Membranoproliferative glomerulonephritis: Treatment and prognosis

INTRODUCTION — Membranoproliferative glomerulonephritis (MPGN), also known as mesangiocapillary glomerulonephritis, is a pattern of glomerular injury viewed by light microscopy. Its name is derived from the characteristic histologic changes, including hypercellularity and thickening of the glomerular basement membrane, that often lead to a lobular appearance of the glomerular tuft (picture 1A-B) [1]. MPGN is a histologic lesion and not a specific disease entity or diagnosis. As such, the discovery of the lesion of MPGN in a kidney biopsy is the start of an exploratory process leading to a diagnosis, not an end in itself.

The treatment of an MPGN "pattern of injury" lesion will be reviewed here. The classification, clinical features, and diagnosis of MPGN and the treatment of recurrent MPGN after kidney transplantation are presented elsewhere:

●(See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

●(See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)

OVERVIEW OF TREATMENT — The overall approach to the treatment of an MPGN lesion depends upon identification of the underlying cause. Treatment based upon lesion identification rather than upon the basis of an understanding of the underlying causes and pathogenesis is not advised. Most patients with an MPGN lesion can be classified as having immune complex-mediated disease or complement-mediated disease based upon the immunofluorescence findings on kidney biopsy. This classification system, which provides insight into the pathogenesis of the MPGN lesion, has largely supplanted the older classification system based upon electron microscopy (ie, types I, II, and III). Once the patient has been classified as having immune complex-mediated MPGN or complement-mediated MPGN, a thorough evaluation is performed to identify possible underlying causes, such as infections, autoimmune disorders, monoclonal gammopathies, or activation of the alternative pathway of complement. Patients with an identifiable underlying cause should receive specific treatment as appropriate for the specific disorder. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Evaluation of the patient with an MPGN lesion'.)

In rare cases of immune complex-mediated MPGN, as can be seen in some children and young adults, an identifiable underlying cause cannot be found despite extensive evaluation. Such patients are considered to have an "idiopathic" immune complex-mediated MPGN or immune complex-mediated MPGN of unknown etiology. The optimal treatment of patients with "idiopathic" MPGN is not known. In the absence of high-quality evidence to guide therapy, we suggest a treatment approach below based upon disease severity at the time of presentation. (See 'Idiopathic immune complex-mediated MPGN' below.)

An MPGN lesion can less commonly be associated with thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome). Such patients do not have evidence of immune complex or complement deposition by immunofluorescence on kidney biopsy. In general, the treatment of patients with an MPGN lesion associated with thrombotic microangiopathy should address the underlying disorder thought to be responsible for the thrombotic microangiopathy. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'MPGN without immunoglobulin or complement deposition' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

TREATMENT OF IMMUNE COMPLEX-MEDIATED MPGN — Immune complex-mediated MPGN results from chronic antigenemia and/or circulating immune complexes and can be seen in chronic infections, autoimmune diseases, and monoclonal gammopathies. An underlying cause can be found in the great majority of cases, but despite a thorough evaluation, a small minority remain "idiopathic" or of unknown etiology. This is more commonly seen in children and young adults. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Immune complex/monoclonal immunoglobulin-mediated MPGN'.)

Patients with an underlying cause — Most patients with immune complex-mediated MPGN have an identifiable underlying cause, such as a chronic infection, autoimmune disease, or monoclonal gammopathy. Such patients should receive therapy directed against the underlying cause of the MPGN since resolution of the MPGN usually occurs after successful treatment of the primary disease. As examples, patients with the hepatitis C virus (HCV) should receive antiviral therapy, while patients with an underlying monoclonal gammopathy should receive systemic therapy directed against the pathologic plasma cell or B cell clone.

Infections — Infections, particularly hepatitis C and B viral infections, are among the most common underlying causes of immune complex-mediated MPGN. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Infections'.)

