What is the differential diagnosis and initial lab workup for a patient presenting with proteinuria?

Differential Diagnosis and Initial Lab Workup for Proteinuria

The initial evaluation of proteinuria should include quantification of protein excretion, assessment of renal function, and targeted testing for specific causes based on clinical presentation, with a urine protein-to-creatinine ratio being the preferred initial quantitative test.

Differential Diagnosis of Proteinuria

Benign/Functional Causes

• Transient/Functional Proteinuria
  • Fever
  • Intense exercise or physical activity
  • Emotional stress
  • Dehydration
  • Orthostatic proteinuria (occurs in upright position, normalizes when recumbent)

Glomerular Causes (typically >2g/day)

• Primary Glomerular Diseases

  • IgA nephropathy
  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • Membranous nephropathy
  • Membranoproliferative glomerulonephritis

• Secondary Glomerular Diseases

  • Diabetic nephropathy
  • Lupus nephritis
  • Amyloidosis
  • HIV-associated nephropathy (HIVAN) 1
  • Hepatitis B or C-associated nephropathy

Tubular Causes (typically <2g/day)

• Interstitial nephritis
• Acute tubular necrosis
• Heavy metal poisoning
• Drug-induced nephropathy

Overflow Proteinuria

• Multiple myeloma 1
• Monoclonal gammopathies

Other Causes

• Hypertensive nephrosclerosis
• Preeclampsia in pregnancy 1
• Congestive heart failure
• Malignancy

Initial Laboratory Workup

Step 1: Confirm and Quantify Proteinuria

• Urinalysis with dipstick (initial screening)

  • If positive (≥1+), proceed to quantitative testing 1

• Urine protein-to-creatinine ratio (PCR) on spot urine sample

  • Preferred over 24-hour collection due to convenience and accuracy 1
  • PCR ≥30 mg/mmol (0.3 mg/mg) is abnormal 1
  • Values >500-1000 mg/g may warrant measurement of total protein instead of albumin 1

• 24-hour urine collection (when needed)

  • Gold standard but less practical
  • Indicated for confirmation of nephrotic syndrome (>3.5g/24h) 1

Step 2: Basic Renal Function Assessment

• Serum creatinine and estimated GFR (eGFR)

  • Using CKD-EPI equation for adults 1
  • Assess for reduced kidney function (eGFR <60 ml/min/1.73m²)

• Complete blood count (CBC)

  • To evaluate for anemia associated with chronic kidney disease

• Serum electrolytes, BUN, calcium

  • To assess for electrolyte imbalances and renal function

Step 3: Targeted Testing Based on Clinical Suspicion

For Suspected Glomerular Disease:

• Serum albumin

  • Low levels suggest nephrotic syndrome

• Lipid panel

  • Hyperlipidemia often accompanies nephrotic syndrome

• Complement levels (C3, C4)

  • Low in lupus nephritis, membranoproliferative GN 1

• Antinuclear antibody (ANA)

  • For suspected lupus nephritis 1

• Hepatitis B and C serology

  • Associated with various glomerulonephritides 1

• HIV testing

  • Especially in high-risk patients or those with HIVAN suspicion 1

For Suspected Multiple Myeloma:

• Serum and urine protein electrophoresis
• Serum free light chain assay
• Serum immunofixation electrophoresis 1

For Suspected Diabetic Nephropathy:

• Hemoglobin A1c
• Fasting blood glucose

Step 4: Urinary Sediment Examination

• Microscopic examination of urine
  • Red cell casts suggest glomerulonephritis
  • White cell casts suggest interstitial nephritis
  • Fatty casts suggest nephrotic syndrome

Step 5: Imaging

• Renal ultrasound
  • To assess kidney size, echogenicity, and rule out obstruction
  • Particularly helpful if hematuria, infection, or renal insufficiency is present 1

When to Refer to Nephrology

Referral to a nephrologist is warranted for:

• Persistent significant proteinuria (PCR >0.3 mg/mg on repeated testing)
• Proteinuria with hematuria
• Nephrotic-range proteinuria (>3.5g/24h)
• Proteinuria with reduced eGFR
• Proteinuria with hypertension
• Proteinuria with systemic disease
• When diagnosis remains unclear after initial workup 1

Common Pitfalls to Avoid

• False positive dipstick results can occur with:

  • Highly alkaline urine
  • Concentrated urine
  • Gross hematuria
  • Presence of mucus, semen, or white blood cells

• Transient proteinuria should not be over-investigated:

  • Repeat testing after resolution of acute illness or stress
  • Confirm persistence before extensive workup

• Orthostatic proteinuria should be distinguished from pathological causes:

  • Split urine collection (supine vs. upright) may be necessary

• Isolated proteinuria without other abnormalities may still indicate significant renal disease:

  • Don't dismiss mild proteinuria without appropriate follow-up

Remember that proteinuria >2g/day typically suggests glomerular disease, while lower levels may indicate tubular or other causes 2, 3.