【摘要】：第一部分腎移植術后早期持續(xù)監(jiān)測外周血視黃醇結合蛋白-4的臨床意義 目的：探討腎移植術后受者早期外周血中視黃醇結合蛋白-4含量與移植腎功能恢復水平的相關性。 方法：采用回顧性巢式病例對照研究，將經(jīng)臨床診斷為急性排斥反應的受者20例列為排斥組（AR組），腎功能延遲恢復者20列例為DGF組，腎功能恢復良好者20例列為對照組（Control組）。對60例患者的外周血視黃醇結合蛋白-4（RBP-4）、血肌酐（SCr）、血尿素氮（BUN）等三系Biomarker指標，通過免疫透射比濁法、肌氨酸氧化酶法等操作平臺進行持續(xù)動態(tài)監(jiān)測，并對數(shù)據(jù)進行縱橫對比分析。 結果：急性排斥組、腎功能延遲恢復組的RBP、Cr均明顯高于對照組，BUN的兩兩組間差異無統(tǒng)計學意義；急性排斥組中除BUN外其余指標在處于排斥時間段內與處于非排斥時間段內有顯著性差異；腎功能延遲恢復組中，RBP、Cr在腎功能異常期的指標與正常期指標有顯著性差異；外周血視黃醇結合蛋白-4與血清肌酐、尿素氮成正相關；總之無論在急性排斥組還是在腎功能延遲恢復組，外周血視黃醇結合蛋白-4出現(xiàn)改變的時間均早于血肌酐變化的時間，在提示腎功能變化的時間上存在一定優(yōu)勢。 結論：外周血視黃醇結合蛋白-4在AR組、DGF組以及對照組中均與血清肌酐呈正性相關；臨床DGF嚴重程度與RBP-4含量高度相關，DGF越嚴重，外周血RBP-4測定值也越高；AR組中，RBP-4出現(xiàn)升高時間早于血肌酐變化，DGF組中，RBP-4出現(xiàn)下降的時間同樣早于血肌酐變化。最終本中心通過一系列持續(xù)序貫研究，認為RBP-4為一獨立于血肌酐的Biomarker指標，并希望其能廣泛應用于早期腎移植術后人群腎功能的持續(xù)監(jiān)測中。 第二部分尿液IP-10、Mig和OPG檢測在移植腎急性排斥反應中的應用 目的：檢測患者尿液IP-10、Mig和OPG水平，探討這三個指標在診斷移植腎急性排斥反應中的臨床應用價值。 方法：排斥組與對照組與第一部分受者相同，尿液樣本為同期同批次留取。對兩組術后連續(xù)30天的每天晨尿樣本，利用Luminex100流式熒光檢測儀和Plexmark三聯(lián)腎損傷標志物試劑盒檢測30天內每天的尿液IP-10、Mig和OPG的水平。并對兩組尿液中IP-10、Mig和OPG水平進行統(tǒng)計學分析比較，是否在診斷移植腎急性排斥反應中有意義。 結果：尿液IP-10和Mig水平在移植腎急性排斥腎功能損害的患者中均有高表達，OPG表達水平在兩組患者中無明顯差異。1、排斥組的尿液IP-10峰值水平為（317.10±61.99）pg/mL，明顯高于對照組的（5.33±1.40）pg/mL（P0.01)；排斥組的尿液Mig峰值水平為（451.00±29.01）pg/mL，亦明顯高于對照組的（22.16±5.96）pg/mL（P0.01)；排斥組尿OPG的峰值水平為（375.55±28.22）pg/mL，，對照組為（325.0±14.94）pg/mL，而兩組的差異無統(tǒng)計學意義（P0.05)。2、排斥組尿IP-10和Mig水平在不同的時刻與血肌酐濃度有較明顯的相關性，OPG與血肌酐未呈現(xiàn)明顯的相關性。IP-10水平與血肌酐濃度的相關性的決定系數(shù)R2=0.7835， P0.01； Mig水平與血肌酐濃度的相關性的決定系數(shù)R2=0.7731，P0.01；OPG水平與血肌酐濃度相關性的決定系數(shù)R2=0.0221，P0.05。3、排斥組在排斥時間段尿IP-10、Mig的水平顯著高于非排斥時間段尿IP-10、Mig的水平，尿OPG水平排斥前后差異無統(tǒng)計學意義。4、排斥組尿IP-10水平升高時間比血肌酐濃度升高時間提前（2.64±0.7426）天；尿液Mig水平升高比血肌酐濃度升高提前（2.6±0.7331）天。5、激素沖擊治療后，尿液IP-10、Mig從高表達急劇下降，比血肌酐濃度下降時間要早。 結論：1、尿液IP-10和Mig水平升高與移植腎急性排斥反應相關，在腎功能損害到一定程度的患者中均有升高表達，是移植腎功能異常的動態(tài)診斷指標，尤其對急性排斥反應、腎小管壞死有提前預示作用，且其升高的時間比血肌酐濃度升高時間早2-3天。2、尿液趨化因子IP-10和Mig表達水平，移植腎損害越嚴重，水平表達值越高，但隨著腎功能改善，水平表達值能靈敏的明顯下降，對激素沖擊治療效果的顯示時間比血肌酐顯示要早。3、尿液中各項生物學標志物各有特點，同時存在自身的局限性。能否在今后的進一步研究中，依據(jù)各指標的優(yōu)缺點，建立聯(lián)合應用的“biomark譜”。最終達到優(yōu)勢互補、預測病情、指導治療和監(jiān)測療效的目的。尿液IP-10和Mig水平檢測對于移植腎急性排斥有意義，可以提前預示移植腎急性排斥反應，且能提前顯示激素沖擊治療效果，可以作為無創(chuàng)性、獨立指標來預測急性排斥反應的發(fā)生，并有顯示藥物治療效果的作用。
[Abstract]:Part I Clinical Significance of Early Continuous Monitoring of Retinol-binding Protein-4 in Peripheral Blood after Renal Transplantation
Objective: To investigate the correlation between retinol binding protein-4 (RBP-4) level in peripheral blood and renal function recovery in early stage after renal transplantation.
