Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

Paul Carrier (1, 2) , Marilyne Debette-Gratien (1, 2) , Anais Labrunie (3, 4) , Sophie Alain (5) , Marianne Maynard (6) , Nathalie Ganne-Carrie (7) , Eric Nguyen-Khac (8) , Pauline Pinet (9) , Victor de Ledinghen (10) , Christophe Renou (11) , Philippe Mathurin (12) , Claire Vanlemmens (13) , Vincent Di Martino (13) , Anne Gervais (14) , Juliette Foucher (15) , Fouchard-Hubert Isabelle (10) , Julien Vergniol (16) , Isabelle Hourmand-Ollivier (17) , Daniel Cohen (18, 19) , Xavier Duval (20, 21) , Thierry Poynard (22) , Marc Bardou (23) , Armand Abergel (24) , Manh-Thong Dao (25) , Thierry Thevenot (26) , Jean-Baptiste Hiriart (27) , Valerie Canva (28) , Guillaume Lassailly (29) , Christine Aurieres (30) , Nathalie Boyer (31, 32, 33) , Dominique Thabut (34) , Pierre-Henri Bernard (35) , Matthieu Schnee (36) , Dominique Larrey (37, 38) , Bertrand Hanslik (39) , Severine Hommel (40) , Jeremie Jacques (1) , Veronique Loustaud-Ratti (41) , Anais Brayette (1) , Marie Essig (42, 43)

1 Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges]
2 Pôle Universitaire d’Addictologie en Limousin
3 NET - Neuroépidémiologie Tropicale
4 CEBIMER - Plate forme de bioinformatique et biostatistique
5 RESINFIT - Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques
6 Hôpital de la Croix-Rousse [CHU - HCL]
7 FunGeST - Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC]
8 GRAP - Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247
9 Service des Maladies infectieuses et tropicales [CHU Limoges]
10 CHU Angers - Centre Hospitalier Universitaire d'Angers
11 Hepatology
12 Physiopathologie des Maladies Inflammatoires de l'Intestin
13 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
14 Services de Maladies Infectieuses et Tropicales [CHU Bichat]
15 CHU Bordeaux [Bordeaux]
16 Service d'Hépato-gastro-entérologie et oncologie digestive (CHU de Bordeaux)
17 Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen]
18 PSE - Paris School of Economics
19 PJSE - Paris Jourdan Sciences Economiques
20 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
21 U738 / UMR_S738 - Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques
22 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
23 CIC-P803 - Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie
24 IP - Institut Pascal
25 UNICAEN - Université de Caen Normandie
26 Service d'Hépatologie [CHRU Besançon]
27 Hôpital Haut-Lévêque [CHU Bordeaux]
28 Hôpital Claude Huriez [Lille]
29 INFINITE (Ex-Liric) - Institute for Translational Research in Inflammation - U 1286
30 Service d’Hépatologie [Hôpital Beaujon]
31 UPCité - Université Paris Cité
32 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
33 Hôpital Beaujon [AP-HP]
34 Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière]
35 Service d'Hépato-Gastro-Entérologie
36 Service de gastroentérologie (CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon)
37 Hôpital Saint-Éloi [Montpellier]
38 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
39 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
40 Service d'Hépato-Gastroentérologie [CHU Rouen]
41 IPPRITT - Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation
42 U1018 (Équipe 5) - Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC)
43 Service Néphrologie/Dialyse [AP-HP Ambroise-Paré]

BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use. AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients. METHODS A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naive, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors. RESULTS Of the 196 patients analyzed, 138 (84 naive, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naive and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m(2) or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naive, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naive group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naive, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo. CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naive patients. SPT in the naive population suggests that HBV can induce renal tubular toxicity.

Mots clés: Hepatitis B virus; Proximal tubulopathy; Biomarkers; Renal insufficiency; Nucleoside analogues

Domaines: Sciences du Vivant [q-bio]

Paul Carrier, Marilyne Debette-Gratien, Anais Labrunie, Sophie Alain, Marianne Maynard, et al.. Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus. World journal of hepatology, 2020, 12 (12), pp.1326-1340. ⟨10.4254/wjh.v12.i12.1326⟩. ⟨hal-03590856⟩