Membranous glomerulonephritis

Caused by accumulation of immune deposits in the subepithelial aspect of the glomerular basement membrane, leading to podicyte damage and proteinuria.

70-80% of patients with this condition have antibodies that target the phospholipase A2 receptor on the podocyte surface develop.

The M-type phospholipase A2 receptor is the target antigen  in approximately 70% of patients with primary membranous nephropathy.

Primary membranous nephropathy is an isolated kidney disease resulting from auto antibodies directed against endogenous podocyte specific antigens in the absence of an identifiable cause,accounts for most cases.

These antibodies are predominately IgG4 and or unable to activate the classic complement pathway.

Membranous nephropathy has an incidence of approximately one case per hundred thousand persons per year.

Proliferation predominantly in the mesangium.

B-cell anomalies may play a role in its pathogenesis.

Idiopathic MN is considered an autoimmune disease, whereas secondary forms involve exogenous antigens such as viral, bacterial, and tumor antigens.

Secondary membranous nephropathy can  e related to a pre-disposing condition such as an autoimmune disease, SLE, infection as hepatitis B or syphilis, with medication use such as nonsteroidal anti-inflammatory drugs, cancer or allogeneic stem cell transplantation.

In secondary membrane nephropathy the target antigen is extrinsic to the pocyte and reaches the glomerular basement membrane through the circulation.

In secondary nephropathy the above often results in the generation of subendothelial mesangial deposits in addition to the subepithelial deposits that are characteristic of membranous nephropathy.

The predominant immuno globulin in primary membrane is membranous nephropathy is the IgG4 sub class, where is the other IgG sub classes predominate in most causes of secondary membranous nephropathy.

The leading causes the nephrotic syndrome in white adults.

Clinically, variations exist based on pathogenesis of the process, and timing of diagnostic biopsy.

Hypertension may or may not be present.

In early disease, when biopsy shows proliferative lesions, patients are more likely to have a nephritic phenotype.

Patients with cresecentic membranoproliferativeglomerulonephritis may present with a rapidly progressibe glomerulonephritis.

Biopsy changes with advanced findings of repair and sclerosis are likely to have a nephrotic phenotype.

Patients with classic membranoproliferative glomerulonephritis often have acute nephritic syndrome and nephrotic syndrome, the nephritic-nephrotic phenotype.

Accounts for 10-20% of cases of nephrotic syndrome in children and young adults.

Most commonly presents in childhood, but can occur at any age.

Accounts for 7-10% of all cases of biopsy confirmed glomerulonephritis.

Ranks 3rd to 4th leading cause of ESRD among primary glomerulonephritides.

Course and presentation highly variable from benign to rapidly progressive.

Can present with hematuria, proteinuria in the non-nephrotic phase.

Can present with asymptomatic hematuria and proteinuria, acute nephritic syndrome, nephrotic syndrome, chronic kidney disease and rapidly progressive glomerulonephritis.

Most common cause of the nephrotic syndrome in adults but is rare in children.

Membranous proliferative glomerulonephritis may be related to systemic disorders.

About one fourth of kidney biopsies performed for nephrotic syndrome show this lesion.

Incidence of idiopathic membranous proliferative glomerulonephritis has been decreasing.

One of its hallmarks is the presence of immunoglobulin and complement components on the glomerular membrane.

Pathogenesis involves formation of subepithelial immune deposits responsible gor functional impairment of the capillary wall.

Typical microscopic findings of membranoproliferative glomerulonephritis include mesangial hypercellularity, endocapillary proliferation, and capillary wall remodeling, resulting in lobular accentuation of glomerular tufts.

Two major antigenic membrane glycoproteins have been identified in membranous nephropathy and are the neutral endopeptidase, and the M-type phospholipase A2 receptor (PLA2R1).

Neural endopeptidase is an allo-antigen involved in membranous nephropathy in neonates whose mothers have a deficiency of this enzyme.

M-type phospholipase A2 receptor is an antigen in adults with idiopathic membranous nephropathy, an autoimmune disease.

Auto antibodies against aldose reductase and mitochondrial superoxide dismutase 2 are present In the serum and glomeruli in patients with idiopathic membranous nephropathy.

Diagnosis of PLA2R associated membranous nephropathy can be established by the identification of circulating anti-PLA2R antibodies or with positive staining for PLA2R in a kidney biopsy specimen.

Idiopathic membranous nephropathy has an increased familial occurrence, suggesting a genetic contribution.

Idiopathic membranous nephropathy results from antibodies against podocyte antigens.

The majority of patients with idiopathic membranous nephropathy have IgG4 antibodies against then epitope in the M-type phospholipase A2 receptor, indicating that the receptor is a major antigen involved in the disease.

Spontaneous remissions occur in 20-33% of patients with idiopathic membranous nephropathy.

In patients who continue to have nephrotic syndrome, end stage renal disease develops in 40-50% of patients over a period of 10 years.

A total of 70-80% of patients with membranous nephropathy have circulating autoantibodies to the phospholipase A2 receptor (PLA2R), and 1 to 3% circulating antibodies to thrombospondin type-1 domain iPhone containing 7A (THSD7A).

Initial therapy is supportive, and immunosuppressive treatment is recommended for patients with persistent nephrotic syndrome.

A combination of alternating glucocorticoids and cyclophosphamide is effective in60-70% of patients with associated toxic effects.

Cyclophosphamide has a significant B-cell depleting affect, leading to reducedproduction of nephrotoxic antibodies.

Calcineurin inhibitors, including cyclosporine,are affective and preferred treatment

Calcineurin inhibitors are associated with a high incidence of relapse when discontinued and with frequent side effects including hypertension and nephrotoxic effects.

Management includes inhibition of the renin-angiotensin system.

An HLA-DQA1 allele on chromosome 6p21 is associated with idopathic membranous nephropathy in whites (Stanescu HC et al).

Most common cause of nephrotic syndrome in white adults.

Can have a long and indolent course with preserved renal function.

Most cases, at this time, are secondary to hepatitis C virus and concurrent cryoglobulinemia.

Prolonged prednisone reduces proteinuria and improves renal survival.

Prospective randomized trials of aspirin and dypyridamole resulted in significant reduction of proteinuria but no long-term benefit on renal survival.

Therapy with ACE inhibitors or angiotensin receptor inhibitors should be given to all patients.

In patients with nephritic syndrome, renal function deterioration and crescent formation a course of prednisone is indicated.

Cyclophosphamide is effective in aggressive cases of MPGN.

Immunosuppressive agents such as glucocorticoids, cyclophosphamide, and the rituximab have been used successfully in the treatment of idiopathic membranous nephropathy.

Rituximab has a 60-80% reduction in proteinuria for a majority of patients for as long as two years after the initiation of therapy.

Rituximab was not inferior to cyclosporine in inducing complete or partial remission of proteinuria at the 12 month period, and was superior in maintaining remission of proteinuria up to 24 months (Fervenza FC).