Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance

Marisa Santostefano; Maria Cappuccilli; Dino Gibertoni; Benedetta Fabbrizio; Deborah Malvi; Marcello Demetri; Irene Capelli; Edoardo Tringali; Valentina Papa; Elena Biagini; Giovanna Cenacchi; Adriana Galdi; Vincenzo Donadio; Rocco Liguori; Giorgio Zoli; Gaetano La Manna; Gianandrea Pasquinelli

doi:10.1053/j.ajkd.2023.03.015

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance

Am J Kidney Dis. 2023 Nov;82(5):581-596.e0. doi: 10.1053/j.ajkd.2023.03.015. Epub 2023 Jun 9.

Authors

Marisa Santostefano¹, Maria Cappuccilli¹, Dino Gibertoni², Benedetta Fabbrizio³, Deborah Malvi³, Marcello Demetri⁴, Irene Capelli¹, Edoardo Tringali¹, Valentina Papa⁵, Elena Biagini⁶, Giovanna Cenacchi⁷, Adriana Galdi⁸, Vincenzo Donadio⁹, Rocco Liguori⁹, Giorgio Zoli⁸, Gaetano La Manna¹⁰, Gianandrea Pasquinelli¹¹

Affiliations

¹ Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna; Alma Mater Studiorum, University of Bologna, Bologna.
² Research and Innovation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
³ Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
⁴ Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
⁵ Department of Biomedical and Neuromotor Sciences, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna.
⁶ Cardiology, University of Bologna, Bologna.
⁷ Biotechnology and Methods in Laboratory Medicine, University of Bologna, Bologna.
⁸ Department of Internal Medicine, S.S. Annunziata Hospital, University of Ferrara, Cento, Italy.
⁹ Neuromuscular and Neuroimmunology Unit, Bellaria Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
¹⁰ Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna; Alma Mater Studiorum, University of Bologna, Bologna. Electronic address: gaetano.lamanna@unibo.it.
¹¹ Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna; Biotechnology and Methods in Laboratory Medicine, University of Bologna, Bologna.

PMID: 37301502
DOI: 10.1053/j.ajkd.2023.03.015

Abstract

Rationale & objective: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex.

Study design: Single-center, case series.

Setting & participants: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System.

Observations: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age.

Limitations: Retrospective design and inclusion of outpatients partially based on family pedigree.

Conclusions: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Keywords: Chronic kidney disease; Fabry disease; Fabry nephropathy; enzymatic replacement therapy; glomerulosclerosis; interstitial fibrosis; kidney biopsy; lysosomal storage disease; podocyte vacuoles; proteinuria; α-GAL A.