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Treatment of primary focal glomerulosclerosis

Last literature review version 17.3: September 2009  |  This topic last updated: July 29, 2009   (More)

INTRODUCTION — Focal segmental glomerulosclerosis (FGS) is a histologic diagnosis that 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 ("secondary") [1]. Primary FGS may present acutely with overt nephrotic syndrome with hypoalbuminemia and edema or, less often, insidiously with less dramatic manifestations, possibly related to the underlying histologic variant. In contrast, secondary FGS most often presents as asymptomatic proteinuria without hypoalbuminemia or edema [2]. Distinguishing between primary and secondary disease is particularly important because of the markedly different approach to therapy in the two disorders. (See "Pathogenesis and diagnosis of focal glomerulosclerosis", section on 'Secondary FGS'.)

Primary FGS was previously considered to be largely unresponsive to immunosuppressive therapy; however, glucocorticoids, cyclosporine, and other immunosuppressive agents have been used with considerable therapeutic success. In contrast, immunosuppression is not indicated in secondary FGS.

Renin-angiotensin-aldosterone system blockade (with angiotensin converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) reduce proteinuria and slow progression in proteinuric kidney diseases, and are therefore likely to be beneficial in primary and secondary FGS. Among the rare patients with FGS related to malignancy, effective therapy of the malignancy may lead to remission of the proteinuria [3].

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

The following discussion does not apply to collapsing FGS, which can be associated with HIV and a variety of other conditions. This variant is discussed separately. (See "Collapsing FGS and other renal diseases associated with HIV infection" and "Collapsing glomerulopathy (collapsing FGS) 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 FGS 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 [4].

Previously, treatment was not considered to substantially improve the prognosis of FGS. 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 degree of proteinuria and renal dysfunction, histologic findings, and the response to therapy.

Degree of proteinuria — Patients with the nephrotic syndrome (proteinuria ≥3.0 or 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 [5-8]. Massive proteinuria (>10 g/day), especially if unresponsive to treatment, is associated with an even worse prognosis, with most patients progressing to ESRD within five years [5]. In 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) [9].

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 ACE inhibitors [5,10-12].

Severity of renal dysfunction — More severe renal dysfunction at presentation is generally associated with worse renal survival [13-15]. 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 [14]. Worse renal function at presentation (unless it is acute) is generally associated with a greater extent of 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 FGS in some cases [7,15-17]. The collapsing variant is particularly associated with a worse prognosis and is often considered a different disorder. Although the association of other histologic findings with 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), although this remains under considerable debate, and the presence of this lesion does not guarantee responsiveness [4,17-20]. (See "Pathogenesis and diagnosis of focal glomerulosclerosis".)

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 [21]. One possible explanation is that these patients actually had minimal change disease and the totally sclerotic glomeruli reflected prior damage. (See 'Glucocorticoid resistance' below.)

Response to therapy — The strongest prognostic indicator of outcome is the initial response to therapy, which is reported in terms of various degrees of reduction in proteinuria [5,13,22,23]. 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 ideally to less than 3.5 g/day.
  • A relapse is 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 or to patients who have some reduction in proteinuria with more prolonged therapy who do not meet the criteria for partial remission.

Some investigators also include normalization of the plasma albumin concentration in the definition of response. 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) [5,6,9,11,13,16,18,24].

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 FGS patients with the nephrotic syndrome who were followed for a minimum of one year in the Toronto Glomerulonephritis Registry [13]. 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 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 to 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 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 FGS appears to respond to glucocorticoids, as well as other agents [16]; however, more prolonged glucocorticoid therapy than in minimal change disease is generally required to induce remission.

For the treatment of steroid-resistant or relapsing disease, cyclosporine is most commonly used, and other agents, including cyclophosphamide, mycophenolate,and sirolimus, have been tried in a small number of cases.

Although not specifically studied in primary or secondary FGS, ACE inhibitors or ARBs reduce proteinuria and slow progression in proteinuric kidney diseases, and are therefore indicated in all patients with primary FGS whether or not immunosuppressive therapy is provided. In addition, patients with nephrotic syndrome are often hypercholesterolemic and require appropriate statin therapy. (See 'Nonimmunosuppressive therapy' below.)

These recommendations do not apply to collapsing FGS, the treatment of which is discussed separately. (See "Collapsing FGS and other renal diseases associated with HIV infection" and "Collapsing glomerulopathy (collapsing FGS) not associated with HIV infection".)

Initial immunosuppressive therapy — The recommendations for initial therapy with prednisone are solely based upon observational studies and the authors' clinical experience. There are no randomized trials comparing prednisone or other agents to placebo for initial therapy of primary FGS. 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 'Glucocorticoid studies' below.)

It is not possible to confidently predict at presentation which patients will respond to steroids. In addition, some patients with primary FGS either have a good prognosis without immunosuppressive therapy or have risks with such therapy that outweigh any possible benefits.

We generally provide immunosuppressive therapy to patients with primary FGS who present with nephrotic range proteinuria. Prednisone is usually administered for a minimum of 12 to 16 weeks [25,26]. The efficacy of immunosuppression in patients with significantly decreased kidney function (eg, GFR <25 to 35 mL/min per 1.73 m2) is unclear. The decision should take into consideration the acuity of the renal failure (better response with acute disease), the findings on renal biopsy (eg, poor response with the presence of significant tubulointerstitial fibrosis and glomerulosclerosis), and the patient's risk for adverse consequences related to immunosuppression. (See 'Monitoring response to and duration of therapy' below.)

