Membranoproliferative Glomerulonephritis

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Practice Essentials

Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephritis that occurs primarily in children and young adults. These patients have a pattern of glomerular injury with the following three characteristic histopathologic findings:



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Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral cap....



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Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear patte....



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Glomerulus with mesangial interposition producing a double contouring of basement membranes, which, in areas, appear to surround subendothelial deposi....

MPGN may be idiopathic or secondary in etiology.[1]  The secondary types are more common than the idiopathic types and are diagnosed by carefully reviewing clinical features, laboratory data, and renal histopathology. Historically, primary (idiopathic) MPGN was subdivided into types I, II, and III based on ultrastructural appearance on electron microscopy, as follows:

These 3 types are nearly indistinguishable by light microscopy, often with considerable overlap between them. Newer classification utilizes immunofluorescence pattern (and pathogenic mechanism) and includes the following[2, 3] :

Although the clinical presentation may be similar for the three types of MPGN, the clinical course is variable, depending on the mechanism of injury,  histopathology, and treatment. Recurrence in kidney transplant receipients is also variable.[4]

Familial forms of MPGN have been described [5]

See also Pediatric Nephritis, Tubulointerstitial Nephritis, and Radiation Nephritis. 

Pathophysiology

The normal complement system consists of the classic and alternative pathways. The classic pathway is activated by the interaction of C1 with an antigen-antibody complex. This interaction results in the formation of C4b2a, which is the classic pathway C3b convertase. The alternative pathway utilizes C3 and factors B and D to form the alternative pathway convertase C3b,Bb.

Small amounts of C3b are constantly being formed in the circulation, and are inactivated by factors H and I. The binding of C3b to a foreign antigen decreases its affinity for factor H and allows for the formation of increasing amounts of the alternate pathway convertase. The classic and alternate pathway convertases cause C3 activation, forming C3a and C3b. C3b is an opsonin itself, and C3 convertase facilitates the activation of the terminal pathway and the formation of the membrane attack complex C5b-9.

Hypocomplementemia in MPGN

Hypocomplementemia is a characteristic finding with all types of membranoproliferative glomerulonephritis (MPGN). Low C3 levels are present in approximately 75% of patients with this condition. Although hypocomplementemia bears no relation to the clinical course or prognosis of MPGN, it plays a role in initiating glomerular inflammation and injury. Hypocomplementemia results from increased catabolism and decreased C3 synthesis. The decreased C3 synthesis is likely caused by the negative feedback by C3 breakdown products. 

Three nephritic antibodies are described in MPGN that play a role in the development of hypocomplementemia[6, 7] : (

The reason for the generation of nephritic antibodies is not known. These autoantibodies are not specific for MPGN and are also seen in poststreptococcal and lupus glomerulonephritis. NFc stabilizes the classic pathway C3 convertase C4b,2a. This nephritic factor does not cause C3 conversion unless C4b,2a production is ongoing. NFa (C3NEF) is an autoantibody to C3b,Bb. The binding of NFa to C3b,Bb stabilizes the complex, preventing degradation by its normal inactivators, resulting in complement activation and chronic consumption of C3.

NFt stabilizes the alternative pathway properdin-dependent C3/C5 convertase (C3Bb2,Bb,P) and leads to C3 activation and consumption. The consumption of C3 caused by NFt is much slower than that caused by NFa. NFt also activates the terminal complement components forming C5b-C9, the membrane attack complex.

Immune complex–mediated glomerulonephritis (ICGN)

In all patients with ICGN, deposits of complement and immunoglobulin are found in the mesangium and subendothelial spaces. These trigger release of cytokines and chemokines, causing an influx of inflammatory cells and leading to mesangial and endothelial cell proliferation. Most patients with circulating immune complexes do not develop MPGN and ICGN can certainly be seen without circulating immune complexes; thus, additional pathogenic factors (eg, nature of the antigen, size of complexes, type and charge on antibodies, local glomerular factors) must play a role. Common etiologies include infections, autoimmune disease, or monoclonal gammopathies.

