Membranous glomerulonephritisN04.2 N06.2

Primary (idiopathic) membranous glomerulonephritis is an immune complex nephritis in which local formation of immune complexes below the podocytes (subepithelial) occurs.

In secondary membranous glomerulonephritis the autoimmunological character has not been proven so far (Couser WG 2017).

In Europe, membranous glomerulonephritis is the most common cause of nephrotic syndrome in adults.

Primary (idiopathic) membranous glomerulonephritis: 75% of MGNs

Secondary membranous glomerulonephritis: 25% of MGNs. Occurs in infectious diseases(hepatitis B or C, HIV, syphilis, malaria), autoimmune diseases (e.g. in SLE) malignancies, drugs (gold salts, penicillamine, bucillamine, non-steroidal anti-inflammatory drugs, mercaptopropionylglycine, high-dose captopril, and monoclonal antibodies such as Etanercept, Infliximab and Adalimumab).

Occurs in all ethnic groups; m: w = 1:1; in adulthood the membranous glomerulonephritis is the most frequent cause of nephrotic syndrome. It is associated with high proteinuria, microhaematuria, edema and hypertension.

Primary (idiopathic) membranous glomerulonephritis:

• In idiopathic membranous glomerulonephritis, circulating antibodies against the M-type phospholipase A2 receptor protein (PLA2R1) are detected in 80% of cases. The receptor protein PLA2R1 is expressed in the podocytes of the glomeruli. In primary membranous glomerulonephritis, PLA2R1 is also detected in the immune depots of the glomeruli.
• In 10% of cases of primary membranous glomerulonephritis, antibodies against thrombospondin type 1 domain 7A (THSD7A) can also be detected (Tomas NM et al. 2014). The THSD7A antigen can also be detected in the walls of the glomerulus capillaries in THSD7A-positive patients (Sharma SG et al. 2018).
• Clinical data indicate that the level of PLA2R1 antibodies correlates with disease activity (Radice A et al. 2016). The depressed immune complexes damage the podocytes and cause proteinuria and nephrotic syndrome.
• The extent to which antibodies against some rare antigens such as a neutral endopeptidase play a pathogenetic role has not yet been clarified (Kronbichler A et al. 2017, see below).
• T-helper cells: Besides antibodies, T-helper cells are also involved in the pathogenesis of glomerulonephritides. In membranous glomerulonephritis, as in minimal change glomerulonephritis, Th2 helper cells predominate.
• Genetics: In a larger genome-wide association study, association with two single nucleotide polymorphisms was detected. On chromosome 2q24 an association was found with the gene for phospholipase A₂ receptor type M (PLA2R1). A closer association was found with an allele on chromosome 6p21, which codes for an HLA class II antigen (HLA-DQA1).

Secondary membranous glomerulonephritis:

• The causes are manifold. So far, no specific autoantibodies have been detected. Nevertheless, an anti-podocyte antibody that has not been identified to date is suspected (Couser WG 2017).
• In systemic lupus erythematosus, membranous glomerulonephritis is found in about 10-20 % of cases with kidney involvement. Kidney disease can precede the manifestation of systemic lupus erythematosus. In young women with "primary membranous glomerulonephritis", the diagnosis SLE (ANA and DNA-AK positive) should always be considered.
• In about 5-20 % of adults with secondary membranous glomerulonephritis (especially in patients > 65 years of age) there is an oncological condition (tumours of the lung, gastrointestinal malignancies, more rarely malignancies of the haematopoietic system).
• Secondary membranous glomerulonephritis can also occur after kidney or stem cell transplantation.
• Less frequent causes of secondary membranous glomerulonephritis are: schistosomiasis, malaria quartana, syphilis, sarcoidosis, Sjögren's syndrome and chronic exposure to formaldehyde. Mercury compounds used e.g. in traditional Chinese medicine or (rarely today) in skin whitening creams may also lead to membranous nephritis.

