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Minimal change disease: Treatment in adults

Minimal change disease: Treatment in adults
Literature review current through: Jan 2024.
This topic last updated: Nov 16, 2023.

INTRODUCTION — Minimal change disease (MCD) is a major cause of nephrotic syndrome (approximately 90 percent) in children and in a minority of adults (approximately 10 percent). MCD and focal segmental glomerulosclerosis (FSGS) are both examples of pathogenic mechanisms that primarily affect the podocyte ("podocytopathies").

The treatment of MCD in adults will be reviewed here. Other aspects of MCD, including the diagnosis and treatment of MCD in children, are discussed separately:

(See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

(See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

(See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)

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

GENERAL PRINCIPLES

Goals of therapy — The goal of therapy for patients with minimal change disease (MCD) is to significantly reduce proteinuria and thereby induce remission of the nephrotic syndrome. This is primarily achieved with the use of immunosuppressive agents, most commonly glucocorticoids. Although some patients may experience spontaneous remission without treatment, immunosuppressive therapy should not be withheld in an attempt to identify such patients. Such an approach exposes patients to the thrombotic and infectious hazards of persistent nephrotic syndrome and, in an older study in children, was associated with appreciable mortality from infection and thromboembolism [1].

Definitions of response — The following are commonly used definitions of treatment response for adults with MCD [2]:

Complete remission – A complete remission is a reduction in proteinuria to <0.3 g/day or urine protein-to-creatinine ratio (UPCR) <300 mg/g, stable serum creatinine, and serum albumin >3.5 g/dL.

Partial remission – A partial remission is a reduction in proteinuria of >50 percent, with absolute values between 0.3 and 3.5 g/day or UPCR between 300 and 3500 mg/g. Partial remission lasting more than two weeks is an unusual event in MCD, occurring in only 2 of 51 patients in one study [3]. Furthermore, it is possible that prolonged partial remission may have focal segmental glomerulosclerosis (FSGS) that was missed on kidney biopsy, since MCD is typically an all-or-none disease [4].

Relapse – A relapse is a return of proteinuria to >3.5 g/day or UPCR >3500 mg/g after complete remission has been achieved.

Frequently relapsing disease – Patients are considered frequent relapsers if they have two or more relapses per six months (or four or more relapses per 12 months).

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

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

INITIAL THERAPY FOR PRIMARY MCD

Choice of initial therapy — For most adults with primary minimal change disease (MCD), we suggest initial therapy with glucocorticoid monotherapy. For patients who cannot tolerate, have contraindications to, or do not wish to take high-dose glucocorticoids, glucocorticoid-sparing regimens are an alternative option and include calcineurin inhibitors (CNI; cyclosporine or tacrolimus) or mycophenolate mofetil/enteric-coated mycophenolate sodium (MMF/EC-MPS) plus reduced-dose glucocorticoids. Dosing and duration of these regimens are discussed elsewhere in this topic. (See 'Dosing and duration of preferred regimens' below.)

Glucocorticoid monotherapy leads to complete remission in 80 to over 95 percent of adults with MCD [3,5-11]. The time course to a complete remission is prolonged, with 50 percent responding by four weeks and 10 to 25 percent requiring more than three to four months of therapy (figure 1) [3,5,8-10]. Most glucocorticoid-responsive patients will respond by 16 weeks, but some may respond as late as 21 weeks [3]. In some adults, remission may be observed during the period of tapering when a "fixed"-duration regimen of glucocorticoids is used for induction of a remission [7]. By contrast, most children will respond within four weeks [12].

The use of glucocorticoids as initial therapy is supported by several large, randomized trials in children, a single randomized trial in adults, and extensive observational studies in children and adults [3,5-8,10,11,13-16]. As noted in several large trials, almost all children (95 percent or more) with MCD respond to glucocorticoid therapy (figure 1) (see "Treatment of idiopathic nephrotic syndrome in children"). In a randomized trial of 31 adults published in 1970 that compared low-dose prednisone (<30 mg/day) with no specific therapy, over 75 percent of those who received prednisone had remission of proteinuria to <1 g/day within six months [5]. By comparison, only 50 percent of those in the untreated group were in remission at 18 months and approximately 70 percent were in remission at three years.

However, relapsing disease, glucocorticoid resistance, and drug-related adverse effects are common issues among adults receiving prolonged high-dose glucocorticoids as first-line therapy for MCD. For this reason, glucocorticoid-sparing immunosuppressive regimens (such as CNIs or MMF/EC-MPS) have been used to try to reduce the toxicity of long-term glucocorticoid therapy. Data from a few randomized trials and observational studies suggest that such glucocorticoid-sparing regimens appear to have similar efficacy and safety compared with glucocorticoid monotherapy and may reduce the rate of relapse [6,17-22]:

A randomized trial found that treatment with intravenous (IV) methylprednisolone for 10 days followed by oral tacrolimus (starting at 0.05 mg/kg/day with a target trough level of 4 to 8 ng/mL) was comparable to prednisone (1 mg/kg/day) at inducing complete remission over 36 weeks [17]. Rates of relapse were also similar between the groups. Similar findings were reported in another randomized trial that compared tacrolimus monotherapy (without IV methylprednisolone) with prednisolone [23].

