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Kidney Week

Abstract: PO1314

Systems Analyses of Fabry Renal Transcriptome and Its Response to Enzyme Replacement Therapy (ERT) Identifies a Cross-Validated and Drugable ERT-Resistant Module

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Eikrem, Oystein, Department of Medicine, Haukeland University Hospital, Bergen, Norway
  • Delaleu, Nicolas, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  • Strauss, Philipp, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  • Sekulic, Miroslav, Columbia University Department of Pathology and Cell Biology, New York, New York, United States
  • Tøndel, Camilla, Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  • Skrunes, Rannveig, Department of Medicine, Haukeland University Hospital, Bergen, Norway
  • Leh, Sabine, Department of Pathology, Haukeland University Hospital, Bergen, Norway
  • Svarstad, Einar, Department of Medicine, Haukeland University Hospital, Bergen, Norway
  • Rusu, Elena-Emanuela, Fundeni Clinical Institute, Bucharest, Romania
  • Gaspert, Ariana, Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
  • Nowak, Albina, Department of Endocrinology and Clinical Nutrition, University Hospital, Zurich and University of Zurich, Zurich, Switzerland
  • Rinaldi, Andrea, Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
  • Marti, Hans-Peter, Department of Clinical Medicine, University of Bergen, Bergen, Norway

Fabry nephropathy (FN) is a rare disorder caused by mutations in the alpha-galactosidase A gene that can, to a certain degree, be managed with enzyme replacement therapy (ERT). Via understanding the molecular basis of FN and ERT’s long-term impact, we aim at providing a framework allowing selection of biomarkers and drug-targets.


Obtained from controls and two independent FN-cohorts, mRNA-isolates from archival kidney biopsies taken prior and up to 10 years of ERT, were subjected to RNAseq. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from glomeruli, proximal tubuli, distal tubuli and arteries and integration with existing proteome, interactome and drug::target data.


Comparing transcriptional landscapes per cohort revealed high inter-cohort heterogeneity. Especially, with timely treatment initiation, FN seemed well controlled via ERT. Pathways consistently altered in both FN-cohorts pre-ERT vs. N_CTRLs were limited to glomeruli and arteries and commonly pertained to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or remerged despite of ERT. Inferring an ERT-resistant genetic module on this basis identified targets suitable for drug repurposing.


Kidney compartments’ transcriptional landscapes comprehensively reflected differences in FN-cohort characteristics. With the exception of few key aspects, in particular concerning arteries, early ERT in classical Fabry patients could lastingly revert FN kidney-compartments’ molecular state to closely match N_CTRLs. Thus, we identified and cross-validated ERT-resistant modules that, when leveraged with external data, allowed estimating their suitability as biomarkers and potential targets for adjunct treatment.


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