Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion
Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion
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DOI：
10.1053/hupa.2001.25586
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发表时间：
2001-07-01
期刊：
影响因子：
3.3
通讯作者：
D'Agati, VD
中科院分区：
文献类型：
--
作者：
Tanji, N;Tanji, K;D'Agati, VD
本文探讨了抗逆转录病毒药物阿德福韦治疗中毒性急性肾小管坏死所致急性肾功能衰竭的发病机制。一名38岁的白人同性恋男子，基思。使用高效抗逆转录病毒疗法(HAART)，包括羟基脲、司他夫定、吲哚那韦、利托那韦和阿德福韦酯，保持了人类免疫缺陷病毒感染和没有机会性感染的历史。肾活检的组织学检查显示严重的急性肾小管变性改变，主要影响近端小管。超微结构检查，近端小管线粒体极度增大和变形，其棘突消失和定向障碍。线粒体酶的功能组织化学染色显示部分由线粒体DNA(MtDNA)编码的呼吸链酶细胞色素C氧化酶(COX)呈局灶性管状缺失，而完全由核DNA(NDNA)编码的呼吸链酶琥珀酸脱氢酶(琥珀酸脱氢酶)保留。COX亚基I(由线粒体DNA编码)的免疫反应在大多数肾小管上皮细胞中很弱或检测不到，而COX亚基IV和呼吸复合体III的铁硫亚基(均由nDNA编码)在所有肾小管上皮细胞中均保持良好的免疫反应。单肾小管聚合酶链式反应显示COX免疫缺陷肾小管线粒体DNA显著减少。我们得出结论，阿德福韦所致的肾毒性是通过抑制线粒体DNA复制而耗尽近端肾小管上皮细胞的线粒体DNA而实现的。这种新形式的肾毒性可以作为逆转录酶抑制剂引起的其他形式的肾毒性的原型。嗡嗡声，32：734-740。版权所有(C)2001，由W.B.Saunders公司提供。
This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man,kith. human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors. Hum PATHOL, 32:734-740. Copyright (C) 2001 by W.B. Saunders Company.