尿β2-微球蛋白作为替诺福韦酯致慢性乙型肝炎患者近端肾小管功能损伤早期预测指标的临床价值
|
摘要
目的探讨替诺福韦酯(tenofovir disoproxil,TDF)导致慢性乙型肝炎(chronic hepatitis B,CHB)患者近端肾小管功能障碍(proximal tubular renal dysfunction,PRTD)的临床流行病学特征及尿β2-微球蛋白(β2 microglobulin,β2-MG)作为预测CHB患者TDF相关近端肾小管损伤标志物的临床价值。方法纳入2013年1月至2016年6月于首都医科大学附属北京地坛医院就诊的慢性乙型肝炎(chronic hepatitis B,CHB)患者62例为研究对象,其中32例接受阿德福韦酯(adefovir dipivoxil,ADV)联合恩替卡韦(entecavir,ETV)治疗,30例接受TDF治疗,疗程均为96周。出现PRTD即认为出现终点事件,患者需停止用药。比较两组患者PRTD的发生率以及PRTD患者和无PRTD患者尿β2-MG升高的发生率。结果 ADV+ETV组中12例(37.5%)出现PRTD,TDF组中3例(10.0%)出现PRTD,差异有统计学意义(χ~2=7.200,P=0.007)。PRTD患者中尿β2-MG升高的比例显著高于无PRTD患者(93.3%vs 6.4%;χ~2=43.198,P<0.001)。尿β2-MG预测TDF相关肾小管损伤的ROC曲线下面积为0.935。结论与ADV相比,TDF具有更高的肾脏安全性,尿β2-MG对慢性乙型肝炎患者TDF相关早期近端肾小管损伤具有较高的诊断价值。
Objective To investigate the clinical epidemiological characteristics of proximal renal tubular dysfunction(PRTD) of chronic hepatitis B(CHB) patients treated with tenofovir disoproxil(TDF) and the clinical value of urinary β2-microglobulin(β2-MG) as an early predictor of PRTD induced by TDF in patients with CHB. Methods A total of 62 patients with CHB were enrolled and observed in Beijing Ditan Hospital, Capital Medical University from January 2013 to June 2016. Among them, 32 cases accepted adefovir dipivoxil(ADV) combined entecavir(ETV) therapy and 30 cases accepted TDF treatment. The course of treatment was 96 weeks. PRTD was regarded as the occurrence of terminal events, once occured, the patients should stop taking drugs. The incidence of PRTD in both groups and the incidence of urinary β2-MG in patients with PRTD and patients without PRTD were compared. Results Total of 12 patients(37.5%) were diagnosed as PRTD in ADV + ETV group, and 3 patients(10.0%) in TDF group, the difference was statistically significant(χ~2 = 7.200, P = 0.007). The proportion of urinary β2-MG increased in CHB patients with PRTD was significantly higher than that in CHB patients without PRTD(93.3% vs 6.4%; χ~2 = 43.198, P < 0.001). The area under the ROC curve for urine β2-MG predicting TDF-associated PRTD was 0.935. Conclusion Compared with ADV, TDF has higher renal safety. Urinary β2-MG has a high diagnostic value for early proximal tubular injury associated with TDF in patients with chronic hepatitis B.
Objective To investigate the clinical epidemiological characteristics of proximal renal tubular dysfunction(PRTD) of chronic hepatitis B(CHB) patients treated with tenofovir disoproxil(TDF) and the clinical value of urinary β2-microglobulin(β2-MG) as an early predictor of PRTD induced by TDF in patients with CHB. Methods A total of 62 patients with CHB were enrolled and observed in Beijing Ditan Hospital, Capital Medical University from January 2013 to June 2016. Among them, 32 cases accepted adefovir dipivoxil(ADV) combined entecavir(ETV) therapy and 30 cases accepted TDF treatment. The course of treatment was 96 weeks. PRTD was regarded as the occurrence of terminal events, once occured, the patients should stop taking drugs. The incidence of PRTD in both groups and the incidence of urinary β2-MG in patients with PRTD and patients without PRTD were compared. Results Total of 12 patients(37.5%) were diagnosed as PRTD in ADV + ETV group, and 3 patients(10.0%) in TDF group, the difference was statistically significant(χ~2 = 7.200, P = 0.007). The proportion of urinary β2-MG increased in CHB patients with PRTD was significantly higher than that in CHB patients without PRTD(93.3% vs 6.4%; χ~2 = 43.198, P < 0.001). The area under the ROC curve for urine β2-MG predicting TDF-associated PRTD was 0.935. Conclusion Compared with ADV, TDF has higher renal safety. Urinary β2-MG has a high diagnostic value for early proximal tubular injury associated with TDF in patients with chronic hepatitis B.
引文
[1]Heathcote EJ,Marcellin P,Buti M,et al.Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B[J].Gastroenterology,2011,140(1):132-143.
