Causes of Proteinuria
Proteinuria is primarily caused by glomerular damage, tubular dysfunction, or overflow mechanisms, with glomerular proteinuria being the most common pathological cause and a significant marker of kidney damage and cardiovascular risk. 1
Classification of Proteinuria
1. Glomerular Proteinuria
- Increased glomerular permeability leading to excessive protein filtration
- Associated with:
- Diabetic nephropathy
- Glomerulonephritis (post-infectious, membranous, membranoproliferative, IgA nephropathy)
- Hypertensive nephrosclerosis
- Focal segmental glomerulosclerosis
- Lupus nephritis
- Genetic disorders (Alport syndrome, mesangial sclerosis)
2. Tubular Proteinuria
- Impaired tubular reabsorption of normally filtered proteins
- Characterized by:
- Presence of low-molecular-weight proteins
- Normal RBCs and tubular casts in urinalysis
- Moderate proteinuria (usually <2g/day)
- Associated with:
- Tubulointerstitial nephritis
- Fanconi syndrome
- Drug toxicity (aminoglycosides, cisplatin)
- Heavy metal poisoning
3. Overflow Proteinuria
- Excessive production of plasma proteins overwhelming normal reabsorption
- Associated with:
- Multiple myeloma (Bence Jones protein)
- Hemoglobinuria
- Myoglobinuria
4. Non-pathological/Functional Proteinuria
- Transient changes in renal hemodynamics without kidney damage
- Associated with:
- Fever
- Exercise
- Orthostatic (postural) changes
- Emotional stress
- Congestive heart failure
Diagnostic Thresholds
According to the American Journal of Kidney Diseases guidelines 2, 1:
| Category | ACR (mg/g creatinine) | 24-h collection (mg/24h) | Timed collection (μg/min) |
|---|---|---|---|
| Normal | <30 | <30 | <20 |
| Microalbuminuria | 30-299 | 30-299 | 20-199 |
| Macroalbuminuria | ≥300 | ≥300 | ≥200 |
Clinical Significance
- Microalbuminuria (30-300 mg/g creatinine) indicates early kidney damage and increased cardiovascular risk 1
- Macroalbuminuria (>300 mg/g creatinine) signals established kidney disease
- Proteinuria >1g/day is associated with:
- Nephrotic-range proteinuria (>3.5g/day) typically indicates significant glomerular disease 5
Pathophysiologic Mechanisms
Glomerular hyperfiltration:
- Shifts glomerular pores to larger dimensions
- Results in excessive protein leakage 3
Endothelial injury:
- Increases local generation of Angiotensin II
- Contributes to progressive kidney damage 3
Tubulotoxicity:
- Filtered proteins directly damage tubular cells
- Contributes to tubulointerstitial inflammation and fibrosis 3
Diagnostic Approach
Confirm persistence:
- Two of three specimens collected within 3-6 months should be abnormal 1
- Rule out temporary causes (exercise, urinary tract infections, marked hyperglycemia)
Determine pattern:
- Glomerular pattern: Significant albuminuria, dysmorphic RBCs, RBC casts
- Tubular pattern: Low-molecular-weight proteins, normal RBCs, tubular casts 1
Assess severity:
Clinical Implications
- Proteinuria is both a marker of kidney damage and a contributor to disease progression 3, 4
- Even low-grade proteinuria increases risk for cardiovascular events and mortality 4
- Non-selective proteinuria (containing higher molecular weight proteins) indicates more severe glomerular damage and worse prognosis 3
- In diabetic patients, persistent microalbuminuria increases risk of developing diabetic nephropathy by approximately 20 times 3
- In hypertension, new-onset proteinuria despite blood pressure control signals likely kidney function decline 3
Common Pitfalls in Evaluation
- Relying solely on dipstick testing may miss cases of microalbuminuria or tubular proteinuria 1
- Failing to distinguish between transient and persistent proteinuria 6, 7
- Not ruling out non-pathological causes before extensive workup 7
- Overlooking orthostatic proteinuria in children and young adults (protein excretion normalizes when recumbent) 7
By understanding the various causes and mechanisms of proteinuria, clinicians can better diagnose underlying kidney diseases, assess cardiovascular risk, and monitor response to treatment.