We generally do not initiate immunosuppressive therapy in patients with the following clinical features:

  • Normal kidney function and less than nephrotic-range proteinuria. These individuals usually have a relatively indolent course and may have spontaneous remission or stabilization of proteinuria; progression is more likely with higher degrees of proteinuria within the sub nephrotic range.
  • Decreased kidney function and less than nephrotic-range proteinuria. These patients may have had more severe proteinuria at an earlier stage of their disease that went undetected, or they may have secondary FGS. Response to therapy in such individuals is poor. (See 'Prognosis' above.)

These patients should receive nonimmunologic therapy with ACE inhibitors and/or ARBs to slow disease progression. (See 'Nonimmunosuppressive therapy' below.)

Although data are limited, we may use cyclosporine or tacrolimus as initial therapy, in conjunction with low dose prednisone, in patients at increased risk for glucocorticoid-associated toxicity. Potential candidates for this approach are the obese, patients with diabetes or at high risk for developing diabetes, patients with severe osteoporosis, and older patients. We avoid using calcineurin inhibitors in patients who have significant vascular or interstitial disease on renal biopsy, or an estimated GFR <40 mL/min per 1.73 m2 because of the nephrotoxicity of these drugs. (See "Major side effects of systemic glucocorticoids" and "Cyclosporine and tacrolimus nephrotoxicity".)

Glucocorticoid studies — 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 remission (variably defined as <2 to 3.5 g/day and/or ≥50 percent decrease in proteinuria) [5,10,11,13,16,18,24,27]. 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, seven also received cyclophosphamide, and the remainder were not treated [10]. 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 to 4 of 37 (11 percent) untreated patients (two of whom were never nephrotic). 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 FGS; 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 [5]. 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 to 76 and 57 percent among nephrotic patients. Among the treated nephrotic patients, half responded. The 5- and 10-year renal survival among responders was 100 percent, compared to 65 and 40 percent among nonresponders, respectively. Similar findings have been described by others [18].

In addition to the presence of nephrotic syndrome, the level of kidney function was predictive of response to treatment in some [11,13,27], but not all studies [5,10]. In the one study providing a stratified analysis, remission was achieved in only 5 of 21 patients with a serum creatinine >1.4 mg/dL (124 micromol/L) compared to 36 of 60 with lower serum creatinine concentrations [27].

Race may also affect the response to steroid therapy. In a retrospective review of 72 individuals with primary FGS, of whom 65 were African Americans, 60 percent received steroid 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, reached ESRD, all of whom were African American. However, this retrospective study does not preclude the possibility that African Americans might respond to steroids; as a result, we feel that race alone should not be an issue in initiating therapy.

Prednisone dose — The optimal dose and duration of therapy are unknown. In many cases, an overall course of treatment of at least six to eight months is required [16,23], and complete remission may not be attained for 12 months or longer [27]. Shorter courses (≤two months) 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 [5].

There are no randomized trials to guide the dose and duration of glucocorticoid therapy. The following dosing recommendations are extrapolated from doses used with apparent success in some of the observational studies and in 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 from glucocorticoids.

Monitoring response to and duration of therapy — 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 two 24-hour urine collections. Once drug therapy is stabilized and/or is being tapered, we monitor at one- to two- month intervals. (See "Patient information: Collection of a 24-hour urine specimen".)

The subsequent management of patients initially treated with prednisone is based upon 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 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, confirmed with two consecutive 24-hour urine collections) is achieved by 12 weeks, we taper prednisone slowly over six to nine months. We initially switch to alternate day dosing, and decrease the dose by approximately one-third approximately every six weeks. If proteinuria increases at any time during the taper, we stop the taper, maintain the current prednisone dose, and add cyclosporine or, if the estimated GFR is <40 mL/min per 1.73 m2, mycophenolate mofetil. (See 'Cyclosporine' below.)

  • 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 steroid toxicity, the risk of continued steroid therapy, and whether protein excretion is continuing to fall (a setting in which high-dose prednisone might be continued) or has plateaued on consecutive 24-hour urine collections. Alternatives to daily prednisone include alternate-day prednisone or switching to cyclosporine or, if the estimated GFR is <40 mL/min per 1.73 m2, mycophenolate mofetil, with a subsequent prednisone taper. (See 'Cyclosporine' below.)

  • Patients who have little or no reduction in proteinuria after 12 to 16 weeks of daily prednisone are presumed steroid-resistant. In such patients, we prefer to add cyclosporine and switch to alternate day prednisone with a progressive taper in prednisone therapy, reducing the dose by approximately one-third every week. (See 'Steroid-dependent and steroid-resistant FGS' below.)

Among patients on prolonged prednisone therapy, the risk of adrenal suppression during tapering must be considered. (See "Glucocorticoid withdrawal".)

Glucocorticoid 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. Thus, patients with little or no reduction in protein excretion at 12 to 16 weeks are considered to be steroid-resistant [9,16,18].

Factors that appear to be associated with a lower likelihood of response to steroids are significant tubulointerstitial disease on renal biopsy (which may reflect secondary FGS in some cases), and an elevated plasma creatinine concentration [5,6,16]. In addition, patients with massive proteinuria (>10 g/day) may be less likely to respond [6,29].

Although certain podocin mutations are associated with steroid-resistance in children, the relevance of these findings to adults is uncertain, and we do not test routinely for this mutation.

At present, it is not possible to confidently predict at presentation which patients with primary FGS will respond to steroid therapy. Even the finding of severe tubulointerstitial fibrosis must be interpreted with caution, given the focal nature of the disease. As a result, such patients should receive a trial of glucocorticoids, unless they are at markedly increased risk of steroid-induced side effects or have a substantial reduction in estimated glomerular filtration rate. (See 'Initial immunosuppressive therapy' above.)

