What are the implications of proteinuria in patients treated with Hydroxychloroquine?

Hydroxychloroquine and Proteinuria: Clinical Implications

Direct Answer

Hydroxychloroquine can both reduce proteinuria in lupus nephritis and other glomerular diseases while paradoxically causing drug-induced proteinuria through phospholipidosis in rare cases. 1

Beneficial Effects: HCQ Reduces Proteinuria

In Lupus Nephritis

• Hydroxychloroquine is recommended for all patients with lupus nephritis as it increases rates of renal response, reduces renal relapses, and decreases accrual of renal damage. 2
• The drug should be dosed at 5 mg/kg/day (or 400 mg/day, whichever is lower) based on real body weight. 2, 3
• Epidemiological studies demonstrate that HCQ use is associated with higher rates of complete renal response and fewer renal flares in lupus nephritis patients. 2
• Blood hydroxychloroquine levels above 0.6 mg/L may be associated with lower risk of lupus nephritis flares. 2

In Other Glomerular Diseases

• In IgA nephropathy, HCQ significantly reduces proteinuria by approximately 50% at 6 months, with effective response rates (>30% proteinuria reduction) of 57.5% compared to 28.9% with RAAS inhibitors alone. 4
• In primary membranous nephropathy, HCQ as adjunctive therapy achieves higher effective response rates (57.5% vs 28.9%) and clinical remission rates (35.0% vs 15.7%) at 6 months compared to RAAS inhibitors alone. 5
• In X-linked Alport syndrome, HCQ ameliorates both hematuria and proteinuria in children, with urinary erythrocyte counts significantly reduced in 8 of 8 patients by 6 months. 6

Adverse Effect: HCQ-Induced Proteinuria

Drug-Induced Renal Toxicity

• The FDA warns that proteinuria with or without moderate reduction in glomerular filtration rate can occur with hydroxychloroquine use. 1
• Renal biopsy in these cases shows phospholipidosis without immune deposits, inflammation, or increased cellularity—a distinct pathologic pattern. 1
• Physicians must consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders receiving HCQ. 1
• HCQ can accumulate in lysosomes causing phospholipidosis with accumulation of multilamellar zebra bodies in podocytes, which may mimic Fabry disease appearance. 7

When to Suspect Drug-Induced Proteinuria

• New or worsening proteinuria in a patient on long-term HCQ therapy, particularly if disease activity is otherwise controlled. 1
• Proteinuria accompanied by declining GFR without other explanation. 1
• Discontinue hydroxychloroquine if renal toxicity is suspected or demonstrated by tissue biopsy. 1

Dosing Adjustments for Renal Impairment

• In patients with eGFR <30 mL/min/1.73 m², reduce HCQ dose by 25%. 2, 3
• Dose adjustments may be necessary in patients with GFR <30 mL/min to prevent accumulation and toxicity. 2

Monitoring Strategy

Baseline Assessment

• Measure G6PD levels in men, especially those of African, Asian, or Middle Eastern origin, before starting HCQ to assess hemolysis risk. 2, 3
• Obtain baseline renal function (serum creatinine, eGFR) and quantify proteinuria using spot urine protein-to-creatinine ratio or 24-hour collection. 2

Ongoing Monitoring

• Monitor proteinuria levels regularly using spot UPCR on first morning void urine samples to assess treatment response and detect potential drug toxicity. 2
• Track serum creatinine and estimated GFR to detect any decline in renal function. 2
• Annual ophthalmologic examination should begin after 1 year of therapy if additional risk factors are present (concomitant tamoxifen, eGFR <60 mL/min/1.73 m², dose >5 mg/kg/day) or after 5 years otherwise. 2, 3
• Retinal toxicity affects 0.5% after 6 years, increasing to 7.5% in long-term users, and can exceed 20% when treatment duration exceeds 20 years. 2, 7

Clinical Decision Algorithm

For patients with lupus nephritis or proteinuric glomerular disease:

1. Start HCQ at 5 mg/kg/day (reduce by 25% if eGFR <30 mL/min/1.73 m²). 2, 3
2. Monitor proteinuria monthly for first 3-6 months, then every 3 months. 3
3. Expect proteinuria reduction within 3-6 months; complete response may take up to 24 months. 2
4. If proteinuria worsens or new proteinuria develops after initial improvement, consider renal biopsy to distinguish disease progression from drug-induced phospholipidosis. 1
5. Continue HCQ indefinitely if effective and well-tolerated, as benefits include reduced flares, organ damage, and mortality. 2, 7

Common Pitfalls

• Failing to distinguish between disease-related proteinuria and HCQ-induced phospholipidosis—the latter shows a distinct biopsy pattern without immune deposits or inflammation. 1
• Discontinuing HCQ prematurely before 6-12 months when proteinuria response may be delayed. 2
• Using inadequate doses (2-3 mg/kg/day) that may not achieve adequate blood levels and are associated with higher flare rates. 2
• Not adjusting dose in patients with eGFR <30 mL/min/1.73 m², leading to drug accumulation and increased toxicity risk. 2