complete or partial response to glucocorticoids (or a calcineurin inhibitor [CNI]) but relapse during the taper or within two weeks after cessation of glucocorticoid (or CNI) therapy are considered glucocorticoid dependent (or CNI dependent). Treatment of such patients is described in the next section. (See 'Glucocorticoid-dependent or glucocorticoid-resistant disease' below.)

Treatment of late relapse in primary FSGS has not been evaluated in controlled trials; the suggestions below are based upon personal experience and limited observational data. The approach to this problem varies with the response to initial therapy and the time to relapse:

●Glucocorticoids as initial therapy – If the patient previously had a complete or partial remission with glucocorticoids, did not have significant side effects, has not developed a condition that increases the risk of glucocorticoid-induced toxicity, and has been in remission for a prolonged period (eg, at least four to six months) after discontinuation of prednisone, then we repeat a course of prednisone. (See 'Glucocorticoids' above.)

However, if the patient had significant glucocorticoid-induced toxicity during initial therapy, has developed a condition that increases the risk of glucocorticoid-induced toxicity, or has had multiple relapses, then we usually treat with a CNI, with or without low-dose glucocorticoids, using a regimen similar to that described above. In such patients who have substantially reduced estimated glomerular filtration rate (eGFR; eg, <30 mL/min per 1.73 m²), we prefer mycophenolate mofetil (MMF)/enteric-coated mycophenolate sodium (EC-MPS) combined with low-dose glucocorticoids rather than a CNI, although evidence to support this approach is weak. Rituximab is another possible alternative to a CNI, particularly for patients with frequent relapses, but data are mixed in terms of response. The MMF/EC-MPS and rituximab regimens are described below. (See 'Calcineurin inhibitors as alternative initial therapy' above and 'Other therapies for patients resistant or intolerant to a calcineurin inhibitor' below.)

●CNI as initial therapy – If the patient previously had a complete or partial remission with a CNI, did not have significant side effects, and has been in remission for a prolonged period (eg, at least four to six months) after discontinuation of the CNI, then we repeat a course of CNI therapy. However, if the patient cannot receive a CNI because of prior toxicity or reduced eGFR (<30 mL/min per 1.73 m²), MMF/EC-MPS or rituximab is a possible alternative. (See 'Calcineurin inhibitors as alternative initial therapy' above and 'Other therapies for patients resistant or intolerant to a calcineurin inhibitor' below.)

Glucocorticoid-dependent or glucocorticoid-resistant disease — Patients who will respond to glucocorticoid therapy generally start to show some reduction in proteinuria within the first 8 to 12 weeks of therapy. Patients who attain a remission but who relapse while still on therapy or within two weeks of discontinuing therapy are considered glucocorticoid dependent. Adult patients with little or no reduction in proteinuria at 16 weeks are considered glucocorticoid resistant.

Calcineurin inhibitors as preferred second-line therapy — For patients with glucocorticoid-dependent or glucocorticoid-resistant FSGS (see 'Definitions of response' above), we recommend treatment with a calcineurin inhibitor (CNI) rather than continued glucocorticoids or no therapy. For patients with glucocorticoid-dependent (but not glucocorticoid-resistant) FSGS, some authors administer the CNI with low-dose prednisone. Most existing data support the use of cyclosporine; however, many experts believe that cyclosporine and tacrolimus are interchangeable and preferably use tacrolimus in females because this drug is associated with fewer cosmetic side effects.

However, we avoid using CNIs in patients who have significant vascular or interstitial disease on kidney biopsy or an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² given the additional risk of nephrotoxicity in these circumstances. Alternative therapeutic options for such patients are discussed elsewhere in this topic. (See 'Other therapies for patients resistant or intolerant to a calcineurin inhibitor' below.)

Dosing and duration of cyclosporine or tacrolimus in patients with glucocorticoid-dependent or glucocorticoid-resistant FSGS are the same as for patients receiving these drugs as initial therapy. (See 'Calcineurin inhibitors as alternative initial therapy' above.)

