Brayette Anaïs, Essig Marie, Carrier Paul, Debette-Gratien Marilyne, Labrunie Anaïs, Alain Sophie, Maynard Marianne, Ganne-Carrié Nathalie, Nguyen-Khac Eric, Pinet Pauline, De Ledinghen Victor, Renou Christophe, Mathurin Philippe, Vanlemmens Claire, Di Martino Vincent, Gervais Anne, Foucher Juliette, Isabelle Fouchard-Hubert, Vergniol Julien, Hourmand-Ollivier Isabelle, Cohen Daniel, Duval Xavier, Poynard Thierry, Bardou Marc, Abergel Armand, Dao Manh-Thong, Thévenot Thierry, Hiriart Jean-Baptiste, Canva Valérie, Lassailly Guillaume, Aurières Christine, Boyer Nathalie, Thabut Dominique, Bernard Pierre-Henri, Schnee Matthieu, Larrey Dominique, Hanslik Bertrand, Hommel Séverine, Jacques Jérémie, Loustaud-Ratti Véronique
U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France.
U1248 INSERM, Department of Nephrology and Transplantation, CHU Limoges, Limoges F-87000, France.
World J Hepatol. 2020 Dec 27;12(12):1326-1340. doi: 10.4254/wjh.v12.i12.1326.
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.
To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated untreated hepatitis B virus (HBV)-monoinfected patients.
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: Naïve, 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.
Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% 30.7%, 0.42 and 50.0% 30.7%, = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² 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 naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group the naïve group (hazard ratio: 2.283, = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.
The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
用于评估核苷酸类似物肾毒性的推荐监测工具，如估算肾小球滤过率（eGFR）和血磷水平，是近端肾小管病变的晚期标志物。有多种早期标志物可供使用，但在其应用方面尚未达成共识。
确定经治疗和未经治疗的乙型肝炎病毒（HBV）单感染患者中，根据早期生物标志物定义的亚临床近端肾小管病变（SPT）的24个月患病率。
对合并肾脏疾病较少的HBV单感染患者进行了一项前瞻性、非随机、多中心研究。患者被分为三组：初治组、开始恩替卡韦（ETV）治疗组或开始替诺福韦酯（TDF）治疗组。每季度收集SPT的早期标志物、eGFR和血磷水平的数据。SPT定义为磷酸盐最大肾小管重吸收/eGFR低于0.8 mmol/L和/或尿酸排泄分数高于10%。计算第24个月（M24）时SPT的患病率和累积发病率。定量数据采用方差分析或Kruskal-Wallis检验进行分析，而定性数据则采用卡方检验或Fisher精确检验进行分析。采用多变量分析来调整任何潜在的混杂因素。
在分析的196例患者中，138例（84例初治、28例开始ETV治疗、26例开始TDF治疗）在纳入时无SPT。在M24时，初治组与任何一个治疗组之间SPT的患病率无统计学差异（ETV组为21.1%对30.7%，P = 0.42；TDF组为50.0%对30.7%，P = 0.32）；没有患者的eGFR低于50 mL/min/1.73 m²或血磷水平低于(0.48 mmol/L)。在多变量分析中，调整后未发现解释变量。24个月内SPT的累积发病率（初治组、ETV组和TDF组分别为25.5%、13.3%和52.9%）在TDF组中倾向于高于初治组（风险比：2.283，P = 0.05）。M24时无SPT的生存率在初治组、ETV组和TDF组中分别为57.6%、68.8%和23.5%。仅在TDF组中评估的无SPT的中位生存时间为5.9个月。
与初治患者相比，接受TDF治疗的患者中SPT的患病率和发病率更高。初治人群中的SPT表明HBV可诱导肾小管毒性。