Special case: The transient membranous glomerulonephritis of the newborn:

• In human glomerulus the podocytes express the enzyme neutral endopeptidase. In rare cases, mutations of the coding gene lead to a loss of this enzyme. Thus, during the first pregnancy, the mother may be immunised (the kidneys of the healthy fetus express this enzyme). During a further pregnancy, maternal antibodies against neutral endopeptidase can pass through the placenta. They then induce membranous glomerulonephritis with nephrotic syndrome in the fetus. As the maternal antibodies disappear from the baby's blood after some time after birth, the immune depots in the kidney also dissolve again. The nephrotic syndrome heals spontaneously.

Increased incidence among Caucasian males > 40 years. In THSD7A-positive patients the m: w-quotient was 1.6 with a mean age of 62 years (Sharma SG et al. 2018). In younger women with membranous glomerulonephritis, lupus nephritis (SLE) should always be considered. In children, membranous glomerulonephritis is rarer and is often associated with hepatitis B.

Nephrotic syndrome (80%), asymptomatic proteinuria (20%), hypertension (30%), microhematuria (50%), creatinine > 2 mg/dl (10%), normal complement levels (local formation), relatively frequent thrombotic complications (renal vein thrombosis).

Classified according to 3 risk groups:

• Low risk: Normal creatinine clearance proteinuria <4g/day, stable renal function over 6 months.
• Medium risk: normal creatinine clearance proteinuria >4g - <8g/day, stable renal function over 6 months
• High risk: Proteinuria >8g/day for 3 months, impaired renal function (development of chronic renal failure within 5 years)

Urine: Proteinuria

The blood test usually shows a reduction in albumin and hyperlipidemia of varying degrees of severity

In primary MGN, serological detection of anti-PLA2R-AK in 80% of cases; detection of anti-THSD7A-AK in 10% of cases.

Antinuclear antibody (ANA). A high titre indicates the presence of systemic lupus erythematosus.

Complement factor C3. A reduction in complement factor C3 is found in systemic lupus erythematosus and hepatitis B. In primary (idiopathic) membranous glomerulonephritis, C3 levels are normal.

Virus diagnostics (HIV, evidence of hepatitis or EBV infection)

others: detection of p- and cANCA, detection of glomerular anti-basement membrane antibodies;

Diffuse thickening of the glomerular basement membrane due to subepithelial accumulation of immune complexes on the outside of the glomerular basement membrane In early stages the glomeruli may appear inconspicuous. In more advanced stages, fine extensions, so-called spikes, are found on the subepithelial side of the basement membrane. As the disease progresses, sclerosis of the glomeruli and changes in tubules occur.

Electron microscopy shows electron-tight deposits on the outside of the glomerular basement membrane, a fusion of the overlying foot processes of the podocytes and a widening of the basement membrane due to the deposition of newly formed extracellular matrix. In the course of the disease (stage IV) the immune depots are finally completely enclosed by the basement membrane.

The degree of changes in the basement membrane allows a histological (fine tissue) classification of the stages (stages I-IV), which, however, does not always correlate with the severity of the disease.

• Stage I: Isolated small immunodepots without thickening of the basement membrane.
• Stage II: More extensive immune depots with spikes between the depots and thickening of the basement membrane.
• Stage III: The immunodepots are completely surrounded by basement membrane (intramembrane immunodepots), the basement membrane is thickened.
• Stage IV: Irregular thickening of the basement membrane which completely encloses the immune complexes.

DIF: In direct immunofluorescence, granular deposits of IgG and complement fractions C3 and C5b-9 as well as anti-PLA2R-Ak are found, and in the THSD7A-positive collective also THSD7A antigens and antibodies along the glomerular capillary loop (Couser WG 2017; Sharma SG et al. 2018).

The diagnosis is made bioptically.

Characteristic are the deposition of immune complexes on the outside of the glomerular basement membrane. Detectable are C3, IgG, as well as anti-PLA2R antibodies and in about 10% of the cases THSD7A antibodies (Cohen CD et al. 2017).

Acute renal vein thrombosis

Increased risk of cardiovascular disease (Lee T et al 2016).

Rapid progressive glomerulonephritis: In about 5% of cases of membranous glomerulonephritis, "Rapid progressive glomerulonephritis" may complicate the primary clinical picture.

Other superimposed glomerular kidney diseases: Membranous glomerulonephritis has also been described together with "focal segmental glomerulosclerosis" or with diabetic nephropathy.

