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Treatment of primary focal segmental glomerulosclerosis
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Treatment of primary focal segmental glomerulosclerosis
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Literature review current through: Nov 2017. | This topic last updated: Nov 28, 2016.

INTRODUCTION — Focal and segmental glomerulosclerosis (FSGS; often incorrectly abbreviated as focal sclerosis) 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 renal biopsy specimen. The lesion may be found either without an identifiable cause (in which case it is called "idiopathic" or "primary") or in response to previous glomerular injury, glomerular hypertension or hypertrophy, or to genetic defects, viral infections, or medications ("secondary") [1]. FSGS is distinct from focal and global glomerulosclerosis, which has a different prognosis and treatment. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".)

Primary FSGS can present acutely with overt nephrotic syndrome characterized by hypoalbuminemia and edema. However, primary FSGS can also present insidiously with less dramatic manifestations, possibly related to the underlying histologic variant. The diagnosis of primary FSGS is confirmed by a renal biopsy that reveals the morphologic features mentioned above as well as, in most cases, diffuse (greater than 80 percent) effacement of the foot processes by electron microscopy. By contrast, secondary FSGS most often presents as asymptomatic proteinuria without profound hypoalbuminemia or edema [2]. In addition, the kidney biopsy usually reveals glomerulomegaly, focal (rather than diffuse) foot process effacement, and, sometimes, evidence of a separate kidney disease that is responsible for the development of secondary FSGS. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".)

Distinguishing between primary and secondary disease is particularly important because of the markedly different approach to therapy in the two disorders. Primary FSGS is often responsive to immunosuppressive therapy, including glucocorticoids, cyclosporine, and other immunosuppressive agents. By contrast, immunosuppression is not indicated in secondary FSGS.

Renin-angiotensin-aldosterone system blockade (with angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) reduces proteinuria and slows progression in proteinuric kidney diseases. However, whether or not this is effective in primary FSGS is unknown.

This topic will review the prognosis and treatment of primary FSGS in adults, focusing on patients with nephrotic-range proteinuria. The causes of FSGS and the treatment of children with FSGS are discussed separately. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of idiopathic nephrotic syndrome in children".)

The following discussion does not apply to collapsing FSGS, which may be associated with HIV and a variety of other conditions. That variant is discussed separately. (See "HIV-associated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis not associated with HIV infection".)

PROGNOSIS — The potential efficacy of therapy must be considered in relation to the natural history of the disease. Untreated primary focal segmental glomerulosclerosis (FSGS) often follows a progressive course to end-stage renal disease (ESRD). 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 proteinuria [3].

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. (See 'Treatment' below.)

Prognostic factors — Factors that appear to influence response to treatment and/or prognosis principally include the degrees of proteinuria and renal dysfunction as well as the histologic findings. The most reliable prognostic indicator remains the patient's response to treatment.

Degree of proteinuria — Patients with the nephrotic syndrome (proteinuria ≥3.5 g/day and low plasma albumin concentration) have five-year renal survival rates of 60 to 90 percent, and 10-year renal survival rates of 30 to 55 percent [4-7]. Massive proteinuria (>10 g/day), when unresponsive to treatment, is associated with an even worse prognosis, with most patients progressing to ESRD within five years [4]. By contrast, renal survival is much better in patients without nephrotic syndrome, especially when this is associated with normal renal function (over 85 percent renal survival at 10 years) [8]. However, these observations could reflect the underlying mechanism of disease (eg, primary versus secondary FSGS).

The rate of spontaneous complete remission among patients with nephrotic-range proteinuria is unknown since most patients are treated. It is probably less than 10 percent; slightly higher spontaneous remission rates in some reports may reflect more widespread use of angiotensin-converting enzyme (ACE) inhibitors [4,9-11].

Severity of renal dysfunction — More severe renal dysfunction at presentation is generally associated with worse renal survival [12-14]. In one series, for example, patients with a plasma creatinine concentration of greater than 1.3 mg/dL (115 micromol/L) had a significantly decreased 10-year renal survival (27 versus 100 percent for those with a lower plasma creatinine) that was independent of the degree of proteinuria [13]. Worse renal 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 interstitial fibrosis at the time of presentation uniformly predicts poor renal survival, although this may reflect secondary FSGS in some cases [6,14-16]. The collapsing variant is particularly associated with a worse prognosis and is often considered a different disorder.

The association of other histologic variants with severity at presentation (ie, presence or absence of nephrotic syndrome) and prognosis is less clear. Patients with segmental scarring at the tubular pole of the glomeruli, the so-called "glomerular tip lesion" (picture 1), have been considered more likely to respond to steroid therapy or to spontaneously remit (if renal function is normal). However, the presence of this lesion does not guarantee responsiveness [3,16-19]. The prognostic relevance of histologic variants is discussed elsewhere.

Interestingly, focal "global" sclerosis (eg, lesions that involve most or all of the glomerular tuft, not just segments) was associated with steroid responsiveness in a small study of children [20]. One possible explanation is that these patients actually had minimal change disease, and the totally sclerotic glomeruli reflected prior damage. It is unclear whether similar lesions in adult populations predict response to therapy. (See 'Identification of steroid dependence and steroid resistance' below.)

Response to therapy — The strongest prognostic indicator of renal survival is the initial response of the proteinuria to therapy, regardless of the type of histology. Response is reported in terms of degree of reduction in proteinuria [4,12,21,22]. We propose the following definitions:

A complete response is a reduction in proteinuria to <200 to 300 mg/day

A partial response in patients presenting with nephrotic-range proteinuria is a reduction of ≥50 percent, and to less than 3.5 g/day

A relapse is a return of proteinuria to ≥3.5 g/day in someone who had undergone a complete or partial remission

Steroid dependence refers to relapse while on therapy or requirement for continuation of steroids to maintain remission

Steroid resistance refers to little or no reduction in proteinuria after 12 to 16 weeks of adequate prednisone therapy in an adult, or to patients who have some reduction in proteinuria with more prolonged therapy who do not meet the criteria for partial remission

Patients who undergo partial or complete remission have a much better chance of renal survival (approximately 80 versus <50 percent at 10 years in nonresponders and untreated patients) [4,5,8,10,12,15,17,23]. Some investigators also include normalization of the plasma albumin concentration in the definition of response.

General outcomes with respect to response to therapy, including the prognosis associated with partial remissions and relapses, were perhaps best shown in a retrospective study of 281 FSGS patients with the nephrotic syndrome who were followed for a minimum of one year in the Toronto Glomerulonephritis Registry [12]. Two-thirds of the patients received immunosuppressive therapy, including high-dose glucocorticoids (50 percent), cytotoxic agents (19 percent), or cyclosporine (12 percent). Over one-half of patients also received an ACE inhibitor or angiotensin receptor blocker (ARB).

At a median follow-up of 64 months, a complete, partial, or no remission was observed in 20, 41, and 39 percent, respectively. The time to remission was 12 to 14 months. Relapses occurred less frequently in those who had a complete remission (36 versus 52 percent among partial responders). Renal failure occurred in 6, 18, and 45 percent of patients with a complete, partial, or no remission, respectively. Patients who remained in remission had a slower rate of decline in renal function and a lower risk of renal failure compared with those who experienced a later relapse.

