本文選題：中性粒細胞明膠酶相關脂質運載蛋白 + 慢性乙型肝炎��； 參考：《第二軍醫(yī)大學》2017年碩士論文

【摘要】：目的:長期口服阿德福韋酯(ADV)治療慢性乙型病毒性肝炎最常見的不良反應是腎功能損傷,目前臨床上常用SCr、BUN、eGFR、血磷等作為ADV腎損傷的診斷指標,但這些傳統指標對診斷早期腎損傷敏感性和特異性較低。已有大量研究證明中性粒細胞明膠酶相關脂質運載蛋白(NGAL)對各種病因引起的急性或慢性腎損傷均有很好的診斷價值。本研究通過橫斷面研究檢測ADV單藥或聯用其它核苷(酸)類似物(NA)的慢性乙型病毒性肝炎(CHB)患者的血清及尿NGAL濃度水平,與SCr、eGFR、CysC、血磷等比較在ADV早期腎損傷的臨床診斷價值。同時通過動物實驗,研究NGAL在長期灌服ADV等核苷(酸)類似物大鼠腎臟損傷模型中的表達水平及部位。方法:本研究共有兩部分:第一部分,臨床橫斷面研究。選取2016年2月到2016年11月在長海醫(yī)院感染科門診長期口服ADV單藥或ADV聯合LAM、ADV聯合ETV的CHB患者124例。跟據患者的eGFR水平分為正常腎功能組(A組:eGFR≥90ml/min)91例,腎功能損傷組(B組:eGFR90ml/min)33例,選取同期在門診隨訪的55例HBV穩(wěn)定攜帶者,63例口服ETV患者作為對照組。整理患者門診檢查的eGFR、SCr、Cys C、血磷等腎臟傳統指標。通過酶聯免疫吸附試驗獲得各組CHB患者的血清和尿NGAL濃度。統計分析比較NGAL與其他傳統腎損傷標記物對診斷ADV引起的早期腎損傷的敏感性,Pearson相關分析進一步了解血清和尿NGAL與年齡、性別、SCr、eGFR,CysC、β2-MG、尿微量白蛋白、血磷之間的相關性。年齡分層下比較ADV腎功能損傷組NGAL濃度差異。第二部分,研究NGAL在ADV、TDF、ETV誘導的大鼠腎臟中的表達及部位。通過長期給予SD大鼠ADV、TDF、ETV,建立相應藥物誘導的腎損傷模型,分別于8周、12周、16周檢測并分析各組大鼠血清和尿NGAL的水平,通過HE染色了解各組大鼠腎臟的病理變化,免疫組化法檢測腎臟組織中NGAL表達程度及部位。采用SPSS 22.0軟件處理數據,P0.05代表差異有統計學意義。結果:1.血清NGAL雖然在ADV腎損傷組高于其它各組,但無統計學意義(P0.05)。ADV腎損傷組尿NGAL明顯高于ETV組和穩(wěn)定攜帶組,差異有統計學意義,但尿NGAL升高并沒有血清肌酐和胱抑素C明顯。2.相關性分析發(fā)現,血清和尿NGAL成正相關,兩者與年齡成正相關(P0.05),與性別、服藥時間、TB、eGFR、肌酐、胱抑素C、血鈣、血磷、β2微球蛋白無相關性,此外尿NGAL與尿微量白蛋白成正相關(r=0.435,P0.05)。根據年齡分層結果顯示,年齡越高,血清和尿NGAL越高,且50-59歲組、大于59歲組與小于50歲組比較有統計學差異(P0.01)。3.動物試驗中,血清和尿NGAL隨著用藥時間延長逐漸升高,在ADV組,16周血NGAL明顯高于12周,差異有統計學意義(P0.05),16周尿NGAL高于8周和12周,差異均有統計學意義;在TDF組中,16周血和尿NGAL明顯高于8周(P0.05);ETV組和對照組在8周、12周、16周均無統計學差異(P0.05)。各組在同一時間點分析發(fā)現,ADV組血清和尿NGAL水平在8周、16周明顯高于空白對照組和ETV組;TDF組血清和尿NGAL僅在16周與對照組比較有差異;ETV組血清和尿NGAL在8周、12周、16周與對照組均無明顯差異。HE染色發(fā)現,在第8周,ADV組腎小管上皮細胞出現腫脹,12周、16周腎小管上皮細胞腫脹加重,可見空泡變性,腎小管細胞刷狀緣脫落,部分管腔內可見蛋白管型。TDF組在16周腎小管上皮細胞有輕度顆粒變性,未見管型;所有各組腎臟間質和腎小球無明顯變化。免疫組化顯示NGAL主要表達于腎小管上皮細胞,腎間質和腎小球有少量表達。ADV組在12周、16周NGAL表達高于對照組,TDF組在16周NGAL免疫組化結果與對照組有統計學差異,且表達強度與病理損傷時間有一定的相關性,ETV組和與對照組無明顯差異(P0.05)。結論:1.ADV腎損傷組患者尿NGAL明顯高于對照組,但尿NGAL診斷ADV早期腎損傷敏感性沒有肌酐、胱抑素C高,血清NGAL對ADV早期腎損傷無診斷價值。2.血清NGAL與年齡成正相關,尿NGAL與年齡、尿微量白蛋白成正相關。NGAL對ADV引起的高齡CHB患者腎損傷有更好的診斷價值。3.在大鼠實驗組,隨著ADV、TDF用藥時間的增加,血清和尿NGAL水平明顯升高,尿NGAL比血清NGAL升高更明顯。腎組織中NGAL主要表達于腎小管上皮細胞,在ADV組表達最強,且表達程度與病理損傷時間有一定的相關性。
[Abstract]:Objective: the most common adverse reaction of long-term oral adfovir (ADV) in the treatment of chronic viral hepatitis is renal impairment. Currently, SCr, BUN, eGFR, and blood phosphorus are commonly used as diagnostic indicators of ADV renal injury, but these traditional indexes are less sensitive and specific for the diagnosis of early renal injury. Cell gelatinase related lipid carrier protein (NGAL) has a good diagnostic value for acute or chronic renal injury caused by various causes. This study examined serum and urinary NGAL levels in patients with chronic hepatitis B (CHB) with ADV single or other nucleoside analogues (NA), and SCr, eGFR, CysC, and blood by cross-sectional study. The clinical diagnostic value of phosphorus and so on in the early renal injury of ADV. At the same time, the expression level and location of NGAL in rat kidney damage model of ADV and other nucleoside (acid) analogues were studied by animal experiments. Methods: This study had two parts: the first part, clinical cross-sectional study, selected from February 2016 to November 2016 in Changhai Hospital. In the outpatient department of infection, 124 cases of CHB with LAM and ADV combined with ETV were taken for a long time. According to the eGFR level of the patients, 91 cases were divided into normal renal function group (A group: eGFR > 90ml/min), 33 cases of renal function injury group (B group: eGFR90ml/min), 55 cases of stable carriers in the same period, and 63 cases of oral administration as the control group. EGFR, SCr, Cys C, blood phosphorus and other renal traditional indicators were examined by an outpatient clinic. The serum and urinary NGAL concentrations of CHB patients in each group were obtained by enzyme linked immunosorbent assay. The sensitivity of NGAL and other traditional renal damage markers to the diagnosis of early renal injury caused by ADV was compared and compared. The Pearson correlation analysis was used to further understand the serum and urinary NGAL. The correlation between age, sex, SCr, eGFR, CysC, beta 2-MG, urine microalbuminuria, and blood phosphorus. The difference of NGAL concentration in ADV renal function injury group was compared under age stratification. The