Primary membranous glomerulonephritis (ORPHA:97560)
A rare glomerular disease, histologically characterized by thickening of the capillary wall, with immune deposits predominantly containing IgG4 and C3 on the sub-epithelial side, and typically manifesting with nephrotic syndrome.
Epidemiology
Globally, the overall incidence of membranous nephropathy (MN) is approximately 1/100,000, of which approximately 80% are Primary membranous nephropathy (PMN). The male to female ratio is 2:1. PMN is rare in children.
Clinical description
Disease onset is typically between 50-60 years of age, presenting with either nephrotic syndrome (edema with confirmed proteinuria, hypoalbuminemia and hyperlipidemia), or nephrotic-range or subnephrotic proteinuria. Renal function is typically normal at presentation. Disease progression is gradual, and occasionally complicated by thrombo-embolic events. Hematuria, hypertension, and reduced glomerular filtration rate can present initially or develop during the disease course. End stage renal disease (ESRD) develops in up to a third of patients 10 years after disease onset.
Etiology
PMN is an auto-immune disease limited to the kidney. Antibodies to the podocytic antigen m-type phospholipase receptor (PLA2R) are detectable in approximately 70% of patients, and antibodies against thrombospondin type-1 domain-containing 7A (THSD7A) in approximately 3% of patients. The pathophysiology of antibody formation is unclear. A genetic predisposition and associations with HLA genes and with polymorphisms in the PLA2R gene have been found.
Diagnostic methods
Typically, diagnosis of PMN is made on kidney biopsy. Diagnostic features include capillary wall thickening, normal cellularity, IgG and C3 along capillary walls on immunofluorescence, and subepithelial deposits on electron microscopy. However, a diagnosis of PMN is strongly suspected on detection of circulating PLA2R antibodies.
Differential diagnosis
Secondary causes of MN should be excluded. These include malignances, infections (Hepatitis B, hepatitis C, syphilis), systemic diseases (SLE, sarcoidosis, IgG4-related kidney disease), drugs (NSAID'S, penicillamine, gold), and paraproteinemia.
Management and treatment
All patients should be managed with optimized conservative therapy, targeting blood pressure, proteinuria, and cholesterol. Use of angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker along with statins is preferred. Patients should also adhere to life-style changes (stop smoking, body weight, dietary sodium and protein restrictions). In patients with severe hypoalbuminemia, prophylactic anticoagulant therapy should be considered. In adults without high risk features, a period of 6 months of conservative therapy is advised before considering additional immunosuppressive therapy. Laboratory parameters (serum creatinine, serum albumin, urine protein to creatinine ratio, anti PLA2R ab levels, urinary LMW proteins) and blood pressure are important parameters to estimate (risk of) progression. In patients with progressive renal insufficiency, or patients with severe nephrotic syndrome and high risk of progression, treatment with immunosuppressive drugs should be started. Current guidelines discuss the use of alkylating agents, calcineurin inhibitors, and rituximab. Prednisone monotherapy is not effective in adults.
Prognosis
Patients with non-nephrotic proteinuria typically have non-progressive disease. In patients with nephrotic syndrome, the natural course of disease is variable ranging from spontaneous remission to ESRD. With current treatment strategies the risk of ESRD has decreased, and only 5-10 % of patients will be non-responsive.

                            Last update: 
                            May 2019


                            - Expert reviewer(s): 
                            Dr Laura CESCA  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet* - Pr J.F.M. [Jack] WETZELS | ERKNet*


                                * European Reference Network