Lupus Nephritis and Hydroxychloroquine-Associated Zebra Bodies: Not Just in Fabry Disease

Abstract

Zebra bodies in kidney biopsy specimens are widely accepted as a specific feature of Fabry disease but they can also be present in a drug-induced mimic of Fabry disease, phospholipidosis. Chloroquine and hydroxychloroquine may both induce zebra body formation and kidney phospholipidosis. However, the frequency and clinical significance of such changes remain unknown. We report 5 serial kidney biopsy cases diagnosed as lupus nephritis during hydroxychloroquine administration. All 5 patients exhibited a few, but varying amounts, of zebra bodies in glomerular intrinsic cells, that is, podocytes, parietal epithelial cells, mesangial cells, and endothelial cells. Most of the zebra bodies detected were subtle, though certainly recognizable; these zebra bodies were much smaller than those observed in Fabry disease. Zebra bodies were not observed in patients with lupus nephritis in the absence of chloroquine or hydroxychloroquine administration. All patients with lupus nephritis who received hydroxychloroquine achieved complete remission during continuous use of hydroxychloroquine, though kidney toxicity of drug-induced phospholipidosis might be masked by immunosuppression. Based on this small series of cases, we speculate that the hydroxychloroquine-associated manifestation of zebra bodies and phospholipidosis in the kidney may be frequent phenomena and may have only a subclinical influence on kidney function, at least in the short term.

Fabry Disease: Screening and Analysis of the Associated Clinical Manifestations in Patients Attending Dialysis and Nephrology Clinics in Durban, South Africa

“…No genetic studies were performed to con rm the diagnosis of FD. A comparison of the number and size of the zebra bodies to FD con rmed a likely diagnosis of hydroxychloroquine-associated phospholipidosis(27). SLEassociated autoantibodies have been reported in FD.…”

Kidney Podocyte Zebra Bodies after Lung Transplantation for Lymphangioleiomyomatosis

“…These drugs include chloroquine, amiodarone, tamoxifen, chlorpromazine, imipramine, propranolol, and sertraline (10)(11)(12)(13). Indeed, lysosomal phospholipidosis is often reported in lupus nephritis under the treatment of hydroxychloroquine (7,8). However, there was also a case of lupus nephritis with kidney podocyte zebra bodies in a young man with no treatment of hydroxychloroquine.…”

“…In terms of pathology, electron microscopy showcases highly electron-dense multilamellar inclusions of myelin figures made of concentric layers and zebra bodies with an elongated, striped appearance (6). The kidney lysosomal deposits are composed of abnormally metabolized phospholipids that are also reported after chronic treatment with hydroxychloroquine (7,8).…”

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model

“…A correlation between the induction of phospholipidosis and antiviral activity has been described for several drugs and demonstrated an in vitro antiviral effect solely due to physicochemical properties and not to a specific targeting of SARS-CoV-2. Hence, the in vitro antiviral activity of HCQ and AZM must be rediscussed since these molecules are known or strongly suspected to induce this biological disorder in various models ( Baronas et al, 2007 ; Tsukimura et al, 2021 ; Tummino et al, 2021 ; Van Bambeke et al, 1996 ) and clinical cases ( Costa et al, 2013 ; Khubchandani and Bichle, 2013 ; Manabe et al, 2021 ; Obeidat et al, 2020 ).…”