Despite initial benefit, relapses are common after cessation of short-term therapy with cyclosporine, although long-term kidney function is preserved. The likelihood of relapse appears to be lower if cyclosporine treatment is prolonged, perhaps up to one year or longer after remission is induced, and then gradually tapered and discontinued [17]. However, the risk of cyclosporine nephrotoxicity with prolonged therapy, particularly if the dose is ≥5 mg/kg per day, must be weighed against potential benefits [17-19]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The reported response rates with cyclosporine therapy in glucocorticoid-resistant disease range from 20 to 70 percent. Although progression of kidney disease is slowed as compared with placebo, the efficacy of cyclosporine in preventing end-stage kidney disease (ESKD) is unclear given the paucity of long-term follow-up data. The following trials illustrate the efficacy of cyclosporine among adults with glucocorticoid-resistant FSGS:

●In one trial that randomly assigned 49 adults with glucocorticoid-resistant FSGS (including 40 percent resistant to cytotoxic therapy) to low-dose prednisone plus either cyclosporine or placebo for 26 weeks, the rate of partial or complete remission of proteinuria was higher with cyclosporine (70 versus 4 percent) [20]. Relapse was common after cyclosporine withdrawal (40 and 60 percent had worsening of proteinuria by weeks 52 and 78, respectively). At four years, patients receiving cyclosporine had a lower risk of a 50 percent reduction in creatinine clearance (25 versus 52 percent).

●In a second trial that randomly assigned 45 adults and children primarily with glucocorticoid-resistant FSGS to supportive therapy or cyclosporine for six months, complete or partial remission was more common with cyclosporine (59 versus 16 percent) [18]. Positive responses occurred as early as two weeks and almost all occurred within two months after initiation of therapy; lack of an antiproteinuric effect at three months was generally indicative of resistance to cyclosporine.

Compared with cyclosporine, experience with tacrolimus for the treatment of glucocorticoid-resistant FSGS is more limited. Although there are no randomized trials in this particular patient population, data from uncontrolled studies suggest that tacrolimus may be an effective alternative to cyclosporine [14,21-25].

Other therapies for patients resistant or intolerant to a calcineurin inhibitor — There is no high-quality evidence to guide the optimal therapy of patients with glucocorticoid-dependent or glucocorticoid-resistant FSGS who do not respond to, are unable to tolerate, or have contraindications to CNIs. In general, such patients should be referred to centers with appropriate expertise and considered for enrollment in a clinical trial if possible. Those with glucocorticoid-dependent FSGS may be alternatively treated with mycophenolate mofetil (MMF)/enteric-coated mycophenolate sodium (EC-MPS), rituximab, or cytotoxic therapy (cyclophosphamide). For those with glucocorticoid-resistant FSGS, commonly used alternative options to a CNI include MMF/EC-MPS and rituximab; cyclophosphamide, adrenocorticotropic hormone (ACTH), plasmapheresis, and low-density lipoprotein (LDL) apheresis are infrequently used but may be beneficial in some patients. Evidence for these therapies is presented below.

Mycophenolate mofetil/sodium — MMF/EC-MPS in combination with low-dose glucocorticoids is an alternative option for patients with glucocorticoid-dependent or glucocorticoid-resistant primary FSGS who have either not responded to or should not be exposed to CNIs, or who have had a partial response to prednisone and/or CNIs but developed signs of toxicity to these drugs.

If MMF is used, we give 750 to 1000 mg twice daily for six months. If EC-MPS is used, we give 540 to 720 mg twice daily for six months. MMF/EC-MPS should be administered with low-dose glucocorticoid therapy. If prednisone is used, we give 0.15 mg/kg per day (maximum 15 mg/day) or 0.4 mg/kg (approximately 30 mg) every other day.

Side effects associated with use of MMF/EC-MPS are discussed separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Observational studies [26-29] and one randomized trial [30] suggest that MMF given with or without glucocorticoids may be beneficial in patients with FSGS [26-29]. In the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS-CT), 138 patients with glucocorticoid-resistant primary FSGS were randomly assigned to MMF plus oral pulse dexamethasone or cyclosporine; all patients were given prednisone 0.3 mg/kg every other day for six months [30]. At 12 months, there was no difference between groups in rates of partial or complete remission (30 percent with MMF plus dexamethasone versus 45 percent with cyclosporine). However, the number of enrolled subjects was smaller than anticipated; whereas the trial was designed to include 500, only 138 patients were actually enrolled. Moreover, it was designed as a pediatric trial but eventually included patients up to 42 years of age. As a result, the trial was not well designed and was underpowered to detect clinically significant benefits associated with cyclosporine.

