Lupus nephritis: Therapy of lupus membranous nephropathy

INTRODUCTION — 

The optimal treatment of lupus nephritis (LN) is informed by the morphologic findings present on kidney biopsy. Immunosuppressive therapy is used to treat active focal (class III) or diffuse (class IV) LN or lupus membranous nephropathy (LMN; class V LN), whereas it is not usually used to treat minimal mesangial (class I), mesangial proliferative (class II), or advanced sclerosing (class VI) LN.

The treatment of LMN will be reviewed here. The various types of LN, the treatment of focal and diffuse LN, and management of the patient with end-stage kidney disease (ESKD) are presented separately:

●(See "Lupus nephritis: Diagnosis and classification".)

●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

●(See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)

●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)

GOALS OF THERAPY — 

The goals of therapy in patients with LMN include reduction of proteinuria, especially if the patient has the nephrotic syndrome and is at high risk for complications, as well as prevention of glomerular damage and progression of chronic kidney disease (picture 1 and picture 2). In addition, another goal of therapy is to induce resolution of immunologic activity and resolution of extrarenal manifestations of systemic lupus erythematosus (SLE), if present. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Overview of therapy'.)

GENERAL MEASURES FOR ALL PATIENTS

Hydroxychloroquine — All patients with systemic lupus erythematosus (SLE), regardless of the degree and type of disease activity, should receive treatment with hydroxychloroquine unless contraindicated. Hydroxychloroquine has been associated with several benefits in patients with SLE, including improved survival, lower flare rates, and a reduction in organ damage accrual. This is discussed in detail separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Hydroxychloroquine for all patients'.)

Supportive measures for kidney disease — General supportive measures in patients with LMN include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit, although studies in patients with LMN are lacking.

Anticoagulation may also be indicated in selected patients since patients with LMN and the nephrotic syndrome, similar to those with primary membranous nephropathy, appear to be at high risk for thromboembolism (see "Hypercoagulability in nephrotic syndrome", section on 'Risk factors for thromboembolism'). These measures are consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) practice guidelines for glomerulonephritis [1] and are discussed in greater detail elsewhere:

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

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

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

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

●Lipid lowering. (See "Lipid abnormalities in nephrotic syndrome" and "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia'.)

●Anticoagulation. (See "Hypercoagulability in nephrotic syndrome", section on 'Patients with membranous nephropathy'.)

INITIAL IMMUNOSUPPRESSIVE THERAPY

Indications for immunosuppressive therapy — There is a lack of consensus on the indications for immunosuppressive therapy in patients with pure (ie, without concurrent focal or diffuse LN) LMN:

●In general, most experts agree that immunosuppressive drugs should be administered to patients with pure LMN who have nephrotic syndrome or, in the absence of nephrotic syndrome, persistent proteinuria >3.5 g/day despite nonimmunosuppressive therapy; a progressive rise in serum creatinine above baseline; or mixed membranous and proliferative lesions on kidney biopsy. (See 'Patients with both LMN and focal or diffuse LN' below.)

●There is less agreement regarding the role of immunosuppressive therapy in patients with a lesser degree of proteinuria. The following represents the range of opinions:

•Some experts suggest that patients with LMN and proteinuria ≥1 g/day (some experts use a threshold of ≥0.5 to 0.7 g/day) without evidence of extensive chronic damage (eg, glomerulosclerosis, interstitial fibrosis and tubular atrophy) on kidney biopsy should receive immunosuppressive therapy. The rationale for this approach is that patients with LMN do not generally experience spontaneous remission, and this amount of proteinuria increases the risk of progressive kidney damage long term. The presence of chronic damage on kidney biopsy could suggest that proteinuria is associated more with glomerulosclerosis than with immune complex deposition and is less likely to respond to immunosuppressive therapy. This approach is consistent with the joint guidelines of the European Alliance of Associations for Rheumatology (formerly known as European League Against Rheumatism)/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) [2].

•In patients with proteinuria <1 g/day (some experts use a threshold of <0.5 to 0.7 g/day), some experts do not treat LMN with immunosuppressive therapy but rather base the need for immunosuppression on the presence of extrarenal manifestations. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Approach to drug therapy'.)

•Some experts suggest that all patients with LMN, regardless of the degree of proteinuria, should receive immunosuppressive therapy, given that patients with LMN often do not spontaneously remit.

All patients with LMN should receive general supportive therapies as appropriate (such as renin-angiotensin system inhibition, sodium-glucose cotransporter 2 [SGLT2] inhibition, dietary sodium and protein restriction, and antihypertensive therapy), as well as hydroxychloroquine, as discussed elsewhere in this topic. (See 'Supportive measures for kidney disease' above and 'Hydroxychloroquine' above.)

