title: A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease.
abstract: CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP,δ-aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA. We tested the hypothesis thatPEPT2genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped forPEPT2At last follow-up, carriers of thePEPT2*1*1genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variantsPEPT2*1/*2andPEPT2*2/*2(mean±SD eGFR: 54.4±19.1, 66.6±23.8, and 78.1±19.9 ml/min per 1.73 m2, respectively). Change in eGFR (mean±SD) over the 10-year period was -11.0±3.3, -2.4±1.9, and 3.4±2.6 ml/min per 1.73 m2forPEPT2*1/*1,PEPT2*1*2, andPEPT*2*2*2carriers, respectively. At the end of follow-up, 68% ofPEPT2*1*1carriers had an eGFR<60 ml/min per 1.73 m2, compared with 37% ofPEPT2*1*2carriers and 15% ofPEPT2*2*2carriers. Multiple regression models including all confounders indicated that thePEPT2*1*1genotype independently associated with an eGFR<60 ml/min per 1.73 m2(odds ratio, 6.85; 95% confidence interval, 1.34 to 46.20) and an annual decrease in eGFR of >1 ml/min per 1.73 m2(odds ratio, 3.64; 95% confidence interval, 1.37 to 9.91). Thus, a gene variant is predictive of the severity of a chronic complication of AIP. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation.
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Tchernitchko
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Tavernier
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lamoril
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.|Université Paris Diderot, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.
authors.forename: Neila
authors.initials: N
authors.lastname: Talbi
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.|Université Versailles Saint Quentin, Versailles, France; and.
authors.forename: Said
authors.initials: S
authors.lastname: Lyoumi
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Robreau
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.|Université Paris Diderot, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France.|Université Paris Diderot, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France.|Université Paris Diderot, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1149, Center for Research on Inflammation (CRI), Site Bichat, Paris, France.|Université Paris Diderot, Paris, France.|Laboratory of Excellence, GR-Ex, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; nicolas.pallet@aphp.fr.|Université Paris Descartes, Paris, France.|Service de Néphrologie and.|Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
mesh_terms: D000208:Acute Disease; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011164:Porphyrias / Q000150:complications* / Q000235:genetics*; D011379:Prognosis; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D012720:Severity of Illness Index; D027981:Symporters / Q000235:genetics*
chemical_list: D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2
keywords: Acute Intermittent Porphyria; Delta-aminolevulinic acid; PEPT2; SLC15A2; chronic kidney disease