Membranoproliferative glomerulonephritis N05.5

Membranoproliferative glomerulonephritis" is a genetically heterogeneous group of immune-mediated, chronic progressive renal diseases that occur at any age and are characterized by superimposed nephritic and nephrotic symptoms and by a common histopathological renal finding of thickening of the glomerular basement membrane (GBM) and proliferation of mesangial cells.

Idiopathic membranoproliferative glomerulonephritis (diagnosis of exclusion)

Secondary membranoproliferative glomerulonephritis

• Secondary membranoproliferative glomerulonephritis with mixed cryoglobulinemia
• Secondary membranoproliferative glomerulonephritis without detectable cryoglobulinemia

The MPGN occurs worldwide with varying incidences (Nakagawa N et al. 2018). The primary (idiopathic) MPGN affects children and young adults between the ages of 8 and 30; the primary MPGN accounts for 10% of cases of nephrotic syndrome in children. The secondary MPGN mainly affects adults > 30 years of age. M:w=1:1.

This group of diseases is caused by an immune complex deposition, which is idiopathic in the primary MPGN, in the secondary MPGN due to a systemic disorder (e.g. cryoglobulin Sethi S et al. 2017). Reports of individual family cases also suggest genetic factors in these forms.

In the secondary form of membranoproliferative glomerulonephritis an uncontrolled activation of the alternative pathway of the complement cascade seems to be pathogenetically significant. In more than 80 % of the affected persons an autoantibody against the C3-convertase of the alternative pathway C3bBb is found, which means that it can no longer be deactivated by factor H.

Men and women are equally affected. The primary (idiopathic) type of MPGN affects children and young adults between the ages of 8 and 30 (and accounts for 10% of the nephrotic syndrome in children. The secondary MPGN mainly affects adults > 30 years of age.

The MPGN is conspicuous at the initial diagnosis in 60-80% of cases by a nephrotic syndrome. 30% of patients have hypertension and 20% renal insufficiency. Superimposed symptoms of glomerulonephritis are detectable in about 15-20% of cases.

An important indication is hypocomplementaemia in about 75% of MPGN patients (Larsen CP et al. 2015).

Note: Patients with type 2 MPGN suffer from a higher incidence of eye anomalies (basal laminar drusen, diffuse retinal pigmentation, disc-shaped maculopathy, choroidal neovascularization), which eventually impair visual acuity.

In type I, panhypocomplementaemia is often found: C3↓, C4↓ and CH50↓; possible are positive hepatitis and HBV serology; possible detection of cryoglobulins or cryofibrinogen

The diagnosis is confirmed by renal biopsy. Light microscopy reveals conspicuous thickening of glomerular capillary loops with subendothelial deposits of immunoglobulins including complement (Lionaki S et al. 2016) and proliferation of mesangial cells. The location of the immune complex deposits largely defines the classification of the disease. In general, type 1 deposits are found subendothelially and mesangially, type 2 intramembranously, and type 3 subepithelially. All 3 histopathological types may be idiopathic or have secondary causes.

• Type 1 (80%): Membranoproliferative glomerulonephritis with subendothelial and mesangial deposits of immune complexes (IgG, IgM, C3): Type 1 most commonly occurs secondary to one of the following conditions:
  • Systemic autoimmune diseases: SLE, mixed cryoglobulinemia, Sjögren's syndrome.
  • Chronic infectious diseases e.g. bacterial endocarditis, visceral abscesses, HIV infection, hepatitis B or C infections, ventriculoatrial shunt infections.
  • Tumor diseases e.g. chronic lymphocytic leukemia, T-cell lymphomas (Wu SC et al.2017), melanomas; renal cell carcinomas (Mogili HK et al. 2017).
  • Other diseases e.g. partial lipodystrophy, C2 or C3 deficiencies, sarcoidosis, thrombotic microangiopathy.
• Type 2 (15-20%) Dense Deposite Disease: comparable to type 1; however, less mesangial proliferation; deposition of deposits at the glomerular basement membrane and in the mesangium (OMIM: 609814).
• Type 3 is considered a form similar to type 1 and is rare. The cause is unknown but may be related to immune complex deposition (IgG, C3). An IgG autoantibody against the terminal component of complement is found in 70% of patients.