Rituximab — Several case reports have described successful use of rituximab in adults patients with glucocorticoid-dependent but not glucocorticoid-resistant FSGS; the efficacy of this therapy appears limited to patients with glucocorticoid-dependent disease [31-34]. If rituximab is used, some clinicians administer 375 mg/m² weekly for four weeks, while others prefer to administer 1 g once followed 14 days later by another 1 g dose.

●In three patients with glucocorticoid-dependent FSGS, rituximab therapy (375 mg/m² weekly for four weeks) induced a complete remission, with reduction or discontinuation of other immunosuppressive drugs that persisted for at least 10 to 15 months [31].

●By contrast, in eight patients with glucocorticoid-resistant FSGS, rituximab did not induce remission, although two of these patients had an improvement in proteinuria that remained above 3 g/day [33].

Side effects associated with use of rituximab are discussed separately. (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis")

Cytotoxic therapy — We do not use cyclophosphamide in patients with primary FSGS who do not respond to an adequate trial of glucocorticoid or CNI therapy. However, cyclophosphamide may be considered in patients who have shown a partial response to prednisone (eg, ≥50 percent reduction in protein excretion) and who have extensive interstitial fibrosis and/or vascular disease on biopsy and may therefore be at higher risk of CNI nephrotoxicity. If used, cyclophosphamide (1 to 2 mg/kg per day, maximum daily dose 200 mg) is added before prednisone has been discontinued and is administered for 8 to 12 weeks. More prolonged therapy (>12 weeks) is not beneficial [11,35]. Chlorambucil is not recommended because of greater toxicity.

Side effects associated with use of cyclophosphamide are discussed separately. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Cytotoxic therapy has been used primarily in the treatment of children with relapsing or glucocorticoid-dependent idiopathic nephrotic syndrome [36,37]. In these settings, cyclophosphamide (2 mg/kg per day for 8 to 12 weeks) induced complete or partial remission in approximately 75 percent of cases [36-39].

Data on the use of cytotoxic drugs for glucocorticoid-dependent or glucocorticoid-resistant FSGS in adults are limited to a few retrospective studies and one randomized trial comparing chlorambucil with cyclosporine, which showed no benefit with chlorambucil [9,35].

Adrenocorticotropic hormone (ACTH) — Natural ACTH gel might be effective in a variety of nephrotic diseases; it has been tested in pilot studies, most extensively in patients with idiopathic membranous nephropathy. ACTH stimulates the secretion of glucocorticoids from the adrenal cortex and is also an endogenous agonist of the melanocortin hormone system. Protective effects of melanocortin agonism have been demonstrated in an animal model of FSGS [40]. (See "Membranous nephropathy: Treatment and prognosis", section on 'Treatment of resistant disease'.)

Some patients with glucocorticoid-dependent or glucocorticoid-resistant primary FSGS may respond to natural ACTH therapy [41,42]:

●The largest observational study included 24 patients, most of whom had previously received immunosuppressive therapy that included glucocorticoids and other agents [41]; 15 patients were glucocorticoid resistant. All patients were treated with ACTH gel (80 units subcutaneously twice weekly) and followed for an average of 16 months. At some point during follow-up, two patients achieved complete remission and five patients achieved partial remission (total response rate of 29 percent), although two of these seven patients relapsed.

●In an open-label trial of 13 patients with treatment-resistant primary FSGS, therapy with ACTH gel (40 to 80 units two to three times weekly for six months) induced complete remission in one patient (8 percent) and partial remission in eight patients (62 percent) [43]. Among those with partial remission or no response, the addition of oral tacrolimus (0.03 to 0.06 mg/kg/day, titrated to a trough level of 5 to 10 ng/mL) to ACTH gel for an additional six months resulted in complete remission in two patients.

These findings have not been confirmed in a randomized trial; in addition, the cost of ACTH gel in some countries may limit the capacity to test this agent.