In a trial that randomly assigned 144 adults with MCD to receive tacrolimus (0.05 mg/kg twice daily) plus low-dose prednisolone (0.5 mg/kg daily) or prednisolone alone (1 mg/kg daily) for up to eight weeks or until achieving complete remission, rates of complete remission at eight weeks were comparable between the groups (79 versus 77 percent, respectively) [24]. Fewer patients in the tacrolimus group experienced relapse over 24 weeks (6 versus 23 percent), and rates of adverse effects were similar between the groups.

In a multicenter, open-label, randomized trial of 116 adults with MCD that compared EC-MPS (720 mg twice daily) plus reduced-dose prednisone (0.5 mg/kg/day, maximum dose 40 mg daily) with conventional high-dose prednisone alone (1 mg/kg/day, maximum dose 80 mg daily), there was no significant difference between the treatment arms in the rates of complete remission after 4, 8, or 24 weeks of treatment [18]. Among patients who achieved a complete remission after four weeks of treatment, rates of relapse were comparable between the two groups. The frequency of serious adverse effects was also similar between the treatment arms.

Rituximab has been used as initial therapy for MCD in small case series [25,26]; however, studies comparing its efficacy with that of glucocorticoids are lacking. The use of rituximab in patients with frequently relapsing or glucocorticoid-dependent MCD is discussed elsewhere in this topic. (See 'Rituximab' below.)

Dosing and duration of preferred regimens

Glucocorticoid monotherapy — If glucocorticoid monotherapy is used, we administer oral prednisone as follows:

Initial dose – We initiate oral prednisone at a daily dose of 1 mg/kg of body weight (maximum dose 80 mg/day) [2,6-8,10]. Some clinicians prefer alternate-day prednisone at an initial dose of 2 mg/kg every other day (maximum dose of 120 mg) to minimize the toxicity of long-term daily prednisone [2,8,11]. Therapy is usually given as a single dose upon awakening (usually between 7:00 and 9:00 AM) in an attempt to minimize adrenal suppression [27]. We continue the initial dose for a minimum of four weeks.

Tapering – Slow tapering is performed to sustain the remission and to avoid adrenal suppression. Shorter tapering regimens, in which glucocorticoids are tapered rapidly after remission is induced, are associated with an increased risk of relapse [3], suggesting a "rebound effect."

For patients who respond with complete remission, we start tapering prednisone one to two weeks after complete remission is attained. Approaches to tapering prednisone vary among clinicians. One approach is to reduce the daily prednisone dose by 5 to 10 mg per week for a total period of glucocorticoid exposure of approximately 16 to 20 weeks.

In patients who have not attained complete remission, the usual maximum duration of daily or alternate-day prednisone at the initial dose is 16 weeks, and patients who do not respond by this time are often considered glucocorticoid resistant. In such patients, prednisone therapy is gradually tapered to lower doses, and cyclosporine is preferably started along with prednisone, as described below. (See 'Glucocorticoid-resistant MCD' below.)

Data comparing one glucocorticoid regimen to another (eg, daily versus alternate-day therapy, oral regimen versus IV pulse therapy, short versus long duration) are limited. The optimal initial treatment regimen is unclear as the few randomized trials and multiple observational studies most commonly used different regimens [11,15,28,29]. One observational study comparing a shorter-duration (two months) glucocorticoid regimen with a more conventional glucocorticoid regimen in adults with MCD found similar rates of overall and frequent relapse between the groups; the cumulative glucocorticoid dose was markedly lower in the shorter-duration group [30].

Glucocorticoid-sparing regimens — Glucocorticoid-sparing regimens are an alternative treatment option for patients who cannot tolerate, have contraindications to, or do not wish to take high-dose glucocorticoids. The most commonly used regimens are CNIs (cyclosporine or tacrolimus) and MMF/EC-MPS plus reduced-dose glucocorticoids. (See 'Choice of initial therapy' above.)

CNIs – If a CNI inhibitor-based regimen is used as initial therapy, either cyclosporine or tacrolimus is a reasonable choice.

If cyclosporine is used, the initial dose is 3 to 5 mg/kg per day in two divided doses to maintain whole blood trough levels between 150 and 200 ng/mL [2]. If tacrolimus is used, the preferred regimen is 0.05 to 0.1 mg/kg per day in two divided doses to maintain whole blood trough levels between 4 and 7 ng/mL [2]. Once the patient has achieved complete remission, we continue these doses for an additional 12 weeks, then gradually taper the dose over eight weeks to discontinuation. The total duration of treatment is approximately six months.