Furthermore, a co-occurrence of membranous glomerulonephritis with IgA nephropathy, Goodpasture 's syndrome or Wegener's granulomatosis has been described (Hu R et al. 2016).

General therapy measures: All patients with PMN should receive a general internal therapy specifically geared to the predominant symptoms. It has the following goals (Couser WG 2017)

• Control of edema with diuretics
• Ensuring an adequate food supply
• Reduction of proteinuria
• Adjustment of existing hypertension (ACE inhibitors / AT1 antagonists)
• Therapy of an often pronounced hyperlipidemia with statins
• Prevention of thromboembolic complications (when the serum albumin level drops < 2 g/dl). Application of anticoagulant substances.

Primary membranous glomerulonephritis

Low risk: General measures for the treatment of nephrotic syndrome (see above; see below nephrotic syndrome)

Medium risk: Immunosuppressive therapy (due to the favourable prognosis of the disease, immunosuppressive therapy is only given if there is evidence of an unfavourable prognosis (van de Logt AE et al.2016):

• Patients without symptoms in whom proteinuria is < 3.5 g/day are generally not treated immunosuppressively (Hofstra JM et al. 2013; long-term prognosis is favourable).
• Patients without symptoms, or with mild diuretic controlled edema, in whom proteinuria is > 3.5 g/day should be observed over a longer period of time before immunosuppressive therapy. In this clientele, spontaneous remission occurs in up to 65 % of patients under general therapy. This is particularly true for women, children and young adults with normal kidney function and a prognostically favourable fine tissue finding.

High risk: Patients with a poor prognosis are treated with various immunosuppressive drugs (Li C et al. 2017). The optimal duration of immunosuppressive treatment is not known.

The following clinical constellations justify an immunosuppressive therapy:

• renal function impairment which cannot be explained by a lack of volume and in case of prognostically unfavourable fine tissue findings (e.g. fibrosis of glomeruli and interstitium of the kidney)
• in case of severe symptomatic nephrotic syndrome with pronounced edema, severe hyperlipidemia and proteinuria above 10 g/day
• if there is clear evidence of progressive renal dysfunction
• in > 50-year-old men with persistent nephrotic syndrome
• in the presence of thromboses and/or embolisms as a complication of nephrotic syndrome (van de Logt AE et al.2016).

Cyclophosphamide and chlorambucil are usually used in combination with prednisone. This combination seems to be the most effective form of treatment (Cave: side effects). Therapy scheme for prednisolone/cyclophosphamide:

• 1st month: Methylprednisolone 1g/day for 3 days, followed by prednisolone 0,5mg/kg bw/day for 4 weeks
• 2nd month: cyclophosphamide 2-2,5mg/kg bw/day
• 3rd and 5th month: same as month 1
• 4th and 6th month: same as month 3
• (Cryopreservation of sperm and oocytes; osteoporosis prophylaxis, ulcer prophylaxis with a proton pump inhibitor, PCP prophylaxis with Cotrimoxazole)

Alternative: monotherapy with cortisone. Therapy is less stressful, but the response rates are generally not satisfactory.

Alternative: Cyclosporine A, possibly in combination with prednisone

Alternative: In a smaller study tacrolimus was shown to be an efficient therapy option both monotherapeutically and combined with prednisolone (Liang Q et al. 2017)

Alternative: Rituximab has been shown to reduce proteinuria. In an Italian study, 10/50 patients experienced a complete remission of the disease. Comparative studies with ACE inhibitors/AT1 antagonists and long-term observations are missing so far.

Alternative: Intravenous administration of immunoglobulins. In individual case reports an improvement of proteinuria has been described.

Note: Mycophenolate-mofetil and azathioprine may not have any effect on the course of the disease. Non-steroidal anti-inflammatory drugs also reduce proteinuria, but should not be used because of their potentially kidney-damaging effect.

The course of primary membranous glomerulonephritis is highly variable. About 30% of cases heals spontaneously, about 30% remains stable during the course and about 30% of cases develops chronic renal failure. Remissions are accompanied by a decrease or complete disappearance of anti-PLA2R antibodies. Since the antibody titer correlates with disease activity, it can be used for therapy decisions and therapy monitoring.

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