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  本文關(guān)鍵詞： 腎病綜合征 環(huán)孢菌素 血藥濃度 足細胞 鈣調(diào)磷酸酶　出處：《北京協(xié)和醫(yī)學院》2014年碩士論文　論文類型：學位論文

【摘要】：研究背景 腎病綜合征是由多種病因引起的,以大量蛋白尿(3.58/d)、低白蛋白血癥(30g/L)、高脂血癥和水腫為特點的一組臨床綜合征。鈣調(diào)磷酸酶抑制劑環(huán)孢菌素治療腎病綜合征已有不短的歷史,但因為其潛在的毒副作用,常需監(jiān)測血藥濃度。研究證實腎移植病人,服藥2小時后的血藥濃度(C2)可較好反映環(huán)孢菌素暴露程度,但如何選擇腎病綜合征患者血藥濃度監(jiān)測點的研究較少,鮮有國產(chǎn)環(huán)孢菌素治療腎病綜合征藥代動力學前瞻性研究,血藥濃度與療效及腎毒性關(guān)系也存有爭論。近年來觀察到部分原發(fā)腎病綜合征(膜性腎病和局灶性節(jié)段性腎小球硬化)足細胞鈣調(diào)磷酸酶表達上調(diào),可能通過增加腎小球濾過屏障的通透性,導致蛋白尿。但是足細胞鈣調(diào)磷酸酶表達差異是否與蛋白尿的量相關(guān),與鈣調(diào)磷酸酶抑制劑療效的關(guān)系尚不清楚。 研究目的 1、前瞻性觀察國產(chǎn)環(huán)孢菌素治療腎病綜合征患者藥代動力學特點,確定最佳血藥濃度監(jiān)測點,進而分析血藥濃度與臨床療效及腎毒性的關(guān)系； 2、觀察原發(fā)性膜性腎病和局灶性節(jié)段性腎小球硬化患者足細胞鈣調(diào)磷酸酶表達差異與蛋白尿及臨床療效的關(guān)系。 研究方法 第一部分為前瞻性研究,自2009年10月至2012年2月在北京協(xié)和醫(yī)院接受國產(chǎn)環(huán)孢菌素田可治療的腎病綜合征患者28例,收集其臨床、病理及資料,前瞻性監(jiān)測服藥前,空腹服藥后1、2、3和4小時血藥濃度(全血高效液相法)。分析不同監(jiān)測點環(huán)孢菌素血藥濃度與0-4小時藥時曲線下面積(the area under the concentration-time curve up to4h post-dose, AUCO-4)的相關(guān)性,確定最佳監(jiān)測點。隨診6月,監(jiān)測第1、2、3、6個月服藥前、空腹服藥后1小時和2小時的血藥濃度,觀察血藥濃度與療效及腎損害的相關(guān)性。第二部分為回顧性病例對照研究,自2009年10月至2013年12月北京協(xié)和醫(yī)院腎內(nèi)科住院病人中選出臨床病理資料完整、且有足夠腎活檢標本的MN(20例)及FSGS(10例)；收集其臨床、病理及隨訪資料。常規(guī)行病理分析,行鈣調(diào)磷酸酶和WT1(足細胞特異性標記)免疫組化染色,Synaptopodin (足細胞骨架蛋白分子)免疫熒光染色,分析足細胞鈣調(diào)磷酸酶表達與足細胞損害程度及療效的相關(guān)性。連續(xù)變量以均值±標準差的形式表示,計數(shù)資料以構(gòu)成比表示,采用SPSS19.0軟件(IBM, USA)。正態(tài)分布計量數(shù)據(jù)比較采用t檢驗,計數(shù)數(shù)據(jù)兩組比較采用卡方檢驗。計量、計數(shù)資料相關(guān)分析分別采用Pearson相關(guān)和Spearman相關(guān)分析。 研究結(jié)果 1、腎病綜合征患者環(huán)孢菌素(田可)AUC0-4與各時間點血藥濃度的相關(guān)性 選擇時間點越多,與AUC0-4的相關(guān)性越好,選3個時間點監(jiān)測血藥濃度時,C1C2C3與AUC0-4相關(guān)性最好(r=0.992,P0.05)；選2個時間點監(jiān)測血藥濃度,C1C3與AUC0-4相關(guān)性最好(r=0.952,P0.05),ClC2與AUC0-4相關(guān)性次之(r=0.913,P0.05)；選1個時間點測量血藥濃度,C2與AUC0-4相關(guān)性最好(r=0.832,P0.05)。目前臨床上常用測定環(huán)孢菌素C0、C2,C0C2與AUC0-4的相關(guān)性(r=0.842,P0.05)略優(yōu)于C2單點監(jiān)測(r=0.832,P0.05)。 2、腎病綜合征患者環(huán)孢菌素血藥濃度與臨床療效無關(guān),與腎毒性相關(guān) 隨訪3個月,完全緩解(8例)、部分緩解(13例)及未緩解(7例)病人的C0(123.77±58.52ng/ml比87.55±37.59ng/ml比152.47±91.3ng/ml)、C1(553.7±414.4ng/ml比420.44±228.05ng/ml比603.9±478.35ng/ml)和C2(680.8±69.56ng/ml比530.92±352.9ng/ml比575.75±377.9ng/ml)之間均無明顯統(tǒng)計學差異。但是發(fā)生腎損害(血肌酐升高超過30%)患者C0、C1血藥濃度明顯高于無腎損害患者(183.86±82.76ng/ml比103.09±38.73ng/ml,P0.05；892.97±367.48ng/ml比479.35±287.9ng/ml,P0.05),而兩組病人的C2(556.85±278.24ng/ml比536.58±247.1ng/ml)水平無統(tǒng)計學差異。 