超声造影评价大鼠肾脏冷缺血—再灌注损伤及肾移植急性排斥反应血流灌注的实验研究
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摘要
实验一超声造影评价大鼠肾脏冷缺血-再灌注损伤血流灌注的实验研究
目的研究应用超声造影(contrast-enhanced ultrasound, CEUS)技术定量测定大鼠肾脏冷缺血-再灌注损伤(cold ischemia-reperfusion injury, CIRI)肾脏不同解剖区域的血流灌注,分析并判断肾内血流动力学指标与血清肾功能、急性肾小管坏死(acute tubular necrosis, ATN)病理损伤程度的相关性,探讨CEUS在ATN诊断上的应用价值。
研究方法封闭群SD雄性大鼠假手术组(sham-surgery group, SSG)、肾冷缺血-再灌注损伤组(cold ischemia-reperfusion injury, CIRI)各5只于术后第1、3、7天进入实验(每组共15只)。在充分麻醉状态下行左颈静脉插管,造影剂选用声诺维TM(SonoVueTM),输注方式为经颈静脉连续注射,输液速度为0.8 ml. kg-1. min-1。采用Philips IU22型彩色超声诊断仪,选用脉冲反相谐波成像(pulse inversion harmonic imaging)技术,经左侧腹壁行左肾超声造影并存储动态图像,脱机后用QLAB分析软件进行分析。皮质感兴趣( region of interest, ROI)放置于与声束垂直的正对肾门处肾脏包膜下皮质区,髓质部分ROI放置在与肾门处对侧肾实质区中段髓质的外髓层和内髓层,经One Minus Exp曲线拟合,软件以指数方程Y =A (1 - e-βt )自动生成造影剂微泡声学强度随时间变化的曲线,获得肾脏皮质血流(renal cortical blood flow, RCBF)、外髓层血流(renal outer medullary blood flow, ROMBF)、内髓层血流(renal inner medullary blood flow, RIMBF)的参数:峰值声学强度( peak signal intensity, A);造影剂灌注速率(signal velocity,β);根据公式计算出感兴趣区局部肾组织血流量(regional renal blood flow): A×β。CEUS检查完毕,开腹,经后腔静脉抽取血液行血清肾功能检测,摘取肾脏,放血处死大鼠。肾组织经固定后行HE染色,光镜下行肾小管坏死病理评分。统计分析CIRI大鼠肾内血流动力学的变化及其与血清肾功能、病理肾小管坏死程度的相关性。
结果SSG组与CIRI组实验大鼠同组之间不同时间点、两组之间对应时间点之间比较血流参数A值均无显著差异(P﹥0.05);SSG组术后第1天肾皮质、外髓层血流量偏低,但与第3、7天比较均无显著差异(P﹥0.05),β值与第3、7天血流量比较有显著差异(P﹤0.05),第1、3、7天血清肾功能指标、病理肾小管坏死积分比较均无显著差异(P﹥0.05)。CIRI组术后第1天肾皮质、外髓层、内髓层血流量均明显减低,血流量的减少主要是速度指标β值的减低所致,其中肾皮质血流量与SSG组比较有显著差异(P﹤0.01)。CIRI组术后第3天肾皮质血流开始恢复,外髓层与内髓层血流量未见明显改善,肾皮质、外髓层、内髓层血流量仍显著低于SSG组(P﹤0.01);术后第7天CIRI组肾皮质、外髓层、内髓层血流全面恢复正常,与SSG组比较无显著差异(P﹥0.05)。与之相对应,CIRI组术后第1天与第3、7天比较血清肾功能指标SCr、BUN以及病理肾小管坏死积分(tubular necrosis score, TNS)均显著高,与SSG组第1天比较差异非常显著(P﹤0.01);第3天肾功能指标SCr、BUN以及病理肾小管坏死积分逐渐降低,但与SSG组比较差异仍非常显著(P﹤0.01);第7天降低至正常,与SSG组比较无显著差异(P﹥0.05)。经统计相关分析CIRI大鼠血清SCr、BUN及病理肾小管坏死积分与皮质、外髓层、内髓层血流参数A值均无显著相关关系(P﹥0.05);血清肾功能指标SCr、BUN及病理肾小管坏死积分与超声造影肾皮质、外髓层、内髓层血流参数均成负相关,其中以与皮质血流参数β、A×β相关性最好。
结论肾脏冷缺血-再灌注损伤肾皮质、髓质血流均明显减少,在随后肾组织损伤修复过程中肾皮质血流早于髓质率先恢复;肾冷缺血-再灌注损伤肾血流量的变化主要是由于血流灌注速度β值的变化所致;超声造影血流灌注参数β、A×β均为评价肾冷缺血-再灌注损伤血流灌注的敏感指标。
实验二超声造影评价大鼠肾移植急性排斥反应血流灌注的实验研究
目的研究应用超声造影技术定量检测肾移植术后急性排斥反应(acute rejection, AR)肾内不同解剖区域血流灌注的变化,动态、全面了解AR早期病理演变过程,探讨肾移植术后AR肾血流动力学变化特点及CEUS的诊断价值。
研究方法同基因(Isograft)组与异基因(Allograft)组肾移植大鼠各3只于术后第1、3、7天进入实验(每组共9只)。超声检查方法、血清肾功能指标测定同实验一。离体肾组织经固定后行常规HE染色、特殊染色(马松三色染色、过碘酸雪夫染色、六胺银染色)及透射电镜下超微结构的观察,依据Banff 2007诊断标准进行肾移植术后AR的诊断,统计分析Isograft组与Allograft组、急性排斥反应与非急性排斥反应大鼠肾内血流动力学的变化及其与血清肾功能、急性排斥反应Banff病理诊断分级的相关性。