Disease progression — Disease progression, either by worsening renal function or, in some studies, histologic parameters, may occur despite partial remission of proteinuria. Some patients have a modest increase in the plasma creatinine concentration and, on repeat renal biopsy, an increased number of glomeruli with segmental or global sclerosis and more severe tubulointerstitial disease. This may be, in part, due to bias in the selection of patients for repeat biopsy and due to tissue sampling bias given the focal nature of the disease. However, it may also reflect a low level of continued disease activity, healing of previous injury, or secondary hemodynamic damage (which may be minimized by administration of an ACE inhibitor or ARB). (See 'Nonimmunosuppressive therapy' below.)

TREATMENT — Although less responsive than minimal change disease, primary focal segmental glomerulosclerosis (FSGS) often responds to glucocorticoids, as well as other agents [15]; however, more prolonged glucocorticoid therapy than in minimal change disease is generally required to induce remission.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) have not been specifically studied in primary FSGS. However, these drugs reduce proteinuria and may slow progression in proteinuric kidney diseases and should therefore be considered in patients with primary FSGS whether or not immunosuppressive therapy is provided. In addition, patients with nephrotic syndrome are often hypercholesterolemic and might benefit from statin therapy. (See 'Nonimmunosuppressive therapy' below.)

These recommendations do not apply to collapsing FSGS, the treatment of which is discussed separately. (See "HIV-associated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis not associated with HIV infection".)

Overall approach to therapy — The treatment suggestions outlined below, and discussed later in detail, are based upon low- or moderate-quality data (eg, personal experience, observational studies, and small trials). There are no available high-quality data to guide treatment recommendations.

Patients with histologic evidence of primary FSGS who have nephrotic syndrome are usually offered disease-modifying therapy with glucocorticoids and other immunosuppressive drugs:

We generally provide such treatment to patients with primary FSGS who present with nephrotic syndrome (ie, proteinuria >3.5 g/day accompanied by hypoalbuminemia <3.5 g/dL [<35 g/L]). Such patients have a poor prognosis without disease-modifying therapy. The majority of patients with primary FSGS present with nephrotic syndrome and a biopsy showing diffuse foot process effacement, or else develop nephrotic syndrome soon after biopsy. However, some patients with nephrotic syndrome at presentation receive glucocorticoids for variable periods of time before a kidney biopsy is performed. In such patients, the clinical status may improve, and histologic evidence of diffuse foot process effacement may be lacking. However, immunosuppressive therapy should be offered to these patients if the clinician suspects that a biopsy performed at the initial presentation would have revealed typical features of primary FSGS. Rare patients may present with histologic evidence of primary FSGS but without nephrotic syndrome; such patients should also receive glucocorticoid therapy if they progress to develop nephrotic syndrome.

We do not usually initiate glucocorticoids or other immunosuppressive drugs in patients who do not have nephrotic syndrome. Patients without nephrotic syndrome who have normal kidney function typically have indolent disease that either spontaneously remits or remains stable for years. Patients without nephrotic syndrome who have decreased glomerular filtration rate (GFR) may have secondary FSGS or else previously severe primary FSGS that went undiagnosed; such patients respond poorly to immunosuppressive therapies.

In addition, we do not usually initiate such treatment in patients with histologic evidence of extensive glomerulosclerosis and interstitial fibrosis, as these findings are manifestations of irreversible damage, particularly in patients with substantially reduced kidney function. Glucocorticoids and other immunosuppressive drugs are unlikely to be beneficial in this setting.

If disease-modifying therapy is used:

Previously untreated patients – In previously untreated patients, we usually use oral glucocorticoids (eg, prednisone) for at least 8 to 16 weeks as initial immunosuppressive therapy. Alternatively, calcineurin inhibitors with or without low-dose glucocorticoids for approximately 12 months can be used in patients who have a high risk for glucocorticoid-induced toxicity (eg, obese patients, diabetic patients, patients with severe osteoporosis, patients >70 years of age). (See 'Initial immunosuppressive therapy' below.)

Late relapse after remission – In patients who relapse more than two months after achieving a complete or partial remission with an initial course of glucocorticoid therapy, and who did not develop significant toxicity from the glucocorticoids, we usually repeat the course of glucocorticoids. However, in such patients who developed significant side effects from glucocorticoids, or who are at high risk for such complications, we treat with calcineurin inhibitors with or without low-dose glucocorticoids for approximately 12 months. (See 'Treatment of late relapsing disease' below.)

Steroid-dependent and steroid-resistant – In patients who either relapse while glucocorticoids are being tapered or within two months after cessation of glucocorticoid therapy (ie, "steroid-dependent FSGS"), and in patients who fail to achieve any remission with glucocorticoid therapy (complete or partial, and without resolution of nephrotic syndrome, called "steroid-resistant FSGS"), we usually treat with calcineurin inhibitors with or without low-dose glucocorticoids. Treatment with mycophenolate mofetil (MMF) combined with glucocorticoids may be beneficial in those who have failed or cannot take calcineurin inhibitors. Rituximab may also be effective in patients with steroid-dependent but not steroid-resistant FSGS. (See 'Treatment of steroid-dependent or steroid-resistant FSGS' below.)

The goal of therapy in primary FSGS is remission of proteinuria, preferably complete remission [4,12,21,22]. We use the following definitions of complete and partial remission, based upon two consecutive urine collections:

A complete remission is a reduction in proteinuria to <200 to 300 mg/day

A partial remission can be defined as a 50 percent or greater reduction in proteinuria to a level that is <3.5 g/day

Regardless of whether or not immunosuppressive therapy is provided, we treat hypertensive patients with either an ACE inhibitor or an ARB, and we treat hyperlipidemic patients with a statin. (See 'Nonimmunosuppressive therapy' below.)

Initial immunosuppressive therapy — We generally treat patients with primary FSGS using immunosuppressive therapy if they present with proteinuria >3.5 g/day accompanied by hypoalbuminemia <3.5 g/dL (<35 g/L).

By contrast, we typically do not initiate immunosuppressive therapy in patients who have the following clinical features:

Absent nephrotic syndrome – Such patients who have normal GFR usually have a relatively indolent course and often have spontaneous remission or stabilization of proteinuria [12,17,24]. Such patients who have decreased kidney function may have had more severe proteinuria at an earlier stage of their disease that went undetected, or they may have secondary FSGS. Response to immunosuppressive therapy in such individuals is poor. (See 'Prognosis' above.)

Histologic evidence of extensive glomerulosclerosis and interstitial fibrosis – These findings are manifestations of irreversible damage, particularly in patients with substantially reduced kidney function. Glucocorticoids and other immunosuppressive drugs are unlikely to be beneficial in this setting.

In previously untreated patients who are suitable for immunosuppressive therapy, we usually use oral glucocorticoids (eg, prednisone) for at least 8 to 16 weeks. Universal agreement about the duration of prednisone therapy is lacking and should be guided by the clinical response and tolerability. Prednisone dosing and duration and monitoring the response to therapy are discussed in detail below. (See 'Prednisone dose' below and 'Duration and monitoring of glucocorticoid therapy' below.)