In patients with infection-associated MPGN, initial therapy should focus on successful treatment of the primary infection, such as antiviral therapy for MPGN due to hepatitis C or B virus. Immunosuppressive therapy is both unnecessary and potentially deleterious in patients with hepatitis, except in selected conditions such as severe HCV-associated mixed cryoglobulinemia or rapidly progressive glomerulonephritis [2].

●(See "Overview of kidney disease associated with hepatitis C virus infection", section on 'Treatment'.)

●(See "Kidney disease associated with hepatitis B virus infection", section on 'Treatment'.)

●(See "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Infections'.)

●(See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

Patients with MPGN associated with chronic bacterial (eg, endocarditis, shunt nephritis, abscesses), fungal, or parasitic (eg, schistosomiasis, echinococcosis) infections should be treated with appropriate antimicrobial therapy for these infections, as discussed in separate topic reviews.

Autoimmune disorders — Immune complex-mediated MPGN can be associated with certain autoimmune disorders, such as systemic lupus erythematosus, Sjögren's disease, or rheumatoid arthritis. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Autoimmune disorders'.)

Patients with MPGN associated with an autoimmune disorder should receive treatment for their underlying disorder as appropriate, which usually involves the use of immunosuppression. The type and duration of immunosuppressive therapy depends upon the aggressiveness of the autoimmune disorder. As an example, an MPGN lesion in a patient with systemic lupus erythematosus (class IV lupus nephritis) is treated with combined immunosuppression, even in the absence of extrarenal signs of disease activity. The management of systemic lupus erythematosus and other autoimmune disorders associated with MPGN is presented in more detail elsewhere:

●(See "Overview of the management and prognosis of systemic lupus erythematosus in adults".)

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

●(See "Kidney disease in primary Sjögren's disease", section on 'Membranoproliferative glomerulonephritis secondary to cryoglobulinemia'.)

●(See "General principles and overview of management of rheumatoid arthritis in adults".)

Monoclonal gammopathies — Monoclonal gammopathies are an important underlying cause of MPGN. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis", section on 'Monoclonal gammopathies'.)

Patients with MPGN associated with a malignant hematologic disorder such as multiple myeloma or a lymphoproliferative disorder (eg, Waldenström macroglobulinemia, chronic lymphocytic leukemia) should be referred to an appropriate specialist and treated for the underlying malignancy. The treatment of MPGN in patients with a nonmalignant or premalignant plasma cell or B cell clone (monoclonal gammopathy of renal significance [MGRS]), such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), should target the underlying pathogenic clone, whenever possible. We suggest treating patients with a non-immunoglobulin M (IgM) MGRS with a regimen targeting a plasma cell clone, similar to what is used to treat multiple myeloma. In patients with an IgM MGRS, we suggest a regimen used to treat Waldenström macroglobulinemia. Details are discussed separately:

●(See "Multiple myeloma: Overview of management".)

●(See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Initial treatment'.)

●(See "Overview of the treatment of chronic lymphocytic leukemia".)

●(See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Treatment'.)

Idiopathic immune complex-mediated MPGN — Patients with immune complex-mediated MPGN who do not have an identifiable underlying cause are considered to have "idiopathic" MPGN or MPGN of unknown etiology. However, such cases are now rare, especially among adults, since an underlying etiology is likely to be found in the majority of patients with MPGN.

Approach to common clinical presentations — Making therapeutic decisions for patients with idiopathic immune complex-mediated MPGN is difficult given the lack of large, randomized, controlled trials or any other evidence clearly demonstrating the efficacy of any treatment regimen. Several parameters at the time of presentation may influence clinical decision-making, including the severity of kidney dysfunction, degree of proteinuria, presence or absence of hematuria, and the histologic findings on kidney biopsy. Some patients with mild disease present with few abnormalities in these parameters, and aggressive treatment with immunosuppressive therapy is generally not indicated in this setting. Other patients present with more abnormalities in various combinations, and treatment with immunosuppressive agents may be appropriate even in the absence of high-quality evidence to support this approach.

Our approach to the most common clinical scenarios of patients with idiopathic immune complex-mediated MPGN is presented below. This approach is based primarily upon low-quality evidence and our clinical experience, and clinical practice may vary at other centers. For patients with less common clinical presentations not discussed below, we advise referral to a center of expertise for management.