  • Tubulointerstitial disease — 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 ß2-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 FGS reflects tubular dysfunction rather than enhanced glomerular permeability. (See "Evaluation of isolated proteinuria in adults".)

In a report of 37 adults with the idiopathic nephrotic syndrome (many of whom had FGS), those who had little or no low molecular weight proteinuria all went into remission with a 12-week course of prednisone [30]. In 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.

  • Genetic factors — Steroid resistance is present in some of the familial forms of FGS 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 FGS in children from Europe and the Middle East.

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 FGS among patients from European or South America. (See "Pathogenesis and diagnosis of focal glomerulosclerosis", section on 'NPHS2 gene'.)

Routine testing for this variant among steroid resistant patients is not recommended however.

 (see "Pathogenesis and diagnosis of focal glomerulosclerosis" and "Treatment of idiopathic nephrotic syndrome in children".

Additional genetic as well as socioeconomic factors may contribute to treatment resistance [31,32]. 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, and possible effects of socioeconomic status on adherence.

Calcineurin inhibitors — In patients at increased risk for glucocorticoid-associated toxicity, we occasionally use cyclosporine or tacrolimus in conjunction with 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 an estimated GFR <40 mL/min per 1.73 m2 because of the nephrotoxicity of these drugs.

Studies on cyclosporine are restricted to steroid-resistant or steroid-dependent primary FGS, while there is only one uncontrolled study of initial therapy with tacrolimus. In this report, six patients with a mean protein excretion of 11 g/day who were being treated with an ACE inhibitor or ARB but no immunosuppression received tacrolimus (initial dose 2 mg twice daily, adjusted to 12-hr trough levels of 4 to 7 ng/mL) [33]. All entered a partial remission with >75 percent reduction in proteinuria (to a mean of 2.8 g/day) within a mean of six months. 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.

We favor the use of cyclosporine rather than tacrolimus based upon more extensive experience with its use. The dose and monitoring regimen is the same as that used for steroid-dependent and steroid-resistant disease. (See 'Cyclosporine' below and 'Tacrolimus' below.)

Relapsing disease — Following cessation of initial therapy, some patients experience a recurrence of nephrotic range proteinuria. 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 steroids, has not had significant side effects, and has been in remission for more than one year after prednisone has been discontinued, we repeat a course of prednisone. (See 'Initial immunosuppressive therapy' above.)

  • Patients who previously had a complete or partial response to steroids but relapse during the taper or less than one year after cessation of steroid therapy are considered steroid-dependent and are treated as described in the next section.
  • If the patient has had significant steroid-induced toxicity or has subsequent relapses, we usually treat initially with cyclosporine (3.5 mg/kg per day, divided in two doses) and low-dose prednisone, using a similar regimen as described for steroid-dependent or steroid-resistant FGS. (See 'Cyclosporine' below.)

Steroid-dependent and steroid-resistant FGS — Recommendations for the therapy of steroid-dependent and steroid-resistant FGS 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.

FGS is considered steroid-dependent if a patient relapses while on therapy (or requires continuation of steroids to maintain remission) and steroid-resistant if there is little or no reduction in proteinuria after 12 to 16 weeks of adequate prednisone therapy or if there is some reduction in proteinuria with more prolonged therapy that does not meet the criteria for partial remission. (See 'Response to therapy' above.)

We suggest that initial therapy of steroid-dependent or steroid-resistant FGS consist of cyclosporine combined with low-dose prednisone. Among those unresponsive to this combination, additional agents have been evaluated, including cyclophosphamide, chlorambucil, tacrolimus, mycophenolate, and sirolimus [34]. We prefer mycophenolate due to its lower toxicity compared with cyclophosphamide and greater clinical experience than with sirolimus.

Cyclosporine — Randomized controlled trials and uncontrolled studies cited below have demonstrated the effectiveness of cyclosporine in reducing proteinuria in steroid-dependent and steroid-resistant FGS [6,22,35-39]. The reported response rates in steroid-resistant disease range from 20 to 70 percent; however, efficacy in preventing progression to ESRD is unknown.

 [40]

Thus, a trial of cyclosporine and low-dose prednisone is warranted in patients with steroid-dependent or steroid-resistant FGS, particularly in those with marked or symptomatic nephrotic syndrome [40]. However, we avoid using cyclosporine or other calcineurin inhibitors in patients who have significant vascular or interstitial disease on renal biopsy or an estimated GFR <40 mL/min per 1.73 m2, given the potential nephrotoxicity of these drugs. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The response to cyclosporine in FGS occurs earlier (within three months) than the response to prednisone, although the rate of complete (versus partial) remission appears to be lower than with glucocorticoids [16,22,38].

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 [35]. 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 [35,38,40]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The following randomized trials illustrate the efficacy of cyclosporine among adults with steroid-resistant FGS:

  • In a randomized, placebo-controlled study of 49 adults with steroid-resistant FGS (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 [22].

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 week 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 FGS 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 [38]. 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 to chlorambucil in 57 patients with steroid-resistant primary FGS [39]. 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. All patients in the chlorambucil group required cyclosporine. 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).

Based upon these observations, we treat with cyclosporine and concurrent low-dose prednisone as follows:

  • Initiate cyclosporine at a dose of approximately 3 to 4 mg/kg per day (given in two divided doses) or approximately 100 mg twice daily. We continue cyclosporine 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 (preferably ≤3 mg/kg per day).
  • Prednisone is given concurrently at a dose of 0.15 mg/kg (maximum 15 mg/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 cyclosporine for an additional 6 to 12 months after attaining a remission. In patients with significant steroid toxicity, we taper prednisone earlier and to discontinuation.

