What causes persistent disease activity in lupus nephritis despite chronic dialysis?

Causes of Persistent Disease Activity in Lupus Nephritis Despite Chronic Dialysis

Persistent disease activity in lupus nephritis despite chronic dialysis is primarily caused by ongoing systemic autoimmune inflammation, thrombotic microangiopathy, and inadequate immunosuppression, requiring continued immunosuppressive therapy and targeted interventions based on the specific underlying mechanisms.

Primary Mechanisms of Persistent Disease Activity

1. Ongoing Systemic Autoimmune Inflammation

• Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that can remain active despite dialysis treatment 1
• Dialysis addresses kidney failure but does not treat the underlying autoimmune pathology
• Extrarenal manifestations may persist or flare despite dialysis therapy 2

2. Thrombotic Microangiopathy

• Antiphospholipid antibodies can cause thrombotic microangiopathy contributing to persistent disease activity 1
• Patients with antiphospholipid antibodies have increased risk of vascular access thrombosis during dialysis 3
• Management should be tailored to the underlying etiology (plasma exchange, eculizumab, or anticoagulation) 1

3. Inadequate Immunosuppression

• Suboptimal immunosuppressive regimens or dosing may fail to control disease activity 1
• Poor medication adherence can contribute to persistent inflammation 1
• Discontinuation of immunosuppression too early can lead to disease flares 3
• Studies show that 28-50% of patients continue to show inflammatory histologic activity on repeat kidney biopsy despite ≥36 months of immunosuppression 3

Diagnostic Approach to Persistent Disease Activity

1. Confirm Active Inflammation

• Measure SLE serologic markers (complement C3, C4, anti-dsDNA antibodies) 3, 1
• Monitor extrarenal manifestations of lupus 1
• Consider a kidney biopsy to confirm active inflammation versus chronic damage 1, 4
  • Biopsy-informed management of maintenance immunosuppression may improve lupus nephritis flare rates 4

2. Assess Treatment Adequacy

• Verify medication adherence 1
• Ensure adequate dosing of current immunosuppressives by measuring drug levels when applicable 1
• Regular assessment of SLE activity markers (every 1-3 months) 1

Management Strategies

1. Optimize Immunosuppressive Therapy

• Continue hydroxychloroquine as cornerstone therapy unless contraindicated 1
• Consider adding belimumab to standard therapy for patients with persistent lupus nephritis activity despite dialysis dependence 1, 5
  • Belimumab has shown efficacy in reducing renal flares and improving outcomes in lupus nephritis 5
• Consider rituximab for refractory disease, particularly effective for certain manifestations (e.g., hematologic) 1
• Extended course of IV cyclophosphamide for severe refractory disease not responding to other therapies 1

2. Address Thrombotic Complications

• Patients with antiphospholipid antibodies should receive anticoagulation or antiplatelet therapy 1
• Anticoagulation may be superior for secondary prevention of arterial events 1
• Monitor for vascular access thrombosis in dialysis patients with antiphospholipid antibodies 3

3. Manage Non-Immune Risk Factors

• Control blood pressure (target <130/80 mmHg) 6
• Optimize renin-angiotensin system blockade with ACE inhibitors and/or ARBs 6
• Manage dyslipidemia with statins (target LDL <100 mg/dl) 3, 1
• Address modifiable risk factors that contribute to chronic kidney disease progression 7
  • Obesity, hypertension, sodium- or protein-rich diets, and type 2 diabetes mellitus 7
  • Avoid nephrotoxic agents and smoking 7

Special Considerations for Transplantation

• Transplantation should be considered when lupus activity has been absent or at a low level for at least 3-6 months 3, 1
• Superior results are obtained with living donor and pre-emptive transplantation 3
• Screen for antiphospholipid antibodies during transplant preparation due to increased risk of vascular events in the transplanted kidney 3

Monitoring Recommendations

• Regular monitoring of disease activity every 2-4 weeks for the first 2-4 months after diagnosis or flare, then according to response 3
• Lifelong monitoring for renal and extra-renal disease activity at least every 3-6 months 3
• Monitor body weight, blood pressure, serum creatinine, eGFR, serum albumin, proteinuria, urinary sediment, serum C3 and C4, and anti-dsDNA antibody levels 3

By addressing both the immune and non-immune aspects of persistent lupus nephritis activity in dialysis patients, clinicians can improve outcomes and quality of life for these challenging cases.