Alternatively, in patients who have a high risk for glucocorticoid-induced toxicity (eg, obese patients, diabetic patients, patients with severe osteoporosis, patients >70 years of age), a 12-month course of a calcineurin inhibitor can be used, with or without low-dose glucocorticoids. However, we avoid using calcineurin inhibitors in patients who have significantly reduced kidney function (estimated GFR [eGFR] <30 mL/min per 1.73 m2) because of the potential nephrotoxicity of these drugs. (See 'Calcineurin inhibitors as alternative initial therapy' below and "Cyclosporine and tacrolimus nephrotoxicity".)

The recommendations for initial therapy with prednisone are based upon observational studies and the authors' clinical experience [25,26]. There are no randomized trials comparing prednisone or other agents with placebo for initial therapy of primary FSGS (existing trials have evaluated treatment of steroid-dependent or steroid-resistant FSGS). Prednisone induces complete or partial remission in 40 to 80 percent of patients with relatively preserved renal function, and, as noted above, responders have better long-term outcomes. (See 'Glucocorticoids as initial therapy' below.)

Glucocorticoids as initial therapy — In most patients initiating glucocorticoid therapy for primary FSGS, we use prednisone, 1 mg/kg per day (maximum dose 60 to 80 mg/day) (see 'Prednisone dose' below) with subsequent tapering of the dose. An alternative is to use 120 mg of prednisone every other day for two months with subsequent tapering of the dose. Depending upon the response to and the toxicity from this therapy, the duration of prednisone therapy can vary from as short as 8 to 12 weeks to as long as one year (see 'Duration and monitoring of glucocorticoid therapy' below). Some patients treated with glucocorticoids have only a transient remission or no remission whatsoever. (See 'Identification of steroid dependence and steroid resistance' below.)

Nonrandomized retrospective studies utilizing a variety of glucocorticoid doses have reported 40 to 80 percent rates of complete (proteinuria <200 or 300 mg/day) or partial (variably defined as <2 to 3.5 g/day and/or ≥50 percent decrease in proteinuria) remission [4,9,10,12,15,17,23,27]. One report, for example, evaluated the course of 55 adults with a mean creatinine clearance of 90 mL/min at a mean follow-up 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 (one received cyclophosphamide in combination with glucocorticoids, another as secondary treatment after relapse), compared with 4 of 37 (11 percent) untreated patients (two of whom were never nephrotic). End-stage renal disease (ESRD) occurred significantly less often in treated nephrotic patients (29 versus 53 percent in untreated nephrotic patients).

Another study described renal survival in 60 nephrotic and 21 non-nephrotic patients with FSGS; the serum creatinine at biopsy was 2.3 and 1.8 mg/dL (203 and 160 micromol/L) among nephrotic and non-nephrotic patients, respectively [4]. Half of the nephrotic patients were treated with prednisone. The 5- and 10-year renal survival in the non-nephrotic patients was 92 percent, compared with 76 and 57 percent among the treated and non-treated nephrotic patients. Among the treated nephrotic patients, half responded. The 5- and 10-year renal survival among responders was 100 percent, compared with 65 and 40 percent among nonresponders, respectively. Similar findings have been described by others [17].

In addition to the presence of nephrotic syndrome, the level of kidney function was predictive of response to treatment in some [10,12,27], but not all, studies [4,9]. In the only study that provided a stratified analysis, remission was achieved in only 5 of 21 patients with a serum creatinine >1.4 mg/dL (124 micromol/L) compared with 36 of 60 who had lower serum creatinine concentrations [27].

Race may also affect the response to steroid therapy. In a retrospective review of 72 individuals with primary FSGS, of whom 65 were African American, 60 percent received glucocorticoid therapy [28]. The mean maximum dose was 60 mg/day, and duration including taper was almost one year. At a mean follow-up of approximately four years, 26 and 21 percent of the treated and untreated patients, respectively, all of whom were African American, reached ESRD. However, this retrospective study does not preclude the possibility that African Americans might respond to glucocorticoids; as a result, we feel that race alone should not be an issue in initiating therapy. Many African Americans with glomerulosclerosis have focal and global (rather than focal and segmental) glomerulosclerosis, as well as lower levels of proteinuria. Such patients should not be treated as if they have primary FSGS.

Prednisone dose — The optimal dose of prednisone therapy is unknown, as there are no randomized trials to provide guidance in patients with FSGS. The following dosing recommendations are extrapolated from doses used with success and are extracted from the observational studies [4,9,10,12,15,17,23,27], as well as from trials of other renal diseases:

Prednisone, 1 mg/kg per day (maximum dose 60 to 80 mg/day) or

Prednisone, 2 mg/kg every other day (maximum dose 80 to 120 mg/day)

We 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 steroid course. Despite this general recommendation, alternate-day dosing may be a better option in patients at higher risk of complications due to glucocorticoids, including elderly patients and those who are obese.

Duration and monitoring of glucocorticoid therapy — The optimal duration of glucocorticoid therapy is unknown. In many cases, an overall course of treatment of at least six months is required [15,22], and complete remission may not be attained for 12 months or longer [27]. Shorter courses (two months or less) result in much lower remission rates (20 to 30 percent) and may have led to the earlier belief that this condition was not steroid responsive [4]. In general, the duration of therapy will vary according to the degree and rapidity of response (eg, faster taper for patients who achieve a quick remission), whether full or partial remission is achieved, and the degree of steroid toxicity:

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 (≥50 percent reduction in protein excretion to less than 3.5 g/day and with resolution of nephrotic syndrome) is achieved by 12 weeks, we taper prednisone slowly over three to nine months. We initially switch to alternate-day dosing and decrease the dose by approximately one-third approximately every six weeks.

For patients who have had a substantial reduction in proteinuria at 12 to 16 weeks but do not meet criteria for partial remission, 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 calcineurin inhibitor or, if the eGFR is <30 mL/min per 1.73 m2, MMF. (See 'Treatment of steroid-dependent or steroid-resistant FSGS' below.)

Patients who have little or no reduction in proteinuria after 8 to 12 weeks of daily prednisone are presumed to be steroid resistant. In such patients, we prefer to add a calcineurin inhibitor (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 'Treatment of steroid-dependent or steroid-resistant FSGS' below.)

There are no specific guidelines for monitoring the response to therapy, but it seems reasonable to obtain routine blood chemistries, including a plasma creatinine concentration for estimation of GFR, and to follow the urine protein-to-creatinine ratio. During the initial two to three months of therapy, we evaluate for a response (or toxicity) at two- to four-week intervals. Prior to tapering immunosuppression, we confirm the level of proteinuria with a 24-hour urine collection. Once drug therapy is stabilized and/or is being tapered, we monitor at one- to two-month intervals. Among patients on prolonged prednisone therapy, the risk of adrenal suppression during tapering must be considered. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)" and "Glucocorticoid withdrawal".)