However, many patients with monoclonal deposits on immunofluorescence or ultrastructural evidence on electron microscopy do not have an identifiable circulating clone. Monoclonal gammopathies that are associated with kidney disorders but lack an identifiable clone (ie, those that do not meet the criteria for myeloma or cancer) are categorized as monoclonal gammopathies of renal significance (MGRS). Some MPGNs are good examples of MGRS.[8]

In addition to circulating immune complexes becoming entrapped in the glomerular basement membrane (GBM), experimental evidence indicates that complexes may be formed in situ when antigens adhere to the GBM, and antibodies subsequently bind to these antigens. Formation of such immune complexes triggers the same cascade as described above.

Complement-mediated disease

Complement-dominant disease, or complement-mediated disease, is the classification of MPGN that has immunofluorescence and stains intensely and primarily for complement rather than immunoglobulin. This pattern is seen in both C3 glomerulonephritis (C3GN)  and C3 dense deposit disease (C3 DDD), as well as in C4-dominant versions of the former.  

C3 dense deposit disease 

This is a systemic disorder, as evidenced by dense deposits in the kidney, splenic sinusoids, Bruch membrane of the retina, as well as its association with acquired partial lipodystrophy.[9, 10]  It has a high rate of recurrence in allografts.  However, dense deposit disease is associated with hypocomplementemia in only about half of cases. 

The chemical composition and origin of the dense deposits are not known, although bright staining with thioflavine-T and wheat germ agglutinin suggests the presence of N-acetyl-glucosamine.  It is also important to know that dense deposits can mask the presence of monoclonal immunoglobulins, which can be seen after digestion with pronase. One hypothesis is that the dense deposits themselves cause complement activation.[11] This hypothesis is supported by the tram-track distribution of C3 deposits along the basement membrane.

NFa is present in 80% of patients with dense deposit disease. NFa stabilizes the alternative pathway convertase and results in complement activation and chronic C3 consumption. Deficiency of factor H, functionally defective factor H, mutant factor H binding site of C3 (Marder disease), and presence of inhibitory or blocking factor H antibodies, described in MPGN, may lead to an accumulation of the alternative pathway convertase and chronic C3 consumption.

Partial lipoid dystrophy (PLD) is associated commonly with CDGN and the presence of NFa. Adipocytes produce adipsin, which is identical to complement factor D and is responsible for activating the preconvertase C3b,Bb. NFa causes a lysis of adipocytes that produce adipsin, and the distribution of fat atrophy in partial lipoid dystrophy follows variations in the amount of adipsin produced by adipocytes. By analogy, NFa may cause damage to glomerular cells that produce complement.

C3 glomerulonephritis

C3 glomerulonephritis is an entity with immunofluorescence findings of isolated glomerular C3 deposits.[12] C3 glomerulonephritis is similar in etiology to dense deposit disease, arising as a result of alternate complement activation or mutations in the complement-regulating proteins, but deposits tend to be in endocapilary and mesangial and of lesser intensity that in C3DDD. C3NeF is commonly present. C3 glomerulonephritis has been associated with antifactor H activity and monoclonal gammopathies.

Serum C3 levels are usually low, but they can be normal, along with normal C4 levels.[13]  It is important to note that a normal serum C3 level does not exclude C3 glomerulonephritis. Dense deposit disease and C3GN both lack immunoglobulin staining on immunofluorescence and are the result of alternative pathway dysregulation.[14]  In the literature, these 2 entities are often referred to as C3 glomerulopathy.

MPGN without immune complexes or complement staining

This category of membranoproliferative disease is defined by lack of an infectious or immunologic pathway or complement dysregulation and is therefore heterogeneous in nature. Common causes of MPGN pattern without complement or immunoglobulin staining include the following[3] :

Etiology

The MPGN pattern of injury in the kidneys can be caused by various diseases. The immunofluorescence pattern can aid in identifiying the underlying disease. 

Immunoglobulin/immune-complex mediated disease

Autoimmune diseases

Autoimmune diseases associated with a membranoproliferative pattern of kidney injury include the following:

Chronic infections

The following chronic viral, bacterial, and protozoal infections are associated with a membranoproliferative pattern of kidney injury:

Rare cases of MPGN have been reported with infections including Haemophilus parainfluenzae endocarditis,[18]  anaplasmosis,[19]  and nocardia.[20]  

COVID-19 immunizations

Both relapse and de novo cases of MPGN have been reported following administration of Pfizer and AstraZeneca vaccines against COVID-19.[21, 22]

Paraprotein deposition diseases

Paraprotein deposition diseases that are associated with a membranoproliferative pattern of kidney injury include the following:

Malignant neoplasms

Lymphoma, leukemia, and carcinoma are also associated with a membranoproliferative pattern of kidney injury.

