title: Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct diagnosis.
abstract: OBJECTIVE
  Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy.
  
  
  METHODS
  A modified Delphi procedure was conducted to reach consensus among 11 FD experts. A systematic review was performed to identify possible criteria that could confirm or exclude FD nephropathy.
  
  
  RESULTS
  The gold standard for FD nephropathy was defined as characteristic storage on electron microscopy (EM) in a kidney biopsy in the absence of medication that may induce similar storage. The suggested criteria to confirm FD nephropathy are as follows: 'renal cysts', 'Maltese cross sign', 'immunohistochemical staining of Gb3 in urine' and 'high urinary Gb3'; and to exclude FD nephropathy: 'absence of renal cysts', 'small kidneys' and 'high protein excretion' were rejected because of low or uncertain specificity. Urinary Gb3 may be increased in other kidney diseases and there was no agreement on this criterion, although a third of the panel indicated that it is sufficient to diagnose FD nephropathy. The 'Maltese cross sign' and 'high urinary Gb3' were selected as red flags to suggest the possibility of FD nephropathy, but are not sufficient for a definite diagnosis of FD nephropathy.
  
  
  CONCLUSIONS
  In adults with chronic kidney disease, an α-galactosidase A gene variant and an uncertain diagnosis of FD, a kidney biopsy with EM analysis should be performed to confirm or reject the diagnosis of FD nephropathy. Other criteria currently cannot substitute for a biopsy in these cases.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam Lysosome Center 'Sphinx', Amsterdam, Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: van der Tol
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Svarstad
authors.affiliation: Unidad de Dialisis, IIS-Fundacion Jimenez Diaz/UAM, IRSIN, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Tøndel
authors.affiliation: Medical Genetics, Hospital São João, Faculty of Medicine of University of Porto, Porto, Portugal.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Oliveira
authors.affiliation: Department of Nephrology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Liffert
authors.initials: L
authors.lastname: Vogt
authors.affiliation: Manchester, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Waldek
authors.affiliation: Department of Haematology, Royal Free London NHS Foundation Trust, & University College London, UK.
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.affiliation: Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Lachmann
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Terryn
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam Lysosome Center 'Sphinx', Amsterdam, Netherlands.
authors.forename: Carla E
authors.initials: CE
authors.lastname: Hollak
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Marius A
authors.initials: MA
authors.lastname: van den Bergh Weerman
authors.affiliation: Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.affiliation: Department of Nephrology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Michael L
authors.initials: ML
authors.lastname: West
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam Lysosome Center 'Sphinx', Amsterdam, Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Biegstraaten
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam Lysosome Center 'Sphinx', Amsterdam, Netherlands. Electronic address: g.e.linthorst@amc.nl.
authors.forename: Gabor E
authors.initials: GE
authors.lastname: Linthorst
mesh_terms: D000328:Adult; D000465:Algorithms; D001706:Biopsy; D003697:Delphi Technique; D000795:Fabry Disease / Q000175:diagnosis*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis*; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D000519:alpha-Galactosidase
keywords: Chronic kidney disease; Consensus; Diagnosis; Fabry disease; Kidney pathology