title: Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation.
abstract: BACKGROUND
  Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered.
  
  
  METHODS
  A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure.
  
  
  RESULTS
  After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc.
  
  
  CONCLUSIONS
  Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.
authors.affiliation: 1 Département de Néphrologie et Transplantation d'organes, Centre de reference des maladies rénales rares, Hôpital Rangueil, CHU, Toulouse, France. 2 INSERM U1048 (I2MC, équipe 12), Hôpital Rangueil, Toulouse, France. 3 Service de Néphrologie, Cliniques Universitaires Saint-Luc, Louvain, Belgique. 4 Service de Néphrologie, Médecine interne, Hôpital des Enfants, CHU, Toulouse, France. 5 Service de Néphrologie-Transplantation, Hôpital Huriez, CHRU, Lille, France. 6 Service de Néphrologie-Transplantation, Hôpital Lapeyronie, CHU, Montpellier, France. 7 Service de Néphrologie-Transplantation Pédiatrique, CHU, Hôtel-Dieu, Nantes, France. 8 Service de Néphrologie-Transplantation, Hôpital Pellegrin, CHU, Bordeaux, France. 9 University of Zürich, Institute of Physiology, Zürich Centre for Integrative Human Physiology (ZIHP), Zürich, Switzerland. 10 Service de Diabétologie, Hôpital Rangueil, CHU Toulouse, France. 11 Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Faguer
authors.forename: Laure
authors.initials: L
authors.lastname: Esposito
authors.forename: Audrey
authors.initials: A
authors.lastname: Casemayou
authors.forename: Yves
authors.initials: Y
authors.lastname: Pirson
authors.forename: Stéphane
authors.initials: S
authors.lastname: Decramer
authors.forename: Claire
authors.initials: C
authors.lastname: Cartery
authors.forename: Marc
authors.initials: M
authors.lastname: Hazzan
authors.forename: Valérie
authors.initials: V
authors.lastname: Garrigue
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Roussey
authors.forename: Olivier
authors.initials: O
authors.lastname: Cointault
authors.forename: Thien
authors.initials: T
authors.lastname: Ho
authors.forename: Pierre
authors.initials: P
authors.lastname: Merville
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.forename: Joost-Peter
authors.initials: JP
authors.lastname: Schanstra
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
mesh_terms: D000293:Adolescent; D000328:Adult; D065095:Calcineurin Inhibitors / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003920:Diabetes Mellitus / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005602:France; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D016035:Pancreas Transplantation; D010641:Phenotype; D034622:RNA Interference; D012189:Retrospective Studies; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; C496495:HNF1B protein, human; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D051539:Hepatocyte Nuclear Factor 1-beta