Investigation for Nephrotic syndrome
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Investigations for Nephrotic Syndrome
Nephrotic syndrome is defined by the tetrad of: heavy proteinuria (>3.5 g/day in adults; >40 mg/m²/hr in children), hypoalbuminemia (<3.5 g/dL), edema, and hyperlipidemia/lipiduria. The investigation workup aims to (1) confirm the diagnosis, (2) assess severity and complications, and (3) identify the underlying cause.
1. Urine Investigations
| Test | Purpose | Findings in NS |
|---|---|---|
| Urine dipstick | Screening | 3+ to 4+ protein |
| 24-hour urine protein | Quantify proteinuria | >3.5 g/day (adults); >40 mg/m²/hr (children) |
| Urine protein-to-creatinine ratio (PCR) | Correlates with 24-hr collection; easier in children | >3.0 mg/mg suggests nephrotic-range proteinuria; first morning void is most accurate |
| Urine microscopy | Identify cellular elements | Oval fat bodies, fatty casts, free fat droplets ("Maltese cross" under polarized light); RBCs if nephritic overlap |
| Urine culture | Rule out infection-related proteinuria | Usually sterile in primary NS |
| Urine albumin/creatinine ratio (ACR) | Monitor albuminuria | Markedly elevated |
| Selectivity index | Distinguish selective vs. non-selective proteinuria | Predominantly albumin loss = selective (suggests MCD in children) |
- In children, urine PCR >2.0 mg/mg (or >3.0) indicates nephrotic-range proteinuria; normal is <0.2 in children >2 years and <0.5 in infants 6 months-2 years. - Rosen's Emergency Medicine
2. Blood Investigations
a) Confirm the Diagnosis
| Test | Findings |
|---|---|
| Serum albumin | Low (<3.5 g/dL; often <2.5 g/dL in heavy nephrosis) |
| Serum total protein | Low |
| Serum lipids (fasting) - total cholesterol, LDL, VLDL, triglycerides | Elevated (hyperlipidemia - compensatory hepatic lipoprotein synthesis due to low oncotic pressure) |
b) Assess Renal Function and Electrolytes
| Test | Purpose |
|---|---|
| Serum creatinine, BUN | Baseline GFR; detect AKI/CKD |
| eGFR | Assess degree of renal impairment |
| Serum electrolytes (Na, K, Cl, HCO3) | Detect dilutional hyponatremia, electrolyte disturbances |
| Uric acid | Elevated in chronic disease |
c) Screen for Secondary Causes
This is critical - the entire workup below aims to identify a systemic disease driving the nephrotic state:
| Test | Secondary Cause Detected |
|---|---|
| Fasting blood glucose + HbA1c | Diabetic nephropathy (most common secondary cause worldwide) |
| Antinuclear antibody (ANA), anti-dsDNA, anti-Sm | Systemic lupus erythematosus (lupus nephritis) |
| ANCA (cANCA/pANCA) | Vasculitis (may have nephrotic-nephritic overlap) |
| Anti-GBM antibodies | Goodpasture's syndrome |
| Serum complement (C3, C4) | Low in SLE, cryoglobulinemia, post-infectious GN, C3 glomerulopathy; normal in MCD, FSGS, membranous nephropathy, diabetic nephropathy |
| Hepatitis B and C serologies | HBV/HCV-associated membranous nephropathy or MPGN |
| HIV testing | HIV-associated nephropathy (collapsing FSGS) |
| Cryoglobulins | Cryoglobulinemic glomerulonephritis |
| Antistreptolysin O (ASO), anti-DNase B | Post-streptococcal GN (if nephritic features present) |
| Serum protein electrophoresis (SPEP) + immunofixation | Multiple myeloma, amyloidosis (light chain disease) |
| Anti-PLA2R antibody | Primary membranous nephropathy (highly specific; positive in ~70-80% of primary MN) - can avoid biopsy if positive with intact renal function and no systemic disease |
| Anti-THSD7A antibody | Malignancy-associated membranous nephropathy (~10% of MN) |
| Thyroid function tests (TSH, T4) | Hypothyroidism (myxedema and proteinuria) |
| Tumor markers / cancer screen | Solid tumors associated with membranous nephropathy in adults >60 years |
- Goldman-Cecil Medicine: "Common screening tests include fasting blood sugar and glycosylated hemoglobin tests for diabetes, and antinuclear antibody test for collagen vascular disease... cryoglobulins, hepatitis B and C serologies, HIV testing, ANCAs, anti-GBM antibodies, serum protein and immunofixation... may be useful."