In patients who have contraindications to or who do not wish to receive glucocorticoids, CNIs can be administered as monotherapy [23]. In the absence of contraindications, some clinicians administer the CNI with reduced-dose glucocorticoids, such as prednisone 0.3 mg/kg per day (maximum dose 30 mg/day) [24], although the addition of glucocorticoids to a CNI is not necessary. Once the patient has achieved complete remission, the prednisone is tapered over four to six weeks to discontinuation.

MMF/EC-MPS plus reduced-dose glucocorticoids – If a mycophenolate-based regimen is used as initial therapy, either MMF or EC-MPS is a reasonable choice.

If MMF is used, we give 0.5 g twice daily for the first week, then 1 g twice daily thereafter. If EC-MPS is used, we give 360 mg twice daily for the first week, then 720 mg twice daily thereafter. We usually continue these doses for a total of six months and then discontinue the drug [18].

MMF/EC-MPS should be administered with reduced-dose glucocorticoids [18]. We give prednisone 0.5 mg/kg per day (maximum dose 40 mg/day). Once the patient has achieved complete remission, we taper the prednisone over four to six weeks to discontinuation. Some experts choose to taper the prednisone more gradually over four to five months [18].

Supportive measures in all patients — General supportive measures in all patients with MCD include dietary sodium restriction, blood pressure control, and in selected patients, anticoagulation. Dietary protein restriction, renin-angiotensin system inhibition to treat proteinuria, and statin therapy to treat dyslipidemia are not usually needed in patients with MCD, except in those with glucocorticoid resistance and nephrotic syndrome persisting for several months. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition [31]. This approach is consistent with the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases [2]. These issues are discussed in greater detail elsewhere:

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

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

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

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

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

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

Monitoring the response to therapy — All patients who are receiving treatment for primary MCD should be closely monitored for clinical response to therapy. We perform a clinical assessment and monitor a spot urine protein-to-creatinine ratio, serum albumin, and serum creatinine on a monthly basis. Remissions are typically abrupt, with the patient being free of proteinuria within two to three weeks from the time of initial response. In a majority of cases, response to therapy of nephrotic MCD is of an "all or nothing" type. Partial responses are not characteristic of MCD and, when seen, one should suspect a possible misdiagnosis, most often focal segmental glomerulosclerosis (FSGS) that was missed by sampling error. (See 'Definitions of response' above.)

RELAPSING DISEASE — Disease relapse is defined as a return of proteinuria to >3.5 g/day in patients who had previously undergone a complete remission. This is usually followed by a decrease in the serum albumin concentration from its previous baseline. Approximately 50 to 75 percent of glucocorticoid-responsive adults will have a relapse, and frequent relapses occur in 10 to 25 percent [3,8,10,32]. Glucocorticoid dependence is seen in 25 to 30 percent [3,10]. (See 'Definitions of response' above.)

Most relapses occur within one year after glucocorticoid therapy has been tapered or discontinued, although occasional patients have a glucocorticoid-responsive relapse after as long as 25 years in remission [6,8,33,34]. Relapses may be triggered by allergies or infections, especially viral infections [3]. In such cases, the relapse can last for a limited period and may respond to a shorter treatment duration than initial therapy, often within one month. Cases of relapse following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have also been reported [35-37]. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'COVID-19 vaccine-associated glomerular disease'.)

Monitoring for relapse — Patients who relapse require reinstitution of therapy, and early detection is beneficial. Once patients have achieved complete remission, we ask them to test their urine with a dipstick for protein every one to two weeks for at least the first six months to monitor for disease relapse. A positive test should be repeated the next day and, if still positive, the clinician should be contacted. Most cases of relapse have an abrupt onset, and patients often will self-diagnose relapse when they observe the passage of foamy urine [38] or sudden onset of edema.

Infrequent relapse — For most patients with infrequent relapses (fewer than four per year), we suggest a repeat course of the initial therapy used to achieve complete remission, rather than switching therapy:

If the patient received glucocorticoid monotherapy as initial therapy, we usually administer a repeat course of glucocorticoids. An exception is in patients who have previously developed significant adverse effects related to initial therapy with glucocorticoids; in such patients, switching to a glucocorticoid-sparing regimen may be preferred (see 'Glucocorticoid-sparing regimens' above). The optimal dose and duration of glucocorticoids for infrequent relapse is uncertain. We prefer to give a shorter course of prednisone to minimize overall glucocorticoid exposure, particularly if the relapse has occurred after a relatively long period off prednisone or when it is caused by an intercurrent benign viral or allergic event. We administer oral prednisone at a daily dose of 1 mg/kg (maximum dose of 80 mg per day) for four weeks; if remission is attained, the dose is then tapered in 5 mg decrements every three to five days to discontinuation within one to two months. Some nephrologists choose to repeat the initial prednisone regimen rather than to give a shorter course.