second part was to study the expression and location of NGAL in ADV, TDF, ETV induced rat kidneys. The levels of serum and urine NGAL were detected and analyzed in 8 weeks, 12 weeks and 16 weeks respectively. The pathological changes of kidney in each group were detected by HE staining. The degree and location of NGAL expression in kidney tissues were detected by immunohistochemical method. The data of SPSS 22 were used to deal with the data, P0.05 was statistically significant. The result: 1. serum NGAL was in ADV kidney. The injury group was higher than the other groups, but there was no statistical significance (P0.05) in the.ADV kidney injury group, the urine NGAL was significantly higher than that of the ETV group and the stable carrying group. The difference was statistically significant, but the urine NGAL increased without serum creatinine and cystatin C.2. correlation analysis. The serum and urine NGAL were positively correlated, both were positively correlated with age (P0.05), and sex, and uniform. TB, eGFR, creatinine, creatinine, Cystatin C, blood calcium, blood phosphorus, and beta 2 microglobulin were not related, and urine NGAL was positively correlated with urine microalbumin (r=0.435, P0.05). According to age stratification, the higher the age, the higher the serum and urinary NGAL, and the 50-59 year old group, larger than the 59 year old group and the group less than 50 years of age (P0.01).3. animal test In the group ADV, the serum and urinary NGAL increased gradually with the time of drug use, and the blood NGAL in the 16 week was significantly higher than that in the 12 week. The difference was statistically significant (P0.05). The 16 week urine NGAL was higher than 8 weeks and 12 weeks. In group TDF, the 16 weeks of blood and urine NGAL were significantly higher than 8 weeks (P0.05), and there was no statistical difference between the ETV group and the control group at 8, 12, and 16 weeks. Difference (P0.05). At the same time point analysis, the serum and urinary NGAL levels in group ADV were 8 weeks, 16 Zhou Mingxian was higher than that in the blank control group and ETV group. The serum and urine NGAL in TDF group were only compared with the control group. The serum and urinary NGAL in the ETV group were found to have no significant difference between the control group and the control group at 8 weeks, 12 weeks and the 16 weeks, and in eighth weeks, the ADV group has small kidneys. The tubular epithelial cells were swelling, 12 weeks, 16 weeks of renal tubular epithelial cell swelling increased, visible vacuolation, renal tubular cells brush edge shedding, part of the tubule.TDF group in the 16 weeks in the renal tubular epithelial cells in 16 weeks of mild granular degeneration, no tube type, all groups of renal interstitium and glomeruli have no obvious changes. Immunohistochemistry showed NG AL mainly expressed in renal tubular epithelial cells, renal interstitium and glomeruli had a small amount of expression of.ADV group in 12 weeks, 16 weeks NGAL expression higher than the control group, TDF group in 16 weeks of NGAL immunization results and the control group had statistical difference, and the expression intensity and pathological injury time has certain correlation, ETV group and the control group have no significant difference (P0.05). Conclusion: 1 The urine NGAL of.ADV renal injury group was significantly higher than that of the control group, but the urine NGAL diagnosis of early renal injury was not creatinine, Cystatin C was high, serum NGAL had no diagnostic value for early renal injury,.2. serum NGAL was positively correlated with age, and urine NGAL was positively related to age and urine microalbuminuria. The good diagnostic value.3. was in the experimental group of rats. With the increase of ADV and TDF, the level of serum and urine NGAL increased obviously, and the urine NGAL was more obvious than the serum NGAL. The expression of NGAL in renal tissue was mainly expressed in the renal tubular epithelial cells, and the expression was strongest in the ADV group, and the expression level was related to the time of the disease injury.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R512.62;R692

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