Complement-mediated disease

Disorders of complement dysregulation can also cause membranoproliferative pattern of kidney injury. They can be classified as glomerulonephritis (GN) or dense deposit disease (DDD) —C3GN, C3-DDD, C4 -GN, C4-DDD—and may arise from the following:

Membranoproliferative pattern of injury with negative immunofluorescence  

The following are chronic and recurrent thrombotic microangiopathies associated with a membranoproliferative pattern of kidney injury

Epidemiology

In the United States, membranoproliferative glomerulonephritis (MPGN) is observed in 6-12% of kidney biopsies performed to evaluate glomerular diseases. This entity accounts for 7% of children and 12% of adults with idiopathic nephrotic syndrome. Idiopathic/primary MPGN commonly affects children and young adults from 8 to 30 years of age. Secondary causes are more common in patients who present after 30 years of age.

Men and women are almost equally affected. 

Prognosis

The main predictors of an adverse outcome in membranoproliferative glomerulonephritis (MPGN) are nephrotic syndrome and hypertension at presentation, low glomerular filtration rate (GFR) at 1 year, and older age.[23, 24] Histologic characteristics of crescent formation, interstitial fibrosis, tubular atrophy, and multiple sclerotic glomeruli indicate a poor prognosis. However, hypocomplementemia is not a predictor of disease severity or prognosis. 

Kawasaki et al reported worse prognosis in pediatric patients with MPGN related to complement component C3 than in those with immune complex–mediated MPGN. In their study of 37 patients, those with C3-related MPGN were more likely to be nonresponsive to therapy or progress to end-stage kidney disease (ESKD).[25]  

Similarly in a retrospective cohort study examining disease course in 111 patients with complement-mediated MPGN (C3G-87, DDD-24) the rate of progression to CKD, ESKD or death in 6 years was about 40% for both C3G and DDD.[26]  The rate of progression was similar to that in other national registries. 

In a study of all adult ESKD patients in Australia and New Zealand who commenced kidney replacement therapy from 1996 through 2016, rates of survival on dialysis and following kidney transplantation were comparable in the 456 patients with MPGN and the 12,660 patients with another form of glomerulonephritis.[27]  However, the rate of post-transplant recurrence of MPGN remains high. Patients with recurrent MPGN in the allograft had the worst outcomes compared with any other glomerular disease, with 5-year graft survival of about 25-30%.[4, 28]  

 

History and Physical Examination

Patients with membranoproliferative glomerulonephritis (MPGN) may present in 1 of 5 ways, as follows:

Fatigue may also occur and is secondary to anemia or azotemia. The anemia is often disproportional to the degree of kidney insufficiency and relates to complement-mediated lysis of red blood cells. Conjunctival pallor is also indicative of anemia.

Hypertension is present in approximately 80% of patients at initial presentation. It is typically mild, although an occasional patient with dense deposit disease (MPGN type II) may present with severe hypertension.

A strong association is present between partial lipodystrophy (PLD) and dense deposit disease. Fat atrophy usually affects the upper limbs, trunk, and face.

The finding of a drusen on fundus examination of a patient with glomerulonephritis suggests the diagnosis of dense deposit disease. Drusen are yellowish deposits of extracellular material between the basement membrane of the retinal pigment epithelium and the inner collagenous zone of the Bruch membrane. Choroidal neovascularization, macular degeneration, and visual loss may also develop in dense deposit disease.

Complications

Progressive decline in kidney function and end-stage kidney disease (ESKD) are among the complications seen in patients with membranoproliferative glomerulonephritis (MPGN) (see Overview/Prognosis).

Recurrent disease after transplantation

Recurrent disease is a risk in patients who receive a kidney transplant.[4]  Patients with recurrent MPGN in their allograft had the worst outcomes compared to any other glomerular disease, with a 5-year graft survival of about 25- 30%.[4, 28]  

Recurrent MPGN needs to be differentiated from transplant glomerulopathy, which has a similar histology but lacks immune deposits.