Identification of steroid dependence and steroid resistance — As mentioned above, patients who will respond generally start to show some reduction in protein excretion within the first 8 to 12 weeks of therapy. Patients who attain a remission but who relapse while still on therapy, while therapy is being tapered, or within two months of discontinuing glucocorticoid therapy are considered steroid dependent. Patients with little or no reduction in protein excretion at 12 to 16 weeks are considered steroid resistant [8,15,17]. The treatment of such patients is discussed below. (See 'Treatment of steroid-dependent or steroid-resistant FSGS' below.)

At present, it is not possible to confidently predict at presentation which patients with primary FSGS will respond to glucocorticoid therapy. As a result, such patients should receive a trial of glucocorticoids, unless they are at markedly increased risk of glucocorticoid-induced toxicity, have extensive glomerulosclerosis and interstitial fibrosis, or have a substantial reduction in eGFR. (See 'Initial immunosuppressive therapy' above.)

Factors that appear to be associated with a lower likelihood of response to glucocorticoids include:

Significant tubulointerstitial disease on renal biopsy (which may reflect secondary FSGS in some cases) and an elevated plasma creatinine concentration predict a lower likelihood of response [4,5,15]. The prognostic importance of tubular disease is suggested from the apparent relation between tubular function (as estimated from the rate of excretion of low-molecular-weight proteins, such as beta-2 microglobulin and retinol-binding protein) and the response to therapy. These smaller proteins are normally filtered and then almost entirely reabsorbed in the proximal tubule. Thus, increased excretion in FSGS reflects tubular dysfunction rather than enhanced glomerular permeability. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

As an example, in a report of 37 adults with the idiopathic nephrotic syndrome (many of whom had FSGS), those who had little or no low-molecular-weight proteinuria all went into remission with a 12-week course of prednisone [29]. By comparison, increasing degrees of low-molecular-weight proteinuria carried an increasing likelihood of steroid resistance. Unfortunately, these measurements are not routinely available. In addition, some patients with tubular proteinuria were steroid responsive, limiting the prognostic utility of tubular proteinuria.

Massive proteinuria (>10 g/day) may be less likely to respond [5,30].

Steroid resistance is present in some of the familial forms of FSGS in which mutations involve proteins related to the glomerular podocyte. In addition to familial disease, mutations in the gene (NPHS2) for at least one of these proteins, podocin, have been described in approximately 25 percent of cases of apparently sporadic steroid-resistant FSGS in children from Europe and the Middle East. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'Genetic causes of FSGS'.)

The applicability of these observations to adults and to other populations is under active investigation. One study has suggested that expression of a specific variant of NPHS2 is associated with steroid-resistant, adult-onset FSGS among patients from Europe or South America.

However, the frequency of these abnormalities in nephrotic adults who do not also have family members with FSGS is very low, and we do not test routinely for such mutations. In addition, some patients with FSGS who have these known mutations associated with FSGS have responded to treatment with either glucocorticoids or calcineurin inhibitors, suggesting that, in these circumstances, such therapy should be attempted.

Additional genetic as well as socioeconomic factors may contribute to treatment resistance [31-33]. As an example, the significantly lower response to therapy among African Americans compared with Caucasians may be due to a variety of factors, including a higher frequency of the collapsing variant, a higher incidence and severity of hypertension, a greater likelihood of presenting with significant fibrosis on biopsy, certain genetic variants, and possible effects of socioeconomic status on adherence.

Calcineurin inhibitors as alternative initial therapy — In patients at increased risk for glucocorticoid-associated toxicity (eg, obese patients, diabetic patients, patients with severe osteoporosis, patients >70 years of age), we use cyclosporine or tacrolimus with or without low-dose prednisone as initial therapy, although data evaluating this strategy are limited. We avoid using calcineurin inhibitors in patients who have significant vascular or interstitial disease on renal biopsy, or a chronic reduction in kidney function with an eGFR <30 mL/min per 1.73 m2, because of the nephrotoxicity of these drugs. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Nephrotoxicity is of concern in the usage of calcineurin inhibitors in treatment of steroid-resistant FSGS with chronically impaired renal function. In our opinion, such agents should be avoided in subjects with an eGFR of <30 mL/min/1.73 m2 (stage 4 chronic kidney disease). If the renal biopsy shows little or minor interstitial fibrosis and extensive interstitial edema, then these agents can be used cautiously in subjects with clinically severe nephrotic syndrome and eGFR of <30 mL/min/1.73 m2 at starting doses that are one-half of those usually recommended for subjects with normal renal function. Serum creatinine (and eGFR) should be assessed by one week after starting the drug, and if the values are stable or improving, then the dose can be gradually uptitrated to therapeutic levels depending upon the results of weekly monitoring. If serum creatinine shows a persistent and progressive increase during treatment despite lower-than-normal calcineurin inhibitor doses or levels, then it may be necessary to abandon this approach to treatment altogether and move to alternative regimens. (See 'Mycophenolate mofetil (MMF) as an alternative' below.)

Studies on cyclosporine are restricted to steroid-resistant or steroid-dependent primary FSGS; there is only one uncontrolled study of initial therapy with tacrolimus. In this report, tacrolimus (initial dose 2 mg twice daily, adjusted to 12-hour trough levels of 4 to 7 ng/mL) was administered to six patients with a mean protein excretion of 11 g/day who were being treated with an ACE inhibitor or ARB but no immunosuppression [34]. 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. Estimated GFR declined initially in two patients from >90 to 50 mL/min per 1.73 m2, but subsequently stabilized. The optimal duration of therapy with this approach is uncertain.

Cyclosporine has been studied more extensively than tacrolimus in patients with FSGS. However, there are advantages to tacrolimus, which is used extensively in renal transplantation and other glomerular diseases. As an example, tacrolimus is associated with a lower risk of cosmetic side effects; therefore, many clinicians prefer tacrolimus over cyclosporine as the calcineurin inhibitor of choice, especially in females. Dose, duration, and monitoring for cyclosporine and tacrolimus are presented below. (See 'Calcineurin inhibitor dosing' below and 'Monitoring and duration of calcineurin inhibitor therapy' below.)

Calcineurin inhibitor dosing — There are no controlled trials of cyclosporine or tacrolimus as initial therapy in patients with primary FSGS. Dosing recommendations are extrapolated from the doses used in trials of steroid-dependent or steroid-resistant disease:

If cyclosporine is used, we start with 2 to 4 mg/kg per day (given in two divided doses) or approximately 75 to 100 mg twice daily, adjusting the dose as necessary to target a trough level between 100 and 175 ng/mL. The dose will likely need to be adjusted depending upon the clinical response and toxicity.

If tacrolimus is used, we start with 0.1 mg/kg per day (given in two divided doses) or approximately 2 to 4 mg twice daily, adjusting the dose as necessary to target a trough level between 5 and 10 ng/mL. As with cyclosporine, the dose may need to be adjusted depending upon the clinical response and toxicity.

