Version May 2024
INTRODUCTION — The optimal treatment of lupus nephritis (LN) is informed by the morphological 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".)
GENERAL PRINCIPLES
Goals of therapy — The goals of therapy in patients with lupus membranous nephropathy (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. In addition, another goal of therapy is to induce resolution of immunologic activity. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Goals of therapy'.)
Definitions of response — There is no consensus on the degree of proteinuria reduction that defines a complete or partial response in patients with LMN. We use the same definitions for reduction in proteinuria as those used in patients with focal or diffuse lupus nephritis (LN). Since patients with LMN who are nephrotic may have a higher degree of proteinuria in comparison with other histologic forms of LN, they may respond more slowly to treatment. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Definitions of response'.)
INITIAL THERAPY
Indications for immunosuppressive therapy — There is a lack of consensus on the indications for immunosuppressive therapy in patients with pure lupus membranous nephropathy (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 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 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) [1].
•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. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", 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, dietary sodium and protein restriction, and antihypertensive therapy), as discussed elsewhere in this topic. (See 'General supportive measures in all patients' below.)
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 lupus nephritis (LN) are treated according to the same approach as used for those with focal or diffuse LN alone. (See 'Patients with both LMN and diffuse LN' below and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
In patients with pure LMN selected for immunosuppression, we suggest mycophenolate mofetil (MMF), in combination with glucocorticoids, rather than intravenous (IV) cyclophosphamide or a calcineurin inhibitor (CNI). However, either cyclophosphamide or CNIs in combination with glucocorticoids are a reasonable alternative, particularly among patients who have a contraindication or cannot tolerate MMF. 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 glucocorticoid monotherapy to treat LMN [2].
Our approach is broadly consistent with recommendations made by the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis [3] and the Joint EULAR/ERA-EDTA [1].
Additional issues may influence the choice of therapy, including:
●Patients of childbearing age may want to avoid high-dose, monthly pulse 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 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 "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Female gonadal toxicity' and "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".)
●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 "Cyclosporine and tacrolimus nephrotoxicity".)
Few data are available to inform the choice of immunosuppressive therapy in LMN [2,4-8]. The best data come from a small randomized trial conducted by the National Institutes of Health (NIH) that compared cyclophosphamide- with cyclosporine-based regimens in patients with pure LMN and from post-hoc subgroup analyses of two randomized trials that included patients with pure LMN who were treated with cyclophosphamide- or MMF-based regimens. There are no trials comparing MMF with cyclosporine in patients with LMN.
●The 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 [2]. 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 seven were partial. The probability of remission was lower in patients with proteinuria >5g/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 randomized trial (Aspreva Lupus Management Study [ALMS]) compared MMF with cyclophosphamide in 370 patients with LN, including 60 with pure LMN; all patients also received oral prednisone with a defined taper [4]. The primary outcome was a prespecified reduction in the urine protein-to-creatinine ratio to less than 3 or by at least 50 percent. Secondary outcomes included stabilization or improvement of the serum creatinine, reduction of protein excretion to less than 0.5 g/day, and attainment of inactive urinary sediment. At 24 weeks, the percentage of patients who achieved the primary and secondary outcomes were similar between the two treatment groups. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Initial therapy with mycophenolate or cyclophosphamide'.)
●A second randomized trial compared MMF with IV cyclophosphamide in 140 patients with LN, 27 of whom had LMN [5]. Complete and partial renal responses were attained by 7 of 14 patients treated with MMF, and 4 of 13 treated with cyclophosphamide.
A pooled analysis of patients from the last two trials included 65 patients with pure LMN: 33 patients on MMF and 32 patients on cyclophosphamide completed 24 weeks of treatment [9]. 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.
Mycophenolate-based regimen — If a mycophenolate-based regimen is used, we prefer the regimen used in the ALMS trial [4]. 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 two to three 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 proliferative LN (see "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'). We do not use the alternate-month IV regimen that was used in the NIH trial of LMN, discussed above. Cyclophosphamide is given in combination with glucocorticoids. (See 'Glucocorticoid dosing and taper' below.)
At six months, we usually switch from cyclophosphamide to MMF (1 g twice daily), which is continued for two to three years. This approach is similar to that in patients with diffuse or focal LN initially treated with cyclophosphamide. If such patients were treated with cyclophosphamide because they failed MMF therapy (ie, due to poor clinical response or intolerance), we switch to either a CNI or azathioprine therapy at six months. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Subsequent therapy'.)
Calcineurin inhibitor-based regimen — If a CNI-based regimen is selected, 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 [2].
●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.
●The CNI is given in combination with glucocorticoids. If voclosporin (a second-generation CNI) is used, it should be used in combination with MMF and glucocorticoids. (See 'Glucocorticoid dosing and taper' below and 'Voclosporin plus mycophenolate' below.)
