Case Published: July 2019
Diagnosis: Phospholipase-A2-Receptor (PLA2R) Positive Membranous Nephropathy (or Primary/Idiopathic Membranous Nephropathy)
Case Summary:
In this case, we find an older man who presents with only lower extremity edema. This symptom can be a sign of proteinuria, and as we soon discover on urinalysis, this patient has 4+ protein on dipstick. It is crucial to quantify the proteinuria, as the dipstick gives us only an estimate and only detects albuminuria. Our patient has a urine protein:creatinine ratio of 8700mg/g, or nephrotic range proteinuria.
Nephrotic range proteinuria is defined as greater than 3 to 3.5 grams of protein in a 24-hour urine collection, or a urine protein:creatinine ratio of greater than 3000 to 3500 mg/g. Together, proteinuria, significant edema, hypoalbuminemia, and often hyperlipidemia/lipiduria (lipids in the urine) comprise nephrotic syndrome. Our patient meets criteria for nephrotic syndrome.
Membranous nephropathy
Minimal change disease
Systemic lupus erythematosus (SLE)
Hepatitis B or C (more commonly HBV)
Nonsteroidal anti-inflammatory drugs
HIV
Amyloidosis
Multiple myeloma
Preeclampsia
Now that we have established a broad differential for nephrotic syndrome, let’s try to determine which etiology is most likely in our patient. His clinical presentation, basic laboratory studies, and urinalysis are consistent with nephrotic syndrome but are otherwise unrevealing. We must move to a kidney biopsy to confirm our diagnosis.
Light microscopy and electron microscopy show us thickening of the basement membrane and subepithelial deposits – together, these findings raise suspicion for membranous nephropathy (MN). With focal segmental glomerulosclerosis (FSGS), we would look for areas of sclerosis in some glomeruli. Minimal change disease is also ruled out here, as we would except only podocyte effacement on electron microscopy without light microscopy changes or immune-complex deposits.
MN, like many glomerular diseases, can be primary or secondary (caused by another underlying disease). Distinguishing between primary and secondary glomerular diseases is critical, as this will determine the treatment. We can use the patient’s clinical history, serologic testing, and immunofluoresence (IF) to try to tell the difference.
In primary MN, we expect to find a granular pattern basement membrane staining of IgG and C3 on IF, and the presence of the phospholipase A2 receptor antigen (PLA2R) or thrombospondin type-1 domain-containing 7A (THSD7A) within immune deposits (with PLA2R being more common). PLA2R antibodies can be detected in the serum of primary MN patients, with specificity being near 100%.
Systemic lupus erythematosus (SLE) nephritis
Drugs (i.e. penicillamine, anti-tumor necrosis factor (TNF) antibodies, nonsteroidal anti-inflammatory drugs (NSAIDs))
Syphilis
Hepatitis C virus, Hepatitis B virus (HBV more common)
Immunoglobulin-G4 (IgG4) disease

The disease course and treatment? The classic teaching is that 1/3 of patients will go into spontaneous remission, 1/3 will remain stable, and 1/3 will progress. For those patients at moderate to high risk of progression (more than 4 g proteinuria/24 hours), the treatment is Immunosuppressive therapy. Options include alternating corticosteroids and cyclophosphamide (modified Ponticelli protocol), calcineurin inhibitors (cyclosporine or tacrolimus), or rituximab. Patients should also be treated with angiotensin inhibitors. The MENTOR study, published in 2019, found that treatment with cyclosporine was noninferior to rituximab – though there was no cyclophosphamide arm in this study. In one small randomized study of 32 patients, adrenocorticotropic hormone (ACTH) was shown to be effective when compared to cytotoxic drugs. Anti-PLA2R autoantibody levels can be measured to monitor disease activity and response to therapy. Higher antibody levels may be associated with increased risk of disease recurrence after kidney transplantation.
Case 35 Index
Case 35 Introduction
Case 35 Physical Exam
Case 35 Diagnostic Testing
Case 35 Pathology
Case 35 Additional Pathology
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