Subsequent relapses, if not frequent, can also be treated with prednisone if significant side effects have not developed. A longer course of prednisone (as administered for initial therapy) can be used in patients who relapse during the taper of a short course of glucocorticoids or within four months of completing the short course.

If the patient received a glucocorticoid-sparing regimen (eg, a calcineurin inhibitor [CNI] or mycophenolate mofetil/enteric-coated mycophenolate sodium [MMF/EC-MPS] plus reduced-dose glucocorticoids) as initial therapy, we administer the same regimen that was used to achieve complete remission. (See 'Glucocorticoid-sparing regimens' above.)

There is no high-quality evidence to guide the optimal therapy of infrequent relapse. In observational studies of patients who were able to taper off prednisone after achieving complete remission, a repeat, shorter course of prednisone often resulted in a prompt clinical remission [6-8]. One small, randomized trial that compared cyclosporine combined with prednisolone (0.8 mg/kg/day) versus prednisolone alone (1 mg/kg/day) in 52 adults with a first relapse of minimal change disease (MCD) found a shorter time to remission in the cyclosporine group; however, there was no significant difference between the groups in rates of complete remission at six months [39].

Frequently relapsing or glucocorticoid-dependent MCD — There are a variety of therapeutic approaches in patients who have frequent relapses (defined as two or more relapses per six months, or four or more relapses per 12 months) or who are glucocorticoid dependent (relapse occurring during, or within two weeks of completing, glucocorticoid therapy). (See 'Definitions of response' above.)

General approach — For patients with frequently relapsing or glucocorticoid-dependent (FR/GD) MCD, we recommend treatment with cyclophosphamide, rituximab, a CNI (cyclosporine or tacrolimus), or MMF/EC-MPS, rather than glucocorticoid monotherapy.

The choice among these regimens depends upon several factors, including clinician and patient preference, drug availability and cost, efficacy, toxicity, and tolerability. There is limited evidence directly comparing one drug class with another in the treatment of patients with FR/GD MCD, and available data have not established that one regimen is superior to another. Most of the contributors to this topic prefer cyclophosphamide or rituximab for most patients, particularly those who have previously received a CNI or MMF/EC-MPS as part of a glucocorticoid-sparing regimen, based upon low-quality evidence showing more durable remissions with these agents compared with a CNI. However, any of these drug classes are preferred over glucocorticoids to avoid the morbidity associated with prolonged glucocorticoid exposure.

In general, patients with FR/GD MCD who are in relapse should be retreated with glucocorticoids (or a glucocorticoid-sparing regimen) until remission is attained before a second-line therapy is initiated. Following initiation of the second-line therapy, glucocorticoids (or a glucocorticoid-sparing regimen) are gradually tapered to discontinuation over one month, if possible. If the patient continues to be dependent on glucocorticoids after three to six months of treatment, then the second-line therapy should be discontinued and an alternative regimen should be considered.

Patients receiving treatment for FR/GD MCD should be monitored using the same approach as those receiving initial therapy for MCD. (See 'Monitoring the response to therapy' above.)

Data from observational studies and a few small, randomized, controlled trials suggest that cyclophosphamide, rituximab, CNIs, and MMF/EC-MPS reduce the rate of relapse and induce remission in approximately 70 to 90 percent of adults with FR/GD MCD [3,6,11,39-46]. The dosing and efficacy of specific immunosuppressive regimens used for FR/GD MCD are discussed below.

Dosing and efficacy

Cyclophosphamide — The hazards of cyclophosphamide therapy, especially that of infertility, must be clearly explained to the patient and/or guardians for ethical and legal reasons before beginning this treatment. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity'.)

If cyclophosphamide is used for patients with FR/GD MCD, we administer oral cyclophosphamide at a dose of 2 mg/kg per day (maximum daily dose 200 mg) for 12 weeks. Data in adults and children indicate that an eight-week course may be less effective [3,6,47]. The dose of cyclophosphamide is reduced as needed to maintain a white blood cell count >3500 cells/microL and an absolute neutrophil count (ANC) of >1500 cells/microL. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Daily oral cyclophosphamide'.)

Given the side effects of cyclophosphamide, prolonged therapy (>12 weeks) and repeated courses must be avoided. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Evidence for the efficacy of cyclophosphamide in adults with FR/GD MCD comes primarily from one randomized trial and several observational studies, which collectively show that cyclophosphamide induces remission in approximately 75 percent of such patients [1,3,6,10,11,14,44]. As examples:

In a study of 14 patients, treatment with cyclophosphamide (2 mg/kg per day for eight weeks) resulted in complete, relapse-free remission in four of five FR patients and four of nine GD patients [3]. The remaining five GD patients were able to be weaned off glucocorticoids but had subsequent relapses. At final follow-up, 11 were in complete remission.