Some experts use low-dose glucocorticoid therapy in combination with calcineurin inhibitors. If prednisone is used, we give 0.15 mg/kg per day (maximum 15 mg/day) or 0.4 mg/kg (about 30 mg) every other day. After six months, we taper prednisone to 5 or 7.5 mg/day (or 10 to 15 mg on alternate days) and maintain it along with the calcineurin inhibitor 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.

Monitoring and duration of calcineurin inhibitor therapy — We continue cyclosporine or tacrolimus for at least six months following attainment of a complete remission and one year following attainment of a partial remission, but at the lowest dose required to maintain the remission. Patients are unlikely to respond if there is little or no reduction in protein excretion after six months; the calcineurin inhibitor should be discontinued in such patients, and alternative therapy should be attempted.

We monitor routine blood chemistries, including a plasma creatinine concentration for estimation of GFR, and urine protein-to-creatinine ratio in patients treated with calcineurin inhibitors. Due to concerns about acute nephrotoxicity and hyperkalemia, we measure the serum creatinine and electrolytes approximately one week after initiating therapy. Thereafter, we measure the serum creatinine, electrolytes, fasting serum glucose, and urine protein-to-creatinine ratio at two- to four-week intervals for the first several months. Once drug therapy is stabilized and/or is being tapered, we monitor these laboratory studies at one- to two-month intervals. Prior to tapering immunosuppression, we like to confirm the level of proteinuria with a 24-hour urine collection.

Treatment of late relapsing disease — Some patients achieve a remission that is maintained during prednisone tapering and for at least several months after discontinuation of therapy. A relapse in such patients (ie, a return of proteinuria to ≥3.5 g/day) is considered a late relapse rather than steroid dependence or steroid resistance.

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

If the patient previously had a complete or partial response to 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, more than two months) after discontinuation of prednisone, then we repeat a course of prednisone. (See 'Initial immunosuppressive therapy' above.)

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 calcineurin inhibitors, with or without low-dose glucocorticoids, using a regimen similar to that which is described above. In such patients who have substantially reduced eGFR (eg, <30 mL/min per 1.73 m2), we use MMF combined with low-dose glucocorticoids rather than calcineurin inhibitors. The MMF regimen is described below. (See 'Calcineurin inhibitor dosing' above and 'Monitoring and duration of calcineurin inhibitor therapy' above and 'Mycophenolate mofetil (MMF) as an alternative' below.)

Patients who previously had a complete or partial response to glucocorticoids but relapse during the taper or within two months after cessation of steroid therapy are considered steroid dependent. Those who have little or no reduction in proteinuria during prednisone therapy are considered steroid resistant. Treatment of such patients is described in the next section. (See 'Treatment of steroid-dependent or steroid-resistant FSGS' below.)

Treatment of steroid-dependent or steroid-resistant FSGS — Recommendations for the therapy of steroid-dependent and steroid-resistant FSGS are based upon a few randomized, controlled trials examining the benefits of cyclosporine versus placebo and other agents, as well as observational and uncontrolled studies. The definitions of steroid-dependent and steroid-resistant FSGS are presented above. (See 'Identification of steroid dependence and steroid resistance' above.)

We suggest that initial therapy of steroid-dependent or steroid-resistant FSGS consists of a calcineurin inhibitor (cyclosporine or tacrolimus) with or without low-dose prednisone. Among those unresponsive to this combination, or among those with substantially reduced eGFR (<30 mL/min per 1.73 m2), we use MMF in combination with glucocorticoids. (See 'Calcineurin inhibitors' below and 'Mycophenolate mofetil (MMF) as an alternative' below.)

A variety of other drugs have been evaluated, but the evidence base for these therapies is relatively poor. These include cytotoxic agents (cyclophosphamide and chlorambucil), rituximab, and adrenocorticotropic hormone (ACTH) [35]. Rituximab and cyclophosphamide may be effective in patients with steroid-dependent but not steroid-resistant FSGS.

Calcineurin inhibitors — We usually use a calcineurin inhibitor with or without low-dose glucocorticoids in patients with steroid-dependent or steroid-resistant FSGS. Most existing data support the use of cyclosporine [5,21,36-42]; however, many authorities believe that cyclosporine and tacrolimus are interchangeable, and preferably use tacrolimus in women because this drug is associated with fewer cosmetic side effects.

Dosing and duration recommendations for calcineurin inhibitors in patients with steroid-dependent or steroid-resistant FSGS are the same as for patients receiving these drugs as initial therapy. (See 'Calcineurin inhibitor dosing' above and 'Monitoring and duration of calcineurin inhibitor therapy' above.)

However, we avoid using calcineurin inhibitors in patients who have significant vascular or interstitial disease on renal biopsy or an eGFR <30 mL/min per 1.73 m2 given the additional risk of nephrotoxicity in these circumstances. We usually use MMF rather than calcineurin inhibitors in such patients. (See "Cyclosporine and tacrolimus nephrotoxicity" and 'Mycophenolate mofetil (MMF) as an alternative' below.)

The response to cyclosporine in FSGS may occur earlier (within three months) than the response to prednisone, although the rate of complete (versus partial) remission appears to be lower than with glucocorticoids [15,21,39]. However, this lower remission rate may reflect the fact that patients treated with cyclosporine have often already failed glucocorticoid therapy and may therefore have more severe disease.

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 [36]. 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 [36,39,41]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

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

In a randomized, placebo-controlled study of 49 adults with steroid-resistant FSGS (including 40 percent resistant to cytotoxic therapy), all received low-dose prednisone (0.15 mg/kg per day, with a maximum daily dose of 15 mg) and either cyclosporine (initial dose 3.5 mg/kg, adjusted to maintain a whole blood trough level between 125 and 225 mcg/L) or placebo for 26 weeks, which was then tapered over four weeks [21].

At 26 weeks, partial or complete remission of proteinuria was much more frequent with cyclosporine (70 versus 4 percent with placebo). However, relapse was common after cyclosporine withdrawal (40 and 60 percent had worsening of proteinuria by weeks 52 and 78, respectively). Nevertheless, at four years, active therapy was associated with a lower risk of a 50 percent reduction in creatinine clearance (25 versus 52 percent).

In a second trial, 45 adults and children primarily with steroid-resistant FSGS were randomly assigned to supportive therapy or to cyclosporine at a dose of 5 mg/kg per day in adults and 6 mg/kg per day in children for six months, then tapered by 25 percent every two months until discontinuation [39]. Complete or partial remission was significantly more common with cyclosporine (59 versus 16 percent with supportive therapy). Positive responses occurred as early as two weeks and almost all occurred within two months after the onset of therapy; lack of an antiproteinuric effect at three months was generally indicative of resistance to cyclosporine.

A third trial compared cyclosporine with chlorambucil in 57 patients with steroid-resistant primary FSGS [40]. Patients were assigned to cyclosporine (5 mg/kg per day, adjusted to trough levels between 130 and 180 ng/mL) or chlorambucil (0.1 to 0.4 mg/kg per day) for 6 to 12 weeks, followed by cyclosporine if there was no response. Although there were no differences between groups in the incidence of complete remission (approximately 20 percent), partial remission (approximately 40 percent), or renal survival at four years (83 percent), all patients in the chlorambucil group required cyclosporine, suggesting that chlorambucil is of no benefit in steroid-resistant FSGS.

