Guideline sources The following summarized guidelines for the evaluation and management of membranous nephropathy are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021). 1 Guidelines 1. Classification and risk stratification Prognosis: Use clinical and laboratory criteria to assess the risk of progressive loss of kidney function in patients with membranous nephropathy: Situation Guidance Normal eGFR, proteinuria < 3.5 g/day, and serum albumin > 30 g/L Low risk https://web.pathway.md/diseases/recWmoRu51qD9oP3p 1/5 6/30/23, 1:01 AM Membranous nephropathy Pathway Normal eGFR, proteinuria < 3.5 g/day or a decrease > 50% after 6 months of conservative therapy with ACEI/ARB Normal eGFR, proteinuria > 3.5 g/day and no decrease > 50% after 6 months of conservative therapy with ACEI/ARB, and not meeting high-risk criteria Moderate risk EGFR < 60 mL/min/1.73 m and/or proteinuria > 8 g/day for > 6 months High risk Normal eGFR, proteinuria > 3.5 g/day and no decrease > 50% after 6 months of conservative therapy with ACEI/ARB, and at least one of the following Life-threatening nephrotic syndrome or rapid deterioration of kidney function not otherwise explained. B Very high risk 2. Diagnostic investigations Evaluation for secondary causes: Evaluate patients with membranous nephropathy for associated conditions obtaining the following, regardless of whether anti-PLA2R and/or anti- THSD7A antibodies are present or absent: full medical history (including systemic diseases, thyroid disease), history of medication use (NSAIDs, gold, penicillamine), and physical examination (skin, joints) screening for malignancies (population and age-appropriate) kidney ultrasound CXR (sarcoidosis) ANA HBV, HCV, human immunodeficiency virus, and treponemal infection (on indication). B 3. Diagnostic procedures Kidney biopsy: do not perform kidney biopsy to confirm the diagnosis of membranous nephropathy in patients with nephrotic syndrome and a positive anti-PLA2R antibody test. D 4. Medical management General principles: https://web.pathway.md/diseases/recWmoRu51qD9oP3p 2/5 6/30/23, 1:01 AM Membranous nephropathy Pathway Provide optimal supportive care in all patients with primary membranous nephropathy and proteinuria. B Decide on the treatment strategy based on the risk evaluation: Situation Guidance Observation Low risk Observation, or rituximab, or calcineurin inhibitor with or without corticosteroids Moderate risk Rituximab, or cyclophosphamide with corticosteroids, or calcineurin inhibitors with rituximab High risk Cyclophosphamide with corticosteroids. B Very high risk Immunosuppressive therapy: restrict immunosuppressive therapy to patients considered at risk for progressive kidney injury. B Show 3 more Anticoagulant therapy: decide on prophylactic anticoagulant therapy in patients with membranous nephropathy and nephrotic syndrome based on an estimate of the risk of thrombotic events and the risk of bleeding complications. B Show 2 more 5. Surgical interventions Kidney transplantation: Obtain pretransplant evaluation in patients with membranous nephropathy to ascertain if membranous nephropathy is associated with PLA2Rab. Measure PLA2Rab in patients with known or unknown PLA2Rab-associated membranous nephropathy. B Classify patients into the following categories for risk of recurrence: Situation Guidance Positive PLA2Rab High risk (50%) Negative PLA2Rab and negative native kidney biopsy and stain for PLA2R antigen Medium risk (30%) Negative PLA2Rab and positive native kidney biopsy and stain for PLA2R antigen (antibodies have disappeared). B Low risk (10%) https://web.pathway.md/diseases/recWmoRu51qD9oP3p 3/5 6/30/23, 1:01 AM Membranous nephropathy Pathway 6. Specific circumstances Pediatric patients: perform kidney biopsy in pediatric patients with membranous nephropathy. B Show 6 more 7. Follow-up and surveillance Serial laboratory assessment: consider monitoring the anti-PLA2R antibody levels after 6 months of treatment initiation to evaluate treatment response in patients with membranous nephropathy and to guide adjustments to therapy. C Show 3 more Management of relapse: Adjust treatment as follows for the treatment of relapse after initial therapy: Situation Guidance Repeat rituximab Rituximab Rituximab, or calcineurin inhibitor with or without rituximab Calcineurin inhibitor with or without prednisone Cyclophosphamide + corticosteroids, or rituximab, or calcineurin inhibitor with or without rituximab. B Cyclophosphamide with corticosteroids Management of resistant disease: Adjust treatment as follows for the treatment of patients with treatment-resistant membranous nephropathy: Situation Guidance Calcineurin inhibitor with rituximab if eGFR is stable Rituximab Cyclophosphamide with corticosteroids if eGFR is decreasing Rituximab if eGFR is stable Calcineurin inhibitor Cyclophosphamide with corticosteroids if eGFR is decreasing Rituximab if eGFR is stable Cyclophosphamide with corticosteroids Cyclophosphamide with corticosteroids if eGFR is decreasing. B Show 2 more https://web.pathway.md/diseases/recWmoRu51qD9oP3p 4/5 6/30/23, 1:01 AM Membranous nephropathy Pathway Clinical findings Symptoms Past medical history Fatigue Ankylosing spondylitis Hematuria Crohn's disease Shortness of breath Guillain-barr syndrome Weight gain HBV infection HCV infection Vascular exam Hashimoto's disease Human immunodeficiency virus infection Peripheral edema Hypertension Serological findings Malignancy Anti-PLAR antibodies Myasthenia gravis Nephrotic syndrome Rheumatoid arthritis SLE Sarcoidosis Sj gren's disease Syphilis Systemic sclerosis Lab findings Hyperlipidemia Hypoalbuminemia Urine fatty casts Urine sediment serum creatinine urine protein References 1. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open https://web.pathway.md/diseases/recWmoRu51qD9oP3p 5/5