外周血RBP-4和尿IP-10、Mig、OPG含量在移植肾肾功能恢复和急性排斥反应中的临床研究

发布时间：2018-08-13 13:43

【摘要】：第一部分肾移植术后早期持续监测外周血视黄醇结合蛋白-4的临床意义目的：探讨肾移植术后受者早期外周血中视黄醇结合蛋白-4含量与移植肾功能恢复水平的相关性。方法：采用回顾性巢式病例对照研究，将经临床诊断为急性排斥反应的受者20例列为排斥组（AR组），肾功能延迟恢复者20列例为DGF组，肾功能恢复良好者20例列为对照组（Control组）。对60例患者的外周血视黄醇结合蛋白-4（RBP-4）、血肌酐（SCr）、血尿素氮（BUN）等三系Biomarker指标，通过免疫透射比浊法、肌氨酸氧化酶法等操作平台进行持续动态监测，并对数据进行纵横对比分析。结果：急性排斥组、肾功能延迟恢复组的RBP、Cr均明显高于对照组，BUN的两两组间差异无统计学意义；急性排斥组中除BUN外其余指标在处于排斥时间段内与处于非排斥时间段内有显著性差异；肾功能延迟恢复组中，RBP、Cr在肾功能异常期的指标与正常期指标有显著性差异；外周血视黄醇结合蛋白-4与血清肌酐、尿素氮成正相关；总之无论在急性排斥组还是在肾功能延迟恢复组，外周血视黄醇结合蛋白-4出现改变的时间均早于血肌酐变化的时间，在提示肾功能变化的时间上存在一定优势。结论：外周血视黄醇结合蛋白-4在AR组、DGF组以及对照组中均与血清肌酐呈正性相关；临床DGF严重程度与RBP-4含量高度相关，DGF越严重，外周血RBP-4测定值也越高；AR组中，RBP-4出现升高时间早于血肌酐变化，DGF组中，RBP-4出现下降的时间同样早于血肌酐变化。最终本中心通过一系列持续序贯研究，认为RBP-4为一独立于血肌酐的Biomarker指标，并希望其能广泛应用于早期肾移植术后人群肾功能的持续监测中。第二部分尿液IP-10、Mig和OPG检测在移植肾急性排斥反应中的应用目的：检测患者尿液IP-10、Mig和OPG水平，探讨这三个指标在诊断移植肾急性排斥反应中的临床应用价值。方法：排斥组与对照组与第一部分受者相同，尿液样本为同期同批次留取。对两组术后连续30天的每天晨尿样本，利用Luminex100流式荧光检测仪和Plexmark三联肾损伤标志物试剂盒检测30天内每天的尿液IP-10、Mig和OPG的水平。并对两组尿液中IP-10、Mig和OPG水平进行统计学分析比较，是否在诊断移植肾急性排斥反应中有意义。结果：尿液IP-10和Mig水平在移植肾急性排斥肾功能损害的患者中均有高表达，OPG表达水平在两组患者中无明显差异。1、排斥组的尿液IP-10峰值水平为（317.10±61.99）pg/mL，明显高于对照组的（5.33±1.40）pg/mL（P0.01)；排斥组的尿液Mig峰值水平为（451.00±29.01）pg/mL，亦明显高于对照组的（22.16±5.96）pg/mL（P0.01)；排斥组尿OPG的峰值水平为（375.55±28.22）pg/mL，，对照组为（325.0±14.94）pg/mL，而两组的差异无统计学意义（P0.05)。2、排斥组尿IP-10和Mig水平在不同的时刻与血肌酐浓度有较明显的相关性，OPG与血肌酐未呈现明显的相关性。IP-10水平与血肌酐浓度的相关性的决定系数R2=0.7835， P0.01； Mig水平与血肌酐浓度的相关性的决定系数R2=0.7731，P0.01；OPG水平与血肌酐浓度相关性的决定系数R2=0.0221，P0.05。3、排斥组在排斥时间段尿IP-10、Mig的水平显著高于非排斥时间段尿IP-10、Mig的水平，尿OPG水平排斥前后差异无统计学意义。4、排斥组尿IP-10水平升高时间比血肌酐浓度升高时间提前（2.64±0.7426）天；尿液Mig水平升高比血肌酐浓度升高提前（2.6±0.7331）天。5、激素冲击治疗后，尿液IP-10、Mig从高表达急剧下降，比血肌酐浓度下降时间要早。结论：1、尿液IP-10和Mig水平升高与移植肾急性排斥反应相关，在肾功能损害到一定程度的患者中均有升高表达，是移植肾功能异常的动态诊断指标，尤其对急性排斥反应、肾小管坏死有提前预示作用，且其升高的时间比血肌酐浓度升高时间早2-3天。2、尿液趋化因子IP-10和Mig表达水平，移植肾损害越严重，水平表达值越高，但随着肾功能改善，水平表达值能灵敏的明显下降，对激素冲击治疗效果的显示时间比血肌酐显示要早。3、尿液中各项生物学标志物各有特点，同时存在自身的局限性。能否在今后的进一步研究中，依据各指标的优缺点，建立联合应用的“biomark谱”。最终达到优势互补、预测病情、指导治疗和监测疗效的目的。尿液IP-10和Mig水平检测对于移植肾急性排斥有意义，可以提前预示移植肾急性排斥反应，且能提前显示激素冲击治疗效果，可以作为无创性、独立指标来预测急性排斥反应的发生，并有显示药物治疗效果的作用。
[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.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R699.2

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