There are no randomized trials in patients with pure LMN comparing immunosuppressive therapy in addition to nonimmunosuppressive therapy with nonimmunosuppressive therapy alone. Thus, decisions about which patients should receive immunosuppressive therapy are made based upon lower-quality data, including the clinical experience of experts.

Choice of immunosuppressive therapy — Patients who have concurrent LMN and focal or diffuse LN are treated with the same approach as those with focal of diffuse LN alone. This approach is discussed in detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

For patients with pure LMN selected for immunosuppression, options for initial therapy include the following:

●Dual immunosuppressive therapy – Dual immunosuppressive therapy consists of glucocorticoids plus one of the following agents:

•Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). (See 'Mycophenolate-based regimen' below.)

•Intravenous (IV) cyclophosphamide. (See 'Cyclophosphamide-based regimen' below.)

•A calcineurin inhibitor (CNI; tacrolimus or cyclosporine). (See 'Calcineurin inhibitor-based regimen' below.)

●Triple immunosuppressive therapy – Triple immunosuppressive therapy consists of glucocorticoids plus one of the following combinations of agents:

•A CNI (voclosporin, tacrolimus, or cyclosporine) plus MMF (or EC-MPS). (See 'Calcineurin inhibitor plus mycophenolate' below.)

•Belimumab plus either MMF (or EC-MPS) or cyclophosphamide. (See 'Belimumab plus mycophenolate or cyclophosphamide' below.)

For most patients, we suggest dual therapy with glucocorticoids plus MMF or triple therapy with glucocorticoids plus MMF and a CNI for initial therapy rather than other dual or triple therapies. Some UpToDate contributors prefer triple therapy with glucocorticoids plus MMF and a CNI in patients with higher baseline proteinuria (≥3 g/day) based on data suggesting a benefit with the addition of a CNI to MMF in such patients [3]. We generally use caution when using CNIs in patients who have significantly reduced kidney function (arbitrarily defined as an estimated glomerular filtration rate [eGFR] <45 mL/min per 1.73 m²) because of the potential nephrotoxicity of these drugs. (See 'Mycophenolate-based regimen' below and 'Calcineurin inhibitor plus mycophenolate' below.)

For patients who cannot or do not wish to receive MMF, dual or triple therapy with cyclophosphamide (ie, cyclophosphamide plus glucocorticoids or cyclophosphamide plus belimumab plus glucocorticoids, respectively) or dual therapy with a CNI (ie, CNI plus glucocorticoids) is a reasonable alternative. Patients of childbearing age may want to avoid cyclophosphamide because of its fertility risk. In addition, both cyclophosphamide and MMF are associated with possible risk of congenital malformations. As a result, patients of childbearing age should have a pregnancy test and use contraception prior to the initiation of these drugs. In patients who are already pregnant and wish to retain the pregnancy, glucocorticoids, CNIs, and azathioprine are alternative treatment options. (See "Pregnancy in women with systemic lupus erythematosus" and "Pregnancy and contraception in patients with nondialysis chronic kidney disease" and "Safety of rheumatic disease medication use during pregnancy and lactation" and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects'.)

Our approach is broadly consistent with recommendations made by the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the management of LN [4] and the Joint EULAR/ERA-EDTA [2].

Limited data are available to inform the optimal choice of immunosuppressive therapy in pure LMN [5-10]. Data come primarily from small randomized trials in patients with pure LMN and from post hoc subgroup analyses of larger randomized trials in patients with LN that included patients with pure LMN. The following studies illustrate the range of findings:

●The National Institutes of Health (NIH) trial included 42 patients with pure LMN who were randomly assigned to receive either prednisone plus pulse IV cyclophosphamide, prednisone plus cyclosporine, or prednisone alone for approximately one year [5]. The median proteinuria was 5.4 g/day (range 2.7 to 15.4 g/day), and the median eGFR was 83 mL/min per 1.73 m². Sixteen patients distributed among the three groups were treated with angiotensin inhibition that was begun at least one month before baseline testing. Complete remission was defined as proteinuria <0.3 g/day, and partial remission was defined as proteinuria <2 g/day with a >50 percent reduction in proteinuria. At one year, the remission rate was higher with cyclosporine and cyclophosphamide compared with prednisone alone (83 and 60 versus 27 percent, respectively). Among the 19 remissions that occurred with either cyclosporine or cyclophosphamide, 12 were complete and 7 were partial. The probability of remission was lower in patients with proteinuria >5 g/day.

