What is the recommended treatment for an adult with biopsy-proven NELL-1-positive primary membranous nephropathy?

Treatment of NELL-1-Positive Membranous Nephropathy

Diagnostic Confirmation and Risk Assessment

Treat NELL-1-positive membranous nephropathy using the same therapeutic approach as other forms of primary membranous nephropathy, with heightened vigilance for underlying malignancy. 1, 2

Critical Diagnostic Considerations

• NELL-1 antibody testing lacks the diagnostic accuracy of anti-PLA2R testing and should never be used alone without kidney biopsy confirmation 1, 3

• All patients with NELL-1-positive membranous nephropathy require thorough malignancy screening, as this subtype shows stronger association with cancer than PLA2R- or THSD7A-associated disease 1, 4

• Age-appropriate cancer screening (colonoscopy, mammography, PSA, chest imaging) is mandatory; NELL-1-positive cases have mean age 66.8 years with 33% concurrent malignancy rate 5, 4

• Screen for systemic lupus erythematosus, hepatitis B/C, and medication exposures (particularly DMPS and alpha lipoic acid) regardless of NELL-1 status 5, 6

Initial Conservative Management (All Patients)

Before considering immunosuppression, optimize supportive care for at least 6 months: 2

• RAS blockade (ACE inhibitors or ARBs) targeting blood pressure <130/80 mmHg 2
• Statin therapy for dyslipidemia management 2
• Diuretics for edema control 2
• Anticoagulation assessment based on albumin levels and thromboembolism risk 1, 2

Risk Stratification for Immunosuppression

DO NOT treat if ALL of the following are present: 2, 5

• Proteinuria <3.5 g/day
• Serum albumin >30 g/L
• eGFR >60 mL/min per 1.73 m²

INITIATE immunosuppression when ANY of the following criteria are met: 2, 5

• Persistent nephrotic syndrome (proteinuria ≥4 g/day, ≥50% of baseline) after 6 months of optimal conservative therapy
• Declining kidney function (≥30% rise in serum creatinine over 6-12 months with eGFR still >25-30 mL/min/1.73 m²)
• Severe nephrotic complications (acute kidney injury, infections, thromboembolic events)

ABSOLUTE CONTRAINDICATIONS to immunosuppression: 5

• Serum creatinine persistently ≥3.5 mg/dL (eGFR ≤30 mL/min/1.73 m²)
• Kidney size <8 cm on ultrasound

First-Line Immunosuppressive Therapy

Three regimens are considered equivalent first-line options: 2

1. Rituximab (preferred due to superior safety profile) 2, 5
2. Cyclophosphamide plus alternating monthly glucocorticoids for 6 months 2, 5
3. Tacrolimus-based therapy for ≥6 months 2

Practical Selection Algorithm

• Choose rituximab for most patients given favorable safety profile and equivalent efficacy 2, 7
• Choose cyclophosphamide + glucocorticoids for high-risk patients with rapidly declining eGFR or very high-risk disease (proteinuria >8 g/day with declining function) 2
• Avoid tacrolimus as first-line due to high relapse rates after withdrawal and nephrotoxicity concerns 7, 8

Monitoring During Treatment

Unlike PLA2R-associated disease, NELL-1 antibody monitoring is not established for treatment guidance 1

• Monitor proteinuria and serum albumin every 1-3 months 2
• Assess kidney function (serum creatinine, eGFR) every 1-3 months 2
• Repeat malignancy screening if proteinuria worsens or new symptoms develop 5, 4

Management of Treatment Failure or Relapse

If Initial Therapy Fails (No Response After 6 Months):

• Verify treatment adherence and check drug levels if using calcineurin inhibitors 2
• Consider repeat kidney biopsy to assess for alternative pathology or progression 1, 5
• Switch to alternative first-line agent: 2, 5
  • If rituximab failed → switch to cyclophosphamide + glucocorticoids
  • If cyclophosphamide failed → switch to rituximab
  • If tacrolimus failed → switch to rituximab or cyclophosphamide

If Relapse Occurs After Initial Remission:

• Repeat the same therapy that achieved initial remission 2
• Critical limitation: Only repeat cyclophosphamide/glucocorticoid regimen once for relapse 2
• Alternative: Switch to rituximab if initially treated with cyclophosphamide or tacrolimus 2

Special Clinical Pitfalls

• Do not assume NELL-1 positivity excludes secondary causes—the association with malignancy may be causal or coincidental, requiring ongoing surveillance 1, 5

• Do not delay biopsy when eGFR declines rapidly—this suggests additional pathology requiring histologic evaluation 1, 5

• Do not use NELL-1 antibody levels to guide treatment decisions—unlike PLA2R, this biomarker lacks validation for monitoring 1

• Do not overlook medication-induced triggers—DMPS and alpha lipoic acid have been associated with NELL-1-positive disease; cessation may lead to partial remission 6

• Do not treat based on NELL-1 serology alone—tissue confirmation by immunohistochemistry showing granular glomerular basement membrane staining is mandatory 9, 4