Mild disease — In patients who present with mild disease, characterized by normal kidney function, non-nephrotic-range proteinuria (<3.5 g/day), and no significant hematuria (arbitrarily defined as <10 red blood cells [RBC]/high-power field [HPF]), we suggest conservative therapy (including renin-angiotensin system inhibition) alone (see 'General measures in all patients' below). We do not treat such patients with immunosuppressive therapy given the lack of evidence of benefit in these cases; in addition, such patients generally have a good prognosis, and immunosuppressive drugs have significant toxicity. Studies in children with MPGN, non-nephrotic-range proteinuria, and normal blood pressure have shown excellent long-term outcomes whether or not the patients were treated with glucocorticoids [3].

However, disease progression can occur. As a result, we monitor serum creatinine, urine protein excretion (24-hour urine or spot urine protein-to-creatinine ratio), and a urinalysis at three and six months. If spot urine protein-to-creatinine ratio is used for routine follow-up, a 24-hour urine protein collection should be performed at least once every 6 to 12 months since, in patients with glomerular disease and proteinuria, there is only a moderate correlation between the urine protein-to-creatinine ratio and 24-hour urine protein excretion [4]. If kidney function and proteinuria remain stable or improve, we continue conservative therapy indefinitely with follow-up every six months. If the patient develops increasing proteinuria, worsening hematuria, or worsening kidney function despite conservative therapy, it is reasonable to perform a repeat kidney biopsy to evaluate disease activity and chronicity. If the biopsy shows evidence of ongoing active glomerulonephritis (ie, mesangial proliferation and/or endocapillary hypercellularity), immunosuppressive therapy may be warranted, as discussed below. (See 'Nephrotic syndrome with normal kidney function' below and 'Abnormal kidney function (without rapidly progressive crescentic disease)' below.)

Nephrotic syndrome with normal kidney function — In patients who present with nephrotic syndrome and normal (or near-normal) kidney function, with or without an active urinary sediment (arbitrarily defined as >10 RBC/HPF), we suggest immunosuppressive therapy in addition to conservative therapy, rather than conservative therapy alone. (See 'General measures in all patients' below.)

The optimal immunosuppressive therapy for idiopathic immune complex-mediated MPGN presenting as nephrotic syndrome with normal kidney function is not known. Our preferred initial therapy is a three to six month course of oral glucocorticoids; however, for patients who cannot or do not wish to receive glucocorticoids, treatment with a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) for six months is a reasonable alternative:

●If oral glucocorticoids are used, we administer prednisone 1 mg/kg per day (maximum dose 60 to 80 mg/day) for four weeks, then reduce the dose to 40 mg/day for four weeks, 30 mg/day for two weeks, and 20 mg/day for two to four weeks (total of 12 to 14 weeks).

●If cyclosporine is used, we start with 2 to 4 mg/kg per day (given in two divided doses) or approximately 75 to 100 mg twice daily, adjusting the dose as necessary to target a trough level between 100 and 175 ng/mL.

●If tacrolimus is used, we start with 0.1 mg/kg per day (given in two divided doses) or approximately 2 to 4 mg twice daily, adjusting the dose as necessary to target a trough level between 5 and 10 ng/mL.

We monitor serum creatinine, 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio), and a urinalysis every two to three months to assess the response to treatment. If spot urine protein-to-creatinine ratio is used for routine follow-up, a 24-hour urine protein collection should be performed at least once every 6 to 12 months since, in patients with glomerular disease and proteinuria, there is only a moderate correlation between the urine protein-to-creatinine ratio and 24-hour urine protein excretion [4]. Our subsequent approach is as follows:

●Patients who respond with a ≥30 percent reduction in proteinuria after 12 to 14 weeks are considered to have a satisfactory response to therapy. If the patient is receiving prednisone, we gradually taper prednisone to 10 mg/day for four weeks, 5 mg/day for four weeks, and then discontinue. If the patient is receiving a CNI, we continue treatment for at least 12 months before discontinuing the CNI. We continue to monitor serum creatinine, 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio), and a urinalysis every three to six months, indefinitely.