We monitor cyclosporine levels periodically to ascertain absorption and avoid higher, more nephrotoxic levels (ie, keep the level between 100 and 175 ng/mL) [33,39].

Tacrolimus — There is limited experience with tacrolimus for the treatment of FGS [33,41-44]. The largest study was an open-label uncontrolled study consisting of 25 patients (mean proteinuria of 10.2 g/day and plasma creatinine concentration of 1.2 mg/dL [106 micromol/L]) [42]. The patients were resistant to or dependent upon cyclosporine and glucocorticoids and were given tacrolimus plus prednisone for six months. Seventeen patients had a reduction in proteinuria to <3 g/day and 12 had complete or partial remission. 13 relapsed after discontinuation of tacrolimus; reinstitution of therapy for one year resulted in complete and partial remission in five and four patients, respectively. Reversible mild acute nephrotoxicity occurred in 40 percent of patients and appeared to be associated with an inappropriately high starting dose.

In summary, tacrolimus may be of benefit in some patients with FGS, but its efficacy compared to cyclosporine has not been evaluated. Studies in transplant recipients suggest that the efficacy and nephrotoxicity of the two drugs are similar. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Mycophenolate mofetil — Based in part upon experience with its use in other glomerular diseases, mycophenolate mofetil has been evaluated in patients with FGS in observational studies [45-48]:

  • In a retrospective single center study, 18 patients were treated with mycophenolate mofetil because of steroid-resistance or steroid-dependence with or without cyclosporine, and/or progressive renal dysfunction [45]. 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 FGS and nephrotic-range proteinuria (all resistant to prolonged glucocorticoids and 75 percent to a cytotoxic agent and/or a calcineurin inhibitor) were given mycophenolate mofetil for a mean period of eight months [48]. 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.

Based upon these limited observations, we suggest that mycophenolate mofetil (750 to 1000 mg twice daily for six months) be used in patients with FGS who are resistant to an adequate trial of prednisone and have not responded or should not be exposed to cyclosporine, or who have a partial response to prednisone and/or cyclosporine but have signs of steroid or cyclosporine toxicity.

Cytotoxic therapy — Data on the use of cytotoxic drugs for steroid-dependent or steroid-resistant FGS in adults are limited to a few retrospective observational studies [10,16,33,39,41-43,45-48], and the previously described randomized trial comparing chlorambucil to cyclosporine, which showed no benefit with chlorambucil [39].

Cytotoxic therapy has been used primarily in the treatment of children with relapsing or steroid-dependent idiopathic nephrotic syndrome [49,50]. 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 [6,49-51]. 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 [6,50]. (See "Treatment of idiopathic nephrotic syndrome in children".)

We do not recommend cyclophosphamide in patients with primary FGS 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 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 [16,39]. Chlorambucil is not recommended because of greater toxicity.

Sirolimus — There are a few reports examining the use of sirolimus in patients with FGS who had steroid-resistant disease or were intolerant to continuation of high dose steroids. An initial prospective study suggested benefit from sirolimus [52]. However, the use of sirolimus in the treatment of FGS and other primary glomerulopathies may worsen renal function [53-55]. In one study of six patients with primary FGS treated with sirolimus, five experienced a significant decline in GFR after seven to nine months of therapy, and none had a remission of proteinuria [53]. An additional concern is that sirolimus has been associated with the development of proteinuria and focal sclerosis in renal transplant recipients, as well as acute renal failure when used in combination with calcineurin inhibitors. (See "Sirolimus in renal transplantation".)

We do not advocate the use of sirolimus in the treatment of primary FGS.

Plasmapheresis and related modalities — There may be a limited role for plasmapheresis in the treatment of primary FGS, based in part upon studies in patients who have recurrent FGS in the renal allograft [34,40,56-58]. 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 glomerulosclerosis: Recurrence after transplantation".)

Any benefit in transplant recipients is generally transient, as protein excretion often returns to pretreatment levels within two months. Furthermore, the applicability of data from transplant recipients to patients with primary FGS is unclear.

There are conflicting reports regarding benefits of plasmapheresis in treating primary FGS. In one uncontrolled study of patients with refractory primary FGS, the addition of plasmapheresis seemed beneficial in some individuals [57]. Eleven patients with biopsy proven FGS unresponsive to glucocorticoids and cytotoxic therapy underwent an average of 17 plasmapheresis sessions over approximately 22 weeks. At follow-up at 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.

In contrast, a second uncontrolled study reported a relatively poor response rate with plasmapheresis, with only two of eight patients experiencing transient improvement in proteinuria [58]. The ongoing immunosuppressive therapy in the first study, compared to no consistent post-plasmapheresis immunosuppression in the second study, may explain these widely discrepant findings.

Whether a patient with primary FGS 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 [59]. In this test, 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 [60]; 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 FGS were lower than previously reported for patients with recurrent post-transplant FGS, were not related to severity of disease, and did not decrease despite clinical response to cyclosporine [61].

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

Based upon very limited experience, we only consider plasmapheresis in the following settings:

  • Severe disease manifestations despite an adequate trial of initial immunosuppressive therapy, in whom very high levels of circulating permeability factor have been demonstrated
  • Continued massive proteinuria and hypoalbuminemia despite exposure to an adequate course of prednisone, cyclosporine, and mycophenolate

Plasmapheresis should be performed in conjunction with immunosuppression. (See "Prescription and technique of therapeutic plasma exchange".)