结果Allograft组与Isograft组术后第1天大鼠肾皮质、外髓层、内髓层血流均明显减少,两组比较超声造影血流参数A、β、A×β值均未见显著差异(P﹥0.05)。术后第3天Isograft组皮质血流开始改善,至术后第7天肾皮质、外髓层、内髓层血流均改善明显,β、A×β值与第1、3天比较有非常显著差异(P﹤0.01),但A值1、3、7天三个时间点之间比较均未见显著差异;而Allograft组术后第3天肾皮质、外髓层、内髓层血流均逐渐降低,表现为A、β、A×β值均减少,第7天显著减少,与第1、3天比较有差异非常显著(P﹤0.01)。与Isograft组比较,Allograft组术后第3天肾皮质、外髓层血流参数A、β、A×β值及内髓层血流参数A×β值均显著降低(P﹤0.05);第7天肾皮质、外髓层、内髓层血流参数A、β、A×β值均降低非常显著(P﹤0.01)。血清肾功能指标SCr、BUN术后第1天Allograft组与Isograft组比较无显著差异(P﹥0.05),术后第3、7天Isograft组大鼠血清SCr、BUN逐渐降低,Allograft组显著增高,两组比较均差异非常显著(P﹤0.01)。HE及特殊染色Isograft组在1、3天可见不同程度的肾小管坏死,第7天基本恢复正常,未见明显的淋巴细胞浸润和血管炎症;Allograft组肾移植术后3天肾小管间质和肾小球旁、小动脉周围淋巴细胞灶性浸润,Banff诊断分级为急性细胞性排斥反应IA- IB级;移植后7天间质炎性细胞浸润明显增多,肾小球Bowman囊囊壁增厚,肾小管、小动脉淋巴细胞浸润,肾小动脉外膜结缔组织增生,管壁增厚,Banff诊断分级为急性细胞性排斥反应Ⅱ-Ⅲ级,未见明显体液性排斥反应。电镜下Isograft组肾组织超微结构未见明显异常,Allograft组术后第3天肾小管上皮细胞间隙明显增大,毛细血管内皮细胞轻度增生,间质淋巴细胞浸润,血管平滑肌细胞增厚。术后7天肾小球Bowman囊囊壁明显增厚,间质、肾小管及血管壁均见大量淋巴细胞浸润,小动脉血管壁明显增厚。经统计相关分析AR大鼠超声造影肾皮质、外髓层、内髓层血流参数A、β、A×β值与血清肾功能指标及病理Banff诊断分级均成负相关,其中以与A值的相关性最好。
结论大鼠肾移植术后急性排斥反应肾皮、髓质血流显著降低,超声造影血流灌注参数A、β、A×β值均为检测肾移植术后急性排斥反应肾脏血流灌注的敏感指标,连续、动态监测肾血流变化可早期诊断大鼠肾移植术后急性排斥反应的发生。
实验三大鼠急性肾小管坏死与肾移植术后急性排斥反应血流灌注的对比研究
目的研究应用CEUS探讨肾移植术后缺血-再灌注损伤所致ATN和肾移植术后早期AR肾组织不同的血流动力学变化,以期为两者的鉴别诊断提供依据。
研究方法SSG组、CIRI组各5只分别于术后第1、3、7天进入实验(每组共15只),Isograft组与Allograft组肾移植大鼠各3只分别于术后第1、3、7天进入实验(每组共9只)。实验方法同实验一、实验二相关部分。组间统计方法采用方差分析。
结果术后第1天CIRI组、Isograft组、Allograft组大鼠肾皮质血流与SSG组比较均明显减少,表现为β、A×β值的降低(P﹤0.05),A值各组间未见显著差异;CIRI组、Isograft组、Allograft组三组间比较大鼠肾皮质血流各参数未见显著差异(P﹥0.05)。Isograft组、Allograft组大鼠肾外髓层血流量与CIRI组、SSG组比较均明显减少,表现为A×β值的降低(P﹤0.05);术后第3天,CIRI组、Isograft组肾皮质血流渐趋改善,至第7天各参数与SSG组比较无显著差异(P﹥0.05);Allograft组则渐趋恶化,术后第3天皮质、外髓层、内髓层血流与其余三组比较参数A、A×β有显著降低(P﹤0.05),第7天A、β、A×β值与其余三组比较均差异非常显著(P﹤0.01)。与之相对应,术后第1天CIRI组、Isograft组、Allograft组大鼠血清肾功能指标SCr、BUN与SSG组比较均明显增高(P﹤0.01);CIRI组、Isograft组、Allograft组大鼠三组之间比较未见明显差异(P﹥0.05)。术后第3天,CIRI组、Isograft组SCr、BUN渐趋降低,至术后第7天CIRI组、Isograft组SCr、BUN恢复正常,与SSG组比较未见统计学差异(P﹥0.05);Allograft组则渐趋恶化,增高显著,第3,7天与SSG组、CIRI组、Isograft组比较有非常显著差异(P﹤0.001)
结论急性肾小管坏死发生在术后早期,肾内皮质、髓质血流均明显减少,血流量的变化主要是由于血流灌注速度的变化所致;肾移植术后急性排斥反应的发生晚于急性肾小管坏死,肾皮、髓质血流减少更加显著,血流量的减少与血流速度、血管容积均密切相关;超声造影肾血流定量测定可为二者的临床早期鉴别诊断提供依据。
Part one Evaluation of renal haemodynamics in rat models of cold ischemia-reperfusion injury with CEUS