Secondary hypertension, edema, and infections

Hypertension is present in 80% of patients at presentation; patients generally develop worsening of hypertension with the progression of kidney insufficiency.

Periorbital or dependent edema may occur in patients with a nephritic or nephrotic presentation, and anasarca is present in a few patients.

The propensity for infections with encapsulated bacteria, including Streptococcus, Haemophilus, and Klebsiella species, is increased. Prophylactic antibiotics and hyperimmune globulins may be useful in some patients. Administer the pneumococcal vaccine and yearly influenza vaccination to all patients.

Thromboembolism tendency

Loss of anticoagulant antithrombin III, proteins C and S, increased procoagulants, defective fibrinolysis, increased platelet aggregability, hyperlipidemia, endothelial cell injury, and steroids may lead to thrombosis. The renal vein is a common site of thrombosis because of hemoconcentration and loss of the anticoagulants through glomerular filtration.

Hyperlipidemia

Hyperlipidemia is a significant adverse event in patients with nephrotic syndrome. Very-low density-lipoprotein (VLDL), low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) levels are increased early in the disease. High-density lipoprotein (HDL) levels may be variable, but levels of the cardioprotective fraction HDL2 usually are decreased. Lipoprotein-a levels are increased.

Hyperlipidemia in patients with nephrotic syndrome may cause accelerated atherosclerosis and increased coronary events. Also, hyperlipidemia may accelerate the progression of renal disease.

Other complications of MPGN include the following:

Approach Considerations

Focused laboratory testing, guided by a comprehensive history and physical examination, will help identify membranoproliferative glomerulonephritis (MPGN). However, a kidney biopsy is needed to make the conclusive diagnosis of MPGN, and even then, full elucidation of the pathophysiology may require additional testing based on the biopsy findings. 

 

Laboratory Studies

A complete blood cell count (CBC) can often identify normocytic normochromic anemia. In patients suspected to have thrombotic microangiopathy (TMA), evidence of hemolysis can also be looked for; a peripheral smear examination can identify schistocytes. These patients can also have elevated lactate dehydrogenase (LDH) and low haptoglobin levels. 

Elevated serum creatinine and blood urea nitrogen (BUN) levels and a decreased estimated glomerular filtration rate (GFR) are found in 20-50% of patients with MPGN at presentation. Patients with a nephritic presentation typically have a decreased GFR. In patients with kidney dysfunction, electrolyte abnormalities can also be identified. 

Hyperlipidemia and low albumin levels may be seen with nephrotic syndrome. 

Other testing includes the following:

Urine Studies

Urinalysis in patients with membranoproliferative glomerulonephritis (MPGN) may reveal glomerular hematuria, which is characterized by dysmorphic red blood cells (RBCs) and RBC casts. Proteinuria is almost always present. 

In stable patients, urine protein-to-creatinine ratio (UACR) is a reliable estimate for proteinuria. A 24-hour urine test is the gold standard for assessing proteinuria and may be required for confirmation in cases of heavy proteinuria or acute kidney injury. Nephrotic proteinuria is present in approximately 50% of patients.

 

Complement Testing

Disorders of complement regulation are seen in the complement-mediated MPGN pattern of injury. Identifying these necessitates testing of the alternate complement pathway, as follows[3, 29] :

 

 

Kidney Biopsy and Histologic Features

Perform a kidney biopsy for definitive diagnosis of membranoproliferative glomerulonephritis (MPGN). Under light microscopy, the glomeruli are generally enlarged and hypercellular, with an increase in mesangial cellularity and matrix. Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form (as demonstrated in the image below), giving rise to the alternative name of lobular nephritis. Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.



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Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral cap....

The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall. This gives rise to the tram-track or double-contoured appearance of the capillary wall, which is best appreciated with methenamine silver or periodic acid–Schiff (PAS) staining.

Crescents may be visible in 10% of biopsy specimens. Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in glomerular filtration rate (GFR).

Historically, idiopathic MPGN was classified based on electron microscopy findings as type I, II and III. See the images below.



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Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Min....



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Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original mag....

The current classification of MPGN is based on the presence and type of immunofluorescence. In immune complex–mediated MPGN,  immunofluorescence staining reveals deposition of immunoglobulin (see image below). 



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Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear patte....

