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Membranoproliferative Glomerulonephritis
Dr. Mohit Mathur
29/10/2013
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, often leading to a lobular appearance of the glomerular tuft.
Epidemiology
In North America and Europe, MPGN (types I and III) and DDD constitute less than 5% of all primary glomerulonephritis.
MPGN accounts for 5% to 10% of primary renal causes of nephrotic syndrome in children and adults.
It occurs equally in males and females and in the United States is relatively more common in Caucasians than in African Americans.
Epidemiology
MPGN presenting in childhood (primarily between the ages of 8 and 14 years) includes types I and III MPGN and DDD and is frequently idiopathic or associated with nephritic factors.
MPGN presenting in adults (typically older than 18 years) is usually type I or type III and is commonly associated with cryoglobulinemia and HCV infection
Epidemiology
The prevalence of MPGN type I is decreasing in Europe, presumably because some chronic infections are becoming less common.
On the contrary, in the Middle East (Saudi Arabia), South America (Peru), and Africa (Nigeria), MPGN type I is still quite common because of its association with chronic bacterial, viral, and parasitic infections.
DDD accounts for less than 20% of cases of MPGN in children and a very low percentage of cases in adults.
It is estimated to affect two to three people per million
Epidemiology – Indian scenario
Data from our centre
According to unpublished data by
Dr Sanjeev et al; biopsy regisrty data from 2010 to 2012
Incidence of MPGN is 11.3 % among total biopsy patients
M:F ratio is 2:1 Among MPGN patients, the incidence of C3GN
is 9.5%
Clinical features
The clinical presentation is similar to that in other types of glomerulonephritis.
In patients with active disease, the urine sediment reveals hematuria, typically with dysmorphic red cells and occasionally with red cell casts
There is a variable degree of proteinuria; The serum creatinine may be normal or elevated.
Clinical features…
Occasional patients with indolent disease present late in the course at a time when active inflammation has subsided.
Such patients may have a bland urine sediment with a variable degree of proteinuria and elevation in serum creatinine.
The diagnosis is made by renal biopsy
Clinical features
Among patients who have the different forms of MPGN there are generally no differences in clinical presentation with the possible exception of patients with DDD, which is a form of complement-mediated MPGN that is associated with drusen formation that may be seen on fundoscopic examination and with partial lipodystrophy
Lipodystrophy
Drusen are deposits of extracellular material, lying between the basement membrane of the retinal pigment epithelium and the inner collagenous zone of Bruch's membrane. Clinically, drusen are seen as yellowish deposits
Histopathology The term "MPGN" is derived from the two
characteristic histologic changes: Thickened glomerular basement membrane
(GBM) due to deposition of immune complexes and/or complement factors, interposition of the mesangial cell and other cellular elements between the GBM and the endothelial cell, and new basement membrane formation.
Increased mesangial and endocapillary cellularity, often leading to a lobular appearance of the glomerular tuft. The increase in cellularity results from both proliferation of mesangial cells and influx of circulating monocytes
Normal Glomerulus Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows)
Light micrograph of membranoproliferative glomerulonephritis (MPGN) showing thickening of all capillary walls with double contours (long arrows) and focal areas of cellular proliferation (short arrow). The double-contour or tram-track appearance represents interposition of mesangial cell elements with new glomerular basement membrane synthesis
Light micrograph in membranoproliferative glomerulonephritis showing a lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls (small arrows).
CLASSIFICATION BASED UPON ELECTRON MICROSCOPY
Membranoproliferative glomerulonephritis (MPGN) was initially classified into types I, II, and III based upon electron microscopy (EM).
MPGN type I — MPGN type I is characterized by discrete immune deposits in the mesangium and subendothelial space, similar to that seen in lupus nephritis, that are thought to reflect the deposition of circulating immune complexes.
Normal glomerulus
Electron micrograph in type I membranoproliferative glomerulonephritis shows marked thickening of the glomerular capillary wall by immune deposits (arrowhead) and by interposition of mesangial cell processes (arrow). There are two layers of the glomerular basement membrane (GBM) surrounding the mesangial interposition that account for the double-contour appearance on light microscopy.