●Patients who respond with a <30 percent reduction in proteinuria after 12 to 14 weeks are considered to have an unsatisfactory response to therapy. If the patient is receiving prednisone, we decrease prednisone to 10 mg/day and add a CNI (cyclosporine or tacrolimus) for six months. If the patient is already receiving a CNI as first-line therapy, the CNI should be discontinued, and the patient should be referred to a center of expertise for further management.

We continue to monitor serum creatinine, 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio), and a urinalysis every three to six months, indefinitely. Patients who do not respond to second-line treatment with a CNI plus low-dose prednisone are considered to have resistant disease; such patients should be referred to a center of expertise for further management.

Evidence in support of immunosuppressive therapy for patients with truly idiopathic MPGN, specifically those presenting with nephrotic syndrome and preserved kidney function, is very limited. Most randomized trials and observational studies used the older electron microscopy classification of MPGN (types I, II, and III), rather than classification based upon underlying disease pathogenesis. In addition, early studies were performed before angiotensin inhibitors were commonly used, and the diagnosis of idiopathic MPGN was made before investigators were as aware of secondary causes such as hepatitis C virus (HCV) infection, monoclonal gammopathies, and complement pathway abnormalities that underlie MPGN. Thus, it is unclear how many of the patients enrolled in these studies truly had "idiopathic" MPGN.

The best data come from a trial that randomly assigned 80 children (mean age 10 years) with nephrotic-range proteinuria but preserved kidney function to either prednisone or lactose, 40 mg/m², every other day for a mean duration of 41 months [5]. Fifty-nine (74 percent) of the 80 patients had type I or type III MPGN (which would presently be classified as immune complex-mediated MPGN or possibly C3 glomerulonephritis). At entry, the mean glomerular filtration rate (GFR) was 110 mL/min/1.73 m², mean serum creatinine was 0.75 mg/dL (66 micromol/L), and mean protein excretion was 118 mg/hour/1.73 m². Patients receiving prednisone experienced a lower rate of treatment failure (defined as an increase in baseline serum creatinine of ≥30 percent or >0.4 mg/dL [35 micromol/L]; 33 versus 58 percent among those with MPGN type I or III). Other observational studies have also suggested a benefit from long-term, alternative-day glucocorticoid therapy in children [6-8]. However, there have been no randomized trials of glucocorticoid therapy in adults with idiopathic MPGN, and retrospective studies have not shown a clear benefit [9,10].

Data from small observational studies suggest that CNIs reduce proteinuria in some patients with MPGN, as they do in many other forms of glomerular disease. In one report, for example, 18 patients who were resistant to aspirin, dipyridamole, and/or glucocorticoids were treated with cyclosporine plus low-dose prednisone [11]. At a mean follow-up of two years, all but one patient achieved complete or partial remission of proteinuria. Only one patient relapsed following discontinuation of cyclosporine. A similar benefit has also been observed with the use of tacrolimus [12].

Abnormal kidney function (without rapidly progressive crescentic disease) — Patients presenting with abnormal kidney function (arbitrarily defined as an estimated GFR [eGFR] <60 mL/min/1.73 m²) without rapidly progressive crescentic disease may have varying degrees of proteinuria and hematuria depending upon their disease activity. Patients with active glomerulonephritis (ie, mesangial proliferation and/or endocapillary hypercellularity on kidney biopsy), for example, typically have an active urinary sediment (arbitrarily defined as >10 RBC/HPF) with or without nephrotic-range proteinuria. By contrast, patients with indolent or advanced disease who present late in the disease course when most active inflammation has subsided may have a bland urine sediment and a variable amount of proteinuria. Since clinical features cannot reliably distinguish which patients may benefit from immunosuppressive therapy, we base our treatment approach upon the severity of kidney impairment and the presence or absence of active glomerulonephritis and/or chronic changes on kidney biopsy:

●In patients with an eGFR ≥30 and <60 mL/min/1.73 m² who have evidence of active glomerulonephritis and no significant chronic changes (ie, severe tubulointerstitial fibrosis) on kidney biopsy, we suggest immunosuppressive therapy in addition to conservative therapy, rather than conservative therapy alone. (See 'General measures in all patients' below.)