C3 glomerulonephritis

Immunofluorescence microscopy in C3 glomerulonephritis reveals extensive C3 deposition along the capillary wall and mesangium with no immunoglobulin deposition. On the other hand, electron microscopy does not reveal intramembranous and mesangial deposits in C3 glomerulonephritis, as it does in dense deposit disease.

Approach Considerations

Membranoproliferative glomerulonephritis (MPGN) is a rare glomerulonephritis with a protracted natural history, which makes studies on treatment logistically difficult to conduct. No serologic markers are available to assess disease activity. Most studies are confined to MPGN type I and have a relatively short-term follow-up period; furthermore with the recent re-classification of MPGN based on pathobiology, older treatment results become difficult to interpret. 

Only a handful of randomized controlled trials have been published with sufficient power to determine the benefits of therapy for MPGN. The use of variable end points (eg, reduction in proteinuria, kidney function measured using varying techniques) further confounds the data.

Thus, the optimal treatment of idiopathic MPGN is not clearly defined. Specific therapies should be reserved for patients with MPGN who have one or more of the following indications:

Consultations with nephrology, hepatology (in patients with MPGN associated with hepatitis virus B or C), and nutrition specialists may be helpful in managing patients with this rare disease.

Primary MPGN

General measures

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines recommend that when immune complex–mediated glomerulonephritis (ICGN) is identified, the initial approach to treatment should focus on the underlying pathologic process. For most patients with idiopathic ICGN presenting with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, KDIGO recommends treatment with supportive care alone.[3]

For patients with idiopathic ICGN and proteinuria < 3.5 g/d who do not have nephrotic syndrome and whose eGFR is normal, supportive therapy with renin-angiotensin system (RAS) inhibition alone is recommended. For patients with nephrotic syndrome and a normal or near-normal serum creatinine concentration, a limited treatment course of glucocorticoids should be tried. For patients with abnormal kidney function (but without crescentic involvements) and active urine sediment, with or without nephrotic-range proteinuria, glucocorticoids and immunosuppressive therapy should be added to supportive care. High-dose glucocorticoids and cyclophosphamide are recommended for rapidly progressive crescentic disease.[3]

Moderate-to-severe C3 glomerulonephritis without monoclonal gammopathy should be treated initially with mycophenolate mofetil (MMF) plus glucocorticoids. For refractory cases, eculizumab should be considered.[3]   

Nondihydropyridine calcium channel blockers such as verapamil and diltiazem may also have antiproteinuric effects.

Diuretics are usually needed to control hypertension and manage edema. Thiazide diuretics suffice for many patients. Loop diuretics are indicated for more refractory edema with kidney insufficiency. A combination of diuretics acting at different sites in the tubule may be needed in some patients. Potassium-sparing diuretics may be used concomitantly to prevent hypokalemia. Patients with severe refractory edema and those with hypovolemia and orthostatic hypotension may respond to salt-free albumin infusions.

For management of hyperlipidemia, KDIGO guidelines recommend lifestyle modification in all patients, recommend it as the first-line measure in children, and suggest that it may be used as primary therapy in low-risk patients with mild to moderate hyperlipidemia.[3]  For patients at highest risk of atherosclerotic cardiovascular disease, use of statins with a goal of low-density lipoprotein (LDL) cholesterol levels below 70 mg/dL is recommended.[30]

Patients should be given the pneumococcal vaccine and yearly influenza vaccine.

Specific measures

Approaches to treatment of idiopathic MPGN have included immunosuppression, inhibiting platelet-induced injury with aspirin and dipyridamole, minimizing glomerular fibrin deposition with anticoagulants, and use of steroidal and nonsteroidal anti-inflammatory agents. Anticoagulant and nonsteroidal therapies have been found to have minimal beneficial effects and are associated with severe adverse effects.

Immunosuppression may be indicated for patients with nephrotic syndrome, progressive decline in kidney function, or very active inflammation (crescents) on kidney biopsy. Patients with normal GFR and non-nephrotic proteinuria should be managed conservatively and followed closely.

Corticosteroids

Children with idiopathic MPGN type I who have nephrotic-range proteinuria, interstitial disease, or kidney insufficiency may benefit from corticosteroid therapy. No systemic evaluation of corticosteroid therapy in adults has been conducted.