The decision to treat patients with significantly reduced renal function (eg, GFR <25 to 35 mL/min per 1.73 m2) should take into consideration the acuity of the renal failure, findings on renal biopsy (eg, presence of significant tubulointerstitial fibrosis and glomerulosclerosis), and the individual patient's risk for adverse consequences related to therapy.

LDL apheresis — Several small nonrandomized studies using variable schedules of LDL apheresis in patients with steroid-resistant primary FGS have demonstrated some benefit in terms of reduction in proteinuria and improvement in serum albumin concentration, at least in short term follow-up [62-66]. Why this might work is unclear, but postulated mechanisms include reduction in oxidized LDL and associated inflammatory cytokines, and improvement in hypercoagulability.

Nonimmunosuppressive therapy — Two major nonimmunosuppressive therapies that should be instituted in most patients with primary FGS are angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), and lipid-lowering with a statin. These are also the mainstays of therapy for nonnephrotic patients with primary FGS and for patients with proteinuric chronic kidney disease in general.

Nonsteroidal antiinflammatory 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 FGS, even as specific immunosuppressive treatment is undertaken, or as primary therapy for patients with nonnephrotic proteinuria and patients who have other reasons for not receiving immunosuppression.

ACE inhibitors reduce proteinuria in patients with both primary and secondary FGS and rarely help attain remission without immunosuppressive treatment [9,67-71]. 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 FGS. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

For these reasons, administration of an ACE inhibitor or ARB is recommended for virtually all patients with primary FGS, 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".)

Lipid-lowering — Hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. (See "Hyperlipidemia in nephrotic syndrome".)

The following observations provide the rationale for lipid-lowering therapy with a statin in such patients:

  • Chronic kidney disease is associated with a marked increase in cardiovascular risk, particularly in older patients. As a result, chronic kidney disease is considered a coronary equivalent that should be treated with a statin. (See "Chronic kidney disease and coronary heart disease".)

Thus, patients with FGS who have persistent nephrotic syndrome and/or chronic kidney disease should be treated with a statin. Patients also on cyclosporine are at increased risk for rhabdomyolysis because of a drug interaction with many statins. (See "Hyperlipidemia in nephrotic syndrome" and "Muscle injury associated with lipid lowering drugs".)

NSAIDs — Among patients who do not respond to immunosuppressive therapy, as many as 60 percent given an NSAID have a marked reduction in proteinuria (50 to 75 percent) that presumably reflects a decline in intraglomerular pressure induced by renal vasoconstriction [8,72]. Uncontrolled observations suggest that these responders have a lower rate of progressive renal failure, although the true efficacy of these agents remains to be proven [72].

The possibility of precipitating acute renal failure, a known complication of traditional NSAIDs and the newer selective COX-2 inhibitors, has generally precluded use of these drugs for reducing proteinuria and slowing progression of renal insufficiency. (See "NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome".)

The only circumstance in which we consider NSAIDs in primary FGS is in patients with massive proteinuria and end-stage renal disease in an attempt to induce medical nephrectomy.

Other agents — Limited evidence suggests that an orally active antifibrotic agent, pirfenidone, may slow the rate of progression in patients with FGS. In an open-label trial of 21 patients with biopsy-proven FGS and advanced chronic kidney disease, the rate of decline in kidney function over one year with pirfenidone was compared with that observed with conventional ACE inhibitor and ARB therapy over an equivalent time period [73]. Pirfenidone improved the monthly change in GFR from -.61 mL/min per 1.73 m2 to -.45 mL/min per 1.73 m2 and had no effect on either proteinuria or blood pressure. The drug was well tolerated. Further study in controlled trials is required to clarify the role of this agent.

The thiazolidinedione rosiglitazone has also been shown to have antifibrotic effects in animal models of FGS [74]. A phase 1 clinical trial (FONT-I) showed that this agent was safe and well tolerated in 11 patients with biopsy-proven FGS [75]. Additional studies are in progress (FONT-II).

Role of protein restriction — The role of a protein-restricted diet in nephrotic syndrome and in chronic kidney disease is discussed elsewhere. (Please (see "Protein restriction and progression of chronic kidney disease".

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

SUMMARY AND RECOMMENDATIONS — Focal segmental glomerulosclerosis (FGS) may occur either as a primary disease or as a secondary response to previous glomerular injury. Distinguishing between primary and secondary disease is important because immunosuppressive therapy is indicated in most patients with primary FGS but not in secondary FGS. (See 'Treatment' above and "Pathogenesis and diagnosis of focal glomerulosclerosis".)

Untreated patients with nephrotic syndrome (proteinuria >3.5 g/day and hypoalbuminemia) due to primary FGS typically have a progressive course to ESRD. Treatment with glucocorticoids and other immunosuppressive agents can lead to partial and complete proteinuric response rates of almost 70 percent. Patients without nephrotic syndrome are more likely to remit spontaneously, or to have more slowly progressive disease. (See 'Prognosis' above.)

The most important predictor of outcome in patients with primary FGS is the response to initial therapy.

  • 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 in proteinuria by ≥50 percent, and ideally to less than 3.5 g/day.
  • A relapse is 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 steroids or shortly after discontinuation of steroids, 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, or to some reduction in proteinuria with more prolonged therapy that does not meet the criteria for partial remission.

Over the long-term, there is a much lower rate of renal failure among patients achieving a complete or partial remission, compared to those who are steroid-resistant. Patients with complete remission should not progress to renal failure if they do not relapse. (See 'Response to therapy' above and 'Disease progression' above.)