In a trial of 66 children and adults, 11 adults with FR/GD MCD were randomly assigned to cyclophosphamide (2.5 mg/kg for eight weeks) or cyclosporine (5 mg/kg per day for nine months, then tapered off by month 12) [44]. All of the adults achieved remission; three patients in each group eventually relapsed, occurring in the first year following therapy with cyclophosphamide and earlier after discontinuation of cyclosporine. Among children, the rate of stable disease at two years was significantly higher with cyclophosphamide (68 versus 20 percent). There were too few adults for a meaningful comparison, although other studies have also found a high rate of relapse following cessation of cyclosporine.

Rituximab — Rituximab is an anti-CD20 monoclonal antibody that depletes CD20-positive cells. If rituximab is used for patients with FR/GD MCD, we typically administer rituximab as 1 g initially followed 14 days later by another 1 g dose. Other clinicians may use an alternative regimen, administering 375 mg/m2 weekly for four weeks or a B cell count–driven approach in which a second dose of 375 mg/m2 is given if ≥5 circulating B cells/microL are detected by flow cytometry one week after treatment.

In patients with FR/GD MCD who respond to rituximab, some experts choose to administer maintenance rituximab to prevent relapse. There are no data to guide this approach; some contributors to this topic would give rituximab 1 g every six months for two to three years and then discontinue maintenance therapy.

Observational studies suggest that rituximab may be effective therapy in adults with FR/GD MCD [42,43,48-50]. In a systematic review and meta-analysis of 21 studies involving 382 adults with FR/GD MCD or focal segmental glomerulosclerosis (FSGS), rituximab therapy induced complete remission in 92 percent of those with MCD, although 28 percent of the patients relapsed during follow-up [50]. Rituximab was well tolerated and associated with few adverse events.

Other anti-CD20 monoclonal antibodies such as obinutuzumab have been evaluated for the treatment of FR/GD nephrotic syndrome in children, including disease resistant to rituximab [51], but have not yet been studied in adults with FR/GD MCD.

Data pertaining to the use of rituximab in children with MCD are discussed elsewhere. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Rituximab'.)

Calcineurin inhibitors — If cyclosporine is used for patients with FR/GD MCD, the initial dose is 3 to 5 mg/kg per day in two divided doses to maintain whole blood trough levels between 150 and 200 ng/mL. If tacrolimus is used, the initial dose is 0.05 to 0.1 mg/kg per day in two divided doses to maintain whole blood trough levels between 4 and 7 ng/mL.

The optimal duration of therapy in patients who respond is not known, but prolonged therapy is given to minimize the risk of relapse. We treat with the initial dose of CNI for at least 12 to 18 months, then taper to the smallest dose that maintains a remission and avoids nephrotoxicity (preferably less than 3 mg/kg per day of cyclosporine or less than 0.05 mg/kg per day of tacrolimus). This dose is maintained for 18 to 24 months, then slowly tapered to discontinuation over four to six months.

Numerous observational studies and a small, randomized trial suggest that approximately 70 and 90 percent of GD or FR patients, respectively, will undergo complete or partial remission when treated with cyclosporine [13,44,52-55]. Similar results have been reported with tacrolimus [23,56-59]. Over 60 percent of FR/GD patients who respond to cyclosporine will relapse (usually within six months) after cyclosporine is discontinued if the duration of therapy is relatively short [44,52,60]. A sustained remission is more likely if patients are maintained on cyclosporine for one year or longer, with therapy then slowly tapered to discontinuation [52,53].

Although cyclosporine is potentially nephrotoxic, it appears that prolonged therapy with lower doses of cyclosporine can maintain remission without nephrotoxicity. In one study, for example, patients who went into remission showed no signs of cyclosporine nephrotoxicity on repeat biopsy at a mean of 20 months as long as the daily dose of cyclosporine (non-microemulsion preparation) was below 5.5 mg/kg per day [53]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Mycophenolate mofetil/sodium — If MMF is used for patients with FR/GD MCD, we give 0.5 g twice daily for the first week, then 1 g twice daily thereafter. If EC-MPS is used, we give 360 mg twice daily for the first week, then 720 mg twice daily thereafter. We usually continue these doses of mycophenolate for at least one year and then attempt to gradually taper the drug to discontinuation, if possible.

Data on the use of mycophenolate in patients with FR/GD MCD are limited but suggest some benefit [11,46,61-63]. As an example, in an observational study that included 18 adults with FR/GD MCD who received MMF (2000 mg/day) or EC-MPS (1440 mg/day) plus low-dose prednisone (10 mg/day), 16 (89 percent) achieved complete remission, one achieved partial remission, and one was resistant to MMF [46]. Among the 11 who completed the first cycle of MMF/EC-MPS, seven (64 percent) maintained remission after a mean of 33 months.

