Primary Membranous Nephropathy - Idiopathic Membranous Glomerulonephritis

Primary membranous nephropathy (PMN) is a kidney-specific autoimmune disease that is caused by circulating antibodies against certain native podocyte antigens, specifically phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). PMN is characterized by the deposition of immune complexes to the glomerular filtration barrier, which results in damage to the glomeruli. PMN is the most common cause of idiopathic nephrotic syndrome among nondiabetic adults. The disease course varies greatly; untreated, many patients experience spontaneous remission, whereas others experience progression to end-stage renal disease (ESRD). Although traditional kidney function tests and kidney biopsy are still used in the diagnosis and monitoring of PMN, serum testing for PLA2R and THSD7A antibodies has an important and growing diagnostic, prognostic, and disease-monitoring role.

Quick Answers for Clinicians

How should negative serum antibody test results be interpreted?

When present, phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) antibodies are reliable biomarkers for the diagnosis of primary membranous nephropathy (PMN); however, approximately 25% of patients with PMN do not have detectable antibodies. In approximately 15% of patients with PMN, PLA2R staining indicates recent disease activity despite a lack of detectable antibodies, which suggests the presence of inactive disease. Similarly, THSD7A staining may indicate inactive disease or remission in patients with undetectable antibodies. Approximately 10% of patients with PMN do not present with any evidence of PLA2R or THSD7A immunologic activity. These cases are likely caused by an undiscovered antipodocyte antibody.

How should positive serum antibody test results be interpreted?

Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) antibodies have a specificity of nearly 100% for primary membranous nephropathy (PMN). PLA2R antibodies have been detected in some patients who have diseases that may cause secondary MN (eg, hepatitis B and C [HBV, HCV], sarcoidosis, or cancer). However, most of these cases appear to be instances of PMN with coincidental secondary disease. THSD7A antibodies have not yet been detected in patients who have been diagnosed with other diseases that may cause secondary MN.

What is the association between THSD7A-related primary membranous nephropathy and cancer?

A coexisting malignancy was detected in approximately 20% of one group of patients with thrombospondin type-1 domain-containing 7A (THSD7A) antibodies within 3 months of PMN diagnosis, which led to the recommendation that individuals with THSD7A-related PMN should receive a comprehensive cancer screening.

Indications for Testing

Testing for antibodies that may cause PMN should be considered in patients who present with idiopathic nephrotic syndrome (proteinuria >3.0 g/d, hypoalbuminemia, edema, hyperlipidemia and lipiduria, and normal or slightly altered kidney function).

Laboratory Testing

Diagnosis

Serum Antibodies

Circulating PLA2R antibodies can be detected in approximately 70% of patients with PMN, and the specificity of PLA2R antibodies for PMN is nearly 100%. Because of the high specificity of these antibodies, a kidney biopsy may not be indicated when PLA2R antibodies are detected in patients with a low risk of disease progression or with a high risk of complications due to biopsy. PLA2R antibodies can be detected using either an enzyme-linked immunosorbent assay (ELISA) or an indirect immunofluorescence assay (IFA); the preferred method for diagnosis is IFA due to its increased sensitivity.

Circulating THSD7A antibodies can be detected in 3-9% of patients with PMN. THSD7A antibodies have not yet been detected in either healthy patients or in patients with other renal or systemic diseases, indicating a high specificity (up to 100%) for PMN. However, based on the novelty of this biomarker, biopsy is still the suggested method for diagnosis when THSD7A antibodies are present.

The absence of circulating autoantibodies does not rule out a diagnosis of PMN.

Immunohistochemistry

When PMN is suspected and PLA2R antibodies are not detected, a kidney biopsy and immunohistochemical staining should be performed to detect PLA2R or THSD7A immunologic activity. A biopsy is also indicated in patients with detectable PLA2R antibodies when immunosuppressive therapy is being considered and when nephrotic syndrome is accompanied by acute kidney injury. PLA2R and THSD7A staining are not performed at ARUP Laboratories.

Prognosis

Traditional kidney function markers can be used to help determine the risk of disease progression in patients with PMN. Proteinuria concentrations of <3.5 g/d are indicative of low risk, whereas factors that indicate high risk include:

Serum creatinine of >1.5 mg/dL
Unexplained decrease in estimated glomerular filtration rate (eGFR) by ≥20% over any time period during the preceding 12 months
Proteinuria of >8 g/d for >6 months
Urine immunoglobulin G (IgG) of >250 mg/d

The PLA2R antibody concentration also has prognostic implications. Low antibody concentrations are associated with a higher likelihood of spontaneous remission, whereas higher concentrations are associated with development of nephrotic syndrome (if not initially present) and loss of kidney function. Because the ELISA test is quantitative, unlike the semiquantitative IFA test, it is the preferred methodology for prognostication. Early data suggest an association between THSD7A concentrations and disease activity.

Monitoring

Traditionally, immunosuppressive treatment of PMN was monitored using standard laboratory parameters (eg, proteinuria and eGFR). However, that method is highly unpredictable, and the clinical variables present at diagnosis do not predict relapse. In patients positive for PLA2R antibodies, declining antibody concentrations consistently precede a decline in proteinuria, indicating that serum antibody concentrations can be used to monitor treatment. Patients with undetectable antibody titers after treatment are likely to remain in remission for at least 5 years, whereas patients with <50% reduction of antibodies at the end of treatment likely have resistant disease. Similarly, THSD7A antibodies have been reported to decrease before remission and increase before relapse.

Recurrence of PMN is common after kidney transplantation, with incidence peaking in the first year after transplant and again after 4-5 years. In patients with PLA2R-related PMN who have had a kidney transplant, closely monitoring antibody concentrations can help predict relapse. In patients with THSD7A-related PMN, high antibody titers at the time of the transplant are associated with disease recurrence.