Hydroxychloroquine-Induced Renal Phospholipidosis

Abstract

Background: Systemic Lupus Erythematosus (SLE) is a systemic disease, can manifest as Lupus Nephritis and shown to overlap with other diseases. SLE is treated by a combination of steroids, immune-suppression and anti-malarial like Chloroquine (CQ) and Hydroxychloroquine (HCQ). Fabry is a X-Linked disease due to inactivation of Lysosomal Alpha-galactosidase (GAL) enzyme, renal biopsy is characterized by Zebra bodies on electron microscopy. We report a case of SLE on HCQ with zebra bodies and negative genetic testing. Methods: A 35 y.o. AA woman is known to have SLE for 17 years, with Asthma, Myositis, HTN, Lupus Anticoagulant, PE on Warfarin. SLE treated with Azathioprine, Prednisone and HCQ. Noted to have increased proteinuria and hematuria. FH significant for SLE. She is non-smoker, no alcohol/drug use. Exam only positive for leg edema. Labs showed normal blood counts, sCr 0.8, electrolytes and C3/C4. Urine showed protein >300 mg/dL and RBC 50-100, 24 hr collection showed 2.42 gm of protein. HIV, Hepatitis B/C were negative and ANA/dsDNA positive. Protein electrophoresis and light chains were normal. Renal Biopsy showed areas of Mesangial depostis, rare sub-epithelial deposits and tubulo-reticular inclusion consistent with Class I LN. Abundant Zebra Bodies of varying sizes were noted in the visceral epithelial cell cytoplasm, characteristic of Fabry Disease. Further tests showed normal Plasma Lyso-Gb3 level and negative genetic GLA sequencing, ruled out Fabry. After discontinuation of HCQ, proteinuria improved and renal function stable. Results: Conclusions: Zebra bodies are mostly seen in primary renal phospholipidosis but described with various drugs like CQ, amiodarone and silicon. CQ induced Phospholipidosis was first described as CQ Keratopathy in 1977. CQ Cardiotoxicity was describe in a Mayo study in 2002. The first description of CQ Renal Phospholipidosis was reported in German in 2002. More recently HCQ has been associated with similar findings. Being a weak base HCQ is concentrated in lysosomes and inhibits enzymes like alpha-galactosidase, cathepsin, acid hydroxylase and phospholipases leading to Iatrogenic Phospholipidosis. Accumulation is higher in patients on higher doses of HCQ, prolonged exposure and renal failure. Fabry needs to be ruled out to establish diagnosis. Only few case reports of this association are reported and clinicians need to be aware of Drug Induced Phospholipidosis.