What are the possible causes of hematuria and proteinuria in a patient with a urinalysis showing one plus protein, no leukocytes, no nitrates, and no ketones?

Hematuria with Trace Proteinuria: Differential Diagnosis

The combination of hematuria with 1+ proteinuria (without leukocytes, nitrites, or ketones) most commonly suggests either glomerular disease, urologic malignancy, or benign causes like exercise or hypercalciuria, and requires systematic evaluation to distinguish between these possibilities. 1

Initial Diagnostic Approach

Confirm True Hematuria

• Verify microscopic hematuria with ≥3 RBCs per high-power field on at least two of three properly collected specimens, as dipstick alone has limited specificity (65-99%) and can yield false positives 2, 3
• Exclude benign transient causes: menstruation, vigorous exercise, sexual activity, viral illness, trauma, and recent urologic procedures by repeating urinalysis 48 hours after cessation 1, 2

Quantify Proteinuria

• Obtain 24-hour urine collection or spot urine protein-to-creatinine ratio to determine if proteinuria is significant (>500 mg/24 hours suggests glomerular disease) 1, 2
• 1+ protein on dipstick is typically <500 mg/24 hours, but quantification is essential 2

Determine Source: Glomerular vs. Non-Glomerular

Examine Urinary Sediment

• Look for dysmorphic RBCs (>80% suggests glomerular origin) vs. normal-shaped RBCs (>80% suggests urologic source) 1, 2
• Red cell casts are pathognomonic for glomerular bleeding, though relatively insensitive 1, 2
• Phase contrast microscopy may be needed for accurate RBC morphology assessment 1

Assess Renal Function

• Measure serum creatinine, BUN, and complete metabolic panel 2, 3
• Elevated creatinine strongly suggests renal parenchymal disease 1, 2

Major Diagnostic Categories

Glomerular Causes (if dysmorphic RBCs, proteinuria >500 mg/24h, or elevated creatinine)

• Post-infectious glomerulonephritis (occurs 7-21 days after streptococcal infection, low C3 levels) 4, 5
• IgA nephropathy (Berger disease) - most common primary glomerulonephritis 1, 5
• Thin basement membrane nephropathy (benign familial hematuria) - autosomal dominant, usually benign course 1
• Alport syndrome (hereditary nephritis with hearing loss) 1, 3
• Lupus nephritis or other vasculitis 5

Urologic Causes (if normal-shaped RBCs, minimal proteinuria, normal creatinine)

• Malignancy risk increases with age >40 years, smoking history, occupational chemical exposure 1, 3
  • Bladder cancer (most common malignancy in hematuria cases) 3
  • Renal cell carcinoma 3
  • Transitional cell carcinoma 3
• Urolithiasis (kidney/ureteric stones) - often presents with pain 3
• Urinary tract infection - though your patient lacks leukocytes/nitrites, culture may still be warranted 3
• Benign prostatic hyperplasia (in men) 3

Metabolic/Benign Causes

• Hypercalciuria (common cause of microscopic hematuria, sometimes with mild proteinuria) 1, 3
• Hyperuricosuria 1
• Nutcracker syndrome (left renal vein compression) 3
• Exercise-induced hematuria (transient) 3

Risk Stratification for Urologic Malignancy

High-risk features requiring immediate urologic evaluation: 1, 2

• Age >40 years (men) or >60 years (women)
• Smoking history >30 pack-years
• History of gross hematuria
• Occupational exposure to benzenes or aromatic amines
• History of urologic disorder
• Irritative voiding symptoms
• History of pelvic irradiation

Recommended Evaluation Algorithm

If Glomerular Source Suspected

• Refer to nephrology if: 1, 2
  • Proteinuria >1,000 mg/24 hours
  • Proteinuria >500 mg/24 hours that is persistent or increasing
  • Red cell casts present
  • Predominantly dysmorphic RBCs (>80%)
  • Elevated or rising serum creatinine
• Consider complement levels (C3, C4), ANA, ANCA testing 3
• Renal ultrasound to assess kidney size and echogenicity 1, 3
• Renal biopsy may be needed for definitive diagnosis 1, 6

If Urologic Source Suspected or High-Risk Patient

• Complete urologic evaluation includes: 1, 2
  • Multiphasic CT urography (preferred imaging for upper tract) 2, 3
  • Cystoscopy (mandatory for bladder evaluation) 2, 3
  • Urine cytology (especially in high-risk patients) 2, 3
• Urine culture if infection suspected despite negative dipstick 3

If Low-Risk with Minimal Findings

• Screen for hypercalciuria (urine calcium-to-creatinine ratio) 1, 3
• Screen family members' urine for benign familial hematuria 1
• Renal ultrasound may identify occult anatomic abnormalities, though yield is low 1

Follow-Up Protocol

If initial evaluation is negative but hematuria persists: 2, 3

• Repeat urinalysis at 6,12,24, and 36 months
• Monitor blood pressure at each visit
• Consider nephrology referral if hematuria persists with development of hypertension, proteinuria, or evidence of glomerular bleeding

Critical Pitfalls to Avoid

• Never attribute hematuria to anticoagulation or antiplatelet therapy alone - these medications may unmask underlying pathology but do not cause hematuria 2, 3
• Gross hematuria requires urgent urologic referral even if self-limited, as it has 30-40% association with malignancy 3
• The combination of hematuria and proteinuria significantly increases likelihood of serious renal disease and warrants more aggressive evaluation than isolated findings 7, 6
• Absence of leukocytes/nitrites does not exclude infection - culture may still be indicated 3
• 1+ proteinuria may seem minimal, but requires quantification to determine if it meets threshold for nephrology referral 1, 2