●In patients with an eGFR ≥30 and <60 mL/min/1.73 m² who have no evidence of active glomerulonephritis or have significant chronic changes on kidney biopsy, we treat with conservative therapy alone since immunosuppressive therapy is unlikely to be of benefit in this setting. (See 'General measures in all patients' below.)

●In most patients with an eGFR <30 mL/min/1.73 m², we treat with conservative therapy alone, unless the patient has another indication that could benefit from the use of immunosuppression (eg, minimal interstitial fibrosis or concomitant acute tubulointerstitial nephritis). (See 'General measures in all patients' below.)

If the decision is made to initiate immunosuppressive therapy, our preferred initial therapy is a three to six month course of oral glucocorticoids; however, for patients who cannot or do not wish to receive high-dose glucocorticoids, treatment with mycophenolate mofetil (MMF), with or without low-dose prednisone (10 mg/day), for 6 to 12 months is a reasonable alternative:

●If oral glucocorticoids are used, we administer prednisone 1 mg/kg per day (maximum dose 60 to 80 mg/day) for four weeks, then reduce the dose to 40 mg/day for four weeks, 30 mg/day for two weeks, and 20 mg/day for two to four weeks (total of 12 to 14 weeks).

●If MMF is used, we start MMF at 500 mg twice daily for three days and increase the dose up to 1000 mg twice daily as tolerated. We aim for a mycophenolic acid trough level of 1 to 3 ng/mL.

We monitor serum creatinine, 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio), and a urinalysis every two to three months to assess the response to treatment. If spot urine protein-to-creatinine ratio is used for routine follow-up, a 24-hour urine protein collection should be performed at least once every 6 to 12 months since, in patients with glomerular disease and proteinuria, there is only a moderate correlation between the urine protein-to-creatinine ratio and 24-hour urine protein excretion [4]. Our subsequent approach is as follows:

●Patients who respond with stabilization or improvement in kidney function or ≥30 percent reduction in proteinuria after 12 to 14 weeks are considered to have a satisfactory response to initial therapy. If the patient is receiving prednisone as first-line therapy, we gradually taper prednisone to 10 mg/day for four weeks, 5 mg/day for four weeks, and then discontinue. If the patient is receiving MMF as first-line therapy, we continue MMF until proteinuria reaches its nadir and hematuria (if present) disappears. If the patient has persistent low-grade proteinuria and significant hematuria (arbitrarily defined as >10 RBC/HPF), we continue MMF indefinitely or until hematuria resolves. We continue to monitor serum creatinine, urinalysis, and 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio) every three to six months, indefinitely.

●Patients who respond with worsening kidney function and <30 percent reduction in proteinuria after 12 to 14 weeks are considered to have an unsatisfactory response to initial therapy. At our center, approximately 40 to 50 percent of patients presenting with abnormal kidney function will not respond to initial treatment with glucocorticoids. If the patient is receiving prednisone as first-line therapy, we decrease prednisone to 10 mg/day and add MMF as second-line therapy for 6 to 12 months. We continue to monitor serum creatinine, 24-hour urine protein excretion (or spot urine protein-to-creatinine ratio), and a urinalysis every two to three months.

