Is Extractable Nuclear Antigen Antibody (ENA ABS) testing, including anti-Ribonucleoprotein (anti-RNP) and anti-Smith antibodies, indicated in cases of frank hematuria?

ENA ABS (Anti-RNP & Anti-Smith) Testing in Frank Hematuria

ENA ABS (anti-RNP & anti-Smith) testing is not indicated in the initial evaluation of frank hematuria unless there are specific clinical features suggesting systemic autoimmune disease. 1

Initial Evaluation of Frank Hematuria

The appropriate initial evaluation of frank hematuria should follow a systematic approach:

Primary Evaluation

• Urinalysis with microscopic examination
• Renal function tests (serum creatinine, eGFR)
• Urine protein/creatinine ratio
• Renal and bladder ultrasound

Isolated frank hematuria is typically due to benign processes such as hypercalciuria, IgA nephropathy, or urologic abnormalities 1. The American College of Radiology recommends ultrasound as the first-line imaging test for evaluating macroscopic hematuria to exclude nephrolithiasis, urologic abnormalities, and rarely, renal or bladder tumors 1.

When to Consider Autoimmune Testing

Autoantibody testing, including ENA ABS, should only be considered when:

1. Hematuria is accompanied by other clinical features suggesting systemic autoimmune disease:

   • Proteinuria
   • Abnormal renal function
   • Extrarenal manifestations (joint pain, rash, serositis)
   • Unexplained cytopenias

2. Initial evaluation fails to identify a cause and there are clinical signs of systemic lupus erythematosus (SLE) or other connective tissue diseases

Role of ENA Antibodies in Autoimmune Disease

When systemic autoimmune disease is suspected, the American College of Rheumatology recommends a specific testing sequence 1, 2:

1. ANA testing as the initial screening test
2. If ANA is positive, proceed with specific autoantibody tests:
   • Anti-dsDNA
   • Anti-Smith
   • Anti-RNP
   • Complement levels (C3, C4)

Anti-Smith antibodies are highly specific for SLE and are not found in any other condition 3. They are present in approximately 30-32% of SLE patients 4, 3.

Anti-RNP antibodies can be found in:

• 15% of SLE patients
• 9% of scleroderma patients
• 100% of patients with mixed connective tissue disease 3

Clinical Significance in Renal Disease

The presence of specific autoantibodies has clinical significance in patients with renal involvement:

• SLE patients with anti-RNP antibodies have a significantly lower incidence of nephritis and impaired renal function 3
• Anti-Smith antibodies may be associated with a trend toward increased incidence of renal disease in SLE patients 5
• Patients with anti-ENA antibodies generally have a lower incidence of renal disease compared to other SLE patients 4

Practical Approach to Frank Hematuria

1. Complete initial evaluation with urinalysis, renal function tests, and renal/bladder ultrasound

2. If initial evaluation is negative and hematuria persists:

   • Consider urological causes (cystoscopy may be indicated)
   • Evaluate for hypercalciuria and hyperuricosuria

3. Consider autoimmune testing only if:

   • Proteinuria is present
   • Renal function is abnormal
   • Systemic symptoms suggest autoimmune disease
   • Family history of autoimmune disease exists

Key Caveats

• ENA antibody testing should not be ordered routinely in the initial evaluation of frank hematuria 1
• Testing for autoantibodies should be guided by clinical suspicion of systemic autoimmune disease
• Inappropriate autoantibody testing leads to unnecessary costs and potential misdiagnosis
• In children with isolated macroscopic hematuria, imaging with ultrasound is the appropriate first step, not autoantibody testing 1

Remember that the diagnosis of systemic autoimmune diseases requires a panel of specific laboratory tests, with ANA being the first-level test, followed by more specific antibody testing only when clinically indicated 1, 2.