Objective: We quantified the regional renal blood flow by real-time contrast-enhanced ultrasound (CEUS) and analyzed the correlations of the parameters between renal haemodynamics and serum renal function or the degree of acute tubular necrosis. The aim of this study was to investigate the value of CEUS in the diagnosis of acute tubular necrosis (ATN) after cold ischemia-reperfusion injury.
Methods: There were total 15 male Sprague-Dawley rats recruited into CEUS examinations in each group, namely sham-surgery group(SSG) , which were just removed their right kidneys, and renal cold ischemia - reperfusion injury group (CIRI). Every five rats were performed CEUS examinations on days one, three and seven, respectively, after surgery in each group. After adequate anesthesia by intraperitoneal injection of 40 mg.kg-1 sodium pentobarbital, contrast agent SonoVue was infused continuously via jugular vein at a rate of 0.8ml.kg-1.min-1 and the left kidney CEUS was performed with the commercial ultrasound system IU22 (Philips Medical Systems, Amsterdam,Netherlands) with pulse inversion harmonic imaging technology in this study. All data were digitally recorded and analyzed off-line with QLAB advanced quantification software (Philips Medical Systems, Amsterdam,Netherlands) by two independent radiologists. ROI (region of interest) was positioned on the renal cortex, out medulla and inner medulla opposite to the renal hilum, respectively. The plot of renal signal intensity versus time after FLASH was fitted to an one minus exponential function: y=A (1-e-βt) automaticly, where A is the peak signal intensity,βindicating signal velocity, and the product of A andβrepresenting as the regional renal blood flow of the ROI. After CEUS examination, blood samples were obtained from the inferior vena cava for renal function examination before removing the left kidney. Rats were sacrificed by abdominal aorta dissection. Renal tissue fixed by formalin and sectioned for HE staining later. Tubular necrosis score (TNS) was calculated according to the pathological findings under light microscope. Correlations between renal hemodynamics parameters and serum renal function parameters or TNS of CIRI rats were analyzed statistically.
