Causes of Proteinuria
Primary Classification Framework
Proteinuria results from three main pathophysiologic mechanisms: glomerular disease (most common and clinically significant), tubular dysfunction, and overflow states, with glomerular causes carrying the greatest risk for progressive kidney disease and adverse outcomes. 1, 2
Glomerular Causes (Most Common)
Primary Glomerular Diseases
- Minimal change disease causes nephrotic-range proteinuria through loss of glomerular charge selectivity 1
- Focal segmental glomerulosclerosis (FSGS) results in progressive proteinuria and carries high risk for end-stage renal disease 1
- Membranous nephropathy presents with heavy proteinuria and increased thrombotic risk 1
- IgA nephropathy demonstrates variable proteinuria severity that correlates with progression rate 3
Secondary Glomerular Diseases
- Diabetic nephropathy typically begins with microalbuminuria (30-299 mg/g creatinine) before progressing to clinical albuminuria (≥300 mg/g) 2, 4
- Hypertensive nephrosclerosis damages the glomerular filtration barrier through chronic elevated intraglomerular pressure, particularly in patients with type 2 diabetes 2, 4
- HIV-associated nephropathy (HIVAN) often presents with heavy proteinuria and rapid progression to kidney failure 1
- Lupus nephritis causes immune-mediated glomerular injury with variable proteinuria 5
Mechanism of Glomerular Proteinuria
- Increased glomerular hydraulic pressure from hypertension or reduced nephron mass causes compensatory hyperfiltration and shifts glomerular pores to larger dimensions 2, 6
- Structural damage to the glomerular filtration barrier allows passage of albumin (66 kDa) and larger proteins that are normally restricted 7, 8
- Non-selective proteinuria (loss of both albumin and larger proteins) indicates more severe glomerular damage and worse prognosis 3
Tubular Causes
- Tubular dysfunction impairs protein reabsorption by proximal tubular cells after normal glomerular filtration 7, 8
- Low-molecular-weight proteins (<66 kDa) normally pass through glomeruli but are reabsorbed via the megalin-cubilin complex; tubular disease saturates this mechanism 7
- Fanconi syndrome and other tubulointerstitial diseases cause selective loss of low-molecular-weight proteins 8, 5
Physiologic (Transient) Causes
These require no evaluation if proteinuria resolves:
- Fever temporarily elevates urinary protein excretion 2, 4
- Intense physical activity or exercise within 24 hours causes transient proteinuria 2, 4
- Orthostatic proteinuria occurs with upright posture and normalizes when recumbent 2, 4
- Marked hyperglycemia transiently increases protein excretion 2, 4
- Congestive heart failure temporarily elevates protein levels 2, 4
Pregnancy-Related Causes
- Preeclampsia causes new-onset proteinuria (≥30 mg/mmol or 0.3 mg/mg protein-to-creatinine ratio) after 20 weeks gestation 9, 1
- Gestational proteinuria represents isolated new-onset proteinuria without hypertension or other preeclampsia features; these women have intermediate placental growth factor levels suggesting early preeclampsia 9
- Proteinuria ≥300 mg/24h is abnormal in pregnancy, though proteinuria is no longer required for preeclampsia diagnosis 1
- Massive proteinuria (>5 g/24h) in pregnancy associates with more severe neonatal outcomes and earlier delivery 9, 1
Overflow Proteinuria
- Multiple myeloma produces excess light chains that overwhelm tubular reabsorption capacity 6
- Increased production or concentration of plasma proteins normally filtered by glomeruli causes overflow proteinuria 6
Postrenal/False Positive Causes
- Urinary tract infection causes transient proteinuria that resolves with treatment 2, 4
- Hematuria (blood in urine) causes false-positive protein results on dipstick 2, 4
- Menstrual blood contamination can falsely elevate protein measurements 1
Clinical Significance by Severity
- Persistent proteinuria >3.8 g/day carries 35% risk of end-stage renal disease within 2 years 1
- Proteinuria <2.0 g/day has only 4% risk of progression to end-stage renal disease 1
- Nephrotic-range proteinuria (>3.5 g/day) increases thromboembolism risk: renal vein thrombosis (29%), pulmonary embolism (17-28%), deep vein thrombosis (11%) 1
- At any GFR level, elevated protein-to-creatinine ratio increases risk for cardiovascular disease, CKD progression, and mortality 4
Critical Evaluation Points
- Confirm persistent proteinuria with 2 of 3 abnormal specimens over 3-6 months before establishing diagnosis, as biological variability exceeds 20% 4
- Distinguish transient from persistent causes by repeating testing after eliminating physiologic triggers 2, 4
- Quantify with spot urine protein-to-creatinine ratio (≥30 mg/mmol or 0.3 mg/mg confirms abnormal) rather than relying on dipstick alone 9, 1, 2
- Use albumin-to-creatinine ratio for diabetic patients and suspected CKD, as albumin is the most important protein lost in most CKD cases 4