Plasmapheresis — Based upon very limited experience, we only consider plasmapheresis in patients with primary FSGS who have continued massive proteinuria and hypoalbuminemia despite exposure to an adequate course of prednisone, CNI, MMF/EC-MPS, and rituximab. Plasmapheresis should be performed in conjunction with immunosuppression under expert guidance. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

The limited role for plasmapheresis in the treatment of primary FSGS is based in part upon studies in patients who have recurrent FSGS in the kidney allograft [44-46]. In this setting, removal of a circulating factor by plasmapheresis or a protein adsorption column can dramatically reduce proteinuria and, in some cases, induce complete remission. The benefit in transplant patients may be transient, as protein excretion often returns to pretreatment levels within two months. Furthermore, the applicability of data from transplant recipients to patients with primary FSGS is unclear. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Initial therapy'.)

There are conflicting reports regarding benefits of plasmapheresis in treating primary FSGS:

●In one uncontrolled study of patients with refractory primary FSGS, the addition of plasmapheresis seemed beneficial in some individuals [45]. Eleven patients with biopsy-proven FSGS unresponsive to glucocorticoids and cytotoxic therapy underwent an average of 17 plasmapheresis sessions over approximately 22 weeks. At 27 months, a complete or partial response was observed in six and two patients, respectively. Among complete responders, average proteinuria fell from 5.8 to 0.9 g/day, and the plasma creatinine stabilized.

●By contrast, a second study reported a relatively poor response rate with plasmapheresis, with only two of eight patients experiencing transient improvement in proteinuria [46].

LDL apheresis — Several small, nonrandomized studies using variable schedules of low-density lipoprotein (LDL) apheresis in patients with glucocorticoid-resistant primary FSGS have demonstrated some benefit in terms of reduction in proteinuria and improvement in serum albumin concentration, at least in short-term follow-up [47-51]. Why this might work is unclear, but postulated mechanisms include reduction in oxidized LDL and associated inflammatory cytokines, as well as improvement in hypercoagulability. LDL apheresis is approved by the US Food and Drug Administration for adults and children with treatment-resistant primary FSGS.

Patients who are pregnant — The optimal approach to the treatment of primary FSGS in pregnant patients is not known. Most contributors of this topic would treat, preferably with glucocorticoids. Cyclosporine and tacrolimus also appear to be safe and have been used successfully in pregnant patients. In general, rituximab and MMF/EC-MPS should be avoided in pregnant patients. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

We suggest that pregnant patients with primary FSGS be referred to centers with expertise in the management of glomerular disease in pregnancy. Pregnant patients with kidney disease should be jointly managed by a nephrologist and by a maternal-fetal medicine specialist. (See "Pregnancy and contraception in patients with nondialysis chronic kidney disease", section on 'Management during pregnancy'.)

A detailed discussion of pregnancy with underlying kidney disease and the general management of nephrotic syndrome in pregnancy are presented separately:

●(See "Pregnancy and contraception in patients with nondialysis chronic kidney disease".)

●(See "Proteinuria in pregnancy: Diagnosis, differential diagnosis, and management of nephrotic syndrome", section on 'Management of nephrotic syndrome in pregnancy'.)

TREATMENT OF SECONDARY FSGS OR FSGS OF UNDETERMINED CAUSE — Secondary FSGS most commonly refers to FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration but also includes secondary causes of FSGS such as drugs, toxins, and viral infections. In general, the treatment of secondary forms of FSGS focuses on cessation of the offending drug or effective treatment of the underlying condition. In addition, all patients with secondary FSGS should be treated with supportive measures (such as renin-angiotensin system inhibition, blood pressure control, and dietary sodium and protein restriction). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit. Glucocorticoid or calcineurin inhibitor (CNI) therapy is not recommended in such patients and may potentially cause harm. (See 'Treatment measures for all forms of FSGS' above and "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Similarly, we treat patients with FSGS of undetermined cause with supportive measures only. We do not treat such patients with glucocorticoid or CNI therapy. A repeat kidney biopsy can be considered if there is a change in the patient's clinical status (eg, development of nephrotic syndrome).

TREATMENT OF GENETIC FSGS — The optimal approach to therapy in patients with genetic mutations that have been associated with FSGS is unknown. In general, all patients with genetic FSGS should be treated with supportive measures (such as renin-angiotensin system inhibition, blood pressure control, and dietary sodium and protein restriction). SGLT2 inhibitors may also be of benefit.

