Approach

Initial evaluation should start with a thorough history and physical examination followed by laboratory testing. Renal biopsy remains the diagnostic standard. Because both primary and secondary membranous nephropathy (MN) can present with nephrotic syndrome or proteinuria, further work-up is needed in all patients to look for secondary causes.

History

Patients typically present with oedema or hypertension. The oedema can be mild or severe and most commonly begins in the legs. Oedema of MN is more likely to affect the face than oedema due to other causes such as cardiac failure. Patients may also report foamy urine and non-specific symptoms of malaise, anorexia, and fatigue. They may also present with the incidental finding of proteinuria on urinary dipstick or abnormal renal function on serological testing. A thorough history includes assessing for risk factors of secondary MN, including a history of hepatitis B or C and autoimmune disease, and a full drug history. Systematic review may reveal symptoms suggestive of solid organ malignancy.

Examination

Physical examination findings may include:

  • High BP

  • Xanthelasma due to hypercholesterolaemia

  • White banding of the nails (Muehrcke's lines) due to hypoalbuminaemia

  • Localised oedema or anasarca (extreme generalised oedema)

  • Specific findings of underlying disease (i.e., features of systemic lupus erythematosus (SLE), hepatitis, or malignancy).

Initial investigations

All patients with suspected MN should have the following tests performed:

  • Serum creatinine and creatinine clearance: to assess renal function. Glomerular filtration rate can be calculated using the value of serum creatinine [ Glomerular Filtration Rate Estimate by the IDMS-Traceable MDRD Study Equation Opens in new window ] ​

  • Urea: may demonstrate abnormal renal function

  • Urine microscopy: may show oval fat bodies and fatty casts

  • Urine protein to creatinine ratio: may be followed by 24-hour urine collection, which may reveal significant proteinuria (>3.5 g/24 hours) indicative of nephrotic syndrome

  • Serum albumin: hypoalbuminaemia will be seen in nephrotic syndrome

  • Lipid profile: hyperlipidaemia is commonly seen in nephrotic syndrome.

Investigation for primary membranous nephropathy

Patients can be tested for m-type phospholipase A2 receptor (PLA2R) autoantibodies if primary MN is suspected. Approximately 80% of patients with primary MN have autoantibodies against PLA2R; therefore, these antibodies are highly suggestive of primary MN.[9]​ Two tests for anti-PLA2R autoantibodies have been approved by the US Food and Drug Administration (FDA), and are now commercially available. Some centres in the UK offer testing for anti-PLA2R autoantibodies.

Patients can also be tested for thrombospondin type 1 domain–containing 7A (THSD7A) autoantibodies, which present in around 10% of patients.​[19]​​

Patients with MN should be evaluated for associated conditions regardless of whether anti-PLA2R antibodies and/or anti-THSD7A antibodies are present.[20]

Investigations for secondary causes

Specific laboratory testing for secondary causes should include:

  • Hepatitis B and C serology

  • Liver function tests: if elevated may suggest underlying hepatitis

  • Complement levels (C3, C4, and CH50): may be low if MN is associated with SLE

  • ANA: to exclude underlying SLE

  • Anti-double-stranded DNA or anti-Smith antigen if results from anti-nuclear antibody testing are positive: highly specific tests for SLE

  • Anti-SS-B, anti-SS-A: elevated levels suggest underlying Sjogren's syndrome

  • Syphilis serology: may be required in high-risk groups

  • Investigations for underlying malignancy: if history or clinical examination leads to clinical suspicion of a solid organ tumour, then appropriate screening should be arranged. Not routinely recommended for every patient.

Imaging

Bilateral renal ultrasound with Doppler evaluation of the renal arteries should be performed to assess for other possible causes of decreased renal function. Specifically, ultrasound is useful to assess the size of the kidneys to rule out hydronephrosis; to evaluate systolic arterial pressures to rule out renal artery stenosis; and to evaluate resistive indices for microvascular disease.

Renal biopsy

Patients are referred to a specialist for consideration of a renal biopsy. Definitive diagnosis is based on biopsy findings, and it remains the most sensitive and specific test.

Light microscopy

  • Thickening of the glomerular basement membrane (GBM) is diffuse throughout all glomeruli in the absence of significant hypercellularity.

Immunofluorescence microscopy

  • IgG is seen in a diffuse granular pattern, with C3 along the GBM.

Electron microscopy

  • Stage 1: light microscopy is normal; small electron-dense sub-epithelial deposits with segmental distribution can be observed; focal foot process effacement is a constant feature.

  • Stage 2: sub-epithelial electron-dense deposits are seen with small GBM extensions (spikes); GBM spikes can be seen with silver staining (segments of GBM between dense deposits).

  • Stage 3: dense deposits are incorporated in the GBM; thickening of the GBM is detectable by light microscopy.

  • Stage 4: GBM is markedly thickened, with the initial electron-dense deposits now electron lucent.​[21]

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