What are the causes of proteinuria?

Causes of Proteinuria

Proteinuria is a hallmark of kidney disease and can result from various pathological processes including glomerular damage, tubular dysfunction, or systemic conditions affecting the kidneys. 1

Classification of Proteinuria

Physiological/Functional Causes

• Exercise-induced proteinuria 2
• Fever-related proteinuria 3
• Orthostatic proteinuria (protein excretion normalizes when recumbent) 4
• Transient proteinuria (discovered on routine screening, disappears on subsequent testing) 4

Pathological Causes

Glomerular Proteinuria

• Primary Glomerular Diseases

  • Minimal change disease 5
  • Focal segmental glomerulosclerosis (FSGS) 5
  • Membranous nephropathy 5
  • IgA nephropathy 3
  • Membranoproliferative glomerulonephritis 3

• Secondary Glomerular Diseases

  • Diabetic nephropathy 5
  • Lupus nephritis 3
  • Post-infectious glomerulonephritis 3
  • HIV-associated nephropathy (HIVAN) 5
  • Amyloidosis 4

Tubular Proteinuria

• Tubulointerstitial nephritis 4
• Fanconi syndrome 1
• Drug-induced tubular damage 4
• Heavy metal poisoning 4

Overflow Proteinuria

• Multiple myeloma (light chain proteinuria) 6
• Hemoglobinuria 4
• Myoglobinuria 4

Pregnancy-Related Proteinuria

• Preeclampsia 5
• Gestational proteinuria (new onset proteinuria without other features of preeclampsia) 5

Evaluation of Proteinuria

Initial Assessment

• Dipstick urinalysis is the first screening test 5
  • If positive (≥1+, 30 mg/dL), proceed to quantification 5
  • Negative dipstick can usually rule out significant proteinuria 5

Quantification Methods

• Spot urine protein/creatinine ratio (PCR)
  • PCR ≥30 mg/mmol (0.3 mg/mg) is abnormal 5
  • More convenient than 24-hour collection 5
• 24-hour urine protein collection
  • Gold standard for quantification 5
  • Proteinuria defined as >150 mg/day 3

  • 3.5 g/day indicates nephrotic range proteinuria 5

  • Still indicated to confirm nephrotic syndrome 5

Classification by Severity

• Mild: <1 g/day 4
• Moderate: 1-3.5 g/day 4
• Nephrotic range: >3.5 g/day 5
• Massive proteinuria: >5 g/day (associated with worse outcomes) 5

Clinical Significance

Prognostic Implications

• Persistent proteinuria >3.8 g/day carries a 35% risk of end-stage renal disease within 2 years 5
• Proteinuria <2.0 g/day has only a 4% risk of end-stage renal disease 5
• Massive proteinuria (>5 g/24h) is associated with more severe neonatal outcomes in pregnancy 5

Complications of Proteinuria

• Increased risk of thromboembolism, especially with nephrotic syndrome 5
  • Renal vein thrombosis (29%) 5
  • Pulmonary embolism (17-28%) 5
  • Deep vein thrombosis (11%) 5
• Accelerated coronary heart disease (4x greater risk) 5
• Hypoalbuminemia (decrease of 1.0 g/dL increases morbidity by 89% and mortality by 137%) 5
• Tubular toxicity from elevated protein concentrations 2

Special Considerations

Proteinuria in HIV Patients

• HIV-associated nephropathy (HIVAN) often presents with proteinuria 5
• Annual screening recommended for high-risk HIV patients:
  • African American persons 5
  • Patients with diabetes or hypertension 5
  • Hepatitis C co-infection 5
  • HIV RNA levels ≥14,000 copies/mL 5
  • CD4+ count <200 cells/mL 5

Proteinuria in Pregnancy

• 24-hour protein ≥300 mg/day is abnormal in pregnancy 5
• Proteinuria is no longer required for diagnosis of preeclampsia 5
• Factors affecting urinary protein in pregnancy:
  • Menstrual blood contamination 5
  • Symptomatic urinary tract infection 5
  • Exercise 5
  • Upright posture (orthostatic proteinuria) 5

Pitfalls in Proteinuria Assessment

• Dipstick testing may miss small amounts of proteinuria 5
• Urine PCR <30 mg/mmol occasionally gives false-negative results 5
• Improper 24-hour collection can lead to inaccurate results 5
• Transient causes should be ruled out before extensive workup 4
• Preanalytical factors affecting measurement:
  • Sample storage conditions 5
  • Degradation of albumin before analysis 5
  • Variability in creatinine excretion 5