Treatment with glucocorticoid or CNI therapy is generally not indicated given the low likelihood of response to these agents, although rare case reports of patients with genetic FSGS who have responded to immunosuppressive agents have been described [52-54]. Given that many patients will progress to kidney failure if left untreated, some authors would consider a trial of glucocorticoid or CNI therapy on a case-by-case basis, particularly in patients with the nephrotic syndrome and extensive foot process effacement on kidney biopsy. (See 'Treatment measures for all forms of FSGS' above and "Focal segmental glomerulosclerosis: Genetic causes", section on 'Clinical implications of genetic FSGS'.)

INVESTIGATIONAL THERAPIES — A number of investigational therapies have been proposed for the treatment of FSGS. Evidence for these therapies is discussed below:

●Endothelin receptor antagonists – Sparsentan is an oral selective antagonist of both the angiotensin II receptor and the endothelin A receptor. Endothelin 1, primarily through activation of endothelin A receptors, has been implicated in podocyte injury, proteinuria, fibrosis, and progression of chronic kidney disease [55,56]. Endothelin receptor antagonists (ERAs) have been shown to protect against kidney injury and decrease proteinuria in animal models of FSGS [57]. However, based on data from existing clinical trials, we do not use sparsentan in patients with an FSGS lesion. Sparsentan has been conditionally approved by the US Food and Drug Administration for patients with IgA nephropathy but has not been approved for patients with FSGS.

In a phase III trial in which 371 patients with an FSGS lesion or a documented pathogenic variant in a podocyte protein associated with FSGS, urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² were randomly assigned to sparsentan or irbesartan for up to 108 weeks, a greater proportion of sparsentan-treated patients (42 versus 26 percent) achieved a partial remission (defined as UPCR ≤1.5 g/g and >40 percent reduction in UPCR from baseline) at 36 weeks, a response that was sustained through 108 weeks [58]. However, at week 108, there was no significant difference between the groups in total eGFR slope (from day 1 to week 108) or chronic eGFR slope (from week 6 to week 108). There was no significant difference in the composite of reduction in eGFR ≥40 percent, kidney failure, or death between the groups (20 percent with sparsentan and 23 percent with irbesartan). Overall rates of adverse events were comparable between the treatment groups, although hypotension, hyperkalemia, muscle spasms, elevated blood creatine kinase level, and anemia were more common among sparsentan-treated patients.

The discrepancy between sparsentan's effects on proteinuria and eGFR in this trial may reflect the enrollment of a heterogeneous mix of patients with primary, secondary, and genetic FSGS, who have a fundamentally different pathogenesis and disease course. Given that the median UPCR was 3 g/g and median serum albumin was 35 g/L, it is likely that the majority of patients had secondary or genetic FSGS. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Differentiating between primary, secondary, and genetic FSGS'.)

A clinical trial evaluating the use of atrasentan, another ERA, in patients with FSGS is also in progress (NCT04573920).

●Inaxaplin – Inaxaplin (also known as VX-147) is a selective, oral small molecular inhibitor of APOL1 channel function that was designed to treat the underlying cause of proteinuric kidney disease in patients with FSGS and two APOL1 risk variant alleles (G1G1, G1G2, or G2G2). Such gain-of-function variants are thought to enhance APOL1 channel function, which results in podocyte damage. In preclinical studies, inaxaplin was shown to bind directly to the APOL1 protein, inhibit APOL1 channel function, and reduce proteinuria in a mouse model of APOL1-mediated kidney disease [59]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'APOL1'.)