The therapeutic recommendations that follow do not apply to collapsing FGS and to secondary FGS, which are discussed separately. (See "Collapsing FGS and other renal diseases associated with HIV infection" and "Collapsing glomerulopathy (collapsing FGS) not associated with HIV infection" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

Initial immunosuppression — We recommend immunosuppressive therapy for nephrotic patients with primary FGS (Grade 1A). The decision to provide immunosuppression to patients with significantly decreased kidney function (eg, GFR <25 to 35 mL/min per 1.73 m2) should take into consideration the acuity of the renal failure (suggesting more reversible disease), findings on renal biopsy (eg, presence of significant tubulointerstitial fibrosis and glomerulosclerosis, which suggest less reversible disease), and the individual patient's risk for adverse consequences related to immunosuppression.

  • We recommend treatment with prednisone (or equivalent) for all patients without contraindications to steroid use (Grade 1B). Our usual approach is to treat with an initial dose of 1 mg/kg per day (maximum dose of 60 to 80 mg). (See 'Initial immunosuppressive therapy' above.)

The duration of the initial prednisone dose and rapidity of the steroid taper depends upon whether (and how quickly) a complete or partial remission is attained. (See 'Monitoring response to and duration of therapy' above.)

  • We suggest cyclosporine as initial therapy in patients who cannot tolerate high dose glucocorticoids (eg, poorly controlled diabetes, severe osteoporosis) (Grade 2B). We usually begin with a dose of 3 to 4 mg/kg per day (given in two divided doses) or approximately 100 mg twice daily, with concurrent low dose prednisone (0.15 mg/kg per day, maximum 15 mg/day). We monitor cyclosporine levels periodically to ascertain absorption and avoid higher, more nephrotoxic levels (eg, target levels between 100 and 175 ng/mL).
  • We continue cyclosporine 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 (and preferably ≤3 mg/kg per day). Prednisone is tapered after six months and continued at a lower dose for the duration of cyclosporine therapy. (See 'Cyclosporine' above.)

We avoid using cyclosporine or other calcineurin inhibitors in patients who have significant vascular or interstitial disease on renal biopsy, or an estimated GFR <40 mL/min per 1.73 m2.

We suggest not providing immunosuppressive therapy to patients with nonnephrotic proteinuria (Grade 2B). Patients with preserved kidney function have a relatively good prognosis, whereas those with significant renal dysfunction may have longstanding unrecognized disease or secondary FGS. (See 'Prognosis' above.)

Relapsing disease — A relapse is defined as a return of proteinuria to ≥3.5 g/day in someone who had undergone a complete or partial remission.

If a patient has recurrence of nephrotic syndrome after a complete response to steroids and has not had significant side effects related to this therapy, we suggest a second course of prednisone (Grade 2C). (See 'Initial immunosuppressive therapy' above.)

If the patient has had significant steroid-induced toxicity or has subsequent relapses, we suggest treatment with cyclosporine and low dose prednisone (Grade 2B). The same considerations for its use in initial therapy regarding cautions, dose, and duration of therapy apply.

Steroid-resistant or steroid-dependent disease — We recommend cyclosporine for the treatment of patients who are resistant to or dependent upon glucocorticoids (Grade 1B). The same considerations for its use in initial therapy regarding cautions, dose, and duration of therapy apply. (See 'Initial immunosuppressive therapy' above and 'Cyclosporine' above.)

We suggest treating with mycophenolate mofetil in patients who are resistant to or dependent upon prednisone and have not responded or should not be exposed to cyclosporine, or in patients who have shown a partial response to prednisone and/or cyclosporine but have signs of steroid or cyclosporine toxicity (Grade 2C). We usually treat with 750 to 1000 mg twice daily for six months. (See 'Mycophenolate mofetil' above.)

We suggest plasmapheresis in combination with immunosuppression only in the rare circumstances described above (Grade 2C). (See 'Plasmapheresis and related modalities' above.)

Monitoring — We recommend obtaining routine blood chemistries, including a plasma creatinine concentration for estimation of GFR, and measurement of the urine protein-to-creatinine ratio at two to four-week intervals during the initial two to three months of therapy. Prior to tapering immunosuppression, we confirm the level of proteinuria with two 24-hour urine collections. Once drug therapy is stabilized and/or is being tapered, we suggest monitoring at one to two month intervals. (See 'Monitoring response to and duration of therapy' above.)

Nonimmunosuppressive therapies — For all patients with FGS, we recommend treatment with an ACE inhibitor or an ARB (Grade 1B). ACE inhibitors or ARBs are the principal therapy for nonnephrotic patients and patients not eligible for immunosuppression, and may also be particularly beneficial for nephrotic patients who do not go into a prompt remission following immunosuppressive therapy or who have persistently decreased kidney function. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease".)

For patients with persistent nephrotic syndrome and/or chronic kidney disease, we suggest lipid lowering with a statin, with the goal of reducing the risk of cardiovascular disease (Grade 2B). Patients treated with cyclosporine and a statin should be monitored for rhabdomyolysis. (See "Hyperlipidemia in nephrotic syndrome" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention" and "Muscle injury associated with lipid lowering drugs".)

