Causes of Proteinuria
Primary Classification Framework
Proteinuria results from either glomerular disease (most common), tubular dysfunction, or benign physiological conditions, with glomerular causes representing the most clinically significant category requiring evaluation for chronic kidney disease and cardiovascular risk. 1, 2
Pathological Causes
Glomerular Diseases (Primary)
These represent the most serious causes with significant implications for kidney function and cardiovascular mortality:
- Minimal change disease - causes nephrotic-range proteinuria, particularly in children 1
- Focal segmental glomerulosclerosis (FSGS) - progressive glomerular scarring leading to proteinuria 1
- Membranous nephropathy - immune-mediated glomerular injury 1
- IgA nephropathy - mesangial IgA deposition causing glomerular inflammation 3
- Post-infectious glomerulonephritis - follows streptococcal or other infections 3
Secondary Glomerular Diseases
These occur as complications of systemic conditions:
- Diabetic nephropathy - the most common cause of secondary glomerular disease, initially presenting as microalbuminuria (30-299 mg/24h) before progressing to clinical albuminuria (≥300 mg/24h) 1, 2
- Hypertensive nephrosclerosis - chronic hypertension damages glomerular filtration barrier, especially in type 2 diabetes 4, 2
- HIV-associated nephropathy (HIVAN) - presents with heavy proteinuria in HIV-infected patients 1
- Lupus nephritis - autoimmune glomerular injury 3
- Obesity-related glomerulopathy - obesity activates local renin-angiotensin system causing mesangial hypertrophy and glomerular hyperfiltration 4
Tubular Disorders
Less common but important when proteinuria is <2 g/24h:
- Tubulointerstitial disease - impaired proximal tubular reabsorption of filtered proteins via megalin and cubilin receptors 5
- Alport syndrome - genetic defect in glomerular basement membrane 3
- Fanconi syndrome - generalized proximal tubular dysfunction 3
Benign/Physiological Causes
These are transient and do not indicate kidney disease:
- Orthostatic (postural) proteinuria - protein excretion normalizes completely in recumbent position; long-term studies confirm this is benign 2, 6, 3
- Fever - causes temporary elevation in urinary protein excretion 2, 3
- Intense exercise - physical activity within 24 hours before collection causes transient proteinuria 2, 3
- Marked hyperglycemia - transient elevation in protein excretion 2
- Congestive heart failure - altered renal hemodynamics temporarily increase protein excretion 2, 6
Pregnancy-Related Causes
- Preeclampsia - new-onset hypertension with proteinuria ≥300 mg/24h after 20 weeks gestation (though proteinuria no longer required for diagnosis) 1, 2
- Menstrual blood contamination - can cause false positive results 1
Other Pathological Conditions
- Urinary tract infection - causes transient proteinuria 2
- Hematuria - blood in urine causes false positive protein results 2
Clinical Significance by Severity
Understanding the prognostic implications guides urgency of evaluation:
- Microalbuminuria (30-299 mg/24h) - early marker of kidney damage, particularly in diabetes 2
- Clinical proteinuria (≥300 mg/24h) - indicates established kidney damage requiring full evaluation 2, 7
- Nephrotic-range proteinuria (>3.5 g/24h) - indicates severe glomerular disease with 35% risk of end-stage renal disease within 2 years if >3.8 g/day 1
- Massive proteinuria (>5 g/24h) - associated with severe outcomes including thromboembolism risk (renal vein thrombosis 29%, pulmonary embolism 17-28%) 1
Key Mechanistic Insights
The glomerular filtration barrier has three layers (endothelium, basement membrane, podocytes) that can be damaged by:
- Increased intraglomerular hydraulic pressure - from hypertension or reduced nephron mass causing compensatory hyperfiltration 4, 5
- Direct podocyte injury - malfunction of nephrin or podocin molecules 5
- Inflammatory cell infiltration - immune-mediated glomerular damage 5
- Tubular protein toxicity - filtered albumin induces inflammatory and fibrogenic mediators (TGF-β, chemokines) causing tubulointerstitial fibrosis and progressive kidney damage 5
Critical Pitfalls to Avoid
- Do not diagnose proteinuria from a single dipstick test - always confirm with spot urine protein/creatinine ratio ≥30 mg/mmol (0.3 mg/mg) within 3 months 2
- Rule out benign causes first - check for fever, recent exercise, orthostatic component before pursuing extensive workup 2, 6
- Do not overlook cardiovascular risk - proteinuria is an independent predictor of cardiovascular mortality even in non-diabetic patients 7
- Screen high-risk populations annually - African Americans, patients with diabetes, hypertension, hepatitis C, or family history of kidney disease 1, 2