Compared with cyclosporine, experience with tacrolimus for the treatment of primary FSGS is more limited [34,43-47]. The largest study was an open-label uncontrolled study consisting of 44 individuals (mean proteinuria of 4.5 g/day and plasma creatinine concentration of 0.89 mg/dL [79 micromol/L]) [47]. At baseline, the patients were resistant to glucocorticoids and were treated with maximum tolerable doses of angiotensin inhibition. Tacrolimus plus prednisone was given for up to 48 weeks and was discontinued if complete or partial remission was not achieved by 24 weeks. Complete remission occurred in 17 patients (39 percent), and partial remission occurred in six patients (14 percent); 21 patients were considered tacrolimus resistant (48 percent), although it is possible that some of these patients would have achieved remission if the drug had been continued rather than discontinued at 24 weeks. Of those with complete remission, five relapsed while tapering tacrolimus, and seven relapsed after discontinuing tacrolimus. Reversible nephrotoxicity occurred in seven patients, and irreversible nephrotoxicity occurred in four patients. Similar results were observed with tacrolimus in a smaller study of patients with FSGS who were resistant to both glucocorticoids and cyclosporine [44].

Mycophenolate mofetil (MMF) as an alternative — Observational studies [48-51] and one randomized trial [52] suggest that MMF given with or without glucocorticoids may be beneficial in patients with FSGS [48-51]. Based upon these limited data, we suggest that MMF (750 to 1000 mg twice daily for six months) in combination with low-dose glucocorticoids be used in patients with steroid-dependent or steroid-resistant primary FSGS who have either not responded to or should not be exposed to calcineurin inhibitors, or who have had a partial response to prednisone and/or calcineurin inhibitors but developed signs of toxicity to these drugs.

The FSGS-Clinical trial (FSGS-CT) was a National Institutes of Health (NIH)-funded multicenter trial that compared MMF plus oral pulse dexamethasone to cyclosporine among 138 patients with steroid-resistant primary FSGS [52]. MMF was given at 25 to 36 mg/kg per day; dexamethasone was given at 0.9 mg/kg per day for two consecutive days at the start of weeks 1 through 8, on alternating weeks through week 26, and every four weeks until week 50; cyclosporine was given at 5 to 6 mg/kg per day with target trough levels of 100 to 250 ng/mL. All patients were given prednisone 0.3 mg/kg every other day for six months.

At a follow-up of 12 months, there was no difference between groups in the percentage of patients who achieved partial or complete remission (30 percent with MMF plus dexamethasone versus 45 percent with cyclosporine). There was also no difference in the percentage of patients who had a sustained remission at 26 weeks after the termination of treatment. Among those who responded to therapy, the reduction in proteinuria persisted through 78 weeks of follow-up and was not different between the groups [53]. However, this study has important limitations that hinder its interpretation [54]. First, the number of enrolled subjects was smaller than anticipated; whereas the trial was designed to include 500, only 138 patients were actually randomized. As a result, the trial may have been underpowered to detect clinically significant benefits associated with cyclosporine.

Another limitation is that the inclusion criteria allowed patients to be defined as glucocorticoid resistant after only four weeks of glucocorticoid therapy. This may have resulted in an overestimate of the benefit of immunosuppressive therapy since many patients (especially adults) respond to glucocorticoids after 8 to 12 weeks. The trial also included patients with non-nephrotic proteinuria who generally have a good prognosis and, in practice, would not be considered for immunosuppressive treatment. (See 'Degree of proteinuria' above and 'Initial immunosuppressive therapy' above.)

The permissive eligibility criteria (among the criteria for trial entry was protein excretion >1 g/day as estimated by the protein-to-creatinine ratio) and the lack of electron microscopy data may also have allowed the inclusion of patients with secondary FSGS. This is in contrast to most studies where patients labeled as having primary FSGS have nephrotic-range proteinuria and patients with presumed secondary FSGS have lower levels of protein excretion. The inclusion of patients with secondary FSGS could have potentially lowered the overall response rate that was observed in this trial since such patients generally do not respond to immunosuppressive treatment.

Some smaller observational studies have suggested a possible benefit of MMF given with or without glucocorticoids:

In a retrospective single-center study, 18 patients were treated with MMF because of steroid resistance or steroid dependence with or without cyclosporine, and/or progressive renal dysfunction [48]. Mycophenolate (with or without glucocorticoids), given at variable doses for periods of 4 to 24 months, resulted in complete and partial remission of proteinuria in two and six patients, respectively. Overall, it significantly lowered proteinuria (mean initial urine protein-to-creatinine ratio of 4.7 to a post-treatment ratio of 2.2), stabilized renal function (mean pre- and post-plasma creatinine concentration of 2.3 and 2.5 mg/dL [203 and 221 micromol/L], respectively), and permitted glucocorticoids to be withdrawn without relapse in 8 of 12 patients, at least in the short term.

In an uncontrolled prospective study, 18 patients with biopsy-proven FSGS and nephrotic-range proteinuria (all resistant to prolonged glucocorticoids and 75 percent to a cytotoxic agent and/or a calcineurin inhibitor) were given MMF for a mean period of eight months [51]. A reduction in proteinuria of at least 50 percent was observed in eight patients (44 percent). Although none had a complete remission in proteinuria, none had an increase in the plasma creatinine concentration.

Other therapies — Data are relatively poor for other disease-modifying therapies in patients with primary FSGS.

Cytotoxic therapy — Data on the use of cytotoxic drugs for steroid-dependent or steroid-resistant FSGS in adults are limited to a few retrospective observational studies [9,15,34,40,43-45,48-51] and the previously described randomized trial comparing chlorambucil with cyclosporine, which showed no benefit with chlorambucil [40].

Cytotoxic therapy has been used primarily in the treatment of children with relapsing or steroid-dependent idiopathic nephrotic syndrome [55,56]. 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 [5,55-57]. Cyclophosphamide was less effective in patients who were steroid resistant, with less than 25 percent deriving sustained benefit from an 8- to 12-week course of therapy [5,56]. (See "Treatment of idiopathic nephrotic syndrome in children".)

We do not recommend cyclophosphamide in patients with primary FSGS who do not respond to an adequate trial of prednisone. 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 renal pathology and may therefore be at higher risk of calcineurin inhibitor nephrotoxicity. If used, cyclophosphamide is added before the prednisone has been discontinued and is administered for 8 to 12 weeks. More prolonged therapy (>12 weeks) is not beneficial [15,40]. Chlorambucil is not recommended because of greater toxicity.

Rituximab — Several case reports have described successful use of rituximab in adult patients with steroid-dependent but not steroid-resistant FSGS; the efficacy of this therapy appears limited to patients with steroid-dependent disease [58-60]:

In three patients with steroid-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

By contrast, in 10 patients with steroid-resistant FSGS, rituximab did not induce remission, although two of these patients had an improvement in proteinuria that remained above 3 g/day

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. (See "Alternative agents in the treatment of idiopathic membranous nephropathy", section on 'Adrenocorticotropic hormone (ACTH)'.)