GLUCOCORTICOID-RESISTANT MCD — Glucocorticoid resistance refers to the persistence of proteinuria >3.5 g/day with ≤50 percent reduction from baseline after 16 weeks of adequate glucocorticoid therapy (ie, prednisone 1 mg/kg/day or 2 mg/kg every other day). Approximately 5 to 10 percent of adults with minimal change disease (MCD) appear to be glucocorticoid resistant. However, some experts would argue that glucocorticoid-resistant MCD actually reflects an early stage of focal segmental glomerulosclerosis (FSGS) or unsampled primary FSGS. (See 'Definitions of response' above.)

Causes of glucocorticoid resistance — Glucocorticoid resistance is most often due to one of the following problems:

Inadequate initial glucocorticoid therapy – Inadequate initial glucocorticoid therapy due to treatment nonadherence or treatment for less than 16 weeks may be a cause of apparent glucocorticoid resistance. In addition, in some patients treated with prednisolone (rather than with prednisone), the use of prescribed or over-the-counter aluminum-containing antacids can decrease the bioavailability of the glucocorticoid. A longer course of daily therapy induces remission in some of these cases. In children who do not respond by four weeks, a failure to respond to a trial of pulse methylprednisolone is considered indicative of glucocorticoid resistance. Some nephrologists apply this approach (eg, methylprednisolone 0.5 to 1 g every other day for three doses) to define glucocorticoid resistance in adults who do not have some response to oral glucocorticoids by 8 to 12 weeks.

Incorrect diagnosis – Another common cause for apparent glucocorticoid resistance is an incorrect diagnosis, most often FSGS (either of the primary, secondary, or genetic form) that is missed by sampling error or inadequate examination of the kidney biopsy, particularly if the kidney biopsy comprises few glomeruli and only superficial cortical tufts. As mentioned previously, remissions of MCD are typically abrupt, with the patient being free of proteinuria within two to three weeks from the time of initial response. Partial responses are not characteristic of MCD [7], and when seen, one should suspect a possible misdiagnosis, most often FSGS.

The first step is to reevaluate the original kidney biopsy since segmental sclerosis in one glomerulus is sufficient to establish the diagnosis of FSGS. Most experts, including the authors of this topic, would repeat the kidney biopsy if reevaluation of the original specimen is unrevealing, or if the initial biopsy did not include electron microscopy, and glucocorticoid unresponsiveness is present. (See 'Role of repeat kidney biopsy' below and "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Distinguishing MCD from primary FSGS'.)

Minimal change variants – Glucocorticoid resistance may also be seen in one of the variants of idiopathic nephrotic syndrome other than FSGS, such as idiopathic mesangial proliferation, immunoglobulin M (IgM) nephropathy, or C1q nephropathy. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Minimal change variants'.)

Role of repeat kidney biopsy — The value of repeat kidney biopsy in patients with glucocorticoid-resistant MCD is unclear. Histologic examination will show either FSGS or MCD. However, if MCD is again seen, one cannot exclude underlying FSGS that was missed by sampling error. Furthermore, the findings on repeat biopsy do not affect therapy, since the treatment of choice is cyclosporine for both glucocorticoid-resistant MCD and glucocorticoid-resistant FSGS [3].

On the other hand, some experts (including the authors) consider the finding of FSGS of repeat biopsy to be valuable in glucocorticoid-resistant patients since it identifies a patient with a worse long-term prognosis, even though it does not modify the choice of management over the short term. Repeat kidney biopsy is indicated in patients treated with a calcineurin inhibitor (CNI) in whom serum creatinine rises by >30 percent over baseline to assess for treatment-induced vascular and interstitial lesions [53] or alternatively to diagnose progression to lesions of FSGS.

Data pertaining to repeat kidney biopsy in patients with MCD are limited. In a review of 25 children with MCD who underwent repeat biopsy, most often prior to a change in therapy, four had MCD and 21 had FSGS or IgM nephropathy [64]. The distribution was different in a series of 35 adults with MCD on initial biopsy: Repeat biopsy showed MCD in 22 and FSGS in 13 [65].

Treatment of glucocorticoid-resistant MCD — The optimal therapeutic approach to patients with glucocorticoid-resistant MCD is not known. In general, we treat these patients with a CNI (cyclosporine or tacrolimus) with or without low-dose glucocorticoids, using the same approach as that used for patients with glucocorticoid-resistant FSGS. This is discussed in more detail elsewhere. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Glucocorticoid-dependent or glucocorticoid-resistant disease'.)

