Membranous nephropathy

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Membranous nephropathy thickens glomerular capillary walls because immune deposits form beneath podocytes. Complement-associated podocyte damage disrupts the filtration barrier, producing albumin-predominant proteinuria, oedema, hyperlipidaemia and increased thrombotic susceptibility. Primary disease is commonly associated with autoantibodies to podocyte antigens, especially PLA2R; other antigens and secondary immune triggers create a heterogeneous clinicopathological diagnosis.

A complete assessment asks three parallel questions: is this truly membranous nephropathy, is there a treatable secondary driver, and how likely is untreated disease to cause serious harm? Kidney biopsy remains important when serology and phenotype are discordant, kidney function is falling, another process is possible, or tissue will change therapy. Histology, immunofluorescence, electron microscopy and antigen staining should be interpreted together.

Management is not synonymous with immediate immunosuppression. Some people remit with supportive care, whereas persistent nephrotic syndrome, declining eGFR, high immunological activity or major complications justify specialist disease-modifying treatment. The choice among rituximab and other immunosuppressive strategies depends on risk category, comorbidity, previous exposure, fertility, infection screening and the current renal-unit protocol.

Key points

Membranous nephropathy is an immune-complex glomerular disease in which subepithelial deposits and podocyte injury produce heavy, often nephrotic-range proteinuria.
Anti-PLA2R antibodies strongly support primary membranous nephropathy in the right phenotype, but a negative result neither excludes the disease nor removes the need to search for secondary causes.
Evaluate medicines, malignancy, hepatitis B and C, autoimmune disease and other clinical clues before calling a case primary; biopsy antigen staining may refine this assessment.
Natural history varies from spontaneous remission to persistent nephrosis and kidney failure, so treatment intensity should follow proteinuria, eGFR trajectory, antibody activity and complications rather than one urine result.
Supportive care includes renin–angiotensin system blockade when tolerated, blood-pressure control, salt advice, oedema management, cardiovascular prevention and prompt infection assessment.
Thrombosis risk rises with severe nephrosis and low albumin, but prophylactic anticoagulation is an individual benefit–bleeding decision rather than an automatic albumin threshold.
Immunosuppression belongs in a nephrology pathway after secondary causes and treatment hazards have been addressed; rituximab access and regimen require current NHS and local governance.
Clinical remission can lag behind immunological improvement, while rising or persistent anti-PLA2R may precede continuing disease activity and should be interpreted longitudinally.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary autoimmune disease

Autoantibodies against podocyte-associated antigens, commonly PLA2R in the appropriate phenotype, generate in-situ subepithelial immune complexes along capillary walls.

Systemic secondary disease

Hepatitis, autoimmune disease and malignancy can produce a membranous pattern, so clinical context and biopsy antigen findings remain important even when proteinuria dominates.

Medicine-associated disease

Selected medicines can trigger subepithelial immune deposition; a dated exposure history and improvement after withdrawal help assess causality without deliberate rechallenge.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Subepithelial immune-complex formation
Antibodies bind podocyte antigens or planted antigens beneath epithelial cells, creating deposits along the outer glomerular capillary wall.
2
Complement-mediated podocyte injury
Local complement activation disrupts podocyte cytoskeleton and slit-diaphragm integrity without the prominent endocapillary inflammation seen in nephritic disease.
3
Heavy protein leakage
Loss of filtration selectivity permits substantial albumin loss, producing hypoalbuminaemia, oedema and compensatory hepatic lipid and coagulation-protein synthesis.
4
Remission or chronic scarring
Immune activity may subside spontaneously or with treatment, but persistent deposits and proteinuria can drive glomerulosclerosis and declining filtration.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Nephrotic presentation

Progressive dependent oedema, frothy urine, marked albuminuria, low serum albumin and hyperlipidaemia form the characteristic clinical syndrome.

Thromboembolic complicationRed flag

Sudden pleuritic pain, hypoxia, unilateral leg swelling or loin pain may indicate pulmonary, deep venous or renal-vein thrombosis.