Results: The value of parameters A was no significant difference compared at different time points within the same group of SSG or CIRI and compared between SSG and CIRI groups at the same time points after the surgeries (P>0.05). Renal blood flow in all regions were lower in SSG group on day one compared with those on days three and seven after the surgeries, but there was no significant difference (P>0.05) except the value ofβwith significant difference (P<0.05). Just as the same, no significant differences were found while comparing the serum parameters of renal function and tubular necrosis score of pathological evaluation on days one, three and seven after the surgeries (P>0.05). The renal blood flow in the cortex, the outer medulla and the inner medulla were significant lower on day one compared with those on days three and seven after the surgeries in CIRI group and renal cortical blood flow was significant lower compared with those of SSG group on day one after surgeries (P<0.01). The reduction of renal blood flow was mainly due to the decreaced value ofβ. The regional blood flow in cortex, outer medulla and inner medulla of CIRI group were still significant lower compared with those of SSG group(P<0.01) on days three after the surgeries, but the renal cortical blood flow rose progressively while renal outer and inner medullary blood flow remained relatively unchanged. The regional blood flow in cortex, outer medulla and inner medulla of CIRI group further increased and returned to normal compared with those of SSG group on days seven after the surgeries (no significant difference, P>0.05). Accordingly, the values of the parameters of serum renal function and pathological score of tubular necrosis were significantly higher than those of SSG group on day one (P<0.01), and was gradually decreased on days three but still significantly higher than those of SSG group on day one (P<0.01) and returned to normal on days seven with no significant difference between SSG group and CIRI group (P>0.05). The values of parameters of serum renal function and tubular necrosis score were no significant correlation with the parameters of A in all renal regions (P>0.05), while they have negative correlation with the values of parametersβand A×βin all renal regions, especially those in cortical region. Conclusion: CEUS can display the different perfusion pattern and quantify the blood flow in renal cortex, outer medulla and inner medulla in a real-time status, and confirmed that renal blood flow in cortex and medulla were significantly decreased in rats after cold ischemia - reperfusion injury. At the same time, renal cortical blood flow was preferentially increased than those in renal medullary regions during the recovery phase and renal blood flow varied with the values of signal velocity (β) after renal cold ischemia-reperfusion injury. Bothβand A×βwere sensitive parameters in detecting the microcirculation disturbances after renal cold ischemia-reperfusion injury.
Part two Evaluation of renal haemodynamics of acute renal allograft rejection in rat models with CEUS
Objective: We investigated the changes of regional renal haemodynamics of acute renal allograft rejection (AR) consecutively and comprehensively in rat models in the early stages by CEUS with the pathological evaluation. The aim of this study was to investigate the regularities of intrarenal hemodynamics in different renal regions during AR occurence and the value of CEUS in the diagnosis of AR in the early stages. Methods: Eighteen male rats of orthotopic kidney transplantation were collected in both isograft group (Lewis→Lewis, n=9) and allogrft group (F344→Lewis, n=9) into CEUS examinations. Every three rats were performed CEUS examinations on days one, three and seven, respectively. The methods of CEUS examination and quantitative test of serum renal function were just as the same as those mentioned in part one. Renal tissue fixed by formalin and sectioned later for conventional HE staining, special staining (masson trichrome, periodic acid Schiff and methenamine silver staining) and ultrastructural observation under transmission electron microscope. The diagnoses of acute renal allograft rejection were made according to Banff 2007 criteria. Correlations between renal hemodynamics parameters and serum renal function parameters or Banff classification of acute rejection were analyzed statistically. Results: Prominent reduction of renal blood flow in cortex, outer medulla and inner medulla were seen on day one after transplantation in both isograft and allograft groups. Comparisons of parameter A、βas well as A×βshowed no significant differences between isograft and allograft groups (P>0.05). Renal cortical blood flow began to improve on days three and increased significantly on days seven after transplantation in isograft group. Significant differences were found while comparing the value of parametersβand A×βin days seven with those in days one and three (P<0.01), but no significant differences while comparing the value of parameter A among days one, three and seven in isograft group (P>0.05). Renal blood flow in cortex, outer medulla and inner medulla further decreased from days three by presenting as the reduction of the value of parameters A、βand A×βand showed significant difference comparing the values on days seven with those on days one and three (P<0.01) in allograft group. Comparison with those in isograft group, significant reduction was found with the value of parameters A,βas well as A×βin cortical and outer medulla