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REFERENCES

  1. D'Agati, V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994; 46:1223.
  2. Praga, M, Morales, E, Herrero, JC, et al. Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration. Am J Kidney Dis 1999; 33:52.
  3. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 15-1983. A 24-year-old man with cervical lymphadenopathy and the nephrotic syndrome. N Engl J Med 1983; 308:888.
  4. Deegens, JK, Assmann, KJ, Steenbergen, EJ, et al. Idiopathic focal segmental glomerulosclerosis: a favourable prognosis in untreated patients?. Neth J Med 2005; 63:393.
  5. Rydel, JJ, Korbet, SM, Borok, RZ, Schwartz, MM. Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment. Am J Kidney Dis 1995; 25:534.
  6. Korbet, SM, Schwartz, MM, Lewis, EJ. Primary focal segmental glomerulosclerosis: Clinical course and response to therapy. Am J Kidney Dis 1994; 23:773.
  7. Wehrmann, M, Bohle, A, Held, H, et al. Long-term prognosis of focal sclerosing glomerulonephritis. An analysis of 250 cases with particular regard to tubulointerstitial changes. Clin Nephrol 1990; 33:115.
  8. Velosa, JA, Torres, VE. Benefits and risks of nonsteroidal antiinflammatory drugs in steroid-resistant nephrotic syndrome. Am J Kidney Dis 1986; 8:345.
  9. Korbet, SM. Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. Semin Nephrol 2003; 23:219.
  10. Cattran, DC, Rao, P. Long-term outcome in children and adults with classic focal segmental glomerulosclerosis. Am J Kidney Dis 1998; 32:72.
  11. Stirling, CM, Mathieson, P, Boulton-Jones, JM, et al. Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units. QJM 2005; 98:443.
  12. Abrantes, MM, Cardoso, LS, Lima, EM, et al. Clinical course of 110 children and adolescents with primary focal segmental glomerulosclerosis. Pediatr Nephrol 2006; 21:482.
  13. Troyanov, S, Wall, CA, Miller, JA, et al. Focal and segmental glomerulosclerosis: Definition and relevance of a partial remission. J Am Soc Nephrol 2005; 16:1061.
  14. Korbet, SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol 1998; 9:1333.
  15. Chitalia, VC, Wells, JE, Robson, RA, et al. Predicting renal survival in primary focal glomerulosclerosis from the time of presentation. Kidney Int 1999; 56:2236.
  16. Banfi, G, Moriggi, M, Sabadini, E, et al. The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study. Clin Nephrol 1991; 36:53.
  17. Thomas, DB, Franceschini, N, Hogan, SL, et al. Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006; 69:920.
  18. Chun, MJ, Korbet, SM, Schwartz, MM, Lewis, EJ. Focal segmental glomerulosclerosis in nephrotic adults: Presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004; 15:2169.
  19. Stokes, MB, Markowitz, GS, Lin, J, et al. Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum. Kidney Int 2004; 65:1690.
  20. Beaman, M, Howie, AJ, Hardwicke, J, et al. The glomerular tip lesion: a steroid responsive nephrotic syndrome. Clin Nephrol 1987; 27:217.
  21. Nash, MA, Greifer, I, Olbing, H, et al. The significance of focal sclerotic lesions of glomeruli in children. J Pediatr 1976; 88:806.
  22. Cattran, DC, Appel, GB, Hebert, LA, et al. A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int 1999; 56:2220.
  23. Ponticelli, C, Villa, M, Banfi, G, et al. Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis? Am J Kidney Dis 1999; 34:618.
  24. Pei, Y, Cattran, D, Delmore, T, et al. Evidence suggesting under-treatment in adults with idiopathic focal segmental glomerulosclerosis. Regional Glomerulonephritis Registry Study. Am J Med 1987; 82:938.
  25. Korbet, SM. Treatment of primary focal segmental glomerulosclerosis. Kidney Int 2002; 62:2301.
  26. Meyrier, A. Nephrotic focal segmental glomerulosclerosis in 2004: an update. Nephrol Dial Transplant 2004; 19:2437.
  27. Pokhariyal, S, Gulati, S, Prasad, N, et al. Duration of optimal therapy for idiopathic focal segmental glomerulosclerosis. J Nephrol 2003; 16:691.
  28. Crook, ED, Habeeb, D, Gowdy, O, et al. Effects of steroids in focal segmental glomerulosclerosis in a predominantly African-American population. Am J Med Sci 2005; 330:19.
  29. Velosa, JA, Holley, KE, Torres, VE, Offord, KP. Significance of proteinuria on the outcome of renal function in patients with focal segmental glomerulosclerosis. Mayo Clin Proc 1983; 58:568.
  30. Sesso, R, Santos, AP, Nishida, SK, et al. Prediction of steroid responsiveness in the idiopathic nephrotic syndrome using urinary retinol-binding protein and beta-2-microglobulin. Ann Intern Med 1992; 116:905.
  31. Ingulli, E, Tejani, A. Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol 1991; 5:393.
  32. Kao, WH, Klag, MJ, Meoni, LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40:1185.
  33. Duncan, N, Dhaygude, A, Owen, J, et al. Treatment of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. Nephrol Dial Transplant 2004; 19:3062.
  34. Matalon, A, Valeri, A, Appel, GB. Treatment of focal segmental glomerulosclerosis. Semin Nephrol 2000; 20:309.
  35. Meyrier, A, Noel, LH, Auriche, P, et al. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Kidney Int 1994; 45:1446.
  36. Niaudet, P, for the French Society of Pediatric Nephrology. Treatment of childhood steroid resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. J Pediatr 1994; 125:981.
  37. Lieberman, KV, Tejani, A, for the New York-New Jersey Pediatric Nephrology Study Group. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant focal segmental glomerulosclerosis in children. J Am Soc Nephrol 1996; 7:56.
  38. Ponticelli, C, Rizzoni, G, Edefonti, A, et al. A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome. Kidney Int 1993; 43:1377.