The efficacy and safety of inaxaplin were evaluated in an open-label, multicenter phase 2a clinical study in 16 adults with two APOL1 risk variants, biopsy-proven FSGS, proteinuria (UPCR ≥0.7 and <10 g/g), and an eGFR ≥27 mL/min/1.73 m² [59]. At baseline, three patients had nephrotic-range proteinuria (mean UPCR 3.5 g/g), 13 had subnephrotic-range proteinuria (mean UPCR 1.8 g/g), and mean eGFR was 51 mL/min/1.73 m². Patients received inaxaplin for 13 weeks (15 mg once daily for two weeks, followed by 45 mg once daily for 11 weeks) in addition to standard care, which could include systemic glucocorticoids, immunosuppressive agents, and renin-angiotensin inhibitors. Among the 13 patients who met the treatment-adherence threshold, the mean change from baseline UPCR at week 13 was -47.6 percent (95% CI -60 to -31.3); one patient had no reduction in proteinuria. Following completion of therapy, nine patients were followed for an additional 12 weeks; among these, mean change from baseline UPCR increased from -47.6 to -30.1 percent at week 4 and remained stable thereafter. Adverse events were mild or moderate (headache, back pain, nausea) in severity, and no patients discontinued treatment due to adverse events. While these findings are promising, additional controlled studies in a larger number of patients with uniform criteria for renin-angiotensin inhibition and immunosuppressive drug use are needed to determine longer-term efficacy and safety.

●Other therapies – Other agents under investigation for patients with FSGS include voclosporin (calcineurin inhibitor [CNI]; NCT03598036), losmapimod (p38 mitogen-activated protein [MAP] kinase inhibitor; NCT02000440), PF-06730512 (ROBO2/SLIT2 inhibitor; NCT03448692), bleselumab (anti-CD40 monoclonal antibody; NCT02921789), abatacept (NCT02592798), CCR2 inhibitors (NCT03649152, NCT03536754, NCT03703908), and Nrf2 activators (NCT03366337, NCT03422510).

PROGNOSIS — The potential efficacy of therapy must be considered in relation to the natural history of the disease. Untreated primary FSGS often follows a progressive course to end-stage kidney disease (ESKD). The rate of spontaneous complete remission among patients with nephrotic syndrome is unknown but is probably less than 10 percent. Spontaneous remission is more likely to occur among patients with normal kidney function and non-nephrotic-range proteinuria [60].

Previously, treatment was not considered to substantially improve the prognosis of FSGS. However, longer courses of treatment have resulted in response rates of up to 70 percent and improved overall prognosis. Whether the outcome of patients who present with a substantial reduction in kidney function can be altered is less clear.

Factors that appear to influence response to treatment and/or prognosis include the following:

●Response to therapy – The most reliable prognostic indicator of kidney survival is the initial response of proteinuria to therapy (see 'Definitions of response' above). Patients who undergo partial or complete remission have a much better chance of kidney survival (approximately 80 versus <50 percent at 10 years in nonresponders and untreated patients) [3,4,8,10-12,38,61].

●Degree of proteinuria – Patients with the nephrotic syndrome (proteinuria ≥3.5 g/day and low plasma albumin concentration) have five-year kidney survival rates of 60 to 90 percent and 10-year kidney survival rates of 30 to 55 percent [8,38,62,63]. Massive proteinuria (>10 g/day), when unresponsive to treatment, is associated with an even worse prognosis, with most patients progressing to ESKD within five years [8]. By contrast, kidney survival is much better in patients without nephrotic syndrome, especially when this is associated with normal kidney function [61]. However, these observations could reflect the underlying mechanism of disease (eg, primary versus secondary FSGS).

●Severity of kidney function impairment – More severe kidney function impairment at presentation is generally associated with worse kidney survival [3,64,65]. In one series, for example, patients with a plasma creatinine concentration >1.3 mg/dL (115 micromol/L) had lower 10-year kidney survival (27 versus 100 percent for those with a lower plasma creatinine) that was independent of the degree of proteinuria [64]. Worse kidney function at presentation (unless it is acute) is generally associated with a greater extent of glomerulosclerosis and interstitial fibrosis on biopsy (reflecting more severe disease, disease of longer duration, or other factors such as hypertension or aging); therefore, it is less likely to respond to therapy.

●Histologic findings – The presence of larger amounts of interstitial fibrosis (eg, >50 percent of a good biopsy sample) at the time of presentation uniformly predicts poor kidney survival, although this may reflect secondary FSGS in some cases [11,62,65,66]. Collapsing glomerulopathy is particularly associated with a worse prognosis and is often considered a unique variant associated with kidney function impairment and larger amounts of proteinuria at diagnosis [67]. The prognostic relevance of other histologic variants is discussed elsewhere. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis", section on 'Histologic variants'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●General principles – The goal of therapy in primary focal segmental glomerulosclerosis (FSGS) is remission of proteinuria, preferably a complete remission. This is primarily achieved with the use of a variety of agents having both immunosuppressive properties as well as direct action on glomerular podocytes (most commonly glucocorticoids or calcineurin inhibitors [CNIs]) as well as supportive measures (such as renin-angiotensin inhibition). (See 'General principles' above.)

