A 28-year-old Indian male with a 3-week history of nephrotic syndrome (proteinuria 5.2 g/day, hypoalbuminemia, ankle edema) has normal serum complement C3 and C4 levels, negative ANCA, and negative anti-GBM antibodies. Renal ultrasound is normal. Which single investigation would be most specific in confirming the diagnosis of membranous nephropathy?

## Anti-PLA2R Antibody in Membranous Nephropathy **Key Point:** Anti-phospholipase A2 receptor (anti-PLA2R) antibody is a highly specific serum marker for primary membranous nephropathy and can support the diagnosis before or instead of renal biopsy in appropriate clinical contexts. ### Clinical Significance of Anti-PLA2R **High-Yield:** Anti-PLA2R is present in 70–80% of primary membranous nephropathy cases and is virtually absent in secondary membranous nephropathy (lupus, hepatitis B, malignancy-associated). Its detection strongly supports primary MN diagnosis. ### Diagnostic Algorithm for Nephrotic Syndrome with Normal Complement ```mermaid flowchart TD A[Nephrotic syndrome + Normal complement]:::outcome --> B{ANCA, Anti-GBM negative?}:::decision B -->|Yes| C[Likely primary GN]:::outcome C --> D{Clinical suspicion for MN?}:::decision D -->|Yes| E[Check anti-PLA2R serology]:::action E --> F{Anti-PLA2R positive?}:::decision F -->|Yes| G[Primary MN confirmed]:::outcome F -->|No| H[Renal biopsy for definitive diagnosis]:::action D -->|Uncertain| H ``` ### Anti-PLA2R vs. Other Investigations | Investigation | Role | Specificity for MN | |---|---|---| | **Anti-PLA2R antibody** | Serum marker; supports primary MN diagnosis | 95–98% when positive | | Serum creatinine/eGFR | Assesses renal function; not diagnostic | None | | Urinalysis | Confirms proteinuria; non-specific | None | | Serum albumin/protein | Reflects nephrotic state; non-specific | None | | **Renal biopsy** | Gold standard; shows subepithelial deposits | 100% | **Clinical Pearl:** In a patient with nephrotic syndrome, normal complement, negative ANCA/anti-GBM, and positive anti-PLA2R, primary membranous nephropathy is highly likely. Biopsy may be deferred in some cases if anti-PLA2R is positive and clinical features are classic. **Mnemonic:** **PLA2R = Primary MN Marker** - **P**hospholipase A2 **R**eceptor - Present in ~75% of primary MN - Absent in secondary MN (SLE, HBV, malignancy) - Useful for non-invasive diagnosis [cite:Harrison 21e Ch 279]