d) Complications Screening
| Test | Complication Detected |
|---|---|
| Coagulation screen (PT, aPTT, fibrinogen) | Hypercoagulable state (loss of antithrombin III, protein C, protein S in urine) |
| D-dimer | Screen for thromboembolic events |
| Lipid profile | Cardiovascular risk assessment |
| Serum calcium, phosphate, vitamin D | Hypocalcemia due to loss of vitamin D-binding protein |
| Serum iron, TIBC, ferritin | Iron-deficiency (loss of transferrin) |
| Thyroid function | Loss of thyroxine-binding globulin can cause hypothyroidism |
| Immunoglobulins (IgG, IgA, IgM) | IgG loss predisposes to infections |
3. Imaging
| Investigation | Findings |
|---|---|
| Renal ultrasound | Kidney size and echogenicity; rules out polycystic kidney disease, obstruction, masses, renal vein thrombosis on Doppler; normal or enlarged kidneys in early disease |
| Renal Doppler ultrasound | Screen for renal vein thrombosis (most common in membranous nephropathy) |
| CT pulmonary angiography / V-Q scan | If pulmonary embolism suspected (especially with membranous nephropathy) |
| Chest X-ray | Pleural effusion (transudates from hypoalbuminemia) |
| Echocardiogram | Pericardial effusion, periorbital edema workup |
- Goldman-Cecil: "The presence of sudden flank pain, deterioration of kidney function, or acute pulmonary symptoms in a patient with membranous nephropathy should prompt an investigation for renal vein thrombosis and pulmonary emboli."
4. Kidney Biopsy - The Definitive Investigation
Indications for biopsy:
- All adults with nephrotic syndrome (biopsy is required to determine histological pattern and guide therapy)
- Children with atypical features: age <1 year, macroscopic hematuria, persistent hypertension, hypocomplementemia, steroid resistance, extrarenal features (rash, arthritis)
- Presumed secondary cause requiring confirmation
- Suspicion of unusual/hereditary forms
Not required in:
- Children with typical steroid-sensitive nephrotic syndrome (presumed MCD - treat empirically with steroids)
- Adults with nephrotic syndrome + intact renal function + positive anti-PLA2R antibody (specific enough to diagnose primary membranous nephropathy without biopsy)
Biopsy modalities:
| Technique | Information Obtained |
|---|---|
| Light microscopy (H&E, PAS, Masson's trichrome, Jones silver) | Glomerular architecture, cellularity, sclerosis, deposits |
| Immunofluorescence (IF) | Type and location of immune deposits (IgG, IgA, IgM, C3, C4, C1q, kappa, lambda) |
| Electron microscopy (EM) | Podocyte foot process effacement, deposit location (subepithelial, subendothelial, mesangial) |
Key histological patterns in nephrotic syndrome:
| Pattern | LM | IF | EM | Cause |
|---|---|---|---|---|
| Minimal Change Disease (MCD) | Normal (or minimal changes) | Negative | Diffuse foot process effacement | Idiopathic, drugs, Hodgkin lymphoma |
| Focal Segmental Glomerulosclerosis (FSGS) | Segmental sclerosis in some glomeruli | Variable | Foot process effacement | Primary/idiopathic, HIV, obesity, drugs |
| Membranous Nephropathy (MN) | Thickened GBM, "spike and dome" | IgG + C3 granular subepithelial | Subepithelial deposits | Idiopathic (anti-PLA2R), HBV, drugs, malignancy |
| MPGN | Mesangial proliferation, double contours | C3 ± IgG/IgM granular | Subendothelial/mesangial deposits | HCV, cryoglobulinemia, C3 glomerulopathy |
| Diabetic nephropathy | Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) | IgG/albumin non-specific | GBM thickening | Diabetes mellitus |
| Amyloidosis | Amorphous deposits, Congo red positive (apple-green birefringence) | Monoclonal light chains | Fibrils 8-12 nm | AL/AA amyloid |
5. Investigations Summary by System
URINE
├── Dipstick (3+/4+ protein)
├── Microscopy (oval fat bodies, fatty casts)
├── 24-hr protein OR spot PCR
└── Urine culture
BLOOD
├── Confirm: Albumin, total protein, lipid profile
├── Renal function: Cr, BUN, eGFR, electrolytes
├── Secondary causes:
│ ├── ANA, anti-dsDNA (SLE)
│ ├── HbA1c, fasting glucose (diabetes)
│ ├── C3, C4 (complement)
│ ├── ANCA, anti-GBM
│ ├── HBsAg, anti-HCV, HIV
│ ├── Anti-PLA2R (membranous)
│ ├── SPEP + immunofixation (myeloma)
│ └── Cryoglobulins, ASO
└── Complications: Coagulation, Ca/PO4/Vit D, thyroid, IgG
IMAGING
├── Renal ultrasound + Doppler (renal vein thrombosis)
├── CXR (pleural effusion)
└── CTPA if PE suspected
BIOPSY
└── Light microscopy + Immunofluorescence + Electron microscopy
Special Notes
- Complement levels help categorize: low C3/C4 points toward immune complex disease (SLE, post-infectious, cryoglobulinemia); normal complement is typical of MCD, FSGS, and membranous nephropathy. - Goldman-Cecil Medicine
- Anti-PLA2R antibody is highly specific for primary membranous nephropathy and can substitute for biopsy in selected adults. Circulating anti-THSD7A is associated with malignancy-related MN. - Goldman-Cecil Medicine
- In children with typical presentation (age 1-8, no hematuria, no hypertension, normal complement), MCD is overwhelmingly likely - biopsy is deferred and empiric steroids are started. - Campbell-Walsh-Wein Urology; Rosen's Emergency Medicine
- Fractional sodium excretion (FENa) <0.2% in children can differentiate volume-contracted from volume-expanded nephrotic syndrome, guiding diuretic therapy. - Brenner and Rector's The Kidney
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