How to manage rheumatoid arthritis (RA) in patients with hematuria?

Managing Rheumatoid Arthritis in Patients with Hematuria

When hematuria develops in RA patients, immediately evaluate for drug-induced nephrotoxicity (particularly from NSAIDs and DMARDs), disease-related glomerulonephritis, or biologic-induced vasculitis, and adjust treatment accordingly while maintaining disease control. 1

Initial Assessment and Etiology Determination

When hematuria appears in an RA patient, the cause must be rapidly identified as it fundamentally changes management:

• Isolated hematuria without proteinuria or elevated creatinine is most commonly associated with high RA disease activity itself and may resolve when inflammation is controlled 1
• Persistent proteinuria (≥3 months) is predominantly drug-related in 82% of cases (14 of 17 patients), particularly from NSAIDs and DMARDs 1
• Elevated serum creatinine is drug-induced in 57% of cases (8 of 14 patients) 1
• Biologic agents, particularly TNF inhibitors, can cause necrotizing crescentic glomerulonephritis (NCGN) or ANCA-associated vasculitis with both hematuria and proteinuria 2, 3

Risk factors for drug-induced proteinuria include elevated CRP/ESR and age >50 years 1.

Immediate Management Steps

1. Laboratory Evaluation

• Obtain urinalysis with microscopy (quantify RBCs per high-power field) 1
• Measure serum creatinine and calculate eGFR 4
• Check 24-hour urine protein or spot urine protein-to-creatinine ratio 5
• Test for ANCA (particularly MPO-ANCA) if on biologic therapy 3
• Assess RA disease activity using validated measures (DAS28, SDAI, or CDAI) 6

2. Medication Review and Adjustment

For isolated hematuria with active RA disease:

• Continue methotrexate as the anchor DMARD 6, 7
• Optimize RA disease control first, as hematuria may resolve with improved disease activity 1
• Increase methotrexate to 20-25 mg/week or maximum tolerated dose if disease remains active 6
• Add short-term low-dose glucocorticoids (≤10 mg/day prednisone) if not already prescribed 6, 7

For persistent proteinuria or elevated creatinine:

• Immediately discontinue NSAIDs, as they reduce tubular secretion of methotrexate and cause direct nephrotoxicity 4
• Consider reducing or temporarily holding methotrexate dose while evaluating renal function 4
• Monitor renal function and liver enzymes every 1-2 weeks during this period 4

For suspected biologic-induced glomerulonephritis:

• Discontinue TNF inhibitor immediately if NCGN is suspected 2
• Switch to tocilizumab (IL-6 receptor inhibitor), which can suppress ANCA-associated vasculitis while maintaining RA control 3
• Tocilizumab dosing: 8 mg/kg IV every 4 weeks or 162 mg subcutaneously weekly for patients ≥100 kg 8

Renal Biopsy Indications

Proceed with renal biopsy when:

• Proteinuria persists >3 months despite medication adjustment 5
• Serum creatinine continues rising 5
• Nephrotic-range proteinuria develops 5
• ANCA positivity with declining renal function 3
• Hematuria with RBC casts on microscopy 5

Expected histopathologic findings include mesangial proliferative glomerulonephritis, IgA nephropathy, FSGS, amyloidosis, or pauci-immune NCGN 5, 3.

Treatment Algorithm Based on Biopsy Results

For ANCA-associated vasculitis or NCGN:

• Discontinue causative biologic agent 2, 3
• Initiate or increase glucocorticoids (prednisolone) 2
• Switch to tocilizumab monotherapy, which can normalize both RA activity and ANCA levels 3
• Consider cyclophosphamide or rituximab for severe vasculitis 5

For other glomerulonephritides (IgA, mesangial proliferative, FSGS):

• Remove suspected nephrotoxic drugs 5
• Initiate immunosuppression with glucocorticoids plus cyclophosphamide, cyclosporine, or azathioprine 5
• Continue methotrexate if renal function permits (monitor closely) 4

For amyloidosis:

• Aggressive RA disease control is paramount 5
• Continue methotrexate and optimize to target remission 6
• Consider biologic DMARDs if not at treatment target 6

Ongoing RA Management During Renal Disease

Maintaining Disease Control

Methotrexate remains the anchor drug unless contraindicated by severe renal impairment 6, 7:

• Continue at reduced dose if eGFR 30-60 mL/min with close monitoring 4
• Consider alternative csDMARDs (leflunomide or sulfasalazine) if methotrexate must be discontinued 6, 7

Biologic Selection in Renal Disease

When escalation to biologics is needed:

• Tocilizumab is preferred as it can treat both RA and ANCA-associated vasculitis 3
• IL-6 inhibitors and JAK inhibitors have advantages when csDMARDs cannot be used as comedication 6
• Avoid TNF inhibitors if previous NCGN or ANCA-associated vasculitis 2, 3
• Abatacept may be considered but monitor for ANCA development 3

Monitoring Requirements

• Renal function and urinalysis every 1-2 months during active renal disease 4
• Complete blood count monthly 4
• RA disease activity assessment every 1-3 months until target achieved 6
• More frequent monitoring during dose adjustments or medication changes 4

Critical Pitfalls to Avoid

• Never continue NSAIDs with persistent hematuria or proteinuria - they are nephrotoxic and increase methotrexate toxicity 4
• Do not assume hematuria is always drug-related - it may indicate high RA disease activity requiring intensification, not reduction, of DMARD therapy 1
• Do not delay renal biopsy when proteinuria persists or creatinine rises, as this determines specific immunosuppressive therapy 5
• Avoid writing methotrexate prescriptions on a PRN basis and ensure patients understand weekly (not daily) dosing to prevent fatal toxicity 4
• Do not use high-dose methotrexate with NSAIDs as this combination causes severe hematologic and GI toxicity 4