What set of investigations is necessary to differentiate between nephrotic and nephritic syndrome in a patient presenting with symptoms of kidney disease, such as proteinuria, hematuria, or edema?

Investigations to Differentiate Nephrotic from Nephritic Syndrome

The essential investigations include urinalysis with microscopy for cellular casts and RBCs, quantitative proteinuria measurement (spot urine protein-to-creatinine ratio or albumin-to-creatinine ratio), serum albumin, serum creatinine with eGFR calculation, and complement levels (C3/C4), with renal biopsy reserved for cases requiring definitive histopathological diagnosis. 1, 2

Initial Laboratory Assessment

Urine Studies

• Urinalysis with microscopic examination is the cornerstone test to identify the syndrome pattern—look specifically for red blood cell casts (pathognomonic for nephritic syndrome) and dysmorphic RBCs indicating glomerular bleeding 1, 3, 4
• Quantify proteinuria using spot urine protein-to-creatinine ratio (PCR) or albumin-to-creatinine ratio (ACR)—nephrotic range is defined as PCR >300-350 mg/mmol or total protein >3.5 g/24 hours, while nephritic syndrome typically shows proteinuria <3.5 g/24 hours 1, 2, 5
• Examine urinary sediment for hyaline casts (common in nephrotic syndrome) versus cellular casts, particularly RBC casts (diagnostic of nephritic syndrome) 3, 4

Blood Tests

• Serum albumin measurement is essential—hypoalbuminemia (<3.0 g/dL or <30 g/L) defines nephrotic syndrome, while nephritic syndrome typically maintains normal or near-normal albumin 6, 2, 5
• Serum creatinine with eGFR calculation using CKD-EPI equation to assess renal function—acute kidney injury is more characteristic of nephritic syndrome 1, 7
• Complete blood count to evaluate for anemia and assess overall systemic involvement 1, 3
• Blood urea nitrogen (BUN) as an additional marker of renal function 3

Distinguishing Clinical Features

Nephrotic Syndrome Characteristics

• Heavy proteinuria (>3.5 g/24 hours or PCR >3500 mg/g), hypoalbuminemia (<3.0 g/dL), and peripheral edema form the diagnostic triad 1, 2, 8
• Hyperlipidemia is commonly present and should be measured 2, 5
• Selective proteinuria pattern (predominantly albumin) suggests minimal change disease, particularly in children 9, 5
• Absence of hematuria, normal blood pressure, and preserved renal function are typical 9, 5

Nephritic Syndrome Characteristics

• Hematuria with RBC casts, proteinuria (<3.5 g/24 hours), hypertension, and acute kidney injury characterize this syndrome 4, 5
• Poorly selective proteinuria (mixed protein types) suggests glomerular inflammation 9
• Hypertension and fluid retention are prominent features 4, 5

Serological Testing for Secondary Causes

• Complement levels (C3, C4) are critical—decreased C3 suggests post-infectious glomerulonephritis, lupus nephritis, or membranoproliferative GN (all nephritic patterns) 9, 4
• Antinuclear antibodies (ANA) and anti-dsDNA to exclude systemic lupus erythematosus 1, 4
• ANCA testing (anti-neutrophil cytoplasmic antibodies) for vasculitis-associated nephritic syndrome 4
• Anti-phospholipase A2 receptor (PLA2R) antibodies for membranous nephropathy (nephrotic pattern) 1
• Hepatitis B and C serology, HIV testing as secondary causes of both syndromes 1, 7

When to Perform Renal Biopsy

Renal biopsy is indicated when: 1

• Clinical features suggest nephritic syndrome or diffuse glomerular disease (acute nephritic onset, macroscopic hematuria, marked hypertension, renal insufficiency, decreased C3) 9
• Steroid resistance develops after 4 weeks of treatment in presumed minimal change disease 6
• Adult patients with nephrotic syndrome require histopathological diagnosis before initiating immunosuppression 1, 2
• Active urinary sediment (RBC casts, WBC casts, or cellular casts) is present with proteinuria 3, 7

Common Pitfalls to Avoid

• Do not rely on proteinuria quantity alone—nephrotic syndrome can have hematuria, and nephritic syndrome always has some degree of proteinuria 5
• Do not skip urinary microscopy—the presence or absence of RBC casts is the single most discriminating finding between these syndromes 1, 4
• Do not delay nephrology referral when nephritic features are present (RBC casts, rapidly declining eGFR, hypertension with active sediment)—these patients require urgent evaluation within 2 weeks 7, 2
• In children under 8 years with classic nephrotic syndrome features (no hematuria, normal blood pressure, normal renal function), empiric steroid therapy can be initiated without biopsy, but biopsy is mandatory if steroid-resistant 6, 9