title: High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria.
abstract: Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.
authors.affiliation: 1] INSERM U1147, Centre Universitaire des Saints Pères, Paris, France [2] Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [3] Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [4] Université Paris Descartes, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
authors.affiliation: 1] INSERM U1147, Centre Universitaire des Saints Pères, Paris, France [2] Université Paris Descartes, Paris, France.
authors.forename: Iadh
authors.initials: I
authors.lastname: Mami
authors.affiliation: 1] Centre Francais des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France [2] INSERM U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France [3] Université Paris Diderot, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: 1] INSERM U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France [2] Université Paris Diderot, Paris, France.
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.affiliation: Service d'Anatomopathologie, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: François
authors.affiliation: 1] Université Paris Descartes, Paris, France [2] Service d'Anatomopathologie, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.affiliation: Service d'Anatomopathologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Nochy
authors.affiliation: 1] Centre Francais des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France [2] INSERM U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France [3] Université Paris Diderot, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: 1] Centre Francais des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France [2] INSERM U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France [3] Université Paris Diderot, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.affiliation: 1] INSERM U702, Paris, France [2] Université Pierre et Marie Curie, Paris, France.
authors.forename: Yichum
authors.initials: Y
authors.lastname: Xu-Dubois
authors.affiliation: 1] Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Paris Descartes, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.affiliation: 1] Centre Francais des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France [2] INSERM U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France [3] Université Paris Diderot, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: 1] Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Paris Descartes, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
mesh_terms: D000368:Aged; D000622:Aminolevulinic Acid / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D004848:Epithelium / Q000473:pathology; D005260:Female; D005355:Fibrosis; D005602:France / Q000453:epidemiology; D005919:Glomerular Filtration Rate; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D011163:Hydroxymethylbilane Synthase; D006973:Hypertension / Q000453:epidemiology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000150:complications*; D010641:Phenotype; D011162:Porphobilinogen / Q000494:pharmacology; D017118:Porphyria, Acute Intermittent / Q000150:complications* / Q000453:epidemiology; D015995:Prevalence; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology* / Q000209:etiology* / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D011163:Hydroxymethylbilane Synthase
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