Benefits in children include stabilization of kidney function, slowing of the decline in GFR, and decrease in proteinuria. However, these therapies are associated with multiple complications, including hypertension and seizures in children. Because active inflammation is more likely to be present early in the disease, prompt initiation of therapy may provide better outcomes.

In the International Study of Kidney Disease in Children, investigators suggested that the outcome of children with MPGN may be improved with long-term use of prednisone.[31] Alternate-day prednisone was administered for a mean of 130 months; at the end of the study period, approximately 61% of the treatment group had stable kidney function, compared with 12% of the control group.[31]  In a single-center study of treatment of idiopathic MPGN that included 71 children treated with prednisone for a mean of 7.7 years, the cumulative renal survival was 82% at 10 years and 56% at 20 years after disease onset. Alternate-day prednisone was used in 50 children.[32]  

Antiplatelet therapy

Antiplatelet therapies benefit adults with MPGN. Probable mechanisms that underlie the therapeutic benefits of aspirin include inhibition of platelet aggregation, mesangial proliferation, and alteration of renal hemodynamics. Dipyridamole may enhance the effects of aspirin.

In one randomized controlled study, the use of antiplatelet agents administered over 1 year reduced the incidence of kidney failure at 3-5 years, but the renal survival rate was no different at 10 years[33] . In another study of 18 patients with biopsy-proven MPGN (15 type I, 3 type II) and nephrotic syndrome and moderately reduced kidney function, dipyridamole and aspirin caused a significant reduction in proteinuria at 36 months, while serum creatinine remained unchanged, with no impact on kidney function.[34]  Reduction in proteinuria to a non-nephrotic range was also documented in a group of 14 patients treated with aspirin and dipyridamole for 2 years by Harmakaya et al.[35]  

Cyclophosphamide

Cyclophosphamide therapy is generally recommended for rapidly progressive kidney failure (crescentic glomerulonephritis). Cyclophosphamide is given in conjunction with intravenous steroids.

In a 10-month study of 19 pediatric and adult patients with MPGN, therapy was induced with pulse methylprednisone and cyclophosphamide and maintained with cyclophosphamide and every-other-day prednisone. Steroids were tapered in the third phase of the study. Lastly, cyclophosphamide was stopped and prednisone gradually withdrawn. Remission occurred in 15 patients, improvement in three, and and progression in one. There were eight relapses in six patients: four relapses in three patients were treated with repeat cycles, with complete remissiony. Four patients who had relapsed after 4, 8, 11, and 13 years of remission refused retreatment and progressed rapidly to ESKD.[36]

A study by Cattran et al found no benefit with a treatment regimen of cyclophosphamide, warfarin, and dipyridamole in patients with MPGN types I and II with a GFR of less than 80 mL/min and/or proteinuria greater than 2 g/day.[37]

Mycophenolate mofetil

Data on the use of mycophenolate mofetil (MMF) in MPGN are limited to small observational studies. An observational study reported that five patients with idiopathic MPGN who were treated with oral prednisolone and MMF had significant reduction in proteinuria over an 18-month period, relative to a control group of 6 patients who did not receive immunosuppression. No significant change occurred in serum creatinine or creatinine clearance in the treatment group; however, in the control group, serum creatinine and creatinine clearance deteriorated significantly.[38]   In a small Chinese cohort, 13 patients with steroid-resistant MPGN who were treated with a combination of MMF and glucocorticoids showed improvement, with both decreased proteinuria and improved kidney function.[39]

Calcineurin inhibitors

A small case series demonstrated that cyclosporine was effective in the treatment of MPGN that was refractory to alternative treatments. Eighteen patients were treated with cyclosporine plus low-dose prednisone and were followed for an average 108 weeks. Partial or complete remission of proteinuria occurred in 94% of the patients (P< 0.01). Relapse occurred in one (14.2%) of the remitters after discontinuation of the drug.[40]

Rituximab

Anecdotal reports have demonstrated the efficacy or rituximab in treating MPGN secondary to chronic lymphocytic leukemia.[41, 42] Rituximab has also been shown to be effective in patients with MPGN related to a monoclonal gammopathy.[43]

In an open-label trial with rituximab, six patients with MPGN type I were treated with rituximab 1000 mg on days 1 and 15 and followed for 1 year. Proteinuria decreased in all patients, at all time points, after rituximab administration. Kidney function did not change.[44]

