表现为范可尼综合征的阿德福韦酯相关慢性肾脏病15例分析

摘要

目的：对15例长期服用阿德福韦酯（ADV）引起的慢性肾脏病合并范可尼综合征进行分析，并对早期发现ADV 的肾毒性和避免引发范可尼综合征提出监测和防治措施。方法研究对象为2011年4月至2013年9月在解放军第八五医院南京军区上海肝病研究中心因长期服用 ADV 而确诊为范可尼综合征的15例患者，服药剂量均为10 mg/d，平均服药时间4．72年，平均服药至症状出现时间为3．22年。结果患者临床表现为进行性全身多处骨及关节疼痛，4例伴夜尿增多。所有患者血磷均有不同程度的下降；12例存在低尿酸血症，12例肾小球滤过率降低，9例血清碱性磷酸酶增高；4例患者进行了血半胱氨酸蛋白酶抑制剂 C（Cys-C）检测，3例增高；7例患者出现尿蛋白阳性，8例尿糖阳性；11例患者双能 X 线吸收测定法检测骨密度提示骨质疏松。转归：确诊后均停用 ADV，改用恩替卡韦0．5 mg/d 继续抗病毒治疗。所有患者骨痛均在2～8个月后明显缓解；5例停药后2～12个月血磷恢复正常；12例血尿酸降低的患者中有6例在1～11个月恢复正常；9例碱性磷酸酶增高者有2例分别于1、12个月恢复正常，其余较停药前明显下降；7例尿蛋白阳性患者中2例分别在停药后4、19个月蛋白尿消失；8例尿糖阳性的患者有2例分别于停药后4、7个月转阴。结论与以往的文献报道不同，ADV 除可引起程度不同的低磷血症、低尿酸血症等近端肾小管联合功能缺陷所致的范可尼综合征外，尚可引起肾小球损伤。对 ADV 应用超过1年的患者，要定期监测血磷、肌酐、尿酸、Cys-C 及 GFR。应用 ADV 治疗者应避免同时应用其他具有肾毒性的药物，一旦出现肾损伤，要及时更换为其他抗病毒药物或者根据 GFR 水平延长用药间隔时间。%Objective To analyze 15 cases of Fanconi syndrome caused by long-term treatment of adefovir dipivoxil (ADV),to early diagnose ADV related chronic kidney damage (CKD),and to monitor or find control measurement of Fanconi syndrome.Methods An analysis of 15 patients diagnosed as Fanconi syndrome by our department from April 2011 to September 2013 was performed,including 5 cases with chronic hepatitis B,1 case with compensated HBV related cirrhosis and 9 cases with decompensated HBV related cirrhosis.All of them took the dosage of ADV 10 mg/d.Average duration of treatment in patients was 4.72 years,while average duration from taking the dosage to the syndrome was 3.22 years.Results Clinical manifestation of the patients was progressive systemic multiple bone and joint pain,4 of them showed increased urination frequency and impossible to walk.Serum phosphorus level of all the patients was decreased with varying degrees.Among these patients,12 cases had hyperuricemia,12 cases had reduced glomerular filtration rate (GFR), 9 cases had increased alkaline phosphatase (AKP),blood cysteine protease inhibitors C (Cys-C)was detected in 4 patients, of which 3 cases had increased,7 cases had positive urine protein,8 cases had positive urine sugar,11 patients had as osteoporosis after being measured by dual-energy X-ray absorptiometry.Once diagnosed,the antiviral treatment was switched to entecavir 0.5 mg/d after withdrawal of ADV.All the patients suffering from bone pain had a significantly relief in 2-8 months,of which 5 cases had blood phosphorus recovery to normal in 2-12 months after withdrawal of ADV,6 cases had blood uric acid recovery to normal in 1-11 months,2 cases had AKP recovery to normal in 1 and 12 months and other cases had a remarkable decrease,2 cases had urine protein disappeared in 4 and 19 months,2 cases had negative urine sugar in 4 and 7 months.Conclusions ADV may lead to glomerular damage,and Fanconi syndrome with defection of proximal renal tubule including low phosphorus,low uricemia.Blood phosphorus,creatinine,uric acid,Cys-C and GFR should be monitored in patients treated with ADV more than 1 year .Those who treated with ADV should avoid combining with renal toxic drugs.Other antiviral drugs should be switched to when CKD is diagnosed according to the level of GFR.