Patients who had a remission of proteinuria were followed for up to 10 years. Relapse after cessation of therapy occurred later and less frequently with cyclophosphamide (20 percent within 50 months versus 60 percent within 36 months with cyclosporine). All of the cyclophosphamide relapses occurred four years or more after cessation of therapy. A lower rate of relapse with cyclophosphamide compared with cyclosporine or tacrolimus has also been noted in patients with primary membranous nephropathy. (See "Membranous nephropathy: Treatment and prognosis", section on 'Moderate risk of progression'.)

●A pooled analysis of patients from two larger randomized trials [5,6] comparing MMF with monthly pulse IV cyclophosphamide in patients with LN included 65 patients with pure LMN. Thirty-three patients on MMF and 32 patients on monthly pulse IV cyclophosphamide completed 24 weeks of treatment [11]. Both the percent reduction in proteinuria (including among 40 patients with nephrotic-range proteinuria) and the rate of partial response were similar between the treatment groups. The rates of adverse events were also similar between the groups.

●In one study of 18 patients with LMN who received treatment with tacrolimus for six months followed by maintenance therapy with azathioprine and glucocorticoids, rates of complete and partial remission at 12 weeks were similar to those of an historical control group treated with oral cyclophosphamide or azathioprine (28 and 50 percent versus 16 and 47 percent, respectively) [12]. Tacrolimus has also been shown to be similarly effective as MMF and cyclophosphamide in studies of active LN that included patients with LMN [10,13,14].

Evidence supporting the use of triple-agent regimens for LMN is presented elsewhere in this topic. (See 'Belimumab plus mycophenolate or cyclophosphamide' below and 'Calcineurin inhibitor plus mycophenolate' below.)

Dual immunosuppressive therapy — Dual immunosuppressive therapy consists of glucocorticoids plus either mycophenolate, cyclophosphamide, or a CNI.

Mycophenolate-based regimen — If a mycophenolate-based regimen is used, we prefer the MMF dosing used in the ALMS trial [6]. Mycophenolate is given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)

Specifically, we give 0.5 g of MMF twice daily for the first week, then 1 g twice daily for the second week, and thereafter increase the dose as tolerated to between 1 and 1.5 g twice daily. However, this target dose may not be tolerated, and many patients may only tolerate a total daily dose of 2 to 2.5 g. For patients who are unable to tolerate adequate doses of MMF due to gastrointestinal side effects (eg, nausea, abdominal pain, or diarrhea), enteric-coated mycophenolate sodium (EC-MPS) can be substituted for MMF (1 g of MMF is equivalent to 720 mg of EC-MPS). We usually continue MMF at these doses for six months. At six months, the dose may be reduced to 1 g twice daily, which is continued for three to five years and then slowly tapered. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Mycophenolate-based regimen'.)

Cyclophosphamide-based regimen — If cyclophosphamide is chosen, most experts treat based upon the regimen used in the Euro-Lupus Nephritis Trial and the ACCESS trial (ie, IV cyclophosphamide, 500 mg every two weeks for a total of six doses); these trials included patients with class III or IV LN (see "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'). We do not use the monthly IV regimen that was used in the NIH trials, as discussed above. Cyclophosphamide is given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)

At three months, we usually switch from cyclophosphamide to MMF (1 g twice daily), which is continued for three to five years. This approach is similar to that in patients with class III or IV LN initially treated with cyclophosphamide. If such patients were treated with cyclophosphamide because they did not respond to or could not tolerate MMF therapy, we switch to either a CNI or azathioprine therapy at three months. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Subsequent immunosuppressive therapy'.)

Calcineurin inhibitor-based regimen — If a CNI-based regimen is selected, either cyclosporine or tacrolimus can be used. Cyclosporine has been studied more extensively than tacrolimus in patients with LMN, and therefore, some experts treat with cyclosporine if a CNI is given. Alternatively, tacrolimus is associated with a lower risk of cosmetic and metabolic side effects; as a result, many clinicians prefer tacrolimus over cyclosporine as the CNI of choice, especially in females. We do not use voclosporin, a next-generation CNI, as a lone immunosuppressive agent, as it has only been studied in combination with mycophenolate and glucocorticoids. (See 'Calcineurin inhibitor plus mycophenolate' below.)

Cyclosporine or tacrolimus is given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)

Our approach to administration is as follows:

●If cyclosporine is used, most would start dosing at 100 to 200 mg twice daily. The dose is adjusted to achieve the desired reduction in proteinuria; the dose is reduced by 25 percent if the serum creatinine increases by 33 to 49 percent or by greater than 0.3 mg/dL (27 micromol/L) on two or more determinations [5].

●If tacrolimus is used, we usually start with 1 to 2 mg twice daily to achieve the desired reduction in proteinuria, reducing the dose as needed if there is an increase in the serum creatinine.

