核苷（酸）类似物对慢性乙型肝炎患者肾功能的影响

Effect of nucleoside/nucleotide analogues on kidney function in patient with chronic hepatitis B

用于治疗慢性乙型肝炎（CHB）的核苷（酸） 类似物（NAs）在国内已上市者包括阿德福韦酯（ADV）、替诺福韦酯（TDF）、拉米夫定（LAM）、替比夫定（LDT）和恩替卡韦（ETV）。ADV和TDF均有肾毒性，LAM和ETV对肾功能影响较小，LDT具有一定的改善肾功能作用。NAs致肾损伤的诊断标准为血清肌酐（Scr）连续2次较基线升高＞44.2 μmol/L和/或血磷水平＜0.5 mmol/L。ADV致肾损伤的发生率高于TDF。ADV和TDF致肾损伤的临床表现为范可尼综合征，患者出现局部或全身骨痛、骨质疏松、肌无力，严重时可出现活动受限、骨软化，实验室检查显示Scr升高、血磷降低、血尿酸降低等。ADV和TDF肾毒性机制与其致肾小管上皮细胞线粒体损伤、肾小管相关转运蛋白改变、药物在近曲小管内聚集有关。NAs的肾毒性与剂量、患者年龄、体重、估算肾小球率过滤 （eGFR） 基线水平、基础疾病、遗传因素、饮食和药物等因素有关。长期服用NAs特别是ADV或TDF者应定期监测Scr、血磷、eGFR、血尿酸和尿微量蛋白、尿糖等。出现ADV或TDF相关肾损伤时应及时停药，改用LDT或ETV，并补充磷制剂、活性维生素D和钙剂。

Nucleoside/nucleotide analogues （NAs） which used to treat chronic hepatitis B and had been in the domestic market include adefovir dipivoxil （ADV）, tenofovir （TDF）, lamivudine （ LAM）, telbivudine （LDT） and entecavir （ETV）. ADV and TDF have nephrotoxicity , LAM and ETV have a lesser effects on kidney function , and LDT has certain effect of improving kidney function. The diagnostic criteria of kidney injury due to NAs are serum creatinine （Scr） level higher than that of the baseline value （〉44.2 μmol/L） or serum phosphorus level lower than that of the baseline value （〈0.5 mmol/L） on two successive detections. The incidence rate of kidney injury due to ADV was higher than that due to TDF. The clinical manifestation of kidney injury due to ADV and TDF was Fanconi syndrome. The patient develops local or systemic osteodynia, osteoporosis, and amyasthenia, even limitation of activity and halisteresis in serious cases. The laboratory tests show increase in Scr, decrease in serum phosphorus and uric acid. The mechanisms of nephrotoxicity of ADV and TDF are related to injury of renal tubular epithelial cell mitochondria, change of renal tubular transport protein, and accumulation of drugs in proximal convoluted tubule. The nephrotoxicity of NAs are related to dosage, patients′ age, body weight, baseline level of estimated glomerular filtration rate （eGFR）, primary disease, genetic factor, diet and drug. The patient who takes ADV or TDF for long term should monitor SCr, serum phosphorus, eGFR, uric acid, microalbuminuria,and glucose in urine regularly. ADV or TDF should be stopped timely in the case of appearance of symptom of kidney injury. The medication should be changed to LDT or ETV. Phosphorus compounds, vitamin D and calcium should be given.