Unexpected inflammatory sedimentRed flag

Active urinary casts, systemic inflammation or a rapid creatinine rise should prompt consideration of superimposed crescentic disease, infection or another diagnosis.

Secondary-cause clues

Weight loss, lymphadenopathy, rash, arthralgia, chronic infection risk or exposure to implicated medicines changes the diagnostic and treatment pathway.

Infection vulnerabilityRed flag

Fever or focal symptoms in nephrotic or immunosuppressed patients warrant prompt assessment because urinary immunoglobulin loss and treatment both increase risk.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urine ACR or PCR and urinalysisFirst step
Why
Quantify protein loss and identify blood or an active sediment.
Interpretation and limitations
Repeat a standardised quantitative measure for trajectory; haematuria can occur, but cellular casts or abrupt change demand reassessment for an additional lesion.
02
Creatinine, eGFR, albumin and lipid profile
Why
Stage kidney impairment and document nephrotic complications.
Interpretation and limitations
A stable eGFR does not imply low risk when proteinuria and hypoalbuminaemia persist; trends after haemodynamic therapy need clinical context.
03
Serum anti-PLA2R antibody
Why
Support diagnosis and provide an immunological activity marker in appropriate patients.
Interpretation and limitations
A positive result is persuasive in a typical phenotype, whereas a negative test can reflect another antigen, low activity or secondary disease and must not end evaluation.
04
Secondary-cause screen
Why
Look for infection, autoimmunity, malignancy and medicine associations that alter treatment.
Interpretation and limitations
Tailor hepatitis serology, ANA/complement, paraprotein studies and age-appropriate cancer assessment to history and examination rather than ordering an indiscriminate panel.
05
Kidney biopsy with antigen assessment
Why
Confirm morphology and exclude competing or superimposed renal pathology.
Interpretation and limitations
Subepithelial deposits and capillary-wall immune staining support the diagnosis; chronic scarring and antigen pattern inform prognosis and attribution but require renal-pathology expertise.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Minimal change disease

Both can produce abrupt bland nephrosis, but minimal change disease lacks subepithelial deposits and capillary-wall immune staining on biopsy.

Focal segmental glomerulosclerosis

Segmental scars and an adaptive, genetic or primary podocyte context support FSGS rather than diffuse subepithelial immune-complex disease.

Renal amyloidosis

Systemic deposition clues, monoclonal studies and Congo-red-positive fibrils distinguish amyloid from the granular capillary-wall deposits of membranous nephropathy.

Diabetic kidney disease

Longstanding diabetes with retinopathy and gradual albuminuria supports diabetic glomerulosclerosis, while abrupt nephrosis or disease-specific antibodies prompt assessment for membranous disease.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ConfirmEstablish diagnosis and causeFirst stepAn adult has heavy albuminuria with suspected nephrotic syndrome.

1Confirm quantitative proteinuria, serum albumin, renal trajectory and clinical complications while reviewing previous results.
2Request anti-PLA2R and a history-led secondary screen, including prescribed and non-prescribed medicines, infection risks and malignancy symptoms.
3Discuss biopsy with nephrology when serology is negative or discordant, renal function falls, another lesion is plausible, or tissue classification will guide treatment.

02ProtectReduce immediate nephrotic harmMembranous nephropathy is likely or confirmed and the patient is clinically stable.

1Optimise blood pressure and antiproteinuric therapy cautiously, checking creatinine and potassium after renin–angiotensin system changes.
2Treat oedema with salt advice and individually titrated diuresis while avoiding intravascular depletion, hypotension and avoidable acute kidney injury.
3Assess thrombosis and bleeding risks explicitly; investigate symptoms urgently and seek specialist advice before prophylactic anticoagulation.

03StratifyChoose observation or immune therapySecondary drivers have been addressed and serial activity data are available.

