What is the differential diagnosis for proteinuria?

Differential Diagnosis for Proteinuria

Proteinuria requires systematic categorization into benign versus pathologic causes, with the primary distinction based on whether it represents transient/functional proteinuria, isolated proteinuria, or proteinuria associated with renal parenchymal disease.

Initial Classification Framework

The differential diagnosis should be organized by three key pathophysiologic mechanisms 1:

• Glomerular proteinuria (most common, typically >2 g/24 hours) - results from increased glomerular permeability 1, 2
• Tubular proteinuria - from decreased tubular reabsorption of normally filtered proteins 1, 3
• Overflow proteinuria - from overproduction of filterable plasma proteins 1, 3

Benign/Transient Causes

These conditions resolve spontaneously and do not indicate progressive renal disease 4, 1:

• Functional proteinuria from altered renal hemodynamics: fever, intense exercise, dehydration, emotional stress, acute illness 1, 2
• Orthostatic (postural) proteinuria - protein excretion normalizes completely in recumbent position; long-term studies confirm this is benign 4, 2
• Idiopathic transient proteinuria - discovered on routine screening, disappears on subsequent testing 4

Isolated Persistent Proteinuria

When ≥80% of random urine samples show abnormal protein excretion without other urinary abnormalities 4:

• Idiopathic intermittent proteinuria - 50% of samples show proteinuria; structural abnormalities may exist on biopsy but progressive renal insufficiency is unusual 4
• Persistent isolated proteinuria - represents heterogeneous group; significant proportion have prominent renal pathology and progress to serious renal disease 4

Glomerular Diseases

Primary Glomerular Disorders

These typically present with nephrotic-range proteinuria (>3.5 g/24 hours) 2:

• Minimal change disease 2
• Focal segmental glomerulosclerosis 2
• Membranous nephropathy 2
• Membranoproliferative glomerulonephritis 2
• IgA nephropathy - may benefit from ACE inhibitor therapy 5

Secondary Glomerular Disorders

• Diabetic nephropathy - persistent microalbuminuria carries 20-fold increased risk of progression 5
• Lupus nephritis 2
• Post-infectious glomerulonephritis 2
• Amyloidosis 3

Genetic Disorders

• Alport syndrome 2
• Congenital nephrotic syndrome/mesangial sclerosis 2

Tubulointerstitial Diseases

More likely when proteinuria is <2 g/24 hours 1:

• Acute tubular necrosis 3
• Chronic interstitial nephritis 3
• Polycystic kidney disease 3
• Tubular disorders (Fanconi syndrome, renal tubular acidosis) 2

Overflow Proteinuria

• Multiple myeloma (Bence Jones proteinuria) 1, 3
• Light chain deposition disease 3
• Myoglobinuria (rhabdomyolysis) 3
• Hemoglobinuria (hemolysis) 3

Pregnancy-Related Causes

• Preeclampsia - proteinuria ≥300 mg/24 hours or spot protein/creatinine ratio ≥30 mg/mmol (0.3 mg/mg) 6
• Gestational proteinuria - new-onset proteinuria without other preeclampsia features; may represent early preeclampsia or coincidental primary renal disease 6
• Chronic hypertension with superimposed preeclampsia 6

Vascular Causes

• Hypertensive nephrosclerosis - de novo proteinuria after years of controlled hypertension marks subsequent renal function decline 5
• Renal artery stenosis 3
• Thrombotic microangiopathy 3

Key Clinical Distinctions

Indicators of glomerular disease requiring nephrology referral 6:

• Proteinuria >1,000 mg/24 hours (or >500 mg/24 hours if persistent/increasing) 6
• Red cell casts (virtually pathognomonic for glomerular bleeding) 6
• Dysmorphic red blood cells (irregular/distorted outline, glomerular origin) 6
• Elevated serum creatinine 6

Non-selective proteinuria indicates higher likelihood of progressive renal disease 5.

Massive proteinuria (>5 g/24 hours) is associated with worse outcomes and faster progression 6, 5.

Common Pitfalls

• False-positive dipstick results occur with alkaline/dilute/concentrated urine, gross hematuria, mucus, semen, or white blood cells 1
• Inadequate 24-hour urine collections without creatinine measurement lead to incorrect protein excretion estimates 6
• Dismissing low-grade proteinuria - even <2 g/24 hours can indicate significant tubulointerstitial or vascular disease 1
• Assuming benign orthostatic proteinuria without confirming complete normalization in recumbent position 4