What causes proteinuria (presence of protein in urine)?

Causes of Protein in Urine (Proteinuria)

Proteinuria is a marker of kidney damage that can result from various glomerular, tubular, and systemic disorders, requiring thorough evaluation to determine the underlying cause and prevent progression to chronic kidney disease. 1

Classification of Causes

Glomerular Causes (Most Common)

• Primary Glomerular Diseases:

  • IgA nephropathy (Berger disease)
  • Membranoproliferative glomerulonephritis
  • Membranous nephropathy
  • Crescentic glomerulonephritis
  • Minimal change disease

• Secondary Glomerular Diseases:

  • Diabetic nephropathy
  • Hypertensive nephrosclerosis
  • Lupus nephritis
  • Post-infectious glomerulonephritis
  • HIV-associated nephropathy 2
  • Hepatitis-related glomerulonephritis
  • Amyloidosis
  • Vasculitis

Tubular Causes

• Interstitial nephritis (drug-induced)
  • NSAIDs
  • Antibiotics
• Analgesic nephropathy
• Tubular toxicity
• Fanconi syndrome
• Heavy metal poisoning

Overflow Proteinuria

• Multiple myeloma (light chain proteins)
• Hemoglobinuria
• Myoglobinuria

Transient/Benign Causes

• Fever
• Intense exercise
• Dehydration
• Emotional stress
• Acute illness
• Orthostatic proteinuria 3

Pathophysiology

Proteinuria occurs through three main mechanisms:

1. Glomerular Proteinuria: Results from increased permeability of the glomerular filtration barrier, allowing abnormal passage of albumin and high-molecular-weight proteins. This is the most common mechanism and typically produces protein excretion >2g/24h 3, 4.

2. Tubular Proteinuria: Occurs when proximal tubular cells fail to reabsorb filtered low-molecular-weight proteins. The megalin-cubilin complex in tubular cells normally reabsorbs these proteins, but when damaged, protein reabsorption is impaired 4.

3. Overflow Proteinuria: Happens when plasma proteins exceed the reabsorptive capacity of tubular cells, as seen in multiple myeloma.

Risk Factors for Significant Proteinuria

Certain populations are at higher risk for developing proteinuria and should undergo regular screening:

• African American individuals
• Patients with diabetes
• Patients with hypertension
• Patients with hepatitis C virus coinfection
• Patients with HIV, especially with CD4+ counts <200 cells/mL or HIV RNA levels ≥14,000 copies/mL 2

Diagnostic Approach

When proteinuria is detected, it's essential to determine if it's persistent:

1. Confirm persistence: Repeat testing 2-3 times over 3-6 months, with at least 2 of 3 specimens showing elevated levels 1

2. Quantify proteinuria: Using spot urine protein-to-creatinine or albumin-to-creatinine ratio, which is more convenient and potentially more accurate than 24-hour collections 2, 1

3. Determine pattern: Glomerular vs. tubular

   • Glomerular: Associated with dysmorphic RBCs (>80%), RBC casts, and significant proteinuria
   • Tubular: Associated with normal RBCs, tubular casts, and moderate proteinuria 2

4. Assess for systemic diseases: Evaluate for diabetes, hypertension, autoimmune disorders, infections

5. Imaging: Renal ultrasound to assess kidney size, structure, and rule out obstruction 2

6. Consider renal biopsy: Especially with nephrotic-range proteinuria, rapidly declining renal function, or unclear etiology 2

Clinical Significance

Proteinuria is not just a marker of kidney disease but also:

• Predicts progression of kidney disease (proteinuria >1g/day indicates poorer prognosis) 5
• Directly contributes to renal deterioration through tubulotoxicity
• Indicates endothelial dysfunction and increased cardiovascular risk 1
• In diabetic patients with microalbuminuria, indicates ~20 times higher risk of developing diabetic nephropathy 5

Management Considerations

The approach to management depends on the underlying cause:

• Treat underlying conditions: Diabetes, hypertension, infections, autoimmune disorders
• Reduce proteinuria: ACE inhibitors or ARBs are first-line therapy, with target BP <130/80 mmHg 1, 6
• Consider combination therapy: ACE inhibitor with ARB or other antiproteinuric agents for resistant cases 6
• Corticosteroids: May be indicated for certain glomerular diseases like minimal change disease, lupus nephritis, and idiopathic nephrotic syndrome 7
• Monitor response: Follow ACR every 3-6 months and renal function (eGFR) at least annually 1

Referral to Nephrology

Consider nephrology referral for:

• Uncertain etiology of kidney disease
• Rapidly progressing kidney disease
• eGFR <30 mL/min/1.73 m²
• Unsatisfactory response to medical treatment 1

Proteinuria should be treated as aggressively as hypertension since reducing protein excretion can prevent progression to renal failure 5.