and parameter A×βin inner medulla on days three (P<0.05) which exacerbated on days seven (P<0.01) in allograft group. No significant differences were seen of the values of SCr、BUN in both isograft and allograft groups on day one after transplantations (P>0.05). Statistical significant differences were seen of data SCr and BUN from days three to seven with the gradually decreased in isograft group but obvious increased in allograft group (P<0.01). Histological evaluation with HE and special staining showed different degree of tubular necrosis on days one and three in isograft group and the renal tissue returned to normal on days seven with no obvious inflammatory cell infiltration and vascularities. But inflammatory cell infiltrations were found in renal interstitial and were graded as acute cellular rejectionⅠA -ⅠB according to Banff 2007 criteria on days seven in allograft group. On days seven, more lymphocytic infiltrations were seen in renal interstitial, renal tubules and small arteries with the hypertrophy of Bowman capsule and vascular wall. Their pathological diagnoses were acute cellular rejection ofⅡ-Ⅲclassification with no evidence of humoral rejection in allograft group. The ultrastructure of renal tissue under the electron microscope showed no obvious abnormalities in isograft group. But the ultrastructure of renal tissue in allograft group showed larger clearance among tubular epithelial cells, mild hyperplasia of the capillary endothelial cells, inflammatory cell infiltration in renal interstitial and the hypertrophy of vascular smooth muscle on days three and exacerbated on days seven with markedly thickening of Bowman capsules and arterial wall after transplantations. All the values of parameters A、β、A×βin cortex, outer medulla and inner medulla showed negative correlations with those of the parameters of serum renal function and Banff classification (P<0.05), especially the value of parameter A. Conclusion: Renal blood flow in cortex and medulla regions decreased significantly in acute renal allograft rejection in rat models after transplantations. Parameters A,βand A×βwere sensitive in detecting hemodynamic abnormalities in acute renal rejection. Consecutive and dynamic monitoring the changes of renal hemodynamics can provide early diagnosis of acute rejection after transplantation.
Part three Comparative study of renal haemodynamic abnormalities of acute tubular necrosis and acute renal allograft rejection in rat models
Objective: The aim of this study was to investigate the different renal haemodynamic abnormalities of acute tubular necrosis after ischemia-reperfusion injuries and acute renal allograft rejection in the early stages and provide possible basic theory for differential diagnosis of ATN and AR after renal transplantion.
Methods: Every five rats in both SSG and CIRI groups with every three rats in both isograft and allograft groups were performed CEUS examinations on days one, three and seven, respectively. The methods of CEUS examination and quantitative test of serum renal function were just as the same as those used in experimental one and two. Analysis of variance was used in comparison among each groups.
Results: Renal cortical blood flow decreased in CIRI, Isograft and Allograft groups compared with that in SSG group on day one after sugeries, which presented as the reduction of the value of parametersβ、A×β(P<0.05) with no significant difference of parameter A (P>0.05). All the value of every parameters of renal haemodynamics in cortex showed no significant difference among CIRI, Isograft and Allograft groups on days one after the surgery (P>0.05). Renal outer medullary blood flow also decreased in Isograft and Allograft groups compared with those in CIRI and SSG group on day one after sugeries by presenting as the reduction of the value of parameters A×β(P<0.05). Renal cortical blood flow began to improve in CIRI and Isograft group on days three and increased significantly on days seven with no significant difference compared with those in SSG group (P>0.05). Renal blood flow in cortex, outer medulla and inner medulla were exacerbated and further decreased by presenting as the reduction of the value of parameters A、βand A×βand showed significant difference compared with those in the other three groups on days three (P<0.05) and on days seven (P<0.01). Accordingly, the values of the parameters of serum renal function in CIRI, Isograft and Allograft groups were significantly higher than those of SSG group on day one (P<0.01) with no significant difference among CIRI, Isograft and Allograft groups (P>0.05). The values of of the parameters of serum renal function in CIRI and Isograft groups decreased from days three and returned to normal on days seven with no signifiacant difference compared to those in SSG group (P>0.05). But The values of of the parameters of serum renal function in allogrfat group exacerbated and further increased significantly compared to those in the other three groups on days three and seven (P<0.01).
Conclusion: ATN occurred in the early phase after the surgeries and renal blood flow in cortex and medulla were significantly reduced which were due to the changes of blood flow velocity. AR occurred later than that of ATN after renal transplantation with more severe reduction of renal blood flow in cortex and medulla which was due to both reduction of blood flow velocity and vascular volume. Our studies identified that CEUS examination may be the useful methods in differential diagnosis between AR and ATN in the early stage.
