What is the role of Hydroxychloroquine (HCQ) in the management of lupus nephritis?

Role of Hydroxychloroquine in Lupus Nephritis

Hydroxychloroquine should be prescribed to all patients with lupus nephritis unless contraindicated, as it reduces renal flares, prevents organ damage, decreases cardiovascular complications, and improves long-term survival. 1

Core Recommendation

The KDIGO 2024 guidelines strongly recommend that all patients with SLE, including those with lupus nephritis, be treated with hydroxychloroquine (or equivalent antimalarial) as foundational therapy. 1 This recommendation is echoed by EULAR/ERA-EDTA guidelines, which emphasize hydroxychloroquine's role in reducing renal flares and limiting accrual of renal and cardiovascular damage. 1

Evidence-Based Benefits in Lupus Nephritis

Renal Protection

• Hydroxychloroquine reduces the risk of renal flares by approximately 57%, with patients who discontinue therapy having a 2.5-fold increased risk of lupus flares (HR 2.50,95% CI: 1.08-5.58). 1, 2
• Patients with blood hydroxychloroquine levels >0.6 mg/L demonstrate significantly lower rates of renal flares compared to those with lower levels (0.81 mg/L in remission vs 0.59 mg/L in those who flared, p=0.005). 3
• The medication slows progression of kidney disease and increases complete remission rates in lupus nephritis patients. 1

Systemic Benefits Critical for Lupus Nephritis Outcomes

• Reduces cardiovascular and thrombotic events, particularly important given that CV complications are a major cause of late mortality in lupus nephritis. 1
• Decreases overall organ damage accrual and may provide protective effects against infections. 1
• Improves lipid profiles and preserves bone mass, addressing common comorbidities in lupus nephritis patients on immunosuppression. 1
• Allows for glucocorticoid dose reduction, minimizing steroid-related complications. 4

Pregnancy Safety

• Safe during pregnancy with demonstrated reduction in lupus activity without fetal harm, making it essential for women of childbearing age with lupus nephritis. 1

Dosing Algorithm

Standard Dosing

• Target dose: 5 mg/kg/day of actual body weight (not to exceed this to minimize retinal toxicity risk). 1
• Doses of 2-3 mg/kg/day are insufficient and associated with higher flare rates due to inadequate blood levels. 1
• Target blood level: >0.6 mg/L to reduce renal flare risk. 1, 3

Dose Adjustments

• Patients with eGFR <30 ml/min/1.73 m²: Reduce dose by 25%. 1
• No baseline dose adjustment needed for mild-moderate renal impairment. 1

Monitoring Requirements

Ophthalmologic Surveillance

The risk of retinal toxicity increases with duration of therapy and requires structured monitoring:

• No baseline examination required per updated Royal College of Ophthalmologists guidelines. 1
• Begin annual screening after 1 year if high-risk factors present (concomitant tamoxifen, eGFR <60 ml/min/1.73 m², dose >5 mg/kg/day, or chloroquine use). 1
• Begin annual screening after 5 years in standard-risk patients. 1
• Retinal toxicity occurs in 0.5% at 6 years, 7.5% in long-term users generally, and can exceed 20% after 20 years of use. 1

Pre-Treatment Screening

• Measure G6PD levels in men, especially those of African, Asian, or Middle Eastern origin, to assess hemolysis risk, though this risk appears low in practice. 1

Therapeutic Drug Monitoring

• Consider measuring blood hydroxychloroquine levels to assess adherence and optimize dosing, particularly in patients with renal flares or suspected non-adherence. 3
• Target level >0.6 mg/L correlates with reduced flare risk. 1, 3

Safety Profile and Adverse Effects

Common Adverse Effects (Generally Mild)

• Skin rash, increased pigmentation, muscle weakness, visual changes. 1
• These are uncommon and usually reversible with discontinuation. 1

Serious but Rare Complications

• Retinal toxicity: Most significant long-term concern, managed through surveillance protocol above. 1
• Cardiac toxicity: Rare cardiomyopathy or conduction abnormalities with high cumulative exposure. 1
• Renal phospholipidosis: Accumulation in lysosomes causing zebra bodies in podocytes that can mimic Fabry disease on biopsy. 1

Critical Caveat: Acute Kidney Injury

One preclinical study suggests hydroxychloroquine may worsen acute kidney injury outcomes in lupus nephritis by disrupting autophagy and promoting tubular cell senescence. 5 However, this finding is from animal models and has not altered clinical guideline recommendations. The overwhelming clinical evidence supports continued use, but clinicians should be vigilant when AKI develops in patients on hydroxychloroquine. 5

Duration of Therapy

Hydroxychloroquine should be continued indefinitely (lifelong) in patients with lupus nephritis due to sustained beneficial effects on disease activity, organ protection, and survival. 4, 6 The American College of Rheumatology recommends indefinite continuation. 4

Resource Considerations

• In low-resource settings where hydroxychloroquine is prohibitively expensive, chloroquine may be substituted (dose 2.3 mg/kg/day), though it carries higher toxicity risk. 1
• This substitution should only be considered when hydroxychloroquine is truly unavailable or unaffordable. 1

Integration with Immunosuppressive Therapy

Hydroxychloroquine is adjunctive therapy, not a replacement for immunosuppression in active lupus nephritis. 1 It should be combined with:

• Induction therapy (mycophenolate mofetil or cyclophosphamide plus glucocorticoids for proliferative disease). 1
• Maintenance immunosuppression (mycophenolate or azathioprine). 1
• RAAS blockade for proteinuria control. 1

The synergistic benefits of hydroxychloroquine enhance outcomes when added to standard immunosuppressive regimens. 1