[2]Kearney BP,Flaherty JF,Shah J.Tenofovir disoproxil fumarate:clinical pharmacology and pharmacokinetics[J].Clin Pharmacokinet,2004,43(9):595-612.
[3]Verhelst D,Monge M,Meynard JL,et al.Fanconi syndrome and renal failure induced by tenofovir a first case report[J].Am J Kidney Dis,2002,40(6):1331-1333.
[4]Schweitzer A,Horn J,Mikolajczyk RT,et al.Estimations of worldwide prevalence of chronic hepatitis B virus infection:Asystematic review of data published between 1965 and 2013[J].Lancet,2015,386(10003):1546-1555.
[5]Ott JJ,Stevens GA,Groeger J,et al.Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBsAg seroprevalence and endemicity[J].Vaccine,2012,30(12):2212-2219.
[6]Lu FM,Zhuang H.Management of hepatitis B in China[J].Chin Med J(Engl),2009,122(1):3-4.
[7]Terrault NA,Bzowej NH,Chang KM,et al.AASLD guidelines for treatment of chronic hepatitis B[J].Hepatology,2016,63(1):261-283.
[8]Lok AS,McMahon BJ,Brown RS,et al.Antiviral therapy for chronic hepatitis B viral infection in adults:Asystematic review and metaanalysis[J].Hepatology,2016,63(1):284-306.
[9]Menendez-Arias L,Alvarez B,Pacheco B.Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase:mechanism of action and resistance[J].Curr Opin Virol,2014,8:1-9.
[10]Imaoka T,Kusuhara H,Adachi M,et al.Functional involvement of mutidrug resistance-associated protein 4(MRP4/ABCC4)in the renal elimination of the antiviral drugs adefovir and tenofovir[J].Mol Pharmacol,2007,71(2):619-627.
[11]Rodríguez-Nóvoa S,Labarga P,Soriano V,et al.Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir:a pharmacogenetic study[J].Clin Infect Dis,2009,48(11):e108-e116.
[12]Chuang WL,Agarwal K,Hwang JS,et al.Continued improvement in renal laboratory parameters in CHB patients treated with tenofovir alfenamide(TAF)compared with tenofovir disoproxil fumarate(TDF)over 96 weeks[J].J Hepatol,2017,66:S695.
[13]Zaidan M,Lescure FX,Brochériou I,et al.Tubulointerstitial nephropathies in HIV-Infected patients over the past 15 years:a clinicopathological study[J].Clin J Am Soc Nephrol,2013,8(6):930-938.
[14]Fux CA,Simcock M,Wolbers M,et al.Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study[J].AntivirTher,2007,12(8):1165-1173.
[15]Cooper RD,Wiebe N,Smith N,et al.Systematic review and metaanalysis:renal safety of tenofovir disoproxil fumarate in HIV-infected patients[J].Clin Infect Dis,2010,5l(5):496-505.
[16]Woodward CL,Hall AM,Williams IG,et al.Tenofovir-associated renal and bone toxicity[J].HIV Med,2009,10(8):482-487.
[17]Horberg M,Tang B,Towner W,et al.Impact of tenofovir onrenal funetion in HIV-infected antiretroviral naive patients[J].Jaids,2010,53(1):62-69.
[18]Shimizu M,Furusyo N,Ikezaki H,et al.Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B[J].World J Gastroenterol,2015,21(7):2116-2123.
[19]Gara N,Collins MT,Collins MT,et al.Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B[J].Aliment Pharmacol Ther,2012,35(11):1317-1325.
[20]Mauss S,Berger F,Filmann N,et al.Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B[J].JHepatol,2011,55(6):1235-1240.
[21]European Association For The Study Of The Liver.EASL clinical practice guidelines:management of chronic hepatitis B virus infection[J].J Hepatol,2012,57(1):167-185.
[22]Fontana RJ.Side effects of long-term oral antiviral therapy for hepatitis B[J].Hepatology,2009,49(5 Suppl):S185-S195.
[23]Rodriguez-Nóvoa S,Alvarez E,Labarga P,et al.Renal toxicity associated with tenofovir use[J].Expert Opin Drug Saf,2010,9(4):545-559.
[24]Hall AM,Hendry BM,Nitsch D,et al.Tenofovir-associated kidney toxicity in HIV-infected patients:a review of the evidence[J].Am JKidney Dis,2011,57(5):773-780.
[25]Smeets PH,Van Aubel RA,Wouterse AC,et al.Contribution of multidrug resistance protein2(MRP2/ABCC2)to the renal excretion of p-aminohippurate(PAH)and identification of MRP4(ABCC4)as a novel PAH transporter[J].J Am Soc Nephrol,2004,15(11):2828-2835.
[26]Izzedine H,Hulot JS,Goyenvalle C,et al.Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy[J].J Infec Dis,2006,194(11):1481-1491.
