What causes proteinuria?

What Causes Protein in Urine

Proteinuria results from either glomerular damage allowing excessive protein filtration, tubular dysfunction impairing protein reabsorption, or benign physiological conditions that temporarily increase protein excretion. 1

Pathological Causes

Glomerular Diseases (Most Common)

The glomerular filtration barrier normally prevents albumin (66 kDa) and larger proteins from passing into urine, but damage to this barrier causes proteinuria. 2

Primary glomerular disorders:

• Diabetic nephropathy—typically begins as microalbuminuria (30-299 mg/g creatinine) and progresses to clinical albuminuria (≥300 mg/g creatinine) 1
• Glomerulonephritis (post-infectious, IgA nephropathy, membranous, membranoproliferative, lupus nephritis) 3
• Focal segmental glomerulosclerosis 4
• Minimal change disease 3

Secondary glomerular damage:

• Hypertensive nephrosclerosis—chronic hypertension damages the glomerular filtration barrier, particularly in patients with type 2 diabetes 1
• Obesity-related glomerulopathy—activates the local renin-angiotensin system causing mesangial hypertrophy and glomerular hyperfiltration 1
• Increased intraglomerular hydraulic pressure from any cause (reduced nephron mass, uncontrolled hypertension) leads to compensatory hyperfiltration and protein leakage 1

Tubular Disorders

When low-molecular-weight proteins (<66 kDa) that normally pass through the glomerulus cannot be reabsorbed by proximal tubular cells, tubular proteinuria results. 2 This occurs when the megalin-cubilin reabsorptive complex is saturated or damaged. 2

Overflow Proteinuria (Prerenal)

Excessive production of small proteins (immunoglobulin light chains in multiple myeloma, myoglobin in rhabdomyolysis) overwhelms normal tubular reabsorption capacity. 2

Postrenal Causes

• Urinary tract infection—causes transient proteinuria 1
• Hematuria—blood in urine causes false-positive protein results 1

Benign Physiological Causes

These conditions cause transient proteinuria that resolves when the trigger is removed:

• Fever—temporarily elevates urinary protein excretion 1
• Intense physical activity or exercise within 24 hours before urine collection 1
• Orthostatic (postural) proteinuria—protein excretion occurs only in upright position and normalizes when recumbent; this is a benign condition with excellent long-term prognosis 4, 3
• Marked hyperglycemia—causes transient elevations 1
• Congestive heart failure—temporarily increases protein excretion 1

Clinical Significance and Prognosis

The type and amount of proteinuria predicts outcomes:

• Proteinuria exceeding 1 g/day indicates poorer prognosis in patients with renal disease 5
• Non-selective proteinuria (mixture of albumin and larger proteins) suggests more progressive disease 5
• Proteinuria is directly tubulotoxic and contributes to renal deterioration independent of the underlying cause 5
• Even in patients with normal kidney function, proteinuria may indicate early kidney disease 6

Evaluation Approach

Initial screening algorithm:

1. Begin with automated dipstick urinalysis 1
2. If positive (≥1+ or trace), confirm with spot urine protein-to-creatinine ratio (PCr) within 3 months 1
3. PCr ≥30 mg/mmol (0.3 mg/mg) confirms significant proteinuria 1
4. Before diagnosing pathological proteinuria, exclude transient causes: repeat testing after ensuring no fever, recent exercise, infection, or marked hyperglycemia 1, 7

For confirmed proteinuria:

• Estimate glomerular filtration rate (GFR) 1
• Perform complete urinalysis with microscopy 1
• Obtain kidney imaging 1
• Consider nephrology referral for: persistent proteinuria with unclear etiology, proteinuria >2 g/day, or proteinuria with declining kidney function 1

Important Caveats

• Never rely on a single dipstick test—high day-to-day variability requires confirmation with 2-3 specimens over 3-6 months 7
• Dipstick testing can miss some proteinuric cases; spot PCr <30 mg/mmol occasionally gives false-negative results for abnormal 24-hour proteinuria, though total protein is usually <400 mg/day in such cases 8
• In essential hypertension, new-onset proteinuria after years of adequate blood pressure control signals subsequent decline in renal function 5
• Patients at high risk for chronic kidney disease (African Americans, hepatitis C coinfection, family history of kidney disease) require annual screening 6