目的研究应用超声造影(contrast-enhanced ultrasound, CEUS)技术定量测定大鼠肾脏冷缺血-再灌注损伤(cold ischemia-reperfusion injury, CIRI)肾脏不同解剖区域的血流灌注,分析并判断肾内血流动力学指标与血清肾功能、急性肾小管坏死(acute tubular necrosis, ATN)病理损伤程度的相关性,探讨CEUS在ATN诊断上的应用价值。
研究方法封闭群SD雄性大鼠假手术组(sham-surgery group, SSG)、肾冷缺血-再灌注损伤组(cold ischemia-reperfusion injury, CIRI)各5只于术后第1、3、7天进入实验(每组共15只)。在充分麻醉状态下行左颈静脉插管,造影剂选用声诺维TM(SonoVueTM),输注方式为经颈静脉连续注射,输液速度为0.8 ml. kg-1. min-1。采用Philips IU22型彩色超声诊断仪,选用脉冲反相谐波成像(pulse inversion harmonic imaging)技术,经左侧腹壁行左肾超声造影并存储动态图像,脱机后用QLAB分析软件进行分析。皮质感兴趣( region of interest, ROI)放置于与声束垂直的正对肾门处肾脏包膜下皮质区,髓质部分ROI放置在与肾门处对侧肾实质区中段髓质的外髓层和内髓层,经One Minus Exp曲线拟合,软件以指数方程Y =A (1 - e-βt )自动生成造影剂微泡声学强度随时间变化的曲线,获得肾脏皮质血流(renal cortical blood flow, RCBF)、外髓层血流(renal outer medullary blood flow, ROMBF)、内髓层血流(renal inner medullary blood flow, RIMBF)的参数:峰值声学强度( peak signal intensity, A);造影剂灌注速率(signal velocity,β);根据公式计算出感兴趣区局部肾组织血流量(regional renal blood flow): A×β。CEUS检查完毕,开腹,经后腔静脉抽取血液行血清肾功能检测,摘取肾脏,放血处死大鼠。肾组织经固定后行HE染色,光镜下行肾小管坏死病理评分。统计分析CIRI大鼠肾内血流动力学的变化及其与血清肾功能、病理肾小管坏死程度的相关性。
结果SSG组与CIRI组实验大鼠同组之间不同时间点、两组之间对应时间点之间比较血流参数A值均无显著差异(P﹥0.05);SSG组术后第1天肾皮质、外髓层血流量偏低,但与第3、7天比较均无显著差异(P﹥0.05),β值与第3、7天血流量比较有显著差异(P﹤0.05),第1、3、7天血清肾功能指标、病理肾小管坏死积分比较均无显著差异(P﹥0.05)。CIRI组术后第1天肾皮质、外髓层、内髓层血流量均明显减低,血流量的减少主要是速度指标β值的减低所致,其中肾皮质血流量与SSG组比较有显著差异(P﹤0.01)。CIRI组术后第3天肾皮质血流开始恢复,外髓层与内髓层血流量未见明显改善,肾皮质、外髓层、内髓层血流量仍显著低于SSG组(P﹤0.01);术后第7天CIRI组肾皮质、外髓层、内髓层血流全面恢复正常,与SSG组比较无显著差异(P﹥0.05)。与之相对应,CIRI组术后第1天与第3、7天比较血清肾功能指标SCr、BUN以及病理肾小管坏死积分(tubular necrosis score, TNS)均显著高,与SSG组第1天比较差异非常显著(P﹤0.01);第3天肾功能指标SCr、BUN以及病理肾小管坏死积分逐渐降低,但与SSG组比较差异仍非常显著(P﹤0.01);第7天降低至正常,与SSG组比较无显著差异(P﹥0.05)。经统计相关分析CIRI大鼠血清SCr、BUN及病理肾小管坏死积分与皮质、外髓层、内髓层血流参数A值均无显著相关关系(P﹥0.05);血清肾功能指标SCr、BUN及病理肾小管坏死积分与超声造影肾皮质、外髓层、内髓层血流参数均成负相关,其中以与皮质血流参数β、A×β相关性最好。
结论肾脏冷缺血-再灌注损伤肾皮质、髓质血流均明显减少,在随后肾组织损伤修复过程中肾皮质血流早于髓质率先恢复;肾冷缺血-再灌注损伤肾血流量的变化主要是由于血流灌注速度β值的变化所致;超声造影血流灌注参数β、A×β均为评价肾冷缺血-再灌注损伤血流灌注的敏感指标。
实验二超声造影评价大鼠肾移植急性排斥反应血流灌注的实验研究
目的研究应用超声造影技术定量检测肾移植术后急性排斥反应(acute rejection, AR)肾内不同解剖区域血流灌注的变化,动态、全面了解AR早期病理演变过程,探讨肾移植术后AR肾血流动力学变化特点及CEUS的诊断价值。
研究方法同基因(Isograft)组与异基因(Allograft)组肾移植大鼠各3只于术后第1、3、7天进入实验(每组共9只)。超声检查方法、血清肾功能指标测定同实验一。离体肾组织经固定后行常规HE染色、特殊染色(马松三色染色、过碘酸雪夫染色、六胺银染色)及透射电镜下超微结构的观察,依据Banff 2007诊断标准进行肾移植术后AR的诊断,统计分析Isograft组与Allograft组、急性排斥反应与非急性排斥反应大鼠肾内血流动力学的变化及其与血清肾功能、急性排斥反应Banff病理诊断分级的相关性。
