What is the role of plasma exchange in treating severe ANCA (Antineutrophil Cytoplasmic Antibody)-associated vasculitis, particularly in patients with impaired renal function?

MEPEX Trial and Plasma Exchange in ANCA-Associated Vasculitis

Overview of the MEPEX Trial

The MEPEX trial demonstrated that plasma exchange was superior to intravenous methylprednisolone for achieving renal recovery at 3 months in patients with severe ANCA-associated vasculitis presenting with serum creatinine >500 μmol/L (5.8 mg/dl). 1

Key Trial Design and Results

• The MEPEX trial randomized 137 patients with newly diagnosed ANCA-associated systemic vasculitis and serum creatinine >500 μmol/L to receive either seven plasma exchanges (n=70) or 3000 mg intravenous methylprednisolone (n=67), with both groups receiving oral cyclophosphamide and prednisolone 1

• At 3 months, 69% (48/70) of patients receiving plasma exchange were alive and dialysis-independent compared to only 49% (33/67) receiving methylprednisolone (P=0.02) 1

• Plasma exchange reduced the risk of progression to end-stage renal disease by 24% at 12 months (from 43% to 19%) compared to methylprednisolone 1

• Patient survival at 1 year was similar between groups: 73% with plasma exchange versus 76% with methylprednisolone 1

• Severe adverse event rates were comparable: 50% in the plasma exchange group versus 48% in the methylprednisolone group 1

Current Evidence and the PEXIVAS Trial Challenge

The PEXIVAS Trial Findings

The subsequent PEXIVAS trial (2020), which was larger and more definitive, failed to demonstrate that plasma exchange reduced the composite outcome of death or end-stage kidney disease in severe ANCA-associated vasculitis. 2

• PEXIVAS enrolled 704 patients with severe AAV (defined as eGFR <50 ml/min/1.73 m² or diffuse pulmonary hemorrhage) in a 2-by-2 factorial design 2

• Death or ESKD occurred in 28.4% (100/352) in the plasma exchange group versus 31.0% (109/352) in the control group (hazard ratio 0.86; 95% CI 0.65-1.13; P=0.27) 2

• The trial demonstrated no statistically significant benefit for plasma exchange on the primary composite outcome or secondary outcomes 2

Meta-Analysis Incorporating PEXIVAS

• A systematic review incorporating PEXIVAS and eight other RCTs (total 1060 patients) found very uncertain evidence regarding plasma exchange's effect on death at 1 year (risk difference 1.5% reduction, 95% CI 7.1% reduction to 6.4% increase; very low certainty) 3

• The meta-analysis showed plasma exchange may increase serious infections at 1 year (risk difference 6.8% increase, 95% CI 0.8% to 14% increase; low certainty) 3

Current Guideline Recommendations

When to Use Plasma Exchange

Based on the most recent 2022 BMJ guidelines incorporating PEXIVAS data, plasma exchange should be reserved for highly selected patients at moderate-high to high risk of end-stage kidney disease, specifically those with serum creatinine ≥500 μmol/L or requiring dialysis. 4

Risk Stratification for ESKD 3

• Low risk (creatinine <200 μmol/L): Baseline ESKD risk <2.5% at 1 year
• Moderate risk (creatinine 200-300 μmol/L): Baseline ESKD risk 2.5-7.5%
• Moderate-high risk (creatinine 300-500 μmol/L): Baseline ESKD risk 7.5-25%
• High risk (creatinine >500 μmol/L): Baseline ESKD risk >25%

Specific Clinical Scenarios

For severe renal impairment (creatinine ≥500 μmol/L):

• The American Society for Apheresis recommends plasma exchange as accepted second-line therapy in biopsy-proven rapidly progressive glomerulonephritis with creatinine ≥500 μmol/L 4
• The EULAR/ERA-EDTA guidelines recommend plasma exchange should be considered for patients with serum creatinine >500 μmol/L due to rapidly progressive glomerulonephritis 3

For diffuse alveolar hemorrhage:

• KDIGO 2020 favors plasma exchange for AAV with diffuse alveolar hemorrhage plus hypoxemia 3
• The EULAR/ERA-EDTA guidelines state plasma exchange can be considered for severe diffuse alveolar hemorrhage 3
• However, the 2022 BMJ guideline makes a weak recommendation against plasma exchange for isolated pulmonary hemorrhage without kidney disease 4

For patients with creatinine <500 μmol/L:

• The American College of Physicians recommends against routine use of plasma exchange 4
• The 2022 BMJ guidelines do not recommend plasma exchange for low to low-moderate risk of ESKD 4

Practical Implementation When Indicated

When plasma exchange is used, the following protocol should be followed 4:

• Perform 7 exchanges within 14 days of initiation
• Use centrifugation or filter separation with albumin and/or crystalloid replacement
• Exchange volume should be 1-1.5 plasma volumes (40-60 mL/kg or 3.5-4 L fixed volume)
• Always combine with standard immunosuppression (rituximab or cyclophosphamide) plus glucocorticoids

Important Clinical Considerations

Divergence in Guidelines

There is notable divergence between older guidelines (pre-PEXIVAS) and newer recommendations 3:

• Older guidelines (ASFA 2020, KDIGO 2020) were more liberal in recommending plasma exchange for severe renal impairment and pulmonary hemorrhage 3
• Newer guidelines (BMJ 2022) are more restrictive, limiting plasma exchange to the highest-risk patients based on PEXIVAS results 3, 4

The MEPEX vs. PEXIVAS Paradox

The apparent contradiction between MEPEX showing benefit and PEXIVAS showing no benefit can be explained by several factors:

• MEPEX specifically enrolled only patients with creatinine >500 μmol/L, while PEXIVAS included patients with eGFR <50 ml/min (a broader, less severely affected population) 2, 1
• MEPEX compared plasma exchange to methylprednisolone, while PEXIVAS compared plasma exchange plus standard care to standard care alone 2, 1
• Long-term follow-up of MEPEX showed the initial benefit diminished over time, with no statistically significant difference in long-term outcomes 3

Glucocorticoid Dosing Consideration

The PEXIVAS trial also demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard-dose for the outcome of death or ESKD, with fewer serious infections. 2

• The 2022 BMJ guideline strongly recommends a reduced-dose glucocorticoid regimen during the first 6 months of therapy 4
• Serious infections at 1 year were less common with reduced-dose glucocorticoids (incidence rate ratio 0.69; 95% CI 0.52-0.93) 2

Clinical Algorithm for Decision-Making

For patients with severe ANCA-associated vasculitis:

1. Assess renal function and presence of pulmonary hemorrhage

   • Measure serum creatinine and determine if dialysis-dependent 4
   • Evaluate for diffuse alveolar hemorrhage with hypoxemia 3

2. Risk stratify for ESKD 3

   • Creatinine ≥500 μmol/L or dialysis-dependent = High risk
   • Creatinine 300-500 μmol/L with rapidly deteriorating function = Moderate-high risk
   • Creatinine <300 μmol/L = Lower risk

3. Consider plasma exchange if:

   • Creatinine ≥500 μmol/L or dialysis-dependent 4
   • Creatinine >300 μmol/L with rapidly deteriorating renal function 5
   • Life-threatening pulmonary hemorrhage with hypoxemia 4
   • Double positive for anti-GBM antibodies and ANCA 5

4. Do NOT use plasma exchange routinely if:

   • Creatinine <500 μmol/L with stable renal function 4
   • Isolated pulmonary hemorrhage without kidney disease 4

5. Always combine with:

   • Standard immunosuppression (rituximab preferred over cyclophosphamide) 6
   • Reduced-dose glucocorticoid regimen 4, 2