Some patients with steroid-dependent or steroid-resistant FSGS may also respond to natural ACTH therapy [61,62]. The largest study included 24 patients, most of whom had previously received immunosuppressive therapy that included glucocorticoids and other agents [61]. Fifteen patients were steroid resistant. All patients were treated with subcutaneous ACTH gel (80 units 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. Although encouraging, these findings require confirmation in a randomized trial; however, the cost of ACTH gel may limit the capacity to test this agent.

Plasmapheresis and related modalities — Based upon very limited experience, we only consider plasmapheresis in patients with primary FSGS in the following settings:

Severe disease manifestations despite an adequate trial of initial immunosuppressive therapy, in which very high levels of a circulating permeability factor have been demonstrated

Continued massive proteinuria and hypoalbuminemia despite exposure to an adequate course of prednisone, cyclosporine, MMF, and ACTH

Plasmapheresis should be performed in conjunction with immunosuppression. (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 renal allograft [35,41,63-65]. In the latter setting, removal of a circulating factor by plasmapheresis or a protein adsorption column can dramatically reduce proteinuria and, in some cases, induce complete remission. (See "Focal segmental glomerulosclerosis in the transplanted kidney".)

The benefit in transplant recipients 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.

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 [64]. Eleven patients with biopsy-proven FSGS unresponsive to glucocorticoids and cytotoxic therapy underwent an average of 17 plasmapheresis sessions over approximately 22 weeks. At follow-up of 27 months, a complete or partial response was observed in six and two patients, respectively. Among the complete responders, average proteinuria fell from 5.8 to 0.9 g/day, and the plasma creatinine stabilized.

By contrast, a second uncontrolled study reported a relatively poor response rate with plasmapheresis, with only two of eight patients experiencing transient improvement in proteinuria [65]. The ongoing immunosuppressive therapy in the first study, compared with no consistent post-plasmapheresis immunosuppression in the second study, may explain these widely discrepant findings.

Whether a patient with primary FSGS might respond to plasmapheresis is thought to vary with the presence or absence, and the absolute level, of the circulating permeability factor. The presence of a permeability factor can be assessed via an in vitro examination, referred to as the GVV-test [66]. In this test, which can be performed in research laboratories but is not commercially available, the patient's serum is incubated with isolated rat glomeruli in a hypo-oncotic solution. If albumin leakage is increased because of the presence of a permeability factor, the volume of the rat glomeruli is reduced due to concurrent water transfer.

In one report, two patients with a positive GVV-test responded to plasma immunoadsorption [67]; after therapy, no evidence of a circulating permeability factor was found in either individual. However, when measured serially in another study, the levels of the permeability factor in patients with primary FSGS were lower than previously reported for patients with recurrent post-transplant FSGS, were not related to severity of disease, and did not decrease despite clinical response to cyclosporine [68].

The accurate assessment of the role of plasmapheresis and the GVV-test in the management of patients with FSGS requires further evaluation. This test is not routinely used for diagnostic purposes in patients with primary FSGS.

The decision to treat patients with significantly reduced renal function (eg, GFR <30 mL/min per 1.73 m2) should take into consideration the acuity of the renal failure, the findings on renal biopsy (eg, presence of significant tubulointerstitial fibrosis and glomerulosclerosis), and the individual patient's risk for adverse consequences related to therapy.

Costimulatory inhibition — Abatacept (cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein [CTLA-4-Ig]) inhibits T-cell costimulatory signals mediated by CD80 (B7-1). (See "Transplantation immunobiology", section on 'T-cell costimulation'.)

B7-1 is expressed on podocytes in some patients with primary FSGS and may contribute to the pathogenesis of disease [69,70]. In a case series of four patients with relapsing post-transplant FSGS plus one patient with steroid-resistant FSGS, abatacept therapy (10 mg/kg ranging from a single to a monthly dose) produced a complete remission in three patients and a partial remission in two patients [71]. However, these patients received co-interventions (eg, plasma exchange, immunosuppression), and there was no control group. In addition, co-stimulatory blockade was ineffective in eight other patients with primary FSGS, despite the detection of B7-1 in their kidney biopsies [72,73]. Further studies are required before abatacept therapy can be recommended in patients with primary FSGS.

LDL apheresis — Several small nonrandomized studies using variable schedules of low-density lipoprotein (LDL) apheresis in patients with steroid-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 [74-78]. Why this might work is unclear, but postulated mechanisms include reduction in oxidized LDL and associated inflammatory cytokines, as well as improvement in hypercoagulability.

Nonimmunosuppressive therapy — Two major nonimmunosuppressive therapies that should be instituted in most patients with primary FSGS are ACE inhibitors or ARBs and lipid lowering with a statin. These are also the mainstays of therapy for non-nephrotic patients with primary FSGS and for patients with proteinuric chronic kidney disease, in general. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Nonsteroidal anti-inflammatory drugs (NSAIDs) also may reduce proteinuria, but they are rarely used given their potential to reduce kidney function.

ACE inhibitors or ARBs — An ACE inhibitor or an ARB should be given to all patients with primary FSGS, even as specific immunosuppressive treatment is undertaken, or as primary therapy for patients with non-nephrotic proteinuria and patients who have other reasons for not receiving immunosuppression. This therapy can be used even in patients who are not hypertensive, although care must be taken in these cases to avoid inducing symptomatic low blood pressure.

ACE inhibitors reduce proteinuria in some patients with primary or secondary FSGS but rarely induce a remission without immunosuppressive treatment [8,79-83]. In addition, these drugs slow the rate of progression to kidney failure in patients with proteinuric renal diseases, although such a benefit has not been specifically proven in primary FSGS. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

For these reasons, administration of an ACE inhibitor or ARB is recommended for virtually all patients with primary FSGS, in particular, for those who do not go promptly into remission with immunosuppressive therapy. Specific goals should be met as described elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Lipid lowering — Hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. In addition, chronic kidney disease is associated with a marked increase in cardiovascular risk, particularly in older patients. (See "Lipid abnormalities in nephrotic syndrome" and "Chronic kidney disease and coronary heart disease".)

Thus, patients with FSGS who have persistent nephrotic syndrome and/or chronic kidney disease are often treated with a statin. Patients also on cyclosporine are at increased risk for rhabdomyolysis because of a drug interaction with many statins. (See "Lipid abnormalities in nephrotic syndrome" and "Statin myopathy".)

Role of protein restriction — The role of a protein-restricted diet in nephrotic syndrome and in chronic kidney disease is discussed elsewhere. (See "Dietary recommendations for patients with nondialysis CKD".)

Complications of therapy — The toxicities of the immunosuppressive drugs used to treat primary FSGS are described in detail elsewhere.

Glucocorticoids (see "Major side effects of systemic glucocorticoids")

Cyclosporine and tacrolimus (see "Pharmacology of cyclosporine and tacrolimus")

Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases")

Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases")

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

Focal and segmental glomerulosclerosis (FSGS; often incorrectly abbreviated as focal sclerosis) 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 renal biopsy specimen. The lesion may be found either without an identifiable cause (in which case it is called "idiopathic" or "primary") or in response to previous glomerular injury, glomerular hypertension or hypertrophy, or to genetic defects, viruses, or medications ("secondary"). Distinguishing between primary and secondary disease is particularly important because of the markedly different approach to therapy in the two disorders. (See 'Introduction' above and "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".)