Methods: A retrospective nested case-control study was conducted. Twenty patients with acute rejection diagnosed clinically were classified as rejection group (AR group), 20 patients with delayed recovery of renal function as DGF group, and 20 patients with good recovery of renal function as control group (Control group). Urea nitrogen (BUN) and other three-system biomarker indicators were monitored continuously and dynamically by immune transmission turbidimetry, creatine oxidase and other operating platforms, and the data were compared and analyzed.
Results: RBP and Cr in acute rejection group and delayed renal function recovery group were significantly higher than those in the control group, and there was no significant difference between the two groups of BUN; RBP and Cr in acute rejection group were significantly different from those in non-rejection group except BUN; RBP and Cr in delayed renal function recovery group were significantly different from those in non-rejection group. Retinol binding protein-4 in peripheral blood was positively correlated with serum creatinine and urea nitrogen. In conclusion, the change of retinol binding protein-4 in peripheral blood was earlier than that of serum creatinine in acute rejection group and delayed recovery group. There is a certain advantage in time.
Conclusion: Retinol binding protein-4 in peripheral blood was positively correlated with serum creatinine in AR, DGF and control groups; the severity of clinical DGF was highly correlated with RBP-4 content; the more severe DGF was, the higher the RBP-4 level in peripheral blood was; RBP-4 increased earlier than serum creatinine in AR group, and RBP-4 decreased the same time in DGF group. Finally, through a series of continuous sequential studies, we concluded that RBP-4 is a biomarker independent of serum creatinine, and we hope it can be widely used in the continuous monitoring of renal function in early renal transplant recipients.
The second part is the application of urine IP-10, Mig and OPG in acute rejection of renal allograft.
Objective: To investigate the clinical value of urinary IP-10, Mig and OPG in the diagnosis of acute renal allograft rejection.
Methods:The urine samples of the rejection group and the control group were taken in the same batch at the same time.The urine samples of the two groups were collected at the same time.The urine levels of IP-10,Mig and OPG were detected by Luminex 100 flow fluorescence detector and Plexmark triple kidney injury marker kit for 30 days after operation. Statistical analysis and comparison of IP-10, Mig and OPG levels showed whether there was any significance in the diagnosis of acute rejection of renal allografts.
Results: Urinary IP-10 and Mig levels were significantly higher in patients with acute renal allograft rejection and no significant difference in OPG expression was found between the two groups. The peak level of urinary OPG in rejection group was (375.55+28.22) pg/mL, while that in control group was (325.0+14.94) pg/mL. There was no significant difference between the two groups (P 0.05). There was a significant correlation between the levels of urinary IP-10 and Mig in rejection group and serum creatinine concentration at different times. There was no significant correlation between serum creatinine and IP-10 level. The correlation between IP-10 level and serum creatinine concentration was determined by R2 = 0.7835, P 0.01; Mig level and serum creatinine concentration was determined by R2 = 0.7731, P 0.01; OPG level and serum creatinine concentration was determined by R2 = 0.0221, P 0.05.3, urinary IP-10, Mig in rejection group during rejection period. The levels of urinary IP-10 and Mig in rejection group were significantly higher than those in non-rejection group, and there was no significant difference before and after rejection of OPG. The increase of urinary IP-10 in rejection group was earlier than that of serum creatinine (2.64.7426) days; the increase of urinary Mig was earlier than that of serum creatinine (2.6.7331) days. P-10, Mig decreased dramatically from high expression, earlier than that of serum creatinine.
Conclusion: 1. Increased urinary IP-10 and Mig levels are associated with acute renal allograft rejection, and both of them are up-regulated in patients with renal impairment to a certain extent. They are dynamic diagnostic indicators of renal allograft dysfunction, especially for acute rejection and tubular necrosis, and their time of increase is longer than that of serum creatinine. The expression level of urine chemokine IP-10 and Mig was 2-3 days earlier. The more serious the renal allograft damage was, the higher the expression level was. However, with the improvement of renal function, the sensitivity of the expression level decreased significantly. The display time of hormone shock therapy was earlier than that of serum creatinine. Whether we can establish the biomark spectrum of combined application according to the merits and demerits of each index in the future research, and ultimately achieve the purpose of complementary advantages, predicting the condition, guiding the treatment and monitoring the curative effect. Repulsion can be used as a noninvasive, independent index to predict the occurrence of acute rejection, and has a significant effect of drug therapy.
【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】：2014
【分類號】：R699.2

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