If there is no improvement in kidney function, proteinuria, or hematuria after 6 to 12 months of first-line therapy with MMF or second-line therapy with MMF and low-dose prednisone, we discontinue these agents. In such patients, it is reasonable to repeat a kidney biopsy to reevaluate disease activity and chronicity. If the repeat kidney biopsy shows primarily signs of chronic damage without evidence of active glomerulonephritis (ie, mesangial proliferation and/or endocapillary hypercellularity), we do not give additional immunosuppressive therapy, since it is unlikely to be of benefit. If the repeat kidney biopsy shows evidence of ongoing active glomerulonephritis, cyclophosphamide and rituximab are reasonable alternative treatment options:

•If cyclophosphamide is used, we administer daily oral cyclophosphamide (2 mg/kg per day, maximum dose of 200 mg/day) together with prednisone 10 to 20 mg/day for three to six months. We typically reduce the cyclophosphamide dose by 25 percent in older adults (age >60 years) and adjust the dose appropriately in patients with impaired kidney function (table 1). We use a maximum cumulative cyclophosphamide dose of 16 g.

•If rituximab is used, we give 1 g followed 14 days later by another 1 g. We repeat the same regimen at six months.

Patients who do not respond to treatment with either cyclophosphamide or rituximab are considered to have resistant disease; in such patients, we discontinue immunosuppressive therapy, continue general supportive measures, and refer for kidney transplantation when appropriate.

As discussed above, there are very limited data to support the use of immunosuppressive therapy in patients with idiopathic MPGN, and the overall quality of the evidence is low. However, in patients presenting with abnormal kidney function due to MPGN and active glomerulonephritis on kidney biopsy, we feel that a trial of immunosuppressive therapy is warranted to prevent further disease progression, given their otherwise poor prognosis. Our preference for glucocorticoids as initial therapy is based primarily upon the results of one randomized trial and observational studies in children showing a possible benefit; there are no trials systematically evaluating glucocorticoid therapy in adults. These data are discussed elsewhere in this topic. (See 'Nephrotic syndrome with normal kidney function' above.)

Small observational studies have suggested potential benefit with the use of MMF, typically given with oral glucocorticoids [13-15]. One study included five adults who were treated with MMF and oral prednisolone and six who were not treated with immunosuppressive agents [16]. The initial dose of MMF was 500 mg/day, which was gradually increased to 2000 mg/day or until remission of proteinuria was achieved; the average drug dose was 1100 mg/day. The initial prednisolone dose was 60 mg/day tapered to 20 mg/day within two months and withdrawn at one year. At 18 months, proteinuria decreased from 5.1 to 2.6 g/day in the MMF group compared with no change in proteinuria in patients who were not treated. In addition, the creatinine clearance increased in the MMF group (103 to 159 mL/min) and decreased in the control group (108 to 67 mL/min). However, the relative contribution of MMF and prednisolone could not be ascertained.

The efficacy of rituximab was evaluated in an open-label trial of six adults with MPGN type I, four with idiopathic MPGN, and two with MPGN associated with cryoglobulinemia [17]. Rituximab was administered as 1000 mg intravenously (IV) on days 1 and 15. At baseline, mean serum creatinine was 1.7 mg/dL (150 micromol/L) and mean proteinuria was 3.9 g/day. Proteinuria decreased in all patients at one year (mean proteinuria 2.1 g/day), and there was no significant change in mean serum creatinine. No patients experienced any adverse effects.

Studies evaluating the efficacy of cyclophosphamide have not clearly demonstrated benefit. One observational study of 19 patients with MPGN (unclassified), treatment with daily oral cyclophosphamide and glucocorticoids resulted in complete remission in 15 and partial remission in three; one progressed to end-stage kidney disease (ESKD) [18]. However, a larger randomized trial of 59 patients with MPGN type I or type II (dense deposit disease) found no differences in actuarial survival, rate of decline of kidney function, or proteinuria at two years among patients treated with cyclophosphamide, warfarin, and dipyridamole and those receiving no specific therapy [19].

Rapidly progressive crescentic disease — Patients presenting with a rapidly progressive crescentic MPGN should receive immunosuppressive therapy without delay since they are at high risk for progression to ESKD if untreated. We treat such patients with pulse IV methylprednisolone followed by daily oral prednisone and cyclophosphamide (oral or IV) using a regimen similar to that used for patients with antineutrophil cytoplasmic antibody-associated vasculitis. We do not use plasma exchanges in these cases. This is described in more detail elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Glucocorticoid dosing and taper'.)