Untreated primary FSGS often follows a progressive course to end-stage renal disease (ESRD). 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 proteinuria <3.5 g/day. Factors that appear to influence response to treatment and/or prognosis principally include the degree and duration of proteinuria, a substantial chronic reduction in glomerular filtration rate (GFR), and certain histologic findings (principally, the degree of tubulointerstitial fibrosis). The most reliable prognostic indicator remains the patient's response to treatment. (See 'Prognostic factors' above.)

Patients with histologic evidence of primary FSGS who have nephrotic syndrome are usually offered disease-modifying therapy with glucocorticoids and other immunosuppressive drugs (see 'Overall approach to therapy' above and 'Glucocorticoids as initial therapy' above):

In patients with histologic evidence of primary FSGS who present with nephrotic syndrome (ie, proteinuria >3.5 g/day accompanied by hypoalbuminemia <3.5 g/dL [<35 g/L]), we recommend treating with glucocorticoids or other immunosuppressive drugs rather than treating only with nonimmunosuppressive therapy or observation (Grade 1B). This treatment recommendation may also apply to those patients with nephrotic syndrome at presentation but who receive glucocorticoids for variable periods of time before a kidney biopsy is performed. In such patients, the clinical status may improve, and histologic evidence of diffuse foot process effacement may be lacking. However, immunosuppressive therapy should be offered to such patients if the clinician suspects that a biopsy performed at the initial presentation would have revealed typical features of primary FSGS. In addition, rare patients may present with histologic evidence of primary FSGS but without nephrotic syndrome; such patients should also receive glucocorticoid therapy if they subsequently progress to develop nephrotic syndrome.

By contrast, we do not usually initiate glucocorticoids or other immunosuppressive drugs in patients who do not have nephrotic syndrome. Patients without nephrotic syndrome who have normal kidney function typically have indolent disease that either spontaneously remits or remains stable for years. Patients without nephrotic syndrome who have decreased GFR may have secondary FSGS or else previously severe primary FSGS that went undiagnosed; such patients respond poorly to immunosuppressive therapies.

In addition, we do not usually initiate such treatment in patients with histologic evidence of extensive glomerulosclerosis and interstitial fibrosis, as these findings are manifestations of irreversible damage, particularly in patients with substantially reduced kidney function. Glucocorticoids and other immunosuppressive drugs are unlikely to be beneficial in this setting.

In patients treated with glucocorticoids or other immunosuppressive drugs, the goal of therapy is remission of proteinuria, preferably complete remission. We use the following definitions of complete and partial remission, based upon two consecutive urine collections:

A complete remission is a reduction in proteinuria to <200 to 300 mg/day

A partial remission can be defined as a 50 percent or greater reduction in proteinuria to a level that is <3.5 g/day

If immunosuppressive drugs are used, choice of therapy differs according to the following (see 'Initial immunosuppressive therapy' above):

Previously untreated patients – In previously untreated patients who are not at high risk for glucocorticoid-induced toxicity (eg, patients without obesity, diabetes, severe osteoporosis, and who are younger than 70 years), we suggest oral glucocorticoids (eg, prednisone) as initial immunosuppressive treatment rather than other therapies (Grade 2C). (See 'Glucocorticoids as initial therapy' above.)

Dosing, duration, and monitoring of glucocorticoid therapy are discussed above. (See 'Prednisone dose' above and 'Duration and monitoring of glucocorticoid therapy' above.)

Alternatively, in previously untreated patients who are at high risk for glucocorticoid-induced toxicity, we suggest calcineurin inhibitor therapy (cyclosporin or tacrolimus), with or without low-dose glucocorticoids, rather than other treatments (Grade 2C). Some but not all experts use low-dose glucocorticoid therapy in combination with calcineurin inhibitors.

Dosing, duration, and monitoring of calcineurin inhibitor therapy (and low-dose prednisone therapy, if used) are discussed above. (See 'Calcineurin inhibitor dosing' above and 'Monitoring and duration of calcineurin inhibitor therapy' above.)

Late relapse after remission – In patients who relapse more than two months after achieving a complete or partial remission with an initial course of glucocorticoid therapy, and who did not develop significant toxicity from the glucocorticoids, we suggest repeating the course of glucocorticoids (Grade 2C). However, in such patients who developed significant side effects from glucocorticoids, or who are at high risk for such complications, we suggest treatment using calcineurin inhibitors, with or without low-dose glucocorticoids, rather than high-dose glucocorticoids or other agents (Grade 2C). (See 'Treatment of late relapsing disease' above.)

Steroid-dependent and steroid-resistant – Patients who will respond to glucocorticoids generally start to show some reduction in protein excretion within the first 8 to 12 weeks of therapy. Patients who attain a remission but who relapse while still on therapy, while therapy is being tapered, or within two months of discontinuing glucocorticoid therapy are considered steroid dependent. Patients with little or no reduction in protein excretion at 12 to 16 weeks are considered steroid resistant. (See 'Identification of steroid dependence and steroid resistance' above and 'Treatment of steroid-dependent or steroid-resistant FSGS' above.)

In patients with steroid-dependent or steroid-resistant FSGS, we suggest treatment with calcineurin inhibitors, with or without low-dose glucocorticoids, rather than other therapies (Grade 2B). Dosing, duration, and monitoring are the same as when these drugs are used as initial therapy. (See 'Calcineurin inhibitors' above.)

We avoid using calcineurin inhibitors in patients who have advanced vascular or interstitial disease on renal biopsy, or an estimated GFR (eGFR) <30 mL/min per 1.73 m2, because of the nephrotoxicity associated with these drugs. In addition, patients may fail therapy with these drugs or else develop severe side effects unrelated to nephrotoxicity. Thus, in patients who cannot receive calcineurin inhibitor therapy, we suggest mycophenolate mofetil (MMF), with or without low-dose glucocorticoids, rather than other agents or nonimmunosuppressive therapy alone (Grade 2C). (See 'Mycophenolate mofetil (MMF) as an alternative' above and "Cyclosporine and tacrolimus nephrotoxicity".)

Regardless of whether or not immunosuppressive therapy is provided, we treat patients who have primary FSGS with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). This therapy can be used even in patients who are not hypertensive, although care must be taken in these cases to avoid inducing symptomatic low blood pressure. (See 'Nonimmunosuppressive therapy' above.)

Other disease-modifying therapies have been studied in patients with primary FSGS but should not typically be used unless attempts with glucocorticoids, calcineurin inhibitors, or MMF have failed, or if the patient has repeatedly relapsed despite the use of such treatments. These alternative therapies include cytotoxic agents, rituximab, adrenocorticotropic hormone (ACTH), plasmapheresis, costimulatory inhibition, and low-density lipoprotein (LDL) apheresis. (See 'Other therapies' above.)

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