Hydroxychloroquine-Induced Renal Phospholipidosis: Case Report and Review of Differential Diagnoses

**Background:** Renal phospholipidosis is the accumulation of phospholipids in lysosomes of kidney cells, most classically associated with Fabry disease due to α-galactosidase A deficiency. However, cationic amphiphilic drugs (CADs) such as hydroxychloroquine can also induce phospholipidosis by accumulating in lysosomes and impairing lipid catabolism, leading to lamellar bodies (zebra bodies) on electron microscopy. The clinical significance and risk factors for hydroxychloroquine-induced renal phospholipidosis remain unclear, especially in patients with chronic kidney disease.

**Methods:** This is a single case report of a 69-year-old female with systemic lupus erythematosus (SLE) diagnosed 25 years prior, who had been on hydroxychloroquine 200 mg/day (cumulative dose ~1,800 g) and other immunosuppressants (mycophenolate mofetil 500 mg/day, prednisolone 5 mg/day). She presented in July 2022 with progressive renal impairment (serum creatinine 3.3 mg/dL, eGFR 14 mL/min/1.73 m², proteinuria 2 g/g creatinine). A renal biopsy was performed to rule out lupus nephritis. Light microscopy, immunofluorescence, and electron microscopy were conducted. Genetic testing for Fabry disease (GLA gene sequencing) was performed. The authors also reviewed the literature on causes of renal phospholipidosis and present a summary table.

**Key Results:** The renal biopsy showed moderate chronic parenchymal damage, focal segmental and global glomerulosclerosis (5 of 11 glomeruli), tubulointerstitial inflammation, and mild vacuolization of podocyte cytoplasm. Immunofluorescence was negative for lupus nephritis. Electron microscopy revealed numerous lamellar bodies (zebra bodies) predominantly in podocytes, with podocyte foot process effacement. A prior biopsy from January 2020 (creatinine 1.7 mg/dL, eGFR 31 mL/min/1.73 m²) had shown no lamellar bodies. Genetic testing for Fabry disease was negative. After discontinuation of hydroxychloroquine, renal function remained stable over 1 year (creatinine 2.94 mg/dL, eGFR 16 mL/min/1.73 m²), and proteinuria was unchanged. No SLE flare occurred.

**Clinical Implications:** This case highlights that hydroxychloroquine can induce renal phospholipidosis even after decades of use, and that declining renal function may predispose to drug accumulation and toxicity. The absence of phospholipidosis in the earlier biopsy when kidney function was better supports the hypothesis that reduced renal excretion of hydroxychloroquine in advanced CKD (stage 5) may lead to increased tissue levels and phospholipid accumulation. Although the FDA label recommends dose reduction in renal disease, evidence on optimal dosing in CKD is limited. Discontinuation of hydroxychloroquine should be considered when zebra bodies are found, but must be balanced against the risk of SLE flare. The authors provide a comprehensive table of differential diagnoses for renal phospholipidosis, including other drugs (e.g., chloroquine, amiodarone, aminoglycosides), genetic diseases (Fabry, Niemann-Pick type C, COQ2 mutation, LMX1B-associated nephropathy, familial LCAT deficiency), metals (silicon, chromium), and experimental nutritional factors. This table can guide clinicians when zebra bodies are unexpectedly found on renal biopsy.