  39. Heering, P, Braun, N, Mullejans, R, Ivens, K. Cyclosporine A and chlorambucil in the treatment of idiopathic focal segmental glomerulosclerosis. Am J Kidney Dis 2004; 43:10.
  40. Burgess, E. Management of focal segmental glomerulosclerosis: Evidence-based recommendations. Kidney Int Suppl 1999; 70:S26.
  41. McCauley, J, Shapiro, R, Ellis, D, et al. Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 1993; 8:1286.
  42. Segarra, A, Vila, J, Pou, L, et al. Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up. Nephrol Dial Transplant 2002; 17:655.
  43. Loeffler, K, Gowrishankar, M, Yiu, V. Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr Nephrol 2004; 19:281.
  44. Li, X, Li, H, Ye, H, et al. Tacrolimus therapy in adults with steroid- and cyclophosphamide-resistant nephrotic syndrome and normal or mildly reduced GFR. Am J Kidney Dis 2009; 54:51.
  45. Choi, MJ, Eustace, JA, Gimenez, LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 2002; 61:1098.
  46. Day, CJ, Cockwell, P, Lipkin, GW, et al. Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant 2002; 17:2011.
  47. Montane, B, Abitbol, C, Chandar, J, Strauss, J. Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol 2003; 18:772.
  48. Cattran, DC, Wang, MM, Appel, G, et al. Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin Nephrol 2004; 62:405.
  49. Siegel, NJ, Gaudio, KM, Krassner, LS, et al. Steroid-dependent nephrotic syndrome in children: Histopathology and relapses after cyclophosphamide treatment. Kidney Int 1981; 19:454.
  50. Schulman, SL, Kaiser, BA, Polinsky, MS, et al. Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns. J Pediatr 1988; 113:996.
  51. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of eight week with 12 week course. Report of Arbeitsgemeinschaft fur Padiatrische Nephrologie. Arch Dis Child 1987; 62:1102.
  52. Tumlin, JA, Miller, D, Near, M, et al. A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2006; 1:109.
  53. Fervenza, FC, Fitzpatrick, PM, Mertz, J, et al. Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies. Nephrol Dial Transplant 2004; 19:1288.
  54. Cho, M, Hurley, JK, Kopp, JB. Sirolimus for focal segmental glomerulosclerosis. J Am Soc Nephrol 2005; 16:775A.
  55. Cho, ME, Hurley, JK, Kopp, JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis 2007; 49:310.
  56. Ginsburg, DS, Dau, P. Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis. Clin Nephrol 1997; 48:282.
  57. Mitwalli, AH. Adding plasmapheresis to corticosteroids and alkylating agents: Does it benefit patients with focal segmental glomerulosclerosis? Nephrol Dial Transplant 1998; 13:1524.
  58. Feld, SM, Figueroa, P, Savin, V, et al. Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis in native kidneys. Am J Kidney Dis 1998; 32:230.
  59. Godfrin, Y, Dantal, J, Bouhours, JF, et al. A new method of measuring albumin permeability in isolated glomeruli. Kidney Int 1996; 50:1352.
  60. Haas, M, Godfrin, Y, Oberbauer, R, et al. Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis. Nephrol Dial Transplant 1998; 13:2013.
  61. Cattran, D, Neogi, T, Sharma, R, et al. Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis. J Am Soc Nephrol 2003; 14:448.
  62. Muso, E, Mune, M, Fujii, Y, et al. Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy. Nephron 2001; 89:408.
  63. Stenvinkel, P, Alvestrand, A, Angelin, B, Eriksson, M. LDL-apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion. Eur J Clin Invest 2000; 30:866.
  64. Hattori, M, Chikamoto, H, Akioka, Y, et al. A combined low-density lipoprotein apheresis and prednisone therapy for steroid-resistant primary focal segmental glomerulosclerosis in children. Am J Kidney Dis 2003; 42:1121.
  65. Nakamura, T, Sugaya, T, Kawagoe, Y, et al. Urinary liver-type fatty acid-binding protein levels for differential diagnosis of idiopathic focal glomerulosclerosis and minor glomerular abnormalities and effect of low-density lipoprotein apheresis. Clin Nephrol 2006; 65:1.
  66. Muso, E, Mune, M, Yorioka, N, et al. Beneficial effect of low-density lipoprotein apheresis (LDL-A) on refractory nephrotic syndrome (NS) due to focal glomerulosclerosis (FGS). Clin Nephrol 2007; 67:341.
  67. Praga, M, Hernandez, E, Montoyo, C, et al. Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992; 20:240.
  68. Heeg, JE, de Jong PE, van der Hem, GK, de Zeeuw, D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989; 36:272.
  69. Ferder, LF, Inserra, F, Daccordi, H, Smith, RD. Enalapril improved renal function and proteinuria in chronic glomerulopathies. Nephron 1990; 55 Suppl 1:90.
  70. Crenshaw, G, Bigler, S, Salem, M, Crook, ED. Focal segmental glomerulosclerosis in African Americans: effects of steroids and angiotensin converting enzyme inhibitors. Am J Med Sci 2000; 319:320.
  71. Stiles, KP, Abbott, KC, Welch, PG, Yuan, CM. Effects of angiotensin-converting enzyme inhibitor and steroid therapy on proteinuria in FSGS: a retrospective study in a single clinic. Clin Nephrol 2001; 56:89.
  72. Vriesendorp, R, Donker, AJ, de Zeeuw, D, et al. Effects of nonsteroidal anti-inflammatory drugs on proteinuria. Am J Med 1986; 81:84.
  73. Cho, ME, Smith, DC, Branton, MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007; 2:906.
  74. Weissgarten, J, Berman, S, Efrati, S, et al. Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats. Nephrol Dial Transplant 2006; 21:1198.
  75. Joy, MS, Gipson, DS, Dike, M, et al. Phase I trial of rosiglitazone in FSGS: I. Report of the FONT Study Group. Clin J Am Soc Nephrol 2009; 4:39.
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