What are the causes of proteinuria in adults, particularly those with a family history of kidney disease or pre-existing medical conditions such as diabetes or hypertension?

Causes of Proteinuria in Adults

Proteinuria results from three main pathophysiologic mechanisms: glomerular disease (most common and highest risk), tubular dysfunction, and overflow states, with additional transient physiologic causes that must be excluded before pursuing extensive workup. 1

Pathological Causes

Glomerular Causes (Most Common)

Glomerular malfunction is the most common mechanism and typically produces proteinuria >2 g per 24 hours 2:

• Diabetic nephropathy typically begins with microalbuminuria (30-299 mg/g creatinine) before progressing to clinical albuminuria (≥300 mg/g) 3, 4, 1
• Hypertensive nephrosclerosis damages the glomerular filtration barrier through chronic elevated intraglomerular pressure, particularly in patients with type 2 diabetes 3, 4, 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
• Minimal change disease causes nephrotic-range proteinuria through loss of glomerular charge selectivity 1
• HIV-associated nephropathy (HIVAN) often presents with heavy proteinuria and rapid progression to kidney failure 1

Tubular Dysfunction

Tubular causes result from decreased reabsorption and catabolism of filtered proteins by proximal tubular cells 5, 6:

• Tubulointerstitial disease with increased excretion of low-molecular-weight globulins 3
• Saturation of the megalin-cubilin reabsorptive mechanism when protein load exceeds capacity 5

Overflow Proteinuria

• Multiple myeloma produces excess light chains that overwhelm normal filtration and reabsorption 2, 6
• Increases in production or concentration of plasma proteins normally filtered by the glomerulus 6

Transient/Physiologic Causes (Must Exclude First)

These benign causes resolve spontaneously and should be ruled out before pursuing extensive evaluation 4, 1, 2:

• Fever temporarily elevates urinary protein excretion 4, 1
• Intense physical activity or exercise within 24 hours causes transient proteinuria 4, 1
• Orthostatic proteinuria occurs with upright posture and normalizes when recumbent 4, 1
• Marked hyperglycemia transiently increases protein excretion 4, 1
• Congestive heart failure temporarily elevates protein levels 4, 1
• Dehydration and emotional stress can cause transient increases 2

Postrenal/False Positive Causes

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

Pregnancy-Related Causes

• Preeclampsia causes new-onset proteinuria after 20 weeks gestation, with proteinuria ≥300 mg/24h considered abnormal 1
• Gestational proteinuria represents isolated new-onset proteinuria without hypertension 1

Risk Factors for Pathological Proteinuria

Patients at highest risk include those with 3:

• Diabetes mellitus (present in 48% of CKD patients) 3
• Hypertension (present in 91% of CKD patients) 3
• Family history of kidney disease 3
• Obesity (activates local renin-angiotensin system causing mesangial hypertrophy and glomerular hyperfiltration) 4
• Cardiovascular disease 3
• Older age 3

Critical Evaluation Points

Confirm persistence before establishing diagnosis: Proteinuria must be present in 2 of 3 samples collected over 3 months to establish chronicity and exclude transient causes 3, 4, 1, 7. A common pitfall is pursuing extensive workup before excluding transient causes 7.

Quantify appropriately: Use spot urine protein-to-creatinine ratio (normal <200 mg/g) or albumin-to-creatinine ratio for diabetic patients (normal <30 mg/g) rather than relying on dipstick alone 3, 4, 7. The 24-hour urine collection is discouraged due to inconvenience and inaccuracy 3.

Clinical significance by severity: Persistent proteinuria >3.8 g/day carries 35% risk of end-stage renal disease within 2 years, while proteinuria <2.0 g/day has only 4% risk 1. At any GFR level, elevated protein-to-creatinine ratio increases risk for cardiovascular disease, CKD progression, and mortality 3, 1.