Kidney impairment in Fabry disease and contribution of other kidney co-morbidities

Abstract Background/objectives Fabry disease (FD) results from alpha-galactosidase A deficiency and accumulation of globotriaosylceramide. Classical FD manifests early with acroparasthesia, angiokeratoma, and sweating abnormalities progressing to multi-organ dysfunction. Patients with late-onset FD have higher alpha-galactosidase A activity and single-organ dysfunction, most commonly the heart, although kidney manifestations may occur. Chronic kidney disease (CKD) may progress to end-stage renal disease (ESRD) in classical males. It occurs less commonly in classical females and patients with late-onset FD. Eligible patients with FD and ESRD may be offered dialysis or transplantation. We were concerned that alternative explanations for ESRD might be overlooked in females and patients with late-onset FD, so we conducted a retrospective clinical audit (2001–2019, n = 383) of patients undergoing kidney biopsy. Methods 27 of 383 FD patients underwent a kidney biopsy for clinical indications including decline in eGFR with normal urinary protein excretion, nephrotic range proteinuria despite being on Fabry-specific therapy, microscopic haematuria, significant CKD in late-onset patients, or evidence of an autoimmune disease. Results Median age of biopsy (years, range) for: 11 classical males 36 (20–56), 6 late-onset males 52 (25–76), and 7 classical females 48 (30–62), 3 late-onset females 27(27–47). Biopsy findings unrelated to FD included vasculitis and necrotizing glomerulonephritis, kidney cell carcinoma, drug-induced severe acute tubulointerstitial nephritis, diabetic nephropathy, membranous nephropathy, and nephropathy related to gout. Conclusions In the clinically selected cohort of biopsied patients, the prevalence of secondary pathology was significantly higher in the late-onset FD cohort compared to the classical FD cohort (two-sided Fisher exact test: 55.6% vs. 11.1%, p = 0.0235). Late-onset patients showed a ten-fold increase in the odds of presenting with a secondary pathology (odds ratio = 10.0, 95% CI: 1.39–71.9). These findings should be viewed as exploratory hypothesis-generating, requiring validation in prospective larger multi-Centre cohort studies. In clinically selected patients with late-onset Fabry disease, renal biopsy may identify additional renal pathologies. Patients who did not undergo a biopsy had additional co-morbidities that might contribute to CKD, including hypertension, diabetes, pyelonephritis, kidney stones, rheumatoid arthritis, vasculitis, and gout.