CLASSIFICATION BASED UPON ELECTRON MICROSCOPY MPGN type II — MPGN type II (dense
deposit disease, or DDD) is characterized by continuous, dense ribbon-like deposits along the basement membranes of the glomeruli, tubules, and Bowman's capsule
Electron micrograph in dense deposit disease (DDD) showing dense, ribbon-like appearance of subendothelial and intramembranous material (arrow) and narrowing of the capillary lumen due to proliferation of cells (double arrow).
CLASSIFICATION BASED UPON ELECTRON MICROSCOPY
MPGN type III — MPGN type III is similar to MPGN type I except that subepithelial deposits are noted as well as subendothelial deposits
Membranoproliferative glomerulonephritis type III. This electron micrograph shows the irregular appearance of electron-dense, presumed immune aggregates within, outside, and under the glomerular capillary basement membrane.
CLASSIFICATION BASED UPON ELECTRON MICROSCOPYLimitations of this classification The EM-based classification can result in
overlap between types I and III. Not based on pathogenesis – Multiple
mechanisms of injury may result in a common pattern of injury.
In contrast, a classification that is based upon the pathogenetic process helps to direct the clinical evaluation and to provide disease-specific treatments.
New classification
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol 2011; 31:341.
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med 2012; 366:1119.
New classification
In the new classification system, MPGN is classified as being mediated by
1)Immune complexes, 2) Complement dysregulation that leads to
persistent activation of the alternative complement pathway
3) Mechanisms not involving immunoglobulin or complement deposition, such as endothelial injury (Rare)
Proposed classification of MPGN
Immune complex-mediated MPGN Immune complex-mediated MPGN is
characterized by the presence of immune complexes and complement components.
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
Immune complex-mediated MPGN Immunofluorescence microscopy may
suggest the underlying etiology of immune complex-mediated MPGN
Immune complex-mediated MPGN
Infection Immune complex-mediated MPGN is most
commonly secondary to hepatitis C and B viral infections* ??
The incidence of HCV-associated MPGN varies with location.
HCV-induced MPGN is typically associated with mixed cryoglobulinemia.
Immune complex-mediated MPGN ; Infection MPGN resulting from hepatitis C virus
infection typically shows granular deposition of IgM, C3, and both kappa and lambda light chains.
IgG may or may not be present, and C1q is typically negative.
This pattern may also be seen with MPGN induced by other viral infections .
Immune complex-mediated MPGN; Infection
EM: Fingerprint pattern associated with cryoprecipitates is seen in mixed cryoglobulinemia*
*Rarely with Lupus
High power electron micrograph of a cryoprecipitate in the mesangium, showing the characteristic substructure which often has a "fingerprint" appearance (arrows).
Immune complex-mediated MPGN; Infection
Chronic bacterial (eg, endocarditis, shunt nephritis, abscesses), fungal, and, particularly in the developing world*, parasitic infections (eg, schistosomiasis, echinococcosis) can cause MPGN
Immune complex-mediated MPGN
Autoimmune disorders Immune complex-mediated MPGN is
observed in patients with systemic lupus erythematosus (particularly in the chronic phase of lupus nephritis)
Rarely in Sjögren's syndrome or rheumatoid arthritis
Immune complex-mediated MPGN: Autoimmune disorders
MPGN resulting from autoimmune diseases is typically characterized by the "full house" pattern of immunoglobulin deposition, including IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains
Immune complex-mediated MPGN; Autoimmune disorders EM: Tubuloreticular structures in
endothelial cells in MPGN are suggestive of lupus nephritis
Electron micrograph in diffuse proliferative lupus nephritis shows massive subendothelial deposits (D) and characteristic tubuloreticular structures (arrow) in the endothelial cells (En). The subendothelial deposits cause marked thickening of the glomerular capillary wall, leading to a wire loop appearance on light microscopy
Immune complex-mediated MPGN: Dysproteinemia
Dysproteinemias are an important cause of MPGN and can be associated on immunofluorescence microscopy with:
Monoclonal immunoglobulin deposition
Immune complex-mediated MPGN: Dysproteinemia MPGN resulting from monoclonal
gammopathy is characterized by deposition of monotypic kappa or lambda light chains but not both.
