What causes proteinuria (presence of protein in urine)?

Causes of Proteinuria

Proteinuria is defined as urinary protein excretion exceeding 150 mg/day and serves as an important marker of kidney damage that may indicate the presence of chronic kidney disease (CKD), requiring further evaluation to determine its cause and clinical significance. 1

Physiological (Non-Pathological) Causes

• Fever can cause temporary elevation in urinary protein excretion 2
• Intense physical activity or exercise within 24 hours before urine collection can cause transient proteinuria 2
• Upright posture (orthostatic proteinuria) can cause protein excretion, which normalizes in recumbent position 2
• Marked hyperglycemia can cause transient elevations in urinary protein 2
• Congestive heart failure can temporarily increase protein excretion 2

Pathological Causes

Glomerular Causes

• Diabetic nephropathy - often presents first as microalbuminuria 2
• Hypertensive nephrosclerosis - especially in patients with type 2 diabetes 2
• Glomerulonephritis - including post-infectious, membranous, membranoproliferative, lupus, and IgA nephropathy 3
• Genetic disorders - such as Alport syndrome and mesangial sclerosis 3

Other Causes

• Urinary tract infection - can cause transient proteinuria 2
• Tubular disorders - affect protein reabsorption in the tubules 3
• Hematuria - blood in urine can cause false positive protein results 2

Classification of Proteinuria

• Normal protein excretion: <30 mg/24h or <30 mg/g creatinine 2
• Microalbuminuria: 30-299 mg/24h or 30-299 mg/g creatinine 2
• Clinical albuminuria: ≥300 mg/24h or ≥300 mg/g creatinine 2

Clinical Significance

• Proteinuria is an early sign of kidney disease and may play a role in the progression of glomerular damage 3
• In patients with hypertension or diabetes, increased urinary protein/albumin is an independent risk factor for cardiovascular morbidity and mortality 4
• Proteinuria predicts patients at greatest risk for developing chronic and progressive renal insufficiency, even at levels exceeding 1 g/24 hours 4
• Persistent proteinuria is defined as two or more positive results on quantitative tests over a 3-month period 2

Evaluation Approach

• Initial screening should begin with automated dipstick urinalysis 1
• If positive, confirm with spot urine protein/creatinine (PCr) ratio within 3 months 1
• A spot urine PCr ratio ≥30 mg/mmol (0.3 mg/mg) confirms proteinuria 1
• Patients with confirmed proteinuria should be evaluated for CKD, including estimation of glomerular filtration rate (GFR), urinalysis, and kidney imaging 1
• The National Kidney Foundation recommends that glomerular filtration rate is estimated, and the presence of urinary protein is assessed in all patients with suspected kidney disease 5

Important Considerations

• Avoid relying solely on a single dipstick test for diagnosis 2
• Account for factors that can cause transient proteinuria before establishing a diagnosis 2
• Consider referring patients to nephrology for persistent proteinuria with unclear etiology, proteinuria >2 g/day, and proteinuria with declining kidney function 2
• Reduction in proteinuria through treatments like angiotensin-converting enzyme inhibitors can slow the rate of loss of renal function 4
• Patients at high risk for CKD should undergo annual screening for proteinuria 5