●Some clinicians periodically measure whole blood trough cyclosporine or tacrolimus levels to assess medication adherence and to monitor for supratherapeutic and potentially nephrotoxic levels. (See "Pharmacology of calcineurin inhibitors", section on 'Drug monitoring'.)

If a clinical response is attained, we usually continue CNI therapy for approximately 6 to 12 months, after which time the drug dose is slowly tapered to the lowest effective dose and then eventually discontinued after two to three years.

A discussion of the adverse effects and drug interactions of CNIs is presented separately:

●(See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

●(See "Pharmacology of calcineurin inhibitors", section on 'Food and drug interactions'.)

●(See "Cyclosporine and tacrolimus nephrotoxicity".)

Triple immunosuppressive therapy — Triple immunosuppressive therapy consists of glucocorticoids plus one of the following combinations:

●Belimumab plus either mycophenolate or cyclophosphamide

●A CNI (voclosporin, tacrolimus, or cyclosporine) plus mycophenolate

Triple immunosuppressive regimens have been used as initial therapies in patients with LMN. There are no trials comparing the efficacy and safety of these different regimens. Some authors prefer belimumab plus mycophenolate over a CNI plus mycophenolate in patients with an eGFR <45 mL/min/1.73 m² or patients with extrarenal manifestations (that would benefit from belimumab).

Belimumab plus mycophenolate or cyclophosphamide — Belimumab is a human monoclonal antibody that inhibits the soluble form of a B cell survival factor (known as BLyS or BAFF). Belimumab is US Food and Drug Administration (FDA) approved for the treatment of systemic lupus erythematosus (SLE) in adults and children and for LN in combination with standard therapy. However, experience with this regimen for LMN is still limited, and its role has not been clearly established.

Although studies of belimumab in patients with LN used the IV formulation, a subcutaneous form has also been approved for LN. IV belimumab is administered as 10 mg/kg every two weeks for three doses followed by maintenance dosing every four weeks. Subcutaneous belimumab is initiated as 400 mg once weekly for four doses and then 200 mg once weekly thereafter.

Belimumab should be used in combination with either a mycophenolate- or cyclophosphamide-based regimen. These regimens are presented elsewhere in this topic. (See 'Mycophenolate-based regimen' above and 'Cyclophosphamide-based regimen' above.)

The efficacy and safety of belimumab (in combination with standard therapy) were evaluated in a large, multicenter trial of 448 patients with class III, IV, or V LN; 16 percent had pure LMN and 26 percent had concurrent focal or diffuse LN plus LMN [15,16]. While the addition of belimumab to standard therapy was shown to be superior to standard therapy alone, a post hoc analysis found that this benefit was not seen in the small subgroup of patients with LMN [15]. These data are presented in more detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Belimumab plus mycophenolate or cyclophosphamide'.)

Calcineurin inhibitor plus mycophenolate — CNIs used in combination with mycophenolate for LMN include tacrolimus and voclosporin. Although there is more experience with tacrolimus, voclosporin has the additional benefit of not requiring blood drug concentration monitoring. Some clinicians have used cyclosporine as an alternative CNI, but evidence to support this approach is more limited [5]. Tacrolimus and voclosporin have not been directly compared as combination therapy for LMN. CNIs should be used with caution in patients with preexisting chronic kidney disease and eGFR ≤45 mL/min/1.73 m².

When given as part of a combination regimen, CNIs should be used with a mycophenolate-based regimen. This regimen is presented elsewhere in this topic. (See 'Mycophenolate-based regimen' above.)

●Tacrolimus – When tacrolimus is used in combination with mycophenolate, we typically start at 1 to 2 mg orally twice daily and titrate up the dose, depending upon the clinical response (eg, reduction in proteinuria). We reduce the dose of tacrolimus if the patient experiences a >30 percent increase in serum creatinine. Some clinicians target a blood trough tacrolimus concentration of 5 to 7 ng/mL; other clinicians do not target specific blood levels and monitor tacrolimus concentrations to check for adherence or toxicity. However, levels that correlate with efficacy are not clear.

Data supporting the use of tacrolimus in combination with mycophenolate for patients with LN, including those with LMN, are presented separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Calcineurin inhibitor plus mycophenolate'.)

●Voclosporin – Voclosporin is a next-generation CNI that is structurally similar to cyclosporine but is more potent and does not require monitoring of drug levels. Voclosporin is FDA approved for the treatment of LN in combination with mycophenolate and glucocorticoids.