MPGN associated with heavy-chain deposition may show immunoglobulin deposition (heavy-chain isotypes) in the absence of either light chain
Immune complex-mediated MPGN: Dysproteinemia
The clinical features and prognosis of MPGN associated with monoclonal gammopathy are:
Nephrotic syndrome (49%) Renal insufficiency (68%) Hematuria (77%) End-stage renal disease (ESRD) (22%)
Immune complex-mediated MPGN: Dysproteinemia Cases of MPGN in patients with chronic
lymphocytic leukemia have also been described, usually in association with mixed cryoglobulinemia or noncryoprecipitating monoclonal IgG or IgM
Immune complex-mediated MPGN: Rare causesRare causes of MPGN include Non-Hodgkin lymphoma, Renal cell carcinoma, Snake venom Splenorenal shunt surgery for portal
hypertension Melanoma Alpha-1-antitrypsin deficiency.
Complement-mediated MPGN
Complement-mediated MPGN
There are two main pathways: The classic pathway, which is activated when
IgG or IgM antibodies bind to antigens; The alternative pathway, which does not require
the presence of antibodies and can be autoactivated by spontaneous cleavage of C3 to C3b, leading to the formation of C3 convertase
Omplement path
Complement-mediated MPGN
Complement-mediated MPGN is less common than immune complex-mediated MPGN and results from dysregulation and persistent activation of the alternative complement pathway.
Complement-mediated MPGN
This form of MPGN is due to the deposition of complement products along the capillary walls and in the mesangium.
Immunofluorescence microscopy of kidney sections demonstrates bright C3 staining, but NO immunoglobulin staining, in the mesangium and along the capillary walls.
Complement-mediated MPGN
Complement-mediated MPGN may be further classified based upon ultrastructural features observed on EM as DDD or C3GN.
Some genetic mutations that have been associated with these disorders are also associated with atypical hemolytic uremic syndrome.
Hypocomplementemia is a characteristic finding in most patients with MPGN.
Complement-mediated MPGN
A normal C3 concentration does not exclude complement-mediated MPGN, and it is not unusual to find a normal C3 concentration in the chronic phases of the disease, as in adults with DDD or patients with C3GN.
Complement-mediated MPGN:Dense deposit disease (DDD) Dense deposit disease (DDD, also called MPGN type II)
is a rare form of MPGN that affects both children and young adults.
It has also been associated with monoclonal gammopathies in older adults.
On light microscopy, patterns of injury other than MPGN can also be seen:
a) Mesangial proliferative b) Diffuse proliferative c) Crescentic glomerulonephritis d) Sclerosing glomerulopathy.
Complement-mediated MPGN:Dense deposit disease (DDD) C3 convertase-stabilizing antibody (called
C3 nephritic factor or C3NeF) is found in approximately 80 percent of patients with DDD and results in activation of the alternative complement pathway that characterizes DDD
Complement-mediated MPGN:Dense deposit disease (DDD) Immunofluorescence microscopy demonstrates
C3 deposits EM (required to establish the diagnosis) shows
the characteristic sausage-shaped, wavy, densely osmophilic deposits along the glomerular basement membranes (GBM) and mesangium (from which the disease receives its name)
Complement-mediated MPGN:C3 Glomerulonephritis (C3GN) C3 glomerulonephritis (C3GN, also called
glomerulonephritis with isolated C3 deposits) is, like DDD, caused by excessive activation of the alternative complement cascade due to mutations in or antibodies to complement regulating proteins
C3GN has also been reported in association with monoclonal gammopathies and anti-factor H activity.
Complement-mediated MPGN:C3 Glomerulonephritis (C3GN) Light microscopy often shows an MPGN
pattern of injury Other forms of glomerulonephritis may be seen (mesangial
proliferative, diffuse proliferative, crescentic glomerulonephritis,sclerosing glomerulopathy)
Immunofluorescence microscopy shows extensive C3 deposition along the capillary walls and mesangium with NO significant immunoglobulin deposition
Immunofluorescence microscopy showing bright granular C3 staining on the mesangium and along capillary walls in a patient with C3 glomerulonephritis (40x).