结果Allograft组与Isograft组术后第1天大鼠肾皮质、外髓层、内髓层血流均明显减少,两组比较超声造影血流参数A、β、A×β值均未见显著差异(P﹥0.05)。术后第3天Isograft组皮质血流开始改善,至术后第7天肾皮质、外髓层、内髓层血流均改善明显,β、A×β值与第1、3天比较有非常显著差异(P﹤0.01),但A值1、3、7天三个时间点之间比较均未见显著差异;而Allograft组术后第3天肾皮质、外髓层、内髓层血流均逐渐降低,表现为A、β、A×β值均减少,第7天显著减少,与第1、3天比较有差异非常显著(P﹤0.01)。与Isograft组比较,Allograft组术后第3天肾皮质、外髓层血流参数A、β、A×β值及内髓层血流参数A×β值均显著降低(P﹤0.05);第7天肾皮质、外髓层、内髓层血流参数A、β、A×β值均降低非常显著(P﹤0.01)。血清肾功能指标SCr、BUN术后第1天Allograft组与Isograft组比较无显著差异(P﹥0.05),术后第3、7天Isograft组大鼠血清SCr、BUN逐渐降低,Allograft组显著增高,两组比较均差异非常显著(P﹤0.01)。HE及特殊染色Isograft组在1、3天可见不同程度的肾小管坏死,第7天基本恢复正常,未见明显的淋巴细胞浸润和血管炎症;Allograft组肾移植术后3天肾小管间质和肾小球旁、小动脉周围淋巴细胞灶性浸润,Banff诊断分级为急性细胞性排斥反应IA- IB级;移植后7天间质炎性细胞浸润明显增多,肾小球Bowman囊囊壁增厚,肾小管、小动脉淋巴细胞浸润,肾小动脉外膜结缔组织增生,管壁增厚,Banff诊断分级为急性细胞性排斥反应Ⅱ-Ⅲ级,未见明显体液性排斥反应。电镜下Isograft组肾组织超微结构未见明显异常,Allograft组术后第3天肾小管上皮细胞间隙明显增大,毛细血管内皮细胞轻度增生,间质淋巴细胞浸润,血管平滑肌细胞增厚。术后7天肾小球Bowman囊囊壁明显增厚,间质、肾小管及血管壁均见大量淋巴细胞浸润,小动脉血管壁明显增厚。经统计相关分析AR大鼠超声造影肾皮质、外髓层、内髓层血流参数A、β、A×β值与血清肾功能指标及病理Banff诊断分级均成负相关,其中以与A值的相关性最好。
结论大鼠肾移植术后急性排斥反应肾皮、髓质血流显著降低,超声造影血流灌注参数A、β、A×β值均为检测肾移植术后急性排斥反应肾脏血流灌注的敏感指标,连续、动态监测肾血流变化可早期诊断大鼠肾移植术后急性排斥反应的发生。
实验三大鼠急性肾小管坏死与肾移植术后急性排斥反应血流灌注的对比研究
目的研究应用CEUS探讨肾移植术后缺血-再灌注损伤所致ATN和肾移植术后早期AR肾组织不同的血流动力学变化,以期为两者的鉴别诊断提供依据。
研究方法SSG组、CIRI组各5只分别于术后第1、3、7天进入实验(每组共15只),Isograft组与Allograft组肾移植大鼠各3只分别于术后第1、3、7天进入实验(每组共9只)。实验方法同实验一、实验二相关部分。组间统计方法采用方差分析。
结果术后第1天CIRI组、Isograft组、Allograft组大鼠肾皮质血流与SSG组比较均明显减少,表现为β、A×β值的降低(P﹤0.05),A值各组间未见显著差异;CIRI组、Isograft组、Allograft组三组间比较大鼠肾皮质血流各参数未见显著差异(P﹥0.05)。Isograft组、Allograft组大鼠肾外髓层血流量与CIRI组、SSG组比较均明显减少,表现为A×β值的降低(P﹤0.05);术后第3天,CIRI组、Isograft组肾皮质血流渐趋改善,至第7天各参数与SSG组比较无显著差异(P﹥0.05);Allograft组则渐趋恶化,术后第3天皮质、外髓层、内髓层血流与其余三组比较参数A、A×β有显著降低(P﹤0.05),第7天A、β、A×β值与其余三组比较均差异非常显著(P﹤0.01)。与之相对应,术后第1天CIRI组、Isograft组、Allograft组大鼠血清肾功能指标SCr、BUN与SSG组比较均明显增高(P﹤0.01);CIRI组、Isograft组、Allograft组大鼠三组之间比较未见明显差异(P﹥0.05)。术后第3天,CIRI组、Isograft组SCr、BUN渐趋降低,至术后第7天CIRI组、Isograft组SCr、BUN恢复正常,与SSG组比较未见统计学差异(P﹥0.05);Allograft组则渐趋恶化,增高显著,第3,7天与SSG组、CIRI组、Isograft组比较有非常显著差异(P﹤0.001)
结论急性肾小管坏死发生在术后早期,肾内皮质、髓质血流均明显减少,血流量的变化主要是由于血流灌注速度的变化所致;肾移植术后急性排斥反应的发生晚于急性肾小管坏死,肾皮、髓质血流减少更加显著,血流量的减少与血流速度、血管容积均密切相关;超声造影肾血流定量测定可为二者的临床早期鉴别诊断提供依据。
Part one Evaluation of renal haemodynamics in rat models of cold ischemia-reperfusion injury with CEUS