The diagnosis is a histological diagnosis and is made by kidney biopsy.

Treatment consists, when indicated, in the administration of corticosteroids and antiplatelet drugs.

Corticosteroids in children with proteinuria in the nephrotic area

Kidney transplantation in patients with advanced MPGN

In the case of secondary MPGN, the underlying diseases should always be treated curatively, if possible. Specific nephrological therapy is not indicated in patients with non-nephrotic proteinuria.

In children with nephrotic syndrome, treatment with corticosteroids can stabilize renal function (e.g. prednisone 2.5 mg/kg p.o. once a day every 2 days [up to a maximum of 80 mg] for 1 year, followed by weaning up to a maintenance dose of 20 mg every 2 days for 3-10 years). However, (long-term) therapy with corticosteroids can delay growth and trigger hypertension.

Alternative: Eculizumab (Soliris©): antibody against C5
,Alternative: Rituximab (Mabthera©): antibody against CD20(only in patients with evidence of C3NeF, C3 consumption and absence of CFH mutation)

Alterative: plasmapheresis (only in patients with C3NeF, C3 consumption and absence of CFH mutation)

Alterative: Plasma infusion: 10-15 ml/kg KG FFP every 14 days (for inactivating CFH mutations, possibly also for risk alleles. Cave volume load

Note: Studies on antiplatelet therapy lead to inconsistent results.

Approximately 50% of patients develop end-stage kidney disease after 10 years and approximately 90% after 20 years. The idiopathic membranoproliferative glomerulonephritis type 1 often progresses slowly and progressively, whereas type 2 is fast. A spontaneous remission occurs in < 5% of cases with type 2.

Type 1 membranoproliferative glomerulonephritis recurs in 30% of patients with kidney transplantation. Type 2 recurs in 90%, but despite the high recurrence rate, it rarely leads to loss of the transplant. Overall, the prognosis worsens if the proteinuria is in the nephrotic area. This is particularly true for older patients (Nakagawa N et al. 2018).

The prognosis is favourable if the cause of secondary membranoproliferative glomerulonephritis is successfully treated.

1. Alasfar S et al (2016) Membrane proliferative glomerulonephritis recurrence after kidney transplantation:using the new classification. BMC Nephrol 17:7.
2. Erlij D et al (2016) Polyarthritis and membranoproliferative glomerulonephritis as paraneoplastic manifestation of Hodgkin's lymphoma: A case report and literature review. Reumatol Clin 12:282-284.
3. Larsen CP et al (2015) Membrane proliferative glomerulonephritis with masked monotypic immunoglobulin deposits. Kidney Int 88:867-873.
4. Lionaki S et al (2016) Understanding the complement-mediated glomerular diseases: focus on membranoproliferative glomerulonephritis and C3 glomerulopathies. APMIS 124:725-735.
5. Masani N et al (2014) Update on membranoproliferative GN. Clin J Am Soc Nephrol 9:600-608.
6. Mogili HK et al (2017) Association of membranoproliferative glomerulonephritis with renal cell carcinoma. Nephrology (Carlton) 22:95-96.
7. Nakagawa N et al (2018) Clinical features and pathogenesis of membranoproliferative glomerulonephritis: a nationwide analysis of the Japan renal biopsy registry from 2007 to 2015 Clin Exp Nephrol 22:797-807 .
8. Sethi S et al (2012) Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med 366:1119-1131.
9. Sethi S et al (2017) Cryofibrinogen-associated glomerulonephritis. On J Kidney Dis 69:302-308.
10. Wu SC et al (2017) Hepatosplenic T-cell lymphoma associated with membranoproliferative glomerulonephritis. Leuk lymphoma 58:2734-2737.