Therapies we do not use — Other therapies proposed for the treatment of idiopathic MPGN include antiplatelet agents (dipyridamole and aspirin) [20,21], anticoagulants (eg, combination therapy with aspirin and warfarin) [19,22,23], and adrenocorticotropic hormone (ACTH) [24]. However, we do not routinely use any of these therapies due to the lack of sufficient evidence demonstrating efficacy.

TREATMENT OF COMPLEMENT-MEDIATED MPGN — Complement-mediated MPGN results from dysregulation and persistent activation of the alternative complement pathway. Complement-mediated MPGN can be subdivided into the C3 glomerulopathies (C3 glomerulonephritis and dense deposit disease) and C4 glomerulopathy based upon the complement product identified within glomerular deposits. The management of these disorders is discussed separately:

●(See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Treatment'.)

●(See "C4 glomerulopathy", section on 'Treatment'.)

GENERAL MEASURES IN ALL PATIENTS — All patients with a kidney biopsy lesion of MPGN, irrespective of cause, should be treated with general measures including dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition [25]. 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 'Protein intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake'.)

●Antihypertensive therapy – (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

●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 "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia' and "Chronic kidney disease in children: Complications", section on 'Dyslipidemia'.)

●Treatment of edema – (See "Overview of the management of chronic kidney disease in adults", section on 'Volume overload' and "Chronic kidney disease in children: Complications", section on 'Sodium and water homeostasis'.)

RECURRENT MPGN AFTER KIDNEY TRANSPLANTATION — Immune complex-mediated MPGN secondary to infection or autoimmune disease is less likely to recur after kidney transplantation than MPGN due to a monoclonal gammopathy or complement-mediated disease [26-28]. MPGN due to proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has a high risk of recurrence, even if no circulating serum or urine paraprotein can be detected (which occurs in 70 percent of the cases). Transplantation of such patients is generally not advised unless a plan to address the underlying plasma cell disorder has been established.

The management of this recurrent MPGN after kidney transplantation is discussed elsewhere. (See "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation".)

PROGNOSIS — As with other glomerular diseases, patients with MPGN who present with non-nephrotic proteinuria (less than 3.5 g/day, no hypoalbuminemia, and no edema), normal serum creatinine or estimated glomerular filtration rate (eGFR), absence of hematuria, and normal blood pressure have a benign prognosis as long as the kidney manifestations do not become more prominent. Poor prognostic signs at presentation include the nephrotic syndrome, an elevated serum creatinine, hypertension (or blood pressure well above the patient's previous baseline), and, on kidney biopsy, crescents [3,29-33]. By contrast, patients with non-nephrotic proteinuria and normal blood pressure appear to have an excellent long-term kidney prognosis [3,30]. Greater degrees of hematuria (eg, 50 or more versus 5 to 20 red blood cells [RBC]/high-power field [HPF]) suggest more inflammation, but there is no evidence of an independent effect on prognosis. (See 'Approach to common clinical presentations' above.)

Another important adverse prognostic sign on kidney biopsy is tubulointerstitial disease (interstitial inflammation, fibrosis, and tubular atrophy) [32-34]. The risk of progression usually correlates more closely with the severity of the tubulointerstitial injury than with the degree of glomerular damage. This finding is typical of most glomerular diseases. (See "Secondary factors and progression of chronic kidney disease", section on 'Tubulointerstitial fibrosis'.)

Older reports suggested a relatively poor kidney prognosis in patients with apparently idiopathic MPGN [9,10,30-32]. However, such reports should be interpreted with caution, since they were compiled before our knowledge of the many treatable disorders that can underlie MPGN.

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".)

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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 topics (see "Patient education: Glomerular disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – The overall approach to the treatment of an membranoproliferative glomerulonephritis (MPGN) lesion depends upon identification of the underlying cause. Most patients with an MPGN lesion can be classified as having immune complex-mediated disease or complement-mediated disease based upon the immunofluorescence findings on kidney biopsy. (See 'Overview of treatment' above.)