Cyclosporine has documented efficacy in glucocorticoid-resistant MCD, although long-term results are less well defined [11,40,52,65,66]. The following observations illustrate the range of findings:

A randomized trial evaluated the efficacy of cyclosporine in 13 adults and children with glucocorticoid-resistant MCD compared with supportive care [10]. The cyclosporine dose was 5 mg/kg per day for six months, which was then tapered by 25 percent every two months until discontinuation. Complete or partial remission was induced in five of eight treated adults without significant nephrotoxicity or other side effects. Positive responses occurred within two months after the onset of therapy, while lack of antiproteinuric effect at three months was generally indicative of resistance to cyclosporine. Despite the initial benefit, relapses were common after cessation of therapy, and mean urinary protein excretion at the end of the study was not different between treated and control groups.

In a report from France that combined two prospective, uncontrolled trials, 21 adults with glucocorticoid-resistant MCD were treated with cyclosporine (5 mg/kg per day in two divided doses) with or without prednisone (10 to 15 mg/day) [40]. Fourteen patients were in complete or partial remission at six months, but many had recurrence of proteinuria upon cyclosporine taper. Responses were more likely among those concurrently receiving prednisone.

SIDE EFFECTS OF IMMUNOSUPPRESSIVE THERAPY — The immunosuppressive agents used to treat minimal change disease (MCD) are associated with significant side effects. These toxicities are described in detail elsewhere:

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

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

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

Rituximab (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis")

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

The long-term complications of cytotoxic therapies may be less common in MCD since relatively short courses are used. However, the toxicity of these agents must be considered in treating patients with MCD, particularly since progressive kidney failure is rare in the absence of progression to focal segmental glomerulosclerosis (FSGS) [3].

SPECIAL POPULATIONS

Pregnant patients — The optimal approach to the treatment of primary minimal change disease (MCD) in pregnant patients is not known. Most contributors of this topic would treat with immunosuppressive therapy, preferably with glucocorticoids. Cyclosporine and tacrolimus may also be used but appear to be less safe. Cyclosporine may be associated with increased rates of premature birth and low birth weight [67]. Similarly, infants exposed to tacrolimus in utero are at risk of premature birth, birth defects, low birth weight, and fetal distress. Rituximab, cyclophosphamide, and mycophenolate mofetil/enteric-coated mycophenolate sodium (MMF/EC-MPS) should be avoided in pregnant patients. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

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

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

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

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

Patients with MCD and AKI — Acute kidney injury (AKI) can occur in patients with MCD, and sometimes, the glomerular filtration rate does not fully recover to baseline. Some patients do not recover sufficient kidney function to allow withdrawal from dialysis, despite confirmed MCD on a repeat kidney biopsy [68]. This complication and its management are discussed separately. (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

Patients with secondary causes of MCD — Secondary MCD has been attributed to a variety of agents and conditions. In general, the treatment of secondary MCD focuses on cessation of the offending drug or effective treatment of the underlying disease, which is usually associated with improvement in the nephrotic syndrome. Among patients with MCD associated with malignancy, the decision to treat with glucocorticoids or other immunosuppressive agents should be jointly taken by the nephrologist and the oncologist. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Etiology'.)

MCD is a cause of the nephrotic syndrome that occurs following hematopoietic cell transplantation (HCT). The treatment of MCD after HCT is discussed in more detail elsewhere. (See "Kidney disease following hematopoietic cell transplantation", section on 'Minimal change disease'.)

MCD after kidney transplantation — De novo and recurrent MCD are rare after kidney transplantation [69,70]. The development of recurrent nephrotic syndrome in a transplant recipient with MCD as the cause of end-stage kidney disease (ESKD) should raise concern for the possibility of recurrent primary focal segmental glomerulosclerosis (FSGS) that was originally misdiagnosed in the native kidneys as MCD. (See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

PROGNOSIS — The outcome of treated minimal change disease (MCD) is favorable, with the great majority of patients eventually attaining complete remission [71-73]. The most important prognostic factor appears to be the initial response to glucocorticoid therapy. Without treatment, the rate of spontaneous early remission (eg, within a few months) in adults is approximately 5 to 10 percent [5,8,10]. A substantial proportion of untreated patients eventually undergo remission after a prolonged period [3,5]. In a series of 51 patients, for example, 33 percent had a spontaneous remission at some time during the disease course [3]. However, during the period between disease onset and spontaneous remission (which may take years), untreated patients are exposed to the risks of severe nephrotic syndrome, including thromboembolic events, acute kidney injury (AKI), and infection.

Although many patients with MCD have a modest decrease in the glomerular filtration rate during the nephrotic phase, this may represent "functional kidney impairment," as kidney function returns to normal following resolution of the nephrotic syndrome, even after multiple relapses [3,6-8,10]. In a series of 51 patients, 61 percent had higher-than-normal serum creatinine values when patients were actively nephrotic, but kidney function returned to normal when remission was achieved [3]. In adults, the nephrotic syndrome may also be associated with a rise in blood pressure over prenephrotic baseline levels [3].