When voclosporin is used in combination with mycophenolate, it is administered at 23.7 mg orally twice daily. Dose adjustments are required in patients with kidney function impairment or mild to moderate hepatic impairment (Child-Pugh class A or B). Voclosporin should generally be avoided in patients with a baseline eGFR ≤45 mL/min/1.73 m², unless benefit exceeds risk, and those with severe hepatic impairment (Child-Pugh class C) [17]. Monitoring of blood concentrations is not necessary with voclosporin.

The use of voclosporin in patients with LMN was reported in a phase III trial that randomly assigned 357 patients (61 percent with focal or diffuse LN, 14 percent with LMN, and 25 percent with both) to voclosporin or placebo for 52 weeks, in combination with MMF and rapidly tapered low-dose prednisone [18]. The overall rate of complete renal remission at 52 weeks was higher among patients treated with voclosporin. In a subgroup analysis of those with LMN, there was a trend toward benefit in those receiving voclosporin, but this was not statistically significant. These data are discussed in more detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Calcineurin inhibitor plus mycophenolate'.)

●Cyclosporine – When cyclosporine is used in combination with mycophenolate, we typically start at 100 to 200 mg orally twice daily and titrate up the dose, depending on the clinical response (eg, reduction in proteinuria). We reduce the dose of cyclosporine if the patient experiences a >30 percent increase in serum creatinine. Some clinicians target a blood cyclosporine concentration of 100 to 150 ng/mL; other clinicians do not target specific blood levels and monitor cyclosporine concentrations to check for adherence or toxicity.

In the United States, tacrolimus has largely replaced cyclosporine as the CNI used in LN due to more hirsutism with cyclosporine. However, cyclosporine may still be used in places where it is much less expensive than tacrolimus. There are no large or controlled studies evaluating the efficacy of cyclosporine in combination with mycophenolate in patients with LMN; supportive data come from small case series [19,20].

Glucocorticoid dosing and taper — The optimal glucocorticoid regimen for LMN is not certain. One option for glucocorticoid dosing is suggested by the EULAR/ERA-EDTA guidelines [2]. IV pulse methylprednisolone (250 to 1000 mg given over 30 minutes daily for one to three days) is administered, followed by oral prednisone (or its equivalent) at a dose of ≤0.5 mg/kg/day, then tapered to a dose of less than 5 mg/day by three months and, when possible, withdrawn.

Lower starting doses of glucocorticoids were used in the randomized trial that evaluated the use of voclosporin in combination with MMF and glucocorticoids [18]. Patients received IV methylprednisolone (500 mg for patients weighing >45 kg and 250 mg for patients weighing <45 kg) once daily on days 1 and 2, followed by a rapid taper of oral prednisone starting on day 3 (starting dose 20 to 25 mg/day, decreased to 2.5 mg/day at week 16, and adjusted thereafter at investigator discretion).

MONITORING RESPONSE TO THERAPY

Follow-up evaluation — After starting initial immunosuppressive therapy, patients are monitored closely to assess the renal response, control of extrarenal manifestations, and potential medication toxicity. In the beginning, patients are typically monitored every one to two months, with less frequent monitoring over time if the patient responds and remains stable. If any significant changes are made to the immunosuppression regimen, we have patients return for a visit in two weeks to assess tolerance; if they are doing well, we return to follow-up visits every one to two months.

Renal response is assessed by following the serum creatinine (and estimated glomerular filtration rate [eGFR]), urine protein excretion (usually with a spot urine protein-to-creatinine ratio), and urine sediment examination. Other laboratory tests, such as a complete blood count and liver function tests, are important for medication toxicity monitoring. Patients treated with standard calcineurin inhibitors (CNIs) should have monitoring of trough drug levels (ie, cyclosporine or tacrolimus levels), while those treated with voclosporin should have their serum creatinine checked monthly. Patients treated with mycophenolate mofetil (MMF) who do not respond can have MMF levels measured to assess adherence and adequacy of dosing, although this is not commonly performed in practice.

Definitions of response — There is no consensus on the degree of proteinuria reduction or GFR stabilization that defines a complete or partial response in patients with LMN. We use the same definitions for reduction in proteinuria and GFR stabilization as those used in patients with focal or diffuse LN. Patients with LMN may respond less well to some therapies despite having similar amounts of proteinuria as those with focal or diffuse LN, perhaps due to a differing pathogenesis [15]. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Definitions of response'.)