●Some clinicians periodically measure whole blood trough cyclosporine or tacrolimus levels to assess medication adherence and to monitor for supratherapeutic and potentially nephrotoxic levels. Monitoring of whole blood levels is not required for voclosporin. (See "Pharmacology of cyclosporine and tacrolimus", 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 cyclosporine and tacrolimus", section on 'Side effects'.)
●(See "Pharmacology of cyclosporine and tacrolimus", section on 'Food and drug interactions'.)
●(See "Cyclosporine and tacrolimus nephrotoxicity".)
Glucocorticoid dosing and taper — One option for glucocorticoid dosing is suggested by the EULAR/ERA-EDTA guidelines [1]. Oral prednisone (or its equivalent) is begun at a dose of ≤0.5 mg/kg/day, then tapered to a dose of less than 5 mg/day by three months.
Alternative regimens — Rituximab (with or without MMF), voclosporin (in combination with MMF), and belimumab (in combination with MMF or cyclophosphamide) are alternative regimens in patients with LMN.
Rituximab — The use of rituximab in LMN is generally reserved for patients who have progressive disease despite the use of MMF, cyclophosphamide, or a CNI (cyclosporine or tacrolimus).
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 [10]. 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 [11].
Voclosporin plus mycophenolate — 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 US Food and Drug Administration (FDA) approved for the treatment of LN in combination with mycophenolate and glucocorticoids.
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 [12]. 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 inhibitors plus mycophenolate'.)
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 FDA approved for the treatment of systemic lupus erythematosus (SLE) and for LN in combination with standard therapy. However, experience with this regimen for LMN is limited, and its role has not been clearly established. Data on the efficacy of belimumab (in combination with standard therapy) in patients with LN, which included a smaller number of patients with LMN (16 percent with pure LMN and 26 percent with concurrent focal or diffuse LN plus LMN), are presented elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Belimumab plus mycophenolate or cyclophosphamide'.)
Monitoring the 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.
Renal response is assessed by following the serum creatinine, 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 CNIs should have monitoring of trough drug levels (ie, cyclosporine or tacrolimus levels). Patients treated with MMF who do not respond can have MMF levels measured to assess adherence and adequacy of dosing.
Previous studies of LN patients have demonstrated that the tempo of proteinuria response to immunosuppressive therapy is slow. One longitudinal study of treated patients with various histopathologic classes of LN showed that recovery of proteinuria to <0.5 g occurred in 28 percent of patients at one year and 52 percent at two years. In addition, the higher the level of baseline proteinuria, the longer the time to response [13]. Thus, changes in the immunosuppressive regimen should not be made too early during the course of therapy. Although each patient should be managed on a case-by-case basis, taking into consideration renal response and extrarenal disease activity, the following generalizations may be helpful:
●If the clinical parameters are stable or improving at three months, the initial treatment should be continued.
●If the clinical parameters are worsening after three months of initial therapy (eg, worsening proteinuria and/or worsening kidney function), a change in therapy is typically warranted. As an example, if a patient was initiated on MMF, the patient could be switched to cyclophosphamide or cyclosporine. Another option may be the addition of low-dose tacrolimus to MMF or a switch to tacrolimus.
●If the clinical parameters are not worsening but fail to show any meaningful improvement after six months of initial treatment, a change in therapy is warranted.
A repeat kidney biopsy can be helpful in the following settings (see "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'):
●In patients who have persistent, stable proteinuria >1 g/day despite one year of therapy to differentiate whether proteinuria is due to kidney sclerosis/fibrosis or ongoing active LN.
●In patients who have an initial response to therapy, but who then develop worsening kidney function, worsening proteinuria, and/or an active urinary sediment. In this setting, transformation from membranous to proliferative or crescentic LN should be suspected.
Other treatment considerations
General supportive measures in all patients — 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. Anticoagulation may also be indicated in selected patients since patients with LMN, similar to those with primary MN, 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 KDIGO practice guidelines for glomerulonephritis [3] 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'.)
●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'.)
Treatment-associated toxicity — Immunosuppressive therapy with cyclophosphamide, MMF, CNIs, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. The recommended regimens are discussed elsewhere:
●For prevention of Pneumocystic jirovecii pneumonia – (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
●For prevention of cyclophosphamide-induced bladder and gonadal toxicity – (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prevention of drug-induced cystitis' and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Infertility risk'.)
●For prevention of CNI-associated adverse effects and drug interactions – (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects' and "Cyclosporine and tacrolimus nephrotoxicity", section on 'Prevention of chronic calcineurin inhibitor nephrotoxicity' and "Pharmacology of cyclosporine and tacrolimus", section on 'Food and drug interactions'.)
●For minimizing glucocorticoid-induced bone loss and other adverse effects – (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Major adverse effects of systemic glucocorticoids".)
