Membranous glomerulopathy (membranous nephropathy) is a leading cause of the nephrotic syndrome in White adults. Epidemiology has remained constant over the past several decades. Disease occurs at an approximate rate of 1 case per 100,000 persons per year, with a peak incidence between 30 and 50 years of age. Approximately 75% of cases are considered primary; the remaining 25% are considered secondary to systemic diseases such as systemic lupus erythematosus, hepatitis B virus infection, and solid tumors.
In the past decade, target antigens and their associated autoantibodies responsible for the development of primary membranous glomerulopathy cases have been identified. The M-type phospholipase A2 receptor (PLA2R) is the specific podocyte antigen responsible for eliciting immune complex formation with circulating autoantibodies in most primary cases. Anti-PLA2R antibodies are detected in approximately 75% of primary cases and are rarely found in secondary forms. Additional alternative podocyte autoantigens have been reported in patients with primary membranous glomerulopathy, potentially filling in the missing gaps in PLA2R antibody–negative disease. Membranous glomerulopathy occurs when circulating antibodies permeate the glomerular basement membrane and, in the subepithelial space, form immune complexes with epitopes on podocyte membranes.
Patients typically describe slowly progressive edema, and laboratory testing reveals proteinuria, hypoalbuminemia, and hyperlipidemia, most often with preserved kidney function. Patients with membranous glomerulopathy are particularly prone to thrombotic complications. These clots include lower extremity, pulmonary, and renal vein thromboses; they can occur in up to 25% of patients and are most likely to occur within the first 2 years of diagnosis. The risk of clotting increases when serum albumin is <2.8 g/dL (28 g/L) and is highest when serum albumin is <2.2 g/dL (22 g/L).
The diagnosis of membranous glomerulopathy is traditionally made by kidney biopsy, although FDA approval of serologic testing for anti-PLA2R antibodies in 2015 has introduced the possibility of diagnosing the disease noninvasively.
The hallmark biopsy finding is the presence of subepithelial immune deposits that alter the glomerular capillary wall, classically accompanied by intervening “spikes” of glomerular basement membrane extending between the immune deposits in more advanced cases. In addition to serologic testing for anti-PLA2R antibodies, the biopsy can be stained for the PLA2R antigen, which typically yields a higher sensitivity (>80%) than antibody testing in the serum. This testing is used not to make a diagnosis of membranous glomerulopathy but to help distinguish primary from secondary forms of the disease. Such a distinction is crucial because secondary forms are expected to remit if the underlying systemic disease responsible for the lesion is successfully treated. Notably, in patients with membranous glomerulopathy aged 65 years and older, malignancies have been detected in up to 25% within 1 year of their biopsy diagnosis. Therefore, age- and sex-appropriate cancer screening is recommended for all patients at the time of their diagnosis, even those with PLA2R positivity.
Also associtaed with hepatitis B
Patients with cancer and nephrotic disease: think about membranous due to perineoplastic association.
Patients with newly diagnosed primary forms of membranous glomerulopathy are usually observed for 6 to 12 months on conservative therapy (renin-angiotensin system blockade, cholesterol-lowering medication, and edema management) before initiating a course of immunosuppression for patients with persistent nephrotic-range proteinuria. The observation period allows patients a chance to achieve spontaneous remission, which occurs in approximately 30% within 1 to 2 years of diagnosis. Three first-line immunosuppressive regimens are available for patients who remain nephrotic: (1) a combination of glucocorticoids and alkylating agents, which achieves remission in approximately 75% to 80% of patients within 12 months, or (2) calcineurin inhibitors (cyclosporine or tacrolimus), which have reported remission rates of 70% to 75% in the first year of therapy but for which relapse rates are higher in patients treated with calcineurin inhibitors than alkylating agents; or (3) rituximab, which was noninferior compared with cyclosporine in inducing remission of proteinuria and proved superior in maintaining that remission. Recent reports also suggest that rituximab may have efficacy in membranous glomerulopathy. Treatment of secondary forms of membranous glomerulopathy should be aimed at the underlying systemic disease or etiology (for example, resection of a tumor in malignancy-associated membranous glomerulopathy, treatment of hepatitis B in viral-associated membranous glomerulopathy).
Progression to ESKD depends on remission of proteinuria: The 10-year incidence of ESKD in patients who undergo complete or partial remission of proteinuria ranges from 0 to 10%, compared with a >50% incidence of ESKD in patients who maintain nephrotic-range proteinuria.