End-stage kidney disease (ESKD) is rare and has mostly been reported in glucocorticoid-resistant cases [8,72], including those with persistent AKI [68]. However, focal segmental glomerulosclerosis (FSGS) is often seen on a late kidney biopsy in patients with glucocorticoid-resistant disease and in all patients who develop progressive kidney failure. Whether this represents sampling error on the initial kidney biopsy due to the focal nature of FSGS, or true progression from MCD to FSGS, is uncertain. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Prognosis'.)

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

SUMMARY AND RECOMMENDATIONS

General principles – The goal of therapy for patients with minimal change disease (MCD) is to significantly reduce proteinuria and thereby induce remission of the nephrotic syndrome. This is primarily achieved with the use of immunosuppressive agents, most commonly glucocorticoids. Untreated MCD is associated with potentially fatal complications, including sepsis and thrombosis. (See 'General principles' above.)

Initial therapy for primary MCD

For most adults with primary MCD, we suggest initial therapy with glucocorticoid monotherapy (Grade 2C). Glucocorticoid monotherapy leads to complete remission in 80 to over 95 percent of adults with MCD. For patients who cannot tolerate, have contraindications to, or do not wish to take high-dose glucocorticoids, glucocorticoid-sparing regimens are an alternative option and include calcineurin inhibitors (CNIs; cyclosporine or tacrolimus) or mycophenolate mofetil/enteric-coated mycophenolate sodium (MMF/EC-MPS) plus reduced-dose glucocorticoids. Dosing and duration of these regimens are discussed above. (See 'Choice of initial therapy' above and 'Dosing and duration of preferred regimens' above.)

General supportive measures in all patients with MCD include dietary sodium restriction, blood pressure control, and in select patients, anticoagulation. Dietary protein restriction, renin-angiotensin system inhibition to treat proteinuria, and statin therapy to treat dyslipidemia are not usually needed, except in patients with glucocorticoid resistance. (See 'Supportive measures in all patients' above.)

All patients should be closely monitored for clinical response to therapy. We perform a clinical assessment and monitor a spot urine protein-to-creatinine ratio, serum albumin, and serum creatinine on a monthly basis. Remissions are typically abrupt, with the patient being free of proteinuria within two to three weeks from the time of initial response. Partial responses are not characteristic of MCD, and when seen, one should suspect a possible misdiagnosis, most often FSGS that was missed by sampling error. (See 'Monitoring the response to therapy' above.)

Relapsing disease – Approximately 50 to 75 percent of adults will have a relapse, and frequent relapses (FR) occur in 10 to 25 percent. Glucocorticoid dependence is seen in 25 to 30 percent.

Infrequent relapse – For most patients with infrequent relapses (fewer than four per year), we suggest a repeat course of the initial therapy used to achieve complete remission, rather than switching therapy (Grade 2C). An exception is in patients who have previously developed significant adverse effects related to initial therapy with glucocorticoids; in such patients, switching to a glucocorticoid-sparing regimen may be preferred. (See 'Infrequent relapse' above.)

Frequently relapsing or glucocorticoid-dependent (FR/GD) MCD – For patients with FR/GD MCD, we recommend treatment with cyclophosphamide, rituximab, a CNI (cyclosporine or tacrolimus), or MMF/EC-MPS, rather than glucocorticoid monotherapy (Grade 1B). The choice among these regimens depends upon several factors, including clinician and patient preference, drug availability and cost, efficacy, toxicity, and tolerability. Most of the contributors to this topic prefer cyclophosphamide or rituximab for most patients, particularly those who have previously received a CNI or MMF/EC-MPS as part of a glucocorticoid-sparing regimen, based upon low-quality evidence showing more durable remissions with these agents compared with a CNI. However, any of these drug classes are preferred over glucocorticoids to avoid the morbidity associated with prolonged glucocorticoid exposure. (See 'General approach' above.)

Glucocorticoid-resistant MCD – The optimal therapeutic approach to patients with glucocorticoid-resistant MCD is not known. Some experts argue that glucocorticoid-resistant MCD actually reflects an early stage of focal segmental glomerulosclerosis (FSGS) or unsampled primary FSGS. In general, we treat these patients with a CNI (cyclosporine or tacrolimus) with or without low-dose glucocorticoids, using the same approach as that used for patients with glucocorticoid-resistant FSGS. This is discussed in more detail elsewhere. (See 'Treatment of glucocorticoid-resistant MCD' above and "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Glucocorticoid-dependent or glucocorticoid-resistant disease'.)

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Topic 3045 Version 37.0

References

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