3、原發(fā)性MN和原發(fā)性FSGS患者足細胞鈣調(diào)磷酸酶表達與療效相關(guān) 隨訪6個月,3例足細胞鈣調(diào)磷酸酶無表達患者均對環(huán)孢菌素治療無反應。治療3月有效病人(n=22)足細胞鈣調(diào)磷酸酶表達水平明顯高于8例無效病人(11.26±4.18%比6.92±4.09%,P0.05)；治療6個月,24例有效病人足細胞鈣調(diào)磷酸酶表達水平明顯高于6例無效病人(10.96±3.69%vs3.93±2.38%,P0.05)。本研究中沒有觀察到足細胞鈣調(diào)磷酸酶表達與蛋白尿的關(guān)系,但觀察到存在鈣調(diào)磷酸酶表達的腎小球伴有synaptopodin線性缺失,其中FSGS患者足細胞損傷重,WTl表達明顯低于輕微病變組。 研究結(jié)論 本研究條件下 1、國產(chǎn)環(huán)孢菌素(田可)治療腎病綜合征患者,監(jiān)測服藥后不同時間點血藥濃度中,C1C2C3,C1C3和C2分別為最佳多點和單一血藥濃度時間測量點,可以較準確反映藥物暴露程度； 2、在一定血藥濃度范圍內(nèi),臨床療效與環(huán)孢菌素血藥濃度無關(guān),但C0、C1點血藥濃度與腎毒性相關(guān)； 3、環(huán)孢菌素治療有效原發(fā)性MN和FSGS患者足細胞鈣調(diào)磷酸酶表達明顯高于治療無效患者,沒有觀察到鈣調(diào)磷酸酶表達與蛋白尿程度的關(guān)系。
[Abstract]:Research background
Nephrotic syndrome is caused by a variety of causes, with massive proteinuria (3.58/d), serum albumin (30g/L), hyperlipidemia and edema characterized by a clinical syndrome. The treatment of nephrotic syndrome has not short phosphatase inhibitor cyclosporin a calcium history, but because of its potential toxicity the role, often need to monitoring the blood concentration. The study confirmed that the renal transplant patients, serum concentration of medication after 2 hours (C2) can reflect the cyclosporine exposure, but how to choose the nephrotic syndrome in patients with blood concentration monitoring points less, few domestic cyclosporine treatment nephrotic syndrome prospectively the power generation also has preschool medicine syndrome, blood drug concentration and efficacy and renal toxicity. In recent years, the debate over observed part of primary nephrotic syndrome (membranous nephropathy and focal segmental glomerulosclerosis) podocyte calcineurin expression may be associated with the kidney The permeability of glomerular filtration barrier leads to proteinuria. However, whether the difference in expression of calcineurin in podocytes is related to the amount of proteinuria and the relationship between calcineurin inhibitors and the efficacy of calcineurin inhibitors is not clear.
research objective
1, we prospectively observed the pharmacokinetic characteristics of domestic cyclosporin in the treatment of nephrotic syndrome, determined the best blood concentration monitoring points, and further analyzed the relationship between plasma concentration and clinical efficacy and nephrotoxicity.
