Côté Hélène C F, Magil Alex B, Harris Marianne, Scarth Brian J, Gadawski Izabelle, Wang Nancy, Yu Eugenia, Yip Benita, Zalunardo Nadia, Werb Ron, Hogg Robert, Harrigan P Richard, Montaner Julio S
British Columbia Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver, BC, Canada.
Antivir Ther. 2006;11(1):79-86.
Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddl), their concurrent use was also investigated.
Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV-,n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddl, 10 of those once at unadjusted ddl dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests.
Kidney mtDNA levels were different among the three groups (P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0-12.1]) than in HIV- ones (14.3 [6.0-16.5], P=0.014), but not lower than HIV+/TDF- controls (6.4 [2.8-11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddl- and TDF+/ddl+ (P=0.005), with concurrent TDF/ddl use associated with lower mtDNA (2.1 [1.9-5.5], n=12) than TDF+/ddl- (13.8 [7.5-16.4], n=9, P=0.003). No TDF-/ddl+ biopsies were available. In regression analyses, only HIV infection (P=0.03), and TDF/ddl use (P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together (P<0.001) but not more so in TDF+/ddl+ biopsies than TDF+/ddl- ones (P=0.67).
Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddl therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddl may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddl when used in conjunction with TDF.
替诺福韦（TDF）暴露与肾功能障碍有关。研究了线粒体肾毒性作为潜在机制。鉴于TDF与去羟肌苷（ddI）之间的相互作用，还对它们的联合使用进行了研究。
回顾性测量相对肾活检中线粒体DNA（mtDNA）与核DNA的比率。将活检前6个月内接受TDF的HIV阳性个体（HIV+/TDF+，n=21）与从未接受过TDF的HIV阳性个体（HIV+/TDF-，n=10）以及HIV未感染对照（HIV-，n=22）进行比较。12名HIV+/TDF+个体同时接受ddI，其中10名接受未调整剂量的ddI。还通过电子显微镜检查肾小管线粒体形态。对经对数转换的mtDNA/nDNA进行统计分析，使用非参数检验。
三组之间的肾脏mtDNA水平不同（P=0.046）。HIV+/TDF+受试者的mtDNA比率（7.5[2.0-12.1]）低于HIV-受试者（14.3[6.0-16.5]，P=0.014），但不低于HIV+/TDF-对照（6.4[2.8-11.9]，P=0.82）。在HIV阳性受试者中，TDF-、TDF+/ddI-和TDF+/ddI+之间存在差异（P=0.005），同时使用TDF/ddI与较低的mtDNA（2.1[1.9-5.5]，n=12）相关，低于TDF+/ddI-（13.8[7.5-16.4]，n=9，P=0.003）。没有TDF-/ddI+活检样本。在回归分析中，只有HIV感染（P=0.03）和TDF/ddI的使用（P=0.003）与较低的mtDNA相关。在超微结构水平上，HIV+/TDF+活检中异常肾小管线粒体比HIV+/TDF-和HIV-活检的总和更普遍（P<0.001），但TDF+/ddI+活检中并不比TDF+/ddI-活检更普遍（P=0.67）。
该人群的肾功能障碍可能通过涉及多种药物和/或发病机制的线粒体肾毒性介导。肾脏mtDNA耗竭与HIV感染和同时进行的TDF/ddI治疗有关，但与单独使用TDF无关，而在使用TDF时可见肾脏超微结构线粒体异常。TDF和ddI之间的相互作用可能与两种药物均在肾脏清除有关。鉴于目前关于ddI与TDF联合使用时减少剂量的建议，需要评估我们研究结果的临床相关性。