Fig
Complement-mediated MPGN:C3 Glomerulonephritis (C3GN) EM demonstrates deposits that are similar
to those seen with immune complex-mediated MPGN but does not show the typical sausage-shaped intramembranous and mesangial deposits observed in DDD
Complement-mediated MPGN:C3 Glomerulonephritis (C3GN) Patients with C3GN typically present with proteinuria,
which can be associated with nephrotic syndrome, hematuria (sometimes synpharyngitic), and variable degrees of hypertension and azotemia.
C3 levels are usually low, C4 levels are normal, and some patients have a C3 convertase-stabilizing autoantibody called C3 nephritic factor (or C3NeF), which is also seen in DDD
Normal C3 does not exclude C3GN There may be progression to ESRD, and C3GN can
recur after renal transplantation.
Complement-mediated MPGN: CFHR5 nephropathy Familial form (Cypriots) of C3GN – Autosomal Dominant
with 90% penetration. It is due to a mutation in the gene for complement factor
H-related protein 5 (CFHR5) The clinical manifestations include: - Hematuria in approximately 90 percent ( often
synpharyngitic) - Proteinuria in 38 percent. Men are much more likely than women to develop
chronic kidney disease and ESRD Recurrent nephropathy can occur in transplanted
kidneys. There is no treatment of proven efficacy.
MPGN without immunoglobulin or complement deposition A histologic pattern that may resemble MPGN on light
microscopy can be seen in: a) Healing phase of thrombotic microangiopathies (eg,
thrombotic thrombocytopenia purpura-hemolytic uremic syndrome)
b) Antiphospholipid antibody syndrome, c) Nephropathy associated with bone marrow
transplantation, d) Chronic renal allograft nephropathy e) Radiation nephritis f) Malignant hypertension. g) Scleroderma
MPGN without immunoglobulin or complement deposition The common underlying cause of the MPGN
pattern in such patients is endothelial injury followed by reparative changes.
Immunofluorescence microscopy does not show significant immunoglobulin or complement deposition in the glomeruli, and EM does not show electron dense deposits along the capillary walls.
Idiopathic MPGN is a diagnosis of exclusion
Management of MPGN
The management of MPGN depends upon the underlying cause as most patients have either a circulating immune complex disease or dysregulation of the alternative complement pathway.
Management of MPGN
Immune complex-mediated MPGN —Patients who have such findings should be evaluated for the following disorders before treatment for MPGN is initiated.
Management of MPGN
Infections Hepatitis B and hepatitis C virus should be
excluded by serology. Chronic bacterial infections should be excluded
by culture, including blood cultures. Test for fungi in the presence of a suggestive
history (eg, fever of unknown origin, unexplained pulmonary infiltrates)
Test for Parasitic infections (eg, malaria, schistosomiasis, leishmaniasis) as appropriate.
Management of MPGN
Autoimmune diseases Screening as appropriate according to age
and clinical scenario.
Management of MPGNMonoclonal gammopathy Monoclonal gammopathies should be excluded
by serum protein electrophoresis or serum free light chains and urine electrophoresis and immunofixation.
Most patients with MPGN and a monoclonal gammopathy have no identifiable disease; this disorder has been called MPGN associated with monoclonal gammopathy of uncertain significance (MGUS).
Management of MPGNMonoclonal gammopathy
Occasionally patients with a monoclonal gammopathy and MPGN have a serious and potentially treatable cause.
These include multiple myeloma, low-grade B cell lymphoma, and chronic lymphocytic leukemia.
These disorders may be diagnosed at presentation or later after an initial diagnosis of monoclonal gammopathy of undetermined significance
Treatment of these disorders can lead to improvement in the MPGN.
Evaluation of Complement-mediated MPGN Patients should undergo an evaluation for
activation of the alternative pathway of complement.
Including measuring C3, C4, CH50 (which provides a measure of activation of the classic complement pathway), and AH50 (which provides a measure of activation of the alternative complement pathway).
