What causes proteinuria?

Causes of Proteinuria

Proteinuria occurs due to glomerular filtration barrier damage, tubular reabsorption dysfunction, or both, with the underlying causes ranging from benign transient conditions to serious kidney diseases that require prompt evaluation and treatment. 1

Mechanisms of Proteinuria

Protein appears in urine through three main mechanisms:

1. Glomerular Proteinuria

   • Results from increased permeability of the glomerular filtration barrier
   • The barrier consists of three layers: endothelium, glomerular basement membrane, and podocytes 2
   • Damage to any component allows increased protein filtration
   • May be selective (primarily albumin) or non-selective (includes larger proteins)
   • Non-selective proteinuria indicates more severe glomerular damage and poorer prognosis 3

2. Tubular Proteinuria

   • Occurs when proximal tubular cells fail to reabsorb filtered low-molecular-weight proteins
   • Normal tubular reabsorption involves the megalin-cubilin receptor complex 4
   • Saturation of this reabsorption mechanism with excessive protein load leads to proteinuria

3. Overflow Proteinuria

   • Results from increased plasma levels of low-molecular-weight proteins that overwhelm tubular reabsorption capacity

Classification of Proteinuria

1. Benign Forms

• Functional/Transient Proteinuria

  • Associated with altered renal hemodynamics (fever, exercise, stress)
  • Usually resolves spontaneously
  • Not associated with progressive renal disease 5

• Orthostatic Proteinuria

  • Protein excretion normalizes in recumbent position
  • Generally has excellent long-term prognosis 5

2. Pathological Forms

• Glomerular Disease

  • Nephrotic-range proteinuria (>3.5g/day): Usually indicates primary glomerular disorder
  • Non-nephrotic range (<2g/day): May indicate glomerular, tubular, or vascular disorders 5
  • Examples: Diabetic nephropathy, glomerulonephritis, IgA nephropathy

• Tubular Disease

  • Characterized by low-molecular-weight proteinuria
  • Examples: Acute tubular necrosis, interstitial nephritis

• Systemic Disease

  • Diabetes mellitus (leading cause of proteinuria)
  • Hypertension
  • Autoimmune diseases (lupus, vasculitis)

Quantification and Evaluation

• Normal range: <30 mg albumin/g creatinine 1
• Microalbuminuria: 30-299 mg albumin/g creatinine 1
• Macroalbuminuria: ≥300 mg albumin/g creatinine 1

The National Kidney Foundation recommends using the ratio of urine albumin-to-creatinine on a spot urine sample rather than timed collections 6

Clinical Significance

1. Marker of Kidney Damage

   • Persistent proteinuria is the hallmark of kidney disease 3
   • Proteinuria >1g/day indicates poorer prognosis 3

2. Contributor to Disease Progression

   • Proteinuria is tubulotoxic and directly contributes to renal deterioration 3
   • Filtered proteins induce inflammatory and fibrogenic mediators in tubular cells 2
   • This leads to interstitial inflammation, fibrosis, and progressive nephron loss 2

3. Cardiovascular Risk

   • Microalbuminuria is an independent predictor of cardiovascular risk 1

Diagnostic Approach

1. Initial Screening

   • Random spot urine albumin-to-creatinine ratio (UACR) is preferred 1
   • First morning void samples minimize confounding factors 1

2. Confirmation

   • Repeat testing to confirm persistent proteinuria (2 of 3 measurements >30 mg/g) 6
   • Rule out transient causes (dehydration, exercise, fever) 1

3. Further Evaluation

   • Complete urinalysis with microscopy for casts and cells
   • Serum creatinine and estimated GFR
   • Additional testing based on clinical presentation

Management Principles

1. Address Underlying Cause

   • Identify and treat primary disease process

2. Reduce Proteinuria

   • ACE inhibitors or ARBs are first-line therapy 1
   • Target reduction of urinary albumin by ≥30% 1

3. Control Associated Factors

   • Blood pressure target <130/80 mmHg 1
   • Optimize glycemic control in diabetes (HbA1c <7%) 1
   • Consider dietary protein restriction to ~0.8 g/kg/day 1

4. Monitor Progression

   • Regular assessment of proteinuria and kidney function
   • Consider nephrology referral for rapidly declining GFR, difficult-to-control hypertension, or persistent albuminuria despite optimal therapy 1

Proteinuria should be considered not just a marker of kidney disease but an active contributor to disease progression, making its detection and treatment crucial for preserving kidney function and reducing cardiovascular risk.