Following treatment initiation, we aim for an improvement or stabilization of eGFR and reduction of proteinuria by ≥25 percent by three months, ≥50 percent by six months, and an absolute level of 0.5 to 0.7 g by 12 to 18 months. These goals are largely consistent with the joint guidelines of the European Alliance of Associations for Rheumatology (formerly known as European League Against Rheumatism)/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) [2]. The timeframe to achieve proteinuria reduction is often longer in LMN than in class III or IV LN. Patients in whom these goals are not met should be assessed for a change in immunosuppressive therapy. In addition, if the patient develops worsening proteinuria or a reduction in eGFR during treatment without an alternative explanation for these changes (such as medication nonadherence, hypertension, high salt diet), a change in immunosuppressive is warranted. (See 'Resistant disease' below.)

RESISTANT DISEASE — 

Patients with no reduction in proteinuria despite six months of adequate therapy may have resistant disease and require modification of immunosuppressive therapy. A repeat kidney biopsy may be required to confirm that this is due to persistent LMN or conversion to a different LN class. (See "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'.)

There are no high-quality data to guide the optimal treatment of resistant LMN. The choice of therapy should be individualized based on therapeutic goals, patient preferences, and side effects of therapy. Possible approaches to modifying therapy in patients with resistant disease include the following:

●Switching from one dual immunosuppressive regimen to another dual immunosuppressive regimen – As an example, a patient who has not responded to initial therapy with glucocorticoids plus mycophenolate mofetil (MMF) could be switched to glucocorticoids plus cyclophosphamide or glucocorticoids plus a calcineurin inhibitor (CNI). (See 'Dual immunosuppressive therapy' above.)

In patients who received initial therapy with glucocorticoids plus a CNI, there are insufficient data to recommend the use of a different CNI (eg, tacrolimus or voclosporin to replace cyclosporine); however, for those who are intolerant of one CNI, a second may be substituted.

●Switching from a dual immunosuppressive regimen to a triple immunosuppressive regimen – As an example, for a patient who has not responded to initial therapy with glucocorticoids plus MMF, a CNI could be added to the MMF. We would not add belimumab to MMF for resistant disease based on data suggesting no significant benefit with this combination in patients with LMN [15]. (See 'Triple immunosuppressive therapy' above.)

For a patient who has not responded to initial therapy with glucocorticoids plus cyclophosphamide, we would not switch to triple therapy by adding belimumab. This is based on data suggesting that the addition of belimumab is not effective in achieving a renal response in patients with higher baseline proteinuria (ie, urine protein-to-creatinine ratio ≥3 g/g) [15].

●Switching to rituximab – In patients who continue to have persistent resistant disease despite one of the above approaches to modifying therapy, rituximab (1 g given on days 1 and 15) is an alternative option.

There are no controlled trials evaluating the efficacy of rituximab in patients with LMN. One observational study of 50 patients with class III, IV, or V LN found that treatment with an oral glucocorticoid-free regimen of rituximab (1 g given on days 1 and 15), methylprednisolone (500 mg given intravenously on days 1 and 15), and MMF resulted in complete or partial renal remission in 90 percent of patients by a median of 37 weeks [21]. Another observational study including 15 patients with biopsy-proven pure LMN, preserved kidney function, and nephrotic-range proteinuria in the majority of patients (80 percent) reported complete remission in 13 patients (87 percent) with a median time to remission of five months [22].

When switching from one regimen to another, most UpToDate contributors to this topic would not restart a new course of glucocorticoids if the patient had already completed the initial course of glucocorticoids. Some contributors would administer a short course of glucocorticoids (eg, prednisone 20 to 30 mg once daily for two to four weeks), followed by a taper.

RELAPSING DISEASE — 

Patients who have an initial response to therapy but then develop worsening proteinuria, a new active urinary sediment, or worsening kidney function may have relapsing disease. A repeat biopsy often is required to confirm that this scenario is due to a relapse of LMN or conversion to a different LN class. (See "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'.)

For most patients who develop a relapse of LMN, we suggest reinstitution of the same initial therapy used to achieve the original response. However, it is also reasonable to modify the initial therapy regimen (eg, adding a CNI, belimumab, or rituximab to a mycophenolate-based regimen) or switch to an alternative immunosuppressive regimen. The choice of therapy should be individualized based on patient preferences and adverse effects of therapy. In patients who have received multiple prior courses of cyclophosphamide for whom there is concern for cumulative toxicity or risk of infertility, it may be preferable to use a mycophenolate- or CNI-based regimen.

There are no high-quality data to guide the optimal treatment of relapsing LMN.

TREATMENT-RELATED TOXICITY AND PROPHYLAXIS — 

Immunosuppressive therapy with cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors (CNIs), and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures.

●Vaccinations for all patients – Patients receiving immunosuppressive therapy for LN are at increased risk for infection and should receive age-appropriate vaccinations for immunosuppressed individuals. These are discussed separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Approach to vaccination'.)

