What causes proteinuria and mild hematuria in the absence of a urinary tract infection?

Causes of Proteinuria and Mild Hematuria Without Urinary Tract Infection

The combination of proteinuria and mild hematuria without infection most commonly indicates glomerular disease, with IgA nephropathy, post-infectious glomerulonephritis, and thin basement membrane nephropathy being the leading causes. 1, 2

Primary Glomerular Causes

The presence of both proteinuria and hematuria strongly suggests a glomerular origin, particularly when dysmorphic red blood cells (>80%) or red cell casts are present in the urinary sediment. 3, 1

Most common glomerular causes include:

• IgA Nephropathy (Berger Disease): The most frequent cause of persistent isolated microscopic hematuria with proteinuria, often presenting with episodic gross hematuria following upper respiratory infections. 1, 2

• Post-Infectious Glomerulonephritis: Typically presents with tea-colored urine, moderate proteinuria (1-3 g/day), dysmorphic RBCs, and red cell casts, usually following streptococcal infection. 4, 5

• Thin Basement Membrane Nephropathy: An autosomal dominant condition causing asymptomatic hematuria with variable proteinuria, generally having a benign course but requiring long-term monitoring. 1, 2

• Alport Syndrome: Hereditary nephritis with associated hearing loss and ocular abnormalities, presenting with persistent hematuria and progressive proteinuria. 1, 2

• Lupus Nephritis and Other Vasculitides: Systemic diseases causing immune-complex glomerulonephritis with variable degrees of proteinuria and hematuria. 5

Interstitial and Tubular Causes

When proteinuria is less than 2 g per 24 hours, tubulointerstitial disorders become more likely alongside glomerular causes. 6, 7

• Drug-Induced Interstitial Nephritis: Medications causing interstitial inflammation with tubular proteinuria and hematuria. 3

• Analgesic Nephropathy: Chronic NSAID use leading to interstitial disease with hematuria and low-grade proteinuria. 3

Structural and Metabolic Causes

• Hypercalciuria and Hyperuricosuria: Metabolic abnormalities causing microscopic hematuria, sometimes with mild proteinuria, potentially leading to nephrolithiasis. 3, 2

• Nutcracker Syndrome: Left renal vein compression causing hematuria with variable proteinuria, diagnosed by ultrasound with Doppler. 3

Diagnostic Approach Algorithm

Step 1: Confirm True Hematuria and Proteinuria

• Verify microscopic hematuria (≥3 RBCs per high-power field) on at least two of three properly collected specimens. 1
• Quantify proteinuria using spot urine protein-to-creatinine ratio (normal <0.2 g/g). 3, 7

Step 2: Determine Glomerular vs. Non-Glomerular Origin

• Examine urinary sediment for dysmorphic RBCs (>80% suggests glomerular) and red cell casts (pathognomonic for glomerular disease). 3, 1
• Tea-colored urine with proteinuria >2+ by dipstick strongly suggests glomerular origin. 1, 4

Step 3: Initial Laboratory Evaluation

• Complete metabolic panel including serum creatinine, BUN, albumin, and total protein. 3
• Complement levels (C3, C4) to evaluate for post-infectious GN or lupus nephritis. 3, 5
• Antinuclear antibody (ANA) and ANCA testing if vasculitis suspected. 3, 4
• Spot urine calcium-to-creatinine ratio to assess for hypercalciuria. 2

Step 4: Imaging

• Renal ultrasound to evaluate kidney size, echogenicity, and structural abnormalities (enlarged echogenic kidneys suggest acute glomerulonephritis). 3, 2

Step 5: Nephrology Referral Indications

• Persistent significant proteinuria (protein-to-creatinine ratio >0.2 for three specimens). 3
• Presence of red cell casts or >80% dysmorphic RBCs. 3, 1
• Elevated creatinine or declining renal function. 3, 1
• Hypertension with hematuria and proteinuria. 3, 8
• Nephrotic-range proteinuria (>3.5 g/day in adults, >40 mg/m²/hour in children). 6

Critical Clinical Pearls

The combination of hematuria and proteinuria requires more aggressive evaluation than either finding alone, as it significantly increases the likelihood of progressive kidney disease. 9, 8

• Isolated microscopic hematuria without proteinuria has a benign prognosis in 80% of cases, but adding proteinuria changes the risk profile substantially. 2

• Proteinuria >2 g per 24 hours almost always indicates glomerular disease requiring nephrology evaluation and possible renal biopsy. 6, 7

• In children, persistent proteinuria with hematuria warrants nephrology referral even with normal renal function, as structural glomerular abnormalities may be present. 3, 8

• Anticoagulation does not cause hematuria but may unmask underlying pathology; evaluation should proceed regardless of anticoagulant use. 1

• Follow-up for persistent hematuria with proteinuria should include monitoring blood pressure, renal function, and repeat urinalysis at 6,12,24, and 36 months if initial workup is negative. 1, 2