●For age-appropriate vaccinations in immunosuppressed patients – (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
RESISTANT AND RELAPSING DISEASE — Patients require modification of immunosuppressive therapy if they have persistent heavy proteinuria (over 3 g daily) despite 6 to 12 months of adequate therapy (ie, are nonresponders) or have an initial response but then develop worsening proteinuria, a new active urinary sediment, or worsening kidney function (ie, have relapsing disease). A repeat kidney biopsy is required to confirm that these clinical scenarios are due to persistent lupus membranous nephropathy (LMN) or conversion to a different lupus nephritis (LN) class. (See "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'.)
Our usual approach to modifying immunosuppression in patients who are nonresponders or who have relapsing disease is as follows:
●For patients who do not respond to initial treatment with mycophenolate mofetil (MMF) in combination with glucocorticoids, we typically switch to cyclophosphamide therapy, a calcineurin inhibitor (CNI), or rituximab.
●For patients who initially respond to MMF but then subsequently relapse, modification of immunosuppression depends upon when the relapse occurs:
•If the relapse occurs during long-term therapy (when the MMF dose is being tapered) or after MMF has been discontinued, we resume the original dose of MMF (usually with a goal between 1 and 1.5 g twice daily).
•If the relapse occurs during the first six months of MMF treatment, we typically continue MMF and add either a CNI or rituximab.
●Most often, patients initially treated with cyclophosphamide or a CNI are those who have a contraindication to or who cannot tolerate MMF. Thus, in such patients, those who do not respond to or who relapse despite cyclophosphamide treatment should be converted to a CNI, and those who do not respond to or who relapse despite CNI therapy should be converted to cyclophosphamide. However, if a patient who was successfully treated with a CNI relapses after the drug has been discontinued, the same therapy can be used a second time. There are insufficient data to recommend the use of a different CNI (eg, tacrolimus to replace cyclosporine) if the patient has failed therapy on the first drug. However, for those intolerant of one CNI, a second may be substituted.
SPECIAL POPULATIONS
Pregnant patients — Issues related to pregnancy in patients with lupus nephritis (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 diffuse LN — Patients who have concurrent lupus membranous nephropathy (LMN) and focal or diffuse lupus nephritis (LN) are treated with the same approach as used for those with focal or diffuse LN alone. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Patients with both focal/diffuse LN and lupus membranous nephropathy'.)
PROGNOSIS — The reported kidney survival rates are generally favorable among patients with lupus membranous nephropathy (LMN) [14-19]. Among patients with pure LMN, 10-year kidney survival rates range from 72 to 98 percent [15,16,20]. However, patients who have concurrent proliferative lesions (ie, focal or diffuse lupus nephritis [LN]) have lower long-term kidney survival compared with those who have pure LMN [15,18,19]. As an example, in a retrospective study that examined the impact of concurrent proliferative 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) [15]. 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 proliferative 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 [16,20]. 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 [16]. The probability of a transition from membranous to combined membranous and proliferative 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 [21].
Exostosin-1 and -2 (EXT1/EXT2) have been identified as potential disease biomarkers in a proportion of patients with LMN [22,23]. 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 [23]. 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. (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 5th to 6th 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 10th to 12th 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
●General principles – 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. While there is no consensus definition of a complete or partial response, we use definitions similar to those used to define clinical response in patients with primary membranous nephropathy. (See 'Goals of therapy' above and 'Definitions of response' 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 (see 'Indications for immunosuppressive therapy' above):
•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 used for 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 mycophenolate mofetil (MMF; in combination with glucocorticoids) rather than intravenous (IV) cyclophosphamide or a calcineurin inhibitor (CNI) (Grade 2C). However, either cyclophosphamide or CNIs in combination with glucocorticoids is a reasonable alternative, particularly among patients who have a contraindication to or cannot tolerate MMF. 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 glucocorticoid monotherapy to treat LMN.
●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 the response to therapy' above.)
●Other treatment considerations – General 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. Immunosuppressive therapy with cyclophosphamide, MMF, and/or high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant additional prophylactic measures. (See 'General supportive measures in all patients' above and 'Treatment-associated toxicity' above.)
●Resistant and relapsing disease – Patients require modification of immunosuppressive therapy if they have persistent heavy proteinuria (over 3 g daily) despite 6 to 12 months of adequate therapy (ie, are nonresponders) or have an initial response but then develop worsening proteinuria, a new active urinary sediment, or worsening kidney function (ie, have relapsing disease). A repeat kidney biopsy is required to confirm that these clinical scenarios are due to persistent LMN or conversion to a different LN class. (See 'Resistant and relapsing disease' above.)
For patients with pure LMN who do not respond to initial treatment with MMF in combination with glucocorticoids, we suggest treatment with either cyclophosphamide, a CNI, or rituximab (Grade 2C).
For patients who initially respond to MMF but then subsequently relapse, modification of immunosuppression depends upon when the relapse occurs:
•For patients who relapse during long-term therapy (when the MMF dose is being tapered) or after MMF has been discontinued, we suggest resuming the original dose of MMF rather than switching to another therapy (Grade 2C).
•For patients who relapse during the first six months of MMF treatment, we suggest continuing MMF and adding either a CNI or rituximab (Grade 2C).
●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.
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