Renal ANCA+ Vasculitis Concurrent with Fabry Nephropathy: Coincidence or Complication?

Introduction: Fabry disease (FD in an X-linked disorder of glycosphingolipid metabolism with chronic inflammation triggered by Gb3 and lysoGb3 metabolites. Various forms of glomerulonephritis (GN) and inflammatory disease have been reported with FD. Immune complex GN has complicated enzyme replacement therapy (ERT). GN including antineutrophilic cytoplasmic antibody (ANCA) disease has also been reported in association with COVID19 vaccination and infection. We report the case of a 73 year-old woman with type 1 diabetes mellitus, Fabry disease and COVID19 vaccination on ERT who presented with acute ANCA+ GN. Was Einstein right, there is no such thing as coincidence? Case Description: The patient had stable diabetes since age 27, normal kidney function and low grade proteinuria 1 year prior. ERT (agalsidase alfa 0.2 mg/kg i.v. q2 wks) was given for 3 years for Fabry hypertrophic cardiomyopathy with moderate diastolic dysfunction. COVID19 vaccination was given 4 months prior to development of dyspnea, and acute kidney injury with microscopic hematuria. There was no extra-renal disease. Anti-myeloperoxidase (MPO) ANCA was positive. Renal biopsy showed focal proliferative GN with crescents plus background diabetic and Fabry nephropathies. She required hemodialysis. Despite treatment with glucocorticoids and Rituximab, there was no renal recovery. ANCA measurement in 83 FD adults revealed and negative results in 24M, 59F; transient false positive anti-PR3 ANCA occurred in 1M in which renal biopsy showed Fabry nephropathy plus an immune complex GN. Discussion: FD has been previously reported with with renal vasculitis ANCA+ (antiPR3) in 1 patient and ANCA- in 2 patients. This is the first such case in which FD was already diagnosed and ERT given. ANCA associated vasculitis and other forms of GN usually occur within 90 days of COVID19 vaccination, mean 19 days, which does not fit with the observed time course in this case. The chronic inflammation of FD plus increased circulating MPO, the association with other GNs and other inflammatory conditions including vasculitis, the presence of kidney and lysosomal ANCA antigens, all suggest that vasculitis with or without ANCA is a rare complication of Fabry disease and Einstein was right. While our case did not improve with immunosuppressive therapy, others have, which suggests that FD patients should be treated for this serious but rare complication.

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