Genetic analysis for mutations and allele variants of complement factors are done if indicated (Research laboratories)
Normal C3 levels does not rule out a complement-mediated MPGN
Management of MPGN Treatment of the glomerulonephritis The treatment of secondary MPGN is directed at
treatment of the underlying condition since the renal disease often resolves with treatment of causes such as infection, autoimmune disorders, and monoclonal gammopathy.
When an inciting condition is present (eg, infection), resolution of the MPGN usually occurs after successful treatment of the primary disease, such as antiviral therapy in MPGN due to hepatitis C or B virus.
Immunosuppressive therapy is both unnecessary and potentially deleterious in patients with hepatitis
At least partial remission of MPGN can also be induced with early antimicrobial therapy of bacterial endocarditis or an infected ventriculoatrial shunt .
Management of MPGN
Chemotherapy in chronic lymphocytic leukemia and treatment of multiple myeloma leads to resolution of MPGN.
The optimal therapy of MPGN in patients with a monoclonal gammopathy of undetermined significance (MGUS) is uncertain.
Guidelines suggest treating patients with a non-IgM MGUS with a regimen used to treat multiple myeloma.
In patients with an IgM MGUS, a regimen used to treat Waldenstrom macroglobulinemia is advised.
Management of MPGN Treatment of the glomerulonephritis
Once treatable underlying causes of MPGN have been excluded, three conditions remain:
i) Idiopathic immune complex-mediated MPGN
ii) C3 glomerulonephritis
iii) Dense deposit disease
Management of MPGN Idiopathic immune complex-mediated MPGN
The prevalence of idiopathic immune complex-complex mediated MPGN has not been well defined.
There are no randomized trials upon which to base treatment recommendations for patients with idiopathic immune complex-mediated MPGN
Treatment is generally determined by the severity of kidney dysfunction.
Management of MPGN Idiopathic immune complex-mediated MPGN
Patients who have a normal estimated GFR and non-nephrotic range proteinuria may be treated conservatively with angiotensin inhibitors alone (Grade 1B) in order to control blood pressure and reduce proteinuria – To be followed up regularly for progression.
Management of MPGN Idiopathic immune complex-mediated MPGN
Immunosuppressive therapy Indications for immunosuppressive therapy
include i) Nephrotic range proteinuria, ii) Reduced estimated glomerular filtration, iii) Severe histologic changes on renal biopsy
(eg, crescents) at baseline iv) Progressive disease over time with
angiotensin inhibitors alone.
Management of MPGN Idiopathic immune complex-mediated MPGN
Nephrotic syndrome, normal or near normal creatinine:
Prednisolone at 1 mg/kg per day (maximum dose 60 to 80 mg/day) for 12 to 16 weeks. (Grade 2C)
If the patient responds, prednisone is gradually tapered to alternate day therapy over six to eight months.
If there is less than a 30 percent reduction in proteinuria after 12 to 16 weeks, to taper and discontinue prednisone.
To initiate angiotensin inhibition therapy at the same time.
Calcineurin inhibitors may be considered in patients who do not respond to or tolerate glucocorticoids.
Management of MPGN Idiopathic immune complex-mediated MPGN
Elevated serum creatinine, with or without nephrotic syndrome and/or hypertension, and without crescents:
Initial therapy with prednisone (1 mg/kg per day, maximum dose 60 to 80 mg/day). (Grade 2C)
If there is no response or there are increases in the serum creatinine and/or proteinuria, to add Cyclophosphamide (Grade 2C) for three to six months.
In patients with persistent disease activity despite cyclophosphamide, to stop cyclophosphamide and give a trial of rituximab (ungraded)
Management of MPGN Idiopathic immune complex-mediated MPGN
Rapidly progressive disease with or without crescents
Patients with rapidly progressive crescentic MPGN be treated with glucocorticoids and cyclophophamide as in crescentic GN. (Grade 1B)
Management of MPGN Idiopathic immune complex-mediated MPGN
No proven role in current scenario* Mycophenolate mofetil Antiplatelet agents Anticoagulants
*Previous studies showed uncertain benefit; studies conducted before elucidation of underlying pathogenetic mechanisms
Management of MPGN C3 glomerulonephritis There are no trials that have evaluated therapy in C3
glomerulonephritis. Patients who have nephrotic range proteinuria or a decreased estimated GFR may be treated according to the cause, if one is identified:
Patients with C3 glomerulonephritis due to autoantibodies to a complement protein may benefit from immunosuppressive therapy
(eg: glucocorticoids, rituximab) Patients with a genetic mutation in the complement
cascade may benefit from treatment with drugs that inhibit formation of the membrane attack complex (MAC) such as eculizumab.