1Combine proteinuria duration, eGFR slope, serum albumin, antibody trend, complications, chronic damage and patient priorities rather than relying on a single threshold.
2EscalationContinue structured supportive observation when risk is low and improving, with clear escalation criteria and defined result ownership.
3For persistent or higher-risk disease, use the renal-unit immunosuppression pathway, infection screening, vaccination review and reproductive counselling before treatment.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Lowers intraglomerular pressure, reduces proteinuria and treats hypertension as part of supportive kidney and cardiovascular protection.

ACE inhibitor or angiotensin-receptor blocker

Select and titrate one agent using the current CKD formulary, blood pressure, potassium and eGFR; do not combine ACE inhibition with an ARB.

Check renal function and potassium after initiation and dose changes. Pause or reassess during significant hypovolaemia, marked hypotension, hyperkalaemia or a disproportionate creatinine rise, and follow pregnancy contraindications.

B-cell depletion can reduce pathogenic antibody activity in appropriately risk-stratified primary membranous nephropathy.

Rituximab in selected primary disease

Use only through the specialist membranous-nephropathy protocol and current NHS commissioning arrangements; regimen, premedication and retreatment are determined by the renal team.

Screen for hepatitis B and other infection risks, review vaccination timing, immunoglobulins and prior reactions, and counsel about delayed infection and reproductive considerations. Do not copy a regimen from another autoimmune indication.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Venous thromboembolism

Urinary anticoagulant-protein loss and increased procoagulant synthesis raise deep-vein, pulmonary and renal-vein thrombosis risk during severe nephrosis.

Serious infection

Immunoglobulin loss, oedematous tissue and immunosuppressive exposure can reduce host defence, sometimes blunting the clinical presentation.

Acute kidney injury

Hypovolaemia, sepsis, renal-vein thrombosis, interstitial oedema or treatment toxicity can abruptly reduce filtration on top of the glomerular lesion.

Progressive chronic kidney disease

Persistent immune activity and proteinuria cause glomerular and interstitial scarring, eventually reducing filtration despite an initially preserved eGFR.

Severe oedema

Low oncotic pressure and renal sodium retention can produce anasarca, effusions and impaired mobility while intravascular filling remains clinically variable.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend the same quantitative urine protein measure, serum albumin, creatinine and eGFR at intervals matched to severity and recent treatment changes.
Record blood pressure, weight, oedema and postural symptoms because over-diuresis can worsen kidney perfusion before oedema has resolved.
Follow anti-PLA2R titres when initially positive, recognising that immunological response may occur before proteinuria remits.
Check potassium and renal function after antiproteinuric medicine titration and during intercurrent illness or reduced intake.
After immunosuppression, use the live protocol for blood counts, immunoglobulins, infection surveillance and vaccine planning.
Revisit thrombosis risk whenever albumin, mobility, bleeding risk, surgery, previous thrombosis or nephrotic severity changes.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Serology and tissue complement each other

PLA2R positivity can establish an immune signal, but biopsy still answers chronicity, competing pathology and antigen-discordance questions in selected cases.

Immunological remission comes first

Falling antibody activity may precede repair of the filtration barrier, so early persistent proteinuria does not automatically mean treatment failure.

Renal-vein thrombosis can be subtle

New flank discomfort, haematuria or unexplained kidney deterioration in severe nephrosis deserves deliberate vascular consideration.

Secondary disease changes the target

Treating infection, malignancy or a causal medicine may be more important than applying a primary-disease immunosuppressive algorithm.

Albumin is not a stand-alone anticoagulation rule

Assay method, bleeding probability and individual thrombotic factors must accompany serum albumin in prophylaxis decisions.

11Common pitfallsFrequent interpretation and management errors.

01
Calling all PLA2R-negative membranous nephropathy secondary without considering other podocyte antigens or timing of testing.
02
Starting immunosuppression before excluding chronic infection and clinically indicated malignancy assessment.
03
Using one low albumin result as an automatic instruction for anticoagulation without estimating bleeding harm.
04
Interpreting a haemodynamic eGFR dip after supportive therapy as definite immune progression without repeat assessment.
05
Escalating loop diuretics despite hypotension and intravascular depletion because visible oedema remains.
06
Assuming that persistent proteinuria immediately after antibody improvement proves rituximab failure.