●Treatment measures for all forms of FSGS – General treatment measures in all patients with FSGS include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, treatment of dyslipidemia, and in selected patients, anticoagulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit. (See 'Treatment measures for all forms of FSGS' above.)

●Treatment of primary FSGS

•Initial therapy for primary FSGS – For most patients with presumed primary FSGS who present with nephrotic syndrome (ie, proteinuria >3.5 g/day and serum albumin <3.5 g/dL), we suggest initial therapy with glucocorticoids, rather than a CNI (Grade 2C). In patients who have a high risk for glucocorticoid-induced toxicity (eg, patients with obesity, diabetes, severe osteoporosis, or age >70 years), a CNI (cyclosporine or tacrolimus), with or without low-dose glucocorticoids, is an alternative option for initial therapy. However, we avoid using CNIs in patients with significantly reduced kidney function (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) because of the potential nephrotoxicity of these drugs. Dosing and duration of these regimens are discussed above. (See 'General approach' above and 'Dosing and duration of initial therapy' above.)

By contrast, we typically do not administer glucocorticoids or CNI therapy in patients without nephrotic syndrome, with histologic evidence of extensive glomerulosclerosis and interstitial fibrosis, and with secondary, genetic, or unknown forms of FSGS. Such patients are generally treated with supportive measures only.

•Relapsing disease – For most patients who previously had a complete or partial remission with glucocorticoids, we suggest a repeat course of prednisone rather than switching therapy (Grade 2C). However, in patients who previously developed significant adverse effects related to initial therapy with glucocorticoids, who developed a condition that increases the risk of glucocorticoid-induced toxicity, or had multiple relapses, switching to a CNI, with or without low-dose glucocorticoids, may be preferred. In such patients who have substantially reduced eGFR, mycophenolate mofetil (MMF)/enteric-coated mycophenolate sodium (EC-MPS) or rituximab is a possible alternative. (See 'Relapsing disease' above.)

•Glucocorticoid-dependent or glucocorticoid-resistant disease – For patients with glucocorticoid-dependent or glucocorticoid-resistant FSGS, we recommend treatment with a CNI, rather than continued glucocorticoids or no therapy (Grade 1B). For patients with glucocorticoid-dependent (but not glucocorticoid-resistant) FSGS, some authors administer the CNI with low-dose prednisone. Patients who do not respond to, are unable to tolerate, or have contraindications to CNIs should be referred to centers with appropriate expertise and considered for enrollment in a clinical trial if possible. Those with glucocorticoid-dependent FSGS may be alternatively treated with MMF/EC-MPS, rituximab, or cytotoxic therapy (cyclophosphamide). For those with glucocorticoid-resistant FSGS, commonly used alternative options to a CNI include MMF/EC-MPS and rituximab. Cyclophosphamide, adrenocorticotropic hormone (ACTH), plasmapheresis, and low-density lipoprotein (LDL) apheresis are infrequently used but may be beneficial in some patients. (See 'Glucocorticoid-dependent or glucocorticoid-resistant disease' above.)

●Treatment of secondary FSGS or FSGS of undetermined cause – The treatment of secondary forms of FSGS focuses on cessation of the offending drug or effective treatment of the underlying condition. All patients with secondary FSGS or FSGS of undetermined cause should receive supportive measures. Glucocorticoid or CNI therapy is not indicated in such patients. (See 'Treatment of secondary FSGS or FSGS of undetermined cause' above and 'Treatment measures for all forms of FSGS' above.)

●Treatment of genetic FSGS – The optimal approach to therapy in patients with genetic FSGS is unknown. All patients should be treated with supportive measures. Treatment with glucocorticoid or CNI therapy is generally not indicated given the low likelihood of response to these agents. (See 'Treatment of genetic FSGS' above and 'Treatment measures for all forms of FSGS' above.)