What causes proteinuria?

What Causes Protein in Urine

Proteinuria results from three main pathophysiologic mechanisms: glomerular disease (most common and clinically significant), tubular dysfunction, and overflow states, though transient physiologic causes must first be excluded. 1

Transient (Physiologic) Causes

These benign causes resolve spontaneously and require no treatment:

• Fever temporarily elevates urinary protein excretion 2, 1
• Intense physical activity or exercise within 24 hours before urine collection causes transient proteinuria 2, 1
• Orthostatic proteinuria occurs with upright posture and normalizes when lying down 2, 1
• Marked hyperglycemia can transiently increase protein excretion 2, 1
• Congestive heart failure temporarily elevates protein levels 2, 1
• Dehydration and emotional stress can cause transient proteinuria 3

Glomerular Causes (Most Common Pathologic Mechanism)

Glomerular disease carries the greatest risk for progressive kidney disease and typically produces proteinuria exceeding 2 g per 24 hours 1:

Primary Glomerular Diseases

• Minimal change disease causes nephrotic-range proteinuria through loss of glomerular charge selectivity 1, 4
• Focal segmental glomerulosclerosis (FSGS) results in progressive proteinuria with high risk for end-stage renal disease 1, 4
• Membranous nephropathy presents with heavy proteinuria and increased thrombotic risk 1, 4
• IgA nephropathy can cause persistent proteinuria and progressive renal deterioration 5

Secondary Glomerular Diseases

• Diabetic nephropathy typically begins with microalbuminuria (30-299 mg/g creatinine) before progressing to clinical albuminuria (≥300 mg/g creatinine) 2, 1, 4
• Hypertensive nephrosclerosis damages the glomerular filtration barrier through chronic elevated intraglomerular pressure, particularly in patients with type 2 diabetes 2, 1
• HIV-associated nephropathy (HIVAN) often presents with heavy proteinuria and rapid progression to kidney failure 1, 4
• Post-infectious glomerulonephritis can cause proteinuria following streptococcal or other infections 6
• Lupus nephritis causes proteinuria as part of systemic lupus erythematosus 6

Tubular Causes

Tubular dysfunction impairs protein reabsorption, typically producing lower levels of proteinuria with characteristic low-molecular-weight proteins 7, 8:

• Tubulointerstitial disease causes increased excretion of low-molecular-weight globulins 7
• Genetic tubular disorders such as Fanconi syndrome impair proximal tubular reabsorption 8

Overflow Proteinuria

• Multiple myeloma produces Bence-Jones proteins that overwhelm normal tubular reabsorption capacity 3

Pregnancy-Related Causes

• Preeclampsia causes new-onset proteinuria after 20 weeks gestation, with proteinuria ≥300 mg/24h considered abnormal 1, 4
• Gestational proteinuria represents isolated new-onset proteinuria without hypertension 1
• Massive proteinuria (>5 g/24h) in pregnancy associates with more severe neonatal outcomes and earlier delivery 1, 4

False Positive/Postrenal Causes

These conditions can falsely elevate protein measurements:

• Urinary tract infection causes transient proteinuria that resolves with treatment 2, 1
• Hematuria causes false-positive protein results on dipstick 2, 1
• Menstrual blood contamination can falsely elevate protein measurements 1, 4
• Alkaline, dilute or concentrated urine, gross hematuria, mucus, semen or white blood cells can cause false-positive dipstick results 3

Clinical Significance by Severity

Understanding the severity helps predict outcomes:

• Persistent proteinuria >3.8 g/day carries 35% risk of end-stage renal disease within 2 years 1, 4
• Proteinuria <2.0 g/day has only 4% risk of progression to end-stage renal disease 1, 4
• Nephrotic-range proteinuria (>3.5 g/day) increases thromboembolism risk, including renal vein thrombosis (29%), pulmonary embolism (17-28%), and deep vein thrombosis (11%) 4

Critical Evaluation Approach

Confirm persistent proteinuria with 2 of 3 abnormal specimens collected over 3 months before establishing a diagnosis of chronic kidney disease. 7, 2, 1

• Initial screening should use automated dipstick urinalysis 2
• If positive (≥1+), confirm with spot urine protein-to-creatinine ratio within 3 months 7, 2, 4
• A spot urine protein-to-creatinine ratio ≥30 mg/mmol (0.3 mg/mg) confirms proteinuria 2, 4
• Use albumin-to-creatinine ratio for diabetic patients and suspected CKD, as it is more sensitive for early kidney disease 2
• Eliminate physiologic triggers (fever, exercise, dehydration) before repeating testing to distinguish transient from persistent causes 1

Common Pitfalls to Avoid

• Do not rely solely on a single dipstick test for diagnosis, as false positives are common 2
• Do not routinely obtain 24-hour urine collections for initial evaluation, as spot protein-to-creatinine ratios are more convenient and equally accurate 7, 3
• Account for transient causes before establishing a diagnosis of pathologic proteinuria 2, 1

When to Refer to Nephrology

• Persistent proteinuria with protein excretion >1 g/day (ACR ≥60 mg/mmol or PCR ≥100 mg/mmol), as kidney biopsy and immunosuppressive medications may be indicated 7
• eGFR <30 mL/min/1.73 m² with proteinuria 2
• Proteinuria with declining kidney function or unclear etiology 2