Newer therapies

Eculizumab, an anti-C5 antibody, has been shown to decrease C5-mediated glomerular damage. Case reports have supported the use of eculizumab in refractory MPGN secondary to complement dysregulation. In a single-arm trial in 10 patients, eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in only a subgroup.[45] Other clinical trials are still under way to establish the role of eculizumab in MPGN and C3 glomerulonephritis. In an analysis of post-transplant C3 glomerulopathy, allograft survival was still poor despite use of eculizumab.[46]

Iptacopan, an oral proximal complement inhibitor of factor B is currently in phase 3 clinical trial for the management of idiopathic immune complex-mediated MPGN.[47]   Arnold et al published the first reported case of successful treatment of primary immune complex glomerulonephritis with iptacopan.[48]

Pegcetacoplan, a targeted direct C3 and C3b inhibitor, is also currently being investigated for the treatment of C3 glomerulopathy and other complement-mediated glomerular diseases.[49]

Other potential treatments of MPGN type II include plasma infusion/plasmapheresis and reducing C3NeF (nephritic factor of the amplification loop). Plasma infusion or plasmapheresis with plasma exchange may provide functionally intact factor H in patients with defined pathologic mutation of the factor H gene.

Secondary MPGN

Every patient with membranoproliferative glomerulonephritis (MPGN) must be carefully evaluated for a secondary cause of the disease. An comprehensive history, histopathologic findings, and serologies may help identify the underlying cause.

Appropriate treatment of infections such as endocarditis or infected ventriculoatrial shunts may induce remissions. Antiviral therapy is indicated for hepatitis B and C.[50, 51, 52] . Aggressive immunosuppression and plasmapheresis should be reserved for patients with severe acute MPGN and/or vasculitis with hepatitis C.

For patients with lupus and other rheumatologic conditions, offer treatment based on principles of care for those diseases.

Diet and Activity

Dietary considerations include sodium, protein, and lipid intake.

Dietary sodium needs to be restricted to 3 to 4g/d. These measures, along with the judicious use of diuretics, can be very useful in managing hypertension and edema.

Ensure that patients with normal kidney function have a protein intake of approximately 1 g/kg/d, plus the amount lost in urine. Confirm that the protein is of high biologic value. Higher protein intake does not improve nutrition, because protein catabolism increases proportionally; however, once kidney insufficiency develops, recommend moderate protein restriction (eg, 0.65-0.80 g/kg/d, plus urinary losses).

Recommend a low-cholesterol healthy-heart diet to patients, because hyperlipidemia is common with nephrotic proteinuria.

No restriction of activity is recommended, unless the patient has uncontrolled severe hypertension. Note that diuretics are most effective when the patient is supine. In patients with resistant edema, lying down after taking diuretics may increase their efficacy.

Pregnant Patients

Underlying renal diseases, including membranoproliferative glomerulonephritis (MPGN), increase the risk of fetal loss, intrauterine growth restriction, and prematurity. Patients with hypertension, kidney insufficiency, and nephrotic syndrome are at higher risk for an unfavorable fetal outcome. Preeclampsia develops in 20-40% of patients with underlying kidney disease. The development of preeclampsia increases the risks of fetal wastage.

Patients with MPGN are more likely than those with most other glomerular diseases to develop deterioration of kidney function, increasing proteinuria, or worsening of hypertension during pregnancy. The risk for adverse outcomes depends on the patient's severity of hypertension, 24-hour proteinuria, and the level of kidney function before pregnancy.[53]

Close monitoring of the patient by a high-risk obstetrician and a nephrologist is essential during pregnancy.

Long-Term Monitoring

Patients should be followed at regular intervals. The frequency of visits should be dictated by the level of kidney function, level of proteinuria, and nature of intervention prescribed. Kidney function, proteinuria and clearances, lipid profiles, and serum albumin should be followed during these visits. The urine albumin-to-creatinine ratio may be used as a rough guide to 24-hour urinary albumin excretion. Patients treated with immunosuppressive therapies should also be monitored for adverse effects. The nutritional status should be assessed using the subjective global assessment (SGA) scale.

Patient Education

Ensure that patients with progressive azotemia receive timely education regarding kidney replacement options.[54] In addition, recommend that patients have frequent follow-up visits with a dietitian, which are essential to ensuring patient diet compliance.