●Prophylaxis for specific immunosuppressive agents

•Glucocorticoids – Patients receiving systemic glucocorticoids are at risk for several adverse effects on multiple organ systems (table 1). These adverse effects and potential interventions to minimize them (table 2) are discussed in detail separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Patients receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer should receive prophylaxis for Pneumocystis jirovecii (PJP) pneumonia. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

•Cyclophosphamide – Cyclophosphamide is associated with a variety of toxicities, including hematologic toxicity, infection, gonadal toxicity, malignancy, and bladder toxicity. These toxicities and measures for the prevention of cyclophosphamide-induced bladder and gonadal toxicity are discussed separately. (See "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Prevention of drug-induced cystitis' and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Fertility preservation for adults' and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects'.)

Patients receiving cyclophosphamide, especially when combined with glucocorticoids, should receive prophylaxis for PJP pneumonia. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

SPECIAL POPULATIONS

Pregnant patients — Issues related to pregnancy in patients with LN and the safety of immunosuppressive drugs to treat LN during pregnancy are discussed in detail separately:

●(See "Pregnancy in women with systemic lupus erythematosus".)

●(See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Patients with both LMN and focal or diffuse LN — Patients who have concurrent LMN and focal or diffuse LN are treated with the same approach as those with focal or diffuse LN alone. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Both focal or diffuse LN and lupus membranous nephropathy'.)

PROGNOSIS — 

The reported kidney survival rates are generally favorable among patients with LMN [23-28]. Among patients with pure LMN, 10-year kidney survival rates range from 72 to 98 percent [24,25,29]. However, patients who have concurrent class III or IV lesions (ie, focal or diffuse LN) have lower long-term kidney survival compared with those who have pure LMN [24,27,28,30]. As an example, in a retrospective study that examined the impact of concurrent class III or IV lesions on long-term outcomes in patients with LMN, the percentage of patients with end-stage kidney disease (ESKD) at five years was higher in those who had concurrent diffuse LN compared with those with pure LMN (43 versus 14 percent) [24]. The mean rate of loss of kidney function (estimated from 1/serum creatinine) was lower in patients with pure LMN compared with those who had concurrent focal or diffuse LN (-4.5 versus -18.5 and -15.9 dL/mg per year, respectively).

Patients with LMN may have class III or IV lesions at presentation or develop them over time, often in association with worsening kidney function or a substantial change in the activity of the urinary sediment [25,29]. In one series, 29 patients who were initially diagnosed with LMN with little or no mesangial proliferation underwent a second biopsy at a mean follow-up of 6.9 years [25]. The probability of a transition from membranous to combined membranous and class III or IV LN was 35 percent at 10 years.

Other contributing factors to variable outcomes include differences in patient populations and in immunosuppressive therapies that may be used for extrarenal indications [31].

Exostosin-1 and -2 (EXT1/EXT2) have been identified as potential disease biomarkers in a proportion of patients with LMN [30,32]. In a study of 374 patients with biopsy-proven LMN, of whom approximately one-third were positive for EXT1/EXT2, those who were EXT1/EXT2 positive were younger, had lower serum creatinine levels, and had fewer chronic features (ie, glomerulosclerosis, interstitial fibrosis and tubular atrophy) on kidney biopsy [30]. Compared with patients who were EXT1/EXT2 positive, those who were EXT1/EXT2 negative progressed to ESKD more quickly and more frequently (19 versus 3 percent). These findings suggest that patients who are EXT1/EXT2 positive may represent a subgroup of LMN with a more favorable kidney prognosis. However, a subsequent observational study found no significant difference in rates of kidney failure or estimated glomerular filtration rate (eGFR) decrease of >50 percent between EXT1/EXT2-positive and EXT1/EXT2-negative patients with LMN [33]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens'.)

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" and "Society guideline links: Systemic lupus erythematosus".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lupus and kidney disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The goal of immunosuppressive therapy in patients with lupus membranous nephropathy (LMN) is reduction of proteinuria, as well as prevention of glomerular damage and progression of chronic kidney disease. (See 'Goals of therapy' above.)

●General measures for all patients – All patients with systemic lupus erythematosus (SLE) should receive treatment with hydroxychloroquine unless contraindicated. Supportive measures in all patients with LMN include dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, treatment of dyslipidemia, and in selected patients, anticoagulation. (See 'Hydroxychloroquine' above and 'Supportive measures for kidney disease' above.)