[2]Kearney BP,Flaherty JF,Shah J.Tenofovir disoproxil fumarate:clinical pharmacology and pharmacokinetics[J].Clin Pharmacokinet,2004,43(9):595-612.
[3]Verhelst D,Monge M,Meynard JL,et al.Fanconi syndrome and renal failure induced by tenofovir a first case report[J].Am J Kidney Dis,2002,40(6):1331-1333.
[4]Schweitzer A,Horn J,Mikolajczyk RT,et al.Estimations of worldwide prevalence of chronic hepatitis B virus infection:Asystematic review of data published between 1965 and 2013[J].Lancet,2015,386(10003):1546-1555.
[5]Ott JJ,Stevens GA,Groeger J,et al.Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBsAg seroprevalence and endemicity[J].Vaccine,2012,30(12):2212-2219.
[6]Lu FM,Zhuang H.Management of hepatitis B in China[J].Chin Med J(Engl),2009,122(1):3-4.
[7]Terrault NA,Bzowej NH,Chang KM,et al.AASLD guidelines for treatment of chronic hepatitis B[J].Hepatology,2016,63(1):261-283.
[8]Lok AS,McMahon BJ,Brown RS,et al.Antiviral therapy for chronic hepatitis B viral infection in adults:Asystematic review and metaanalysis[J].Hepatology,2016,63(1):284-306.
[9]Menendez-Arias L,Alvarez B,Pacheco B.Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase:mechanism of action and resistance[J].Curr Opin Virol,2014,8:1-9.
[10]Imaoka T,Kusuhara H,Adachi M,et al.Functional involvement of mutidrug resistance-associated protein 4(MRP4/ABCC4)in the renal elimination of the antiviral drugs adefovir and tenofovir[J].Mol Pharmacol,2007,71(2):619-627.
[11]Rodríguez-Nóvoa S,Labarga P,Soriano V,et al.Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir:a pharmacogenetic study[J].Clin Infect Dis,2009,48(11):e108-e116.
[12]Chuang WL,Agarwal K,Hwang JS,et al.Continued improvement in renal laboratory parameters in CHB patients treated with tenofovir alfenamide(TAF)compared with tenofovir disoproxil fumarate(TDF)over 96 weeks[J].J Hepatol,2017,66:S695.
[13]Zaidan M,Lescure FX,Brochériou I,et al.Tubulointerstitial nephropathies in HIV-Infected patients over the past 15 years:a clinicopathological study[J].Clin J Am Soc Nephrol,2013,8(6):930-938.
[14]Fux CA,Simcock M,Wolbers M,et al.Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study[J].AntivirTher,2007,12(8):1165-1173.
[15]Cooper RD,Wiebe N,Smith N,et al.Systematic review and metaanalysis:renal safety of tenofovir disoproxil fumarate in HIV-infected patients[J].Clin Infect Dis,2010,5l(5):496-505.
[16]Woodward CL,Hall AM,Williams IG,et al.Tenofovir-associated renal and bone toxicity[J].HIV Med,2009,10(8):482-487.
[17]Horberg M,Tang B,Towner W,et al.Impact of tenofovir onrenal funetion in HIV-infected antiretroviral naive patients[J].Jaids,2010,53(1):62-69.
[18]Shimizu M,Furusyo N,Ikezaki H,et al.Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B[J].World J Gastroenterol,2015,21(7):2116-2123.
[19]Gara N,Collins MT,Collins MT,et al.Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B[J].Aliment Pharmacol Ther,2012,35(11):1317-1325.
[20]Mauss S,Berger F,Filmann N,et al.Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B[J].JHepatol,2011,55(6):1235-1240.
[21]European Association For The Study Of The Liver.EASL clinical practice guidelines:management of chronic hepatitis B virus infection[J].J Hepatol,2012,57(1):167-185.
[22]Fontana RJ.Side effects of long-term oral antiviral therapy for hepatitis B[J].Hepatology,2009,49(5 Suppl):S185-S195.
[23]Rodriguez-Nóvoa S,Alvarez E,Labarga P,et al.Renal toxicity associated with tenofovir use[J].Expert Opin Drug Saf,2010,9(4):545-559.
[24]Hall AM,Hendry BM,Nitsch D,et al.Tenofovir-associated kidney toxicity in HIV-infected patients:a review of the evidence[J].Am JKidney Dis,2011,57(5):773-780.
[25]Smeets PH,Van Aubel RA,Wouterse AC,et al.Contribution of multidrug resistance protein2(MRP2/ABCC2)to the renal excretion of p-aminohippurate(PAH)and identification of MRP4(ABCC4)as a novel PAH transporter[J].J Am Soc Nephrol,2004,15(11):2828-2835.
[26]Izzedine H,Hulot JS,Goyenvalle C,et al.Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy[J].J Infec Dis,2006,194(11):1481-1491.