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Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and fibrosis

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Abstract

Background

Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry disease and its relationship to mechanisms of fibrosis. This work aims to quantify TGF-β1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters.

Methods

Renal biopsies from 15 treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-β1, TNF-α, CD3, CD20, CD68 and CD163. Clinical data were retrospectively gathered at time of kidney biopsy.

Results

Our results suggest the production of TNFα and TGFβ1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFβ1 and active caspase 3 tubular expression.

Conclusions

These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFβ1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.

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Data availability

Data is available upon request.

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Funding

This project was funded by Shire Human Genetic Therapies Inc., now part of the Takeda group of companies, Investigator Research program under IIR-ARG-002876 (Japan) and by Universidad Nacional de La Plata [X814 to PR] (Argentina). None of the funders were involved in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication.

Author information

Authors and Affiliations

  1. Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, CONICET, Asociado CIC PBA, Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, Bv 120 Nro 1489, 47 y 115, 1900, La Plata, Argentina

    Constanza Bondar & Paula Adriana Rozenfeld

  2. Servicio de Anatomía Patológica, Hospital San Martin, Calle 1 y 70, 1900, La Plata, Argentina

    Maria de los Angeles de Bolla

  3. Servicio de Diálisis y Nefrologia, IPENSA, Calle 59 N°434, 1900, La Plata, Argentina

    Pablo Neumann

  4. Chair of Nephrology, Federico II University of Naples, Naples, Italy

    Antonio Pisani

  5. Nephrology and Dialysis Unit, Belcolle Hospital, Viterbo, Italy

    Sandro Feriozzi

Authors
  1. Constanza Bondar
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  2. Maria de los Angeles de Bolla
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  3. Pablo Neumann
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  4. Antonio Pisani
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  5. Sandro Feriozzi
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  6. Paula Adriana Rozenfeld
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Contributions

All authors contributed to the study conception and design, writing and revision of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Paula Adriana Rozenfeld.

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Conflict of interest

PN, AP, SF and PR have received travel grants, research grants and/or consulting fees from Takeda and Amicus.

Ethical approval

The procedures were in accordance with the ethical standards of the Ethical Committee of Framingham (La Plata, Argentina) and with the Helsinki Declaration of 1975, as revised in 2013.

Statement of human and animal rights

All procedures were approved by the Ethical Committee of Framingham (La Plata, Argentina) International review Board.

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All patients provided written informed consent to participate in this study.

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Bondar, C., de Bolla, M.A., Neumann, P. et al. Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and fibrosis. J Nephrol (2024). https://doi.org/10.1007/s40620-024-01908-9

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