For patient information, see Chronic Kidney Disease, and Kidney Transplant: End-stage Renal Disease.

Medication Summary

Pharmacologic treatment in patients with membranoproliferative glomerulonephritis (MPGN) may include the following:

Aspirin (Bayer Aspirin, Ascriptin, Ecotrin)

Clinical Context:  Aspirin inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Dipyridamole (Persantine)

Clinical Context:  Dipyridamole is a platelet adhesion inhibitor that possibly inhibits red blood cell (RBC) uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, this agent may inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2.

Class Summary

Platelet consumption is increased in membranoproliferative glomerulonephritis (MPGN) and platelets may play a role in glomerular injury.

Prednisone

Clinical Context:  Prednisone is an immunosuppressant drug used for the treatment of autoimmune disorders. This agent may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear lymphocyte (PMN) activity.

Class Summary

Corticosteroids may be used as monotherapy or in combination with other medications. While corticosteroids appear to be effective in children, there is no convincing evidence of their efficacy as monotherapy in adults with idiopathic membranoproliferative glomerulonephritis (MPGN).

Mycophenolate (CellCept, MMF, Myfortic)

Clinical Context:  MMF is an inosine monophosphate dehydrogenase inhibitor used in the treatment of both immune complex mediated-MPGN and C3 glomerulopathy

Cyclophosphamide (Cytoxan)

Clinical Context:  Cyclophosphamide is classified as an alkylated agent, widely used as an immunosuppressant. It is used in treating immune-complex mediated MPGN, with high risk characteristics. 

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context:  Cyclosporine is a calcineurin inhibitor often used as a adjuct therapy for MPGN in patients with preserved renal function. 

Rituximab (Rituxan, Riabni, Rituximab-abbs)

Clinical Context:  Rituximab is a monoclonal antibody targerting CD20 antigens, and depletes B-cells. Rituximab has been used as a second line agent in treating steroid resistant MPGN or when associated with monoclonal gammopathy or acquired complement regulatory antibodies. 

Eculizumab (Bkemv, Eculizumab-aagh, Eculizumab-aeeb)

Clinical Context:  Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5, preventing its cleavage into C5a and C5b, and subsequent formation of terminal complement complex C5b-9 or membrane attack complex (MAC). Eculizumab has orphan drug designation for idiopathic membranous glomerular nephropathy and is increasingly utilized in the treatment of C3 glomerulopathy. 

Author

Anna Gaddy, MD, FASN, Assistant Professor of Clinical Medicine, Division of Nephrology, Department of Medicine, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Coauthor(s)

Aisha Batool, MD, Assistant Professor Division of Nephrology, Department of Medicine, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Christina Mariyam Joy, MD, Assistant Professor, Department of Medicine, Division of Nephrology, Medical College of Wisconsin; Staff Nephrologist, Department of Medicine, Division of Nephrology, Froedtert Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Akash Patel, MD, Hospitalist, Tulsa Hospitalists, Inc

Disclosure: Nothing to disclose.

F John Gennari, MD, Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor, Department of Medicine, University of Vermont College of Medicine

Disclosure: Nothing to disclose.

Pranay Kathuria, MD, MACP, FASN, FNKF, Professor of Medicine, Gussman Chair in Internal Medicine, Director, Division of Nephrology and Hypertension, Program Director, Nephrology Fellowship Program, University of Oklahoma School of Community Medicine, University of Oklahoma College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Martin Senitko, MD, and Sandeep Singh, MD, to the development and writing of the source article.

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Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.

Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.

Glomerulus with mesangial interposition producing a double contouring of basement membranes, which, in areas, appear to surround subendothelial deposits (Jones silver methenamine–stained section; original magnification × 400). Courtesy of John A. Minielly, MD.

Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.

Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Minielly, MD.

Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original magnification × 11,400). Courtesy of John A. Minielly, MD.

Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.

Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.

Glomerulus with mesangial interposition producing a double contouring of basement membranes, which, in areas, appear to surround subendothelial deposits (Jones silver methenamine–stained section; original magnification × 400). Courtesy of John A. Minielly, MD.

Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Minielly, MD.

Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original magnification × 11,400). Courtesy of John A. Minielly, MD.

Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.