●Indications for immunosuppressive therapy – The authors and reviewers of this topic do not agree about which patients with pure LMN should receive immunosuppressive therapy:

•In patients with pure LMN who have nephrotic syndrome or, in the absence of nephrotic syndrome, persistent proteinuria >3.5 g/day despite nonimmunosuppressive therapy; a progressive rise in serum creatinine above baseline; or mixed membranous and proliferative lesions on kidney biopsy, we suggest treating with immunosuppressive therapy in addition to general supportive measures, rather than general supportive measure alone (Grade 2C). There are no randomized trials in patients with pure LMN comparing immunosuppressive therapy in addition to nonimmunosuppressive therapy with nonimmunosuppressive therapy alone.

•There is less agreement regarding the role of immunosuppressive therapy in patients with a lesser degree of proteinuria. Some experts suggest that patients with LMN and proteinuria >1 g/day without evidence of extensive chronic damage (eg, glomerulosclerosis, interstitial fibrosis and tubular atrophy) on kidney biopsy should receive immunosuppressive therapy. In patients with proteinuria <1 g/day (some experts use a threshold of <0.7 g/day), some experts do not treat LMN with immunosuppressive therapy but rather base the need for immunosuppression on the presence of extrarenal manifestations. Other experts suggest that all patients with LMN, regardless of the degree of proteinuria, should receive immunosuppressive therapy, given that patients with LMN often do not spontaneously remit.

●Choice of immunosuppressive therapy – Our approach to initial therapy is as follows (see 'Choice of immunosuppressive therapy' above):

•Patients who have concurrent LMN and focal or diffuse lupus nephritis (LN) are treated according to the same approach as those with focal or diffuse LN alone. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

•For patients with pure LMN selected for immunosuppression, we suggest dual therapy with glucocorticoids plus mycophenolate mofetil (MMF) or triple therapy with glucocorticoids plus MMF and a calcineurin inhibitor (CNI) as initial therapy rather than other dual or triple therapies (Grade 2C). Some UpToDate contributors prefer triple therapy with glucocorticoids plus MMF and a CNI in patients with higher baseline proteinuria (≥3 g/day). We generally use caution when using CNIs in patients who have significantly reduced kidney function (eg, estimated glomerular filtration rate [eGFR] <45 mL/min per 1.73 m²) because of the potential nephrotoxicity of these drugs. For patients who cannot or do not wish to receive MMF, dual or triple therapy with cyclophosphamide or dual therapy with a CNI is a reasonable alternative. (See 'Choice of immunosuppressive therapy' above.)

●Monitoring response to therapy – After starting initial immunosuppressive therapy, patients are monitored closely to assess the renal response, control of extrarenal manifestations, and potential medication toxicity. In the beginning, patients are typically seen in clinic every one to two months, with less frequent visits over time if the patient responds and remains stable. If any significant changes are made to the immunosuppression regimen, we have patients return to clinic in two weeks to assess tolerance; if they are doing well, we return to follow-up visits every one to two months. (See 'Monitoring response to therapy' above.)

While there is no consensus definition of a complete or partial response, we use the same definitions for reduction in proteinuria and glomerular filtration rate (GFR) stabilization as those used in patients with focal or diffuse LN. (See 'Definitions of response' above.)

●Resistant disease – Patients who have no reduction in proteinuria despite six months of adequate therapy may have resistant disease and require modification of immunosuppressive therapy. A repeat kidney biopsy may be required to confirm that these clinical scenarios are due to persistent LMN or conversion to a different LN class. The choice of therapy should be individualized based on therapeutic goals, patient preferences, and side effects of therapy. Possible approaches to modifying therapy in patients with resistant disease include switching from one dual therapy regimen to another dual therapy regimen, switching from one dual therapy regimen to a triple therapy regimen, and switching to rituximab. (See 'Resistant disease' above.)

●Relapsing disease – Patients who have an initial response but then develop worsening proteinuria, a new active urinary sediment, or worsening kidney function may have relapsing disease. Kidney biopsy is helpful for verification. For most patients who develop a relapse of LMN, we suggest reinstitution of the same initial therapy used to achieve the original response (Grade 2C). However, it is also reasonable to modify the initial therapy regimen (eg, adding a CNI, belimumab, or rituximab to a mycophenolate-based regimen) or switch to an alternative immunosuppressive regimen. The choice of therapy should be individualized based on patient preferences and adverse effects of therapy. (See 'Relapsing disease' above.)

●Treatment-related toxicity and prophylaxis – Immunosuppressive therapy with cyclophosphamide, MMF, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. (See 'Treatment-related toxicity and prophylaxis' above.)

●Prognosis – The reported kidney survival rates are generally favorable among patients with LMN. However, patients who have concurrent proliferative lesions (ie, focal or diffuse LN) have lower long-term kidney survival compared with those who have pure LMN. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to an earlier version of this topic review.