What is the immediate management for a 16-year-old patient with nephrotic syndrome, membranous glomerulopathy, and EXT2 positivity, after ruling out common secondary causes?

Management of EXT2-Positive Membranous Glomerulopathy in a 16-Year-Old

You should initiate supportive management immediately with ACE inhibitors/ARBs and conservative measures, while simultaneously pursuing comprehensive genetic testing and maternal anti-NEP antibody screening before committing to immunosuppressive therapy with steroids.

Additional Causes to Consider for EXT2-Positive Membranous Nephropathy

Maternal Anti-NEP Antibody-Mediated Disease

• Screen for maternal anti-NEP antibodies immediately - this is a critical diagnostic consideration in adolescent membranous nephropathy that can present beyond infancy 1
• Test both the patient and mother for anti-NEP antibodies, as maternal MME gene variants can cause antibody-mediated podocyte injury that may manifest with delayed presentation 1
• This form typically shows membranous nephropathy on biopsy and can present with severe proteinuria in adolescence 1

Comprehensive Genetic Testing

• Perform massively parallel sequencing or whole-exome sequencing as first-line diagnostic measure to identify potential genetic causes of membranous nephropathy 2
• Genetic forms may not respond to immunosuppression, making this distinction critical before initiating steroids 1
• Extended evaluation should assess for syndromic features: neurological examination, ophthalmological assessment, hearing tests, and evaluation for dysmorphic features 1

Occult Malignancy Screening

• While initial cancer screening was negative, membranous nephropathy in adolescents warrants continued vigilance for occult malignancy 3
• Consider more extensive imaging beyond chest X-ray and pelvic ultrasound if clinical suspicion persists
• Hematologic malignancies should be specifically excluded 3

Immediate Management Strategy

Supportive Care Should Begin Now

Initiate conservative management immediately regardless of final etiology 2, 4:

• Start ACE inhibitor or ARB therapy to reduce glomerular protein loss and proteinuria 1, 4
• Implement dietary sodium restriction to manage edema 2, 4
• Use diuretics (furosemide 0.5-2 mg/kg per dose) only if signs of intravascular fluid overload are present with preserved kidney function 1
• Avoid albumin infusions unless there are specific clinical indicators of hypovolemia or failure to thrive, not based solely on serum albumin levels 2, 5

Thromboembolism Prophylaxis Assessment

• Assess thromboembolism risk given membranous nephropathy carries particularly high risk 1
• Consider prophylactic anticoagulation if serum albumin <25 g/L with additional risk factors 1
• Low molecular weight heparin is preferred for prophylaxis (dose reduction needed if creatinine clearance <30 ml/min) 1

Decision on Immunosuppressive Therapy

Hold Steroids Pending Genetic and Antibody Results

Do not initiate corticosteroids until genetic testing and anti-NEP antibody screening are completed 1:

• Genetic forms of nephrotic syndrome typically do not respond to immunosuppressive agents and may only expose the patient to unnecessary toxicity 1
• If genetic testing is negative, infection screening is negative, and kidney biopsy excludes diffuse mesangial sclerosis, then a trial of immunosuppressive therapy may be considered 1
• The timeframe for this workup should be 2-4 weeks maximum to avoid delaying potentially beneficial therapy

If Non-Genetic Disease is Confirmed

Once genetic causes and maternal anti-NEP antibodies are excluded:

• Consider kidney biopsy findings in treatment decisions - membranous nephropathy in adolescents may benefit from immunosuppression if truly idiopathic 1, 3
• For confirmed idiopathic membranous nephropathy with nephrotic-range proteinuria (>3.5 g/day or equivalent), immunosuppressive therapy is reasonable 6, 4
• Prednisone dosing for adolescents: 60 mg/m²/day until remission, then 40 mg/m² on alternate days for 1 week, tapering by 10 mg/m²/week over 4 weeks total 5
• Monitor for steroid response over 6-8 weeks; if no response by 6 weeks, this confirms steroid-resistant disease requiring alternative approaches 1

Alternative Immunosuppression if Steroid-Resistant

• Calcineurin inhibitors (cyclosporine or tacrolimus) are first-line for steroid-resistant membranous nephropathy 1, 7
• Continue CNI therapy for minimum 6 months; if partial or complete remission not achieved, discontinue 1
• If remission achieved, continue for 12-24 months at lowest effective dose to minimize nephrotoxicity 1

Critical Pitfalls to Avoid

• Do not assume idiopathic disease without excluding genetic causes and maternal antibodies - this population can have delayed presentations of congenital forms 1
• Do not start steroids empirically - unlike minimal change disease in younger children, membranous nephropathy in adolescents requires biopsy confirmation and exclusion of secondary causes before immunosuppression 1, 3
• Do not overlook thromboembolism risk - membranous nephropathy has the highest thrombotic risk among nephrotic causes 1
• Avoid routine albumin infusions - these should be reserved for true hypovolemia, not given based on laboratory values alone 2, 5