●Immune complex-mediated MPGN with an underlying cause – Most patients with immune complex-mediated MPGN have an identifiable underlying cause, such as a chronic infection, autoimmune disease, or monoclonal gammopathy. Such patients should receive therapy directed against the underlying cause of the MPGN since resolution of the MPGN usually occurs after successful treatment of the primary disease. (See 'Patients with an underlying cause' above.)

●Idiopathic immune complex-mediated MPGN – Patients with immune complex-mediated MPGN who do not have an identifiable underlying cause are considered to have "idiopathic" MPGN or MPGN of unknown etiology. However, such cases are now rare, especially among adults. Our approach to the most common clinical scenarios is based primarily upon low-quality evidence and our clinical experience (see 'Idiopathic immune complex-mediated MPGN' above):

•Mild disease – In patients who present with mild disease, characterized by normal kidney function, non-nephrotic-range proteinuria (<3.5 g/day), and no significant hematuria (arbitrarily defined as <10 red blood cells [RBC]/high-power field [HPF]), we treat with conservative therapy alone. (See 'Mild disease' above.)

•Nephrotic syndrome with normal kidney function – For patients who present with nephrotic syndrome and normal (or near-normal) kidney function, with or without an active urinary sediment (arbitrarily defined as >10 RBC/HPF), we suggest immunosuppressive therapy in addition to conservative therapy, rather than conservative therapy alone (Grade 2C). We suggest oral glucocorticoids as initial therapy rather than other immunosuppressive agents (Grade 2C). However, in patients who cannot or do not wish to receive glucocorticoids, a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) is a reasonable alternative. (See 'Nephrotic syndrome with normal kidney function' above.)

•Abnormal kidney function (without rapidly progressive crescentic disease) – In patients presenting with abnormal kidney function (arbitrarily defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) without rapidly progressive crescentic disease, our approach depends upon the severity of kidney impairment and the presence or absence of active glomerulonephritis and/or chronic changes on kidney biopsy (see 'Abnormal kidney function (without rapidly progressive crescentic disease)' above):

-For patients with an eGFR ≥30 and <60 mL/min/1.73 m² who have evidence of active glomerulonephritis and no significant chronic changes (ie, severe tubulointerstitial fibrosis) on kidney biopsy, we suggest immunosuppressive therapy in addition to conservative therapy, rather than conservative therapy alone (Grade 2C). We suggest oral glucocorticoids as initial therapy rather than other immunosuppressive agents (Grade 2C). However, in patients who cannot or do not wish to receive high-dose glucocorticoids, mycophenolate mofetil (MMF), with or without low-dose prednisone, is a reasonable alternative.

-In patients with an eGFR ≥30 and <60 mL/min/1.73 m² who have no evidence of active glomerulonephritis or have significant chronic changes on kidney biopsy, we treat with conservative therapy alone since immunosuppressive therapy is unlikely to be of benefit in this setting.

-In most patients with an eGFR <30 mL/min/1.73 m², we treat with conservative therapy alone, unless the patient has another indication that could benefit from the use of immunosuppression (eg, minimal interstitial fibrosis or concomitant acute tubulointerstitial nephritis).

•Rapidly progressive crescentic disease – For patients presenting with a rapidly progressive crescentic MPGN, we suggest pulse intravenous (IV) methylprednisolone followed by daily oral prednisone and cyclophosphamide (oral or IV) rather than other immunosuppressive regimens (Grade 2C). We use a regimen similar to that used for patients with antineutrophil cytoplasmic antibody-associated vasculitis. (See 'Rapidly progressive crescentic disease' above.)

●Complement-mediated MPGN – Complement-mediated MPGN results from dysregulation and persistent activation of the alternative complement pathway. Treatment of complement-mediated MPGN is discussed separately. (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis", section on 'Treatment'.)

●General measures in all patients – All patients with a kidney biopsy lesion of MPGN, irrespective of cause, should be treated with general measures including dietary sodium and protein restriction, blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. (See 'General measures in all patients' above.)