What are the causes and management of proteinuria?

Causes and Management of Proteinuria

Proteinuria is a hallmark of renal disease, with persistent proteinuria exceeding 1 g/day indicating poorer prognosis and requiring aggressive treatment with ACE inhibitors or ARBs as first-line therapy. 1, 2

Causes of Proteinuria

Proteinuria can be categorized based on pathophysiologic mechanisms:

1. Glomerular Proteinuria

• Most common mechanism, typically >2 g/24 hours 3
• Causes include:
  • Glomerulonephritis
  • Diabetic nephropathy
  • Autosomal dominant polycystic kidney disease (ADPKD) 4
  • Hypertensive nephrosclerosis

2. Tubular Proteinuria

• Due to impaired tubular reabsorption of filtered proteins
• Causes include:
  • Tubulointerstitial diseases
  • Drug toxicity
  • Heavy metal poisoning

3. Overflow Proteinuria

• Due to increased production of low molecular weight proteins
• Causes include:
  • Multiple myeloma (Bence-Jones protein)
  • Hemoglobinuria
  • Myoglobinuria

4. Benign/Functional Proteinuria

• Transient and not associated with progressive renal disease 5
• Causes include:
  • Fever
  • Intense exercise
  • Dehydration
  • Emotional stress
  • Orthostatic proteinuria (normalizes when recumbent)

Evaluation of Proteinuria

1. Quantification:

   • Measure albumin/creatinine ratio (ACR) in laboratory rather than dipstick testing 4, 2
   • Categorize severity:
     • Moderate albuminuria: ACR ≥3 mg/mmol
     • Severe albuminuria: ACR ≥30 mg/mmol 4

2. Assessment for underlying causes:

   • Comprehensive metabolic panel including electrolytes, bicarbonate, calcium, phosphorus, PTH, hemoglobin, and albumin 2
   • Evaluate for diabetes, hypertension, and systemic diseases
   • Consider renal imaging in selected cases

Management of Proteinuria

Pharmacological Interventions

1. First-line therapy: ACE inhibitors or ARBs 4, 2

   • Titrate to maximally tolerated doses
   • Goal: Reduce proteinuria to <1 g/day or as low as possible
   • Monitor serum creatinine and potassium within 1-2 weeks after initiating or increasing dose
   • A modest increase in serum creatinine (up to 30%) is acceptable 2

2. Second-line options:

   • Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) have antiproteinuric effects 2
   • Diuretics should be used with caution as they may increase vasopressin levels and have deleterious effects on eGFR 4, 2
   • Avoid amlodipine in patients with glomerular hypertension 2

3. Dual RAS blockade (ACE inhibitor + ARB):

   • May provide additional proteinuria reduction
   • Use cautiously due to increased risk of hyperkalemia and acute kidney injury 2

Blood Pressure Control

• Target blood pressure based on proteinuria level:

  • 1 g/day: <125/75 mmHg

  • <1 g/day: <130/80 mmHg
  • Pediatric patients: ≤50th percentile for age, sex, and height 2

Dietary Modifications

• Restrict sodium intake to <2 g/day
• Maintain protein intake at 0.8 g/kg/day
• Higher protein intake (>1.3 g/kg/day) is associated with increased proteinuria 2, 6
• Recommend diet high in vegetables, fruits, whole grains, fiber, legumes, and plant-based proteins 2

Monitoring and Follow-up

• Check ACR every 3-6 months to assess treatment response 2
• Monitor blood pressure at every clinic visit
• Monitor eGFR every 3 months for Stage 4 CKD 2

Referral to Nephrology

Refer patients if they have:

• Persistent proteinuria >1 g/day
• GFR <30 mL/min/1.73 m²
• Abrupt sustained decrease in eGFR >20%
• Inability to tolerate renoprotective medications
• Uncertainty about diagnosis 2

Clinical Significance of Proteinuria

• Strong independent predictor of increased risk for all-cause and cardiovascular mortality 7
• Marker of kidney damage and reliable predictor of progression of renal failure 6
• In essential hypertension, de novo proteinuria after years of adequate BP control indicates subsequent decline in renal function 1
• In glomerulonephritis, more severe proteinuria is associated with faster rate of progression 1

Treatment Pitfalls to Avoid

• Don't rely solely on dipstick testing for proteinuria assessment; laboratory ACR measurement is more accurate 4
• Don't dismiss mild proteinuria as benign without proper evaluation
• Don't fail to monitor kidney function and potassium after starting ACE inhibitors or ARBs
• Don't use dihydropyridine calcium channel blockers as first-line therapy for proteinuria
• Don't overlook lifestyle modifications in managing proteinuria