2, to observe the relationship between the difference in the expression of calcineurin in the podocytes of patients with primary membranous nephropathy and focal segmental glomerulosclerosis, and the relationship between proteinuria and clinical efficacy.
research method
The first part is a prospective study from October 2009 to February 2012 to accept domestic cyclosporin A in Peking Union Medical College Hospital in Tian can treat the patients with nephrotic syndrome in 28 cases, the clinical and pathological data, and prospective monitoring before taking medication after 4 hours of fasting and 1,2,3 blood drug concentration (whole blood high performance liquid chromatography) analysis. Different monitoring points of cyclosporine blood concentration and 0-4 hours in the area under the concentration time curve (the area under the concentration-time curve up to4h post-dose, AUCO-4) correlation, determine the optimum monitoring point. The follow-up monitoring in June, the first 1,2,3,6 months before medication, fasting medication after 1 hours and 2 hours of blood concentration. To study the correlation between serum drug concentration and efficacy of renal damage. The second part is a retrospective case-control study, patients were selected from the clinical and pathological data were complete in October 2009 to December 2013 in Peking Union Medical College Hospital Department of Nephrology, and Adequate renal biopsy specimens of MN (n = 20) and FSGS (10 cases); the clinical, pathological and follow-up data. Routine pathological analysis, for calcineurin and WT1 (podocyte specific marker) immunohistochemical staining, Synaptopodin (podocyte cytoskeleton protein) by immunofluorescence staining, the correlation analysis of foot cell calcineurin expression and podocyte damage and the effect of continuous variables. Expressed as mean standard deviation form, count data to the constituent ratio, using SPSS19.0 software (IBM, USA). Normal distribution of measurement data were compared using t test, count data of two groups were compared by chi square test. The measurement of Pearson. Correlation and Spearman correlation analysis were used to analysis of count data.
Research results
1, the correlation between cyclosporin (Tian Ke) AUC0-4 and blood concentration at various time points in patients with nephrotic syndrome
Select the time more and better correlation between AUC0-4, 3 time monitoring of blood drug concentration, the best correlation between C1C2C3 and AUC0-4 (r=0.992, P0.05); the 2 time points of monitoring the blood concentration, the best correlation between C1C3 and AUC0-4 (r=0.952, P0.05), ClC2 and AUC0-4 correlation times (r=0.913, P0.05); selected 1 time points to measure the blood concentration, the best correlation between C2 and AUC0-4 (r=0.832, P0.05). The common clinical determination of cyclosporin C0, C2, C0C2 and AUC0-4 correlation (r=0.842, P0.05) C2 is better than that of single point monitoring (r=0.832, P0.05).
2, cyclosporin blood concentration in patients with nephrotic syndrome is not related to clinical efficacy and is associated with renal toxicity.
After 3 months of follow-up, complete remission (8 cases), partial remission (13 cases) and non remission (7 cases) of patients with C0 (123.77 + 58.52ng/ml 87.55 + 37.59ng/ml 152.47 + 91.3ng/ml), C1 (553.7 + 414.4ng/ml 420.44 + 228.05ng/ml 603.9 + 478.35ng/ml) and C2 (680.8 + 69.56ng/ ml 530.92 + 352.9ng/ml 575.75 + 377.9ng/ml) were no significant difference. But the incidence of kidney damage (serum creatinine increased more than 30%) of patients with C0, patients with the blood concentration of C1 was significantly higher than those without renal damage (183.86 + 82.76ng/ml 103.09 + 38.73ng/ml, 892.97 + P0.05; 367.48ng/ml 479.35 + 287.9ng/ml, P0.05), and the two group patients with C2 (556.85 + 278.24ng/ml 536.58 + 247.1ng/ml) no significant difference.
3, the expression of calcineurin in the podocyte of primary MN and primary FSGS patients is associated with the effect
After 6 months of follow-up, 3 cases of podocyte calcineurin expression patients on cyclosporine treatment without reaction. Effective treatment in March patients (n=22) podocyte calcineurin expression level was significantly higher than that of 8 cases of invalid patients (11.26 + 4.18% to 6.92 + 4.09%, P0.05); 6 months of treatment, 24 cases effective patient podocyte calcineurin expression level was significantly higher than that of 6 cases of invalid patients (10.96 + 3.69%vs3.93 + 2.38%, P0.05). This study did not observe podocyte calcineurin expression and proteinuria, but observed glomerular synaptopodin associated with linear missing expression of calcineurin, which FSGS patients with podocyte injury again, the expression of WTl was significantly lower than that in mild lesion group.
research conclusion
Under the conditions of this study
1, the domestic cyclosporin (Tian Ke) treatment of nephrotic syndrome patients, after monitoring the serum concentration of C1C2C3 at different time points, C1C3, C2 were the best multi-point and single blood concentration time measurement points, which can accurately reflect the degree of drug exposure.
2, in a certain blood concentration range, the clinical efficacy was not related to the concentration of cyclosporin, but the concentration of C0 and C1 was associated with renal toxicity.
3, the expression of calcineurin in podocyte in patients with primary MN and FSGS was significantly higher than that in ineffective treatment with cyclosporine.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R692

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