Patients with MPGN secondary to factor H deficiency may benefit from treatment with plasma infusion
Management of MPGNTreatment of DDD/C3GN Plasma infusion or exchange is first line therapy
for patients with DDD or C3 glomerulopathy who have factor H defects, elevated C3NeF, or monoclonal gammopathy.
There are no data, other than at the case report level, that this intervention alters disease prognosis.
Immunosuppressive therapies not specifically targeted to DDD, such as corticosteroids, cyclophophamide, and calcineurin inhibitors, have either been unsuccessful or not studied adequately.
Management of MPGNTreatment of DDD/C3GN Factor H defects — treated with periodic
infusions of fresh frozen plasma (FFP) to replace the missing or mutant protein
Elevated C3NeF and normal factor H — Patients who have circulating C3NeF levels but normal factor H levels and activity should undergo plasma exchange with albumin.
Duration and frequency of the above regimens unclear, to be continued indefinitely or till there is remission.
Management of MPGNPoor prognostic signs at presentation: Nephrotic syndrome Elevated serum creainine Hypertension (or blood pressure well above the
patient’s previous baseline) Crescents on renal biopsy Tubulointerstitial disease* (interstitial
inflammation, fibrosis, and tubular atrophy) Greater degree of hematuria (eg, 50 or more
versus 5 to 20 red blood cells per high power field) suggest more inflammation but there is no evidence of an independent effect on prognosis.
Membranoproliferative glomerulonephritis: Recurrence after transplantation MPGN TYPE I — The reported rate of
recurrent disease in idiopathic MPGN type I has usually ranged between 20 and 30 percent, the incidence in children is generally higher.
According to United Network for Organ Sharing (UNOS) database, the incidence of allograft loss at 10 years due to recurrent MPGN type I was 14.5 percent,
Membranoproliferative glomerulonephritis: Recurrence after transplantation
Patients with recurrent disease may remain asymptomatic, although the majority of patients with recurrent MPGN tend to present with proteinuria, hematuria and hypertension.
Hypocomplementemia may be associated with recurrent disease.
Disease recurrence can occur in the absence of this finding.
Membranoproliferative glomerulonephritis: Recurrence after transplantation
There is no proven beneficial therapy for the treatment of recurrent idiopathic MPGN
Role of Cyclosporine is uncertain. Some investigators have found that the rate of recurrence fell from 30 to 10 percent after the introduction of cyclosporine
Aggressive treatment using plasmapheresis and adjuvant immunosuppression may be warranted in the setting of rapidly worsening graft function or histologic findings suggestive of rapidly progressive disease.
Membranoproliferative glomerulonephritis: Recurrence after transplantation
DENSE DEPOSIT DISEASE: It recurs more frequently than MPGN type I,
ranging from 50 to 100 percent in various series Affected patients typically present within one
year following transplantation with non-nephrotic range proteinuria.
In the UNOS analysis, graft loss due to recurrent MPGN type II was 29.5 percent
Pediatric patients have worse prognosis and outcomes.
Membranoproliferative glomerulonephritis: Recurrence after transplantation
TREATMENT OF Recurrent DDD There is no known effective therapy Suggested interventions included a) Plasmapheresis, b) Substitution of tacrolimus for cyclosporine c) Reduction in the dose or discontinuation of the
calcineurin inhibitor, d) Increase in the corticosteroid dose, or the
administration of pulse methylprednisolone Successful treatment of recurrent MPGN II has been
described with eculizumab. Other treatment measures as discussed before for
DDD/C3GN
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