What are the causes of severe proteinuria?

Causes of Severe Proteinuria

Severe proteinuria (>3-5 g/24h) is primarily caused by glomerular diseases, with nephrotic syndrome representing the most common pathophysiological mechanism, though tubular dysfunction and overflow proteinuria can also contribute in specific clinical contexts. 1, 2

Primary Glomerular Diseases

Glomerular pathology is the predominant cause of severe proteinuria, as the glomerular filtration barrier becomes compromised, allowing massive protein leakage:

Nephrotic Syndrome Conditions

• Membranous nephropathy is a leading cause of nephrotic-range proteinuria in adults, with protein excretion often exceeding 4 g/day and requiring immunosuppressive therapy when persistent 1
• Focal segmental glomerulosclerosis (FSGS) produces severe non-selective proteinuria through podocyte injury and glomerular basement membrane disruption 3
• Minimal change disease causes selective proteinuria, predominantly albumin, through podocyte foot process effacement 2
• IgA nephropathy can present with heavy proteinuria (>3 g/day) in approximately one-third of patients, which correlates with worse renal survival—only 69% maintain serum creatinine ≤2 mg/dL at 5 years compared to 100% with mild proteinuria 4

Secondary Glomerular Diseases

• Diabetic nephropathy progresses from microalbuminuria to massive proteinuria as glomerular hyperfiltration causes progressive basement membrane damage 3
• Lupus nephritis and other autoimmune glomerulonephritides produce immune complex-mediated glomerular injury with severe protein loss 2
• Amyloidosis causes nephrotic-range proteinuria through amyloid deposition in glomeruli 2

Pathophysiological Mechanisms

Glomerular Hyperfiltration

• Progressive glomerular hyperfiltration shifts glomerular pores to larger dimensions, resulting in non-selective proteinuria where both albumin and larger proteins leak into urine 3
• This mechanism is particularly important in the progressive phase of established glomerulonephritis, even when the initial immunological injury has resolved 3
• Endothelial injury from hyperfiltration increases local angiotensin II generation, perpetuating the cycle of proteinuria and renal damage 3

Loss of Glomerular Selectivity

• Non-selective proteinuria (containing both albumin and larger globulins) indicates more severe glomerular damage and predicts faster progression to renal failure 3, 2
• Patients with non-selective proteinuria have worse prognosis than those with selective (predominantly albumin) proteinuria 3

Pregnancy-Related Causes

• Preeclampsia is a critical cause of severe proteinuria in pregnancy, with massive proteinuria (>5 g/24h) associated with significantly worse maternal and neonatal outcomes 1, 5
• Proteinuria is not required for preeclampsia diagnosis, but when present at nephrotic levels, it indicates severe disease requiring close monitoring 1

Tubular Proteinuria (Less Common for Severe Proteinuria)

• Tubular dysfunction causes proteinuria through impaired reabsorption of low-molecular-weight proteins, but typically produces <2 g/day 2
• This pattern includes β2-microglobulin, retinol-binding protein, and other small proteins normally reabsorbed by proximal tubules 2

Overflow Proteinuria (Rare)

• Multiple myeloma produces Bence-Jones proteinuria from excessive light chain production overwhelming tubular reabsorption capacity 6, 2
• This mechanism can produce severe proteinuria but represents a distinct pathophysiology from glomerular disease 2

Clinical Correlation with Severity

Prognostic Implications

• Proteinuria exceeding 1 g/day predicts poorer renal prognosis across all kidney diseases 3
• In IgA nephropathy specifically, heavy proteinuria (>3 g/day) at presentation correlates with more severe histological changes including mesangial proliferation, glomerulosclerosis, and interstitial fibrosis 4
• Proteinuria is directly tubulotoxic, contributing to progressive renal deterioration independent of the underlying cause 3

Hypertension Association

• Increased blood pressure plays a major role in proteinuria development in both diabetic and non-diabetic kidney disease 7
• In essential hypertension, de novo proteinuria after years of adequate blood pressure control marks subsequent decline in renal function 3
• Moderate or heavy proteinuria typically precedes hypertension onset and develops before renal insufficiency becomes apparent 4

Common Pitfalls to Avoid

• Do not assume all severe proteinuria is glomerular—obtain urine protein electrophoresis to differentiate albumin-predominant (glomerular) from light chain (overflow) or mixed patterns (tubular component) 2
• Avoid missing secondary causes—always evaluate for diabetes, autoimmune disease, infections, malignancy, and medications that can cause glomerular injury 2
• Do not delay quantification—when dipstick shows ≥2+ (approximately 1-3 g/L), confirm with spot protein/creatinine ratio or 24-hour collection, as values >1 g/L provide reasonable assessment of true severe proteinuria 1, 8
• Remember that massive proteinuria (>5 g/24h) requires 24-hour urine collection for confirmation, particularly to assess need for thromboprophylaxis in nephrotic syndrome 1