Objective: We quantified the regional renal blood flow by real-time contrast-enhanced ultrasound (CEUS) and analyzed the correlations of the parameters between renal haemodynamics and serum renal function or the degree of acute tubular necrosis. The aim of this study was to investigate the value of CEUS in the diagnosis of acute tubular necrosis (ATN) after cold ischemia-reperfusion injury.
Methods: There were total 15 male Sprague-Dawley rats recruited into CEUS examinations in each group, namely sham-surgery group(SSG) , which were just removed their right kidneys, and renal cold ischemia - reperfusion injury group (CIRI). Every five rats were performed CEUS examinations on days one, three and seven, respectively, after surgery in each group. After adequate anesthesia by intraperitoneal injection of 40 mg.kg-1 sodium pentobarbital, contrast agent SonoVue was infused continuously via jugular vein at a rate of 0.8ml.kg-1.min-1 and the left kidney CEUS was performed with the commercial ultrasound system IU22 (Philips Medical Systems, Amsterdam,Netherlands) with pulse inversion harmonic imaging technology in this study. All data were digitally recorded and analyzed off-line with QLAB advanced quantification software (Philips Medical Systems, Amsterdam,Netherlands) by two independent radiologists. ROI (region of interest) was positioned on the renal cortex, out medulla and inner medulla opposite to the renal hilum, respectively. The plot of renal signal intensity versus time after FLASH was fitted to an one minus exponential function: y=A (1-e-βt) automaticly, where A is the peak signal intensity,βindicating signal velocity, and the product of A andβrepresenting as the regional renal blood flow of the ROI. After CEUS examination, blood samples were obtained from the inferior vena cava for renal function examination before removing the left kidney. Rats were sacrificed by abdominal aorta dissection. Renal tissue fixed by formalin and sectioned for HE staining later. Tubular necrosis score (TNS) was calculated according to the pathological findings under light microscope. Correlations between renal hemodynamics parameters and serum renal function parameters or TNS of CIRI rats were analyzed statistically.
Results: The value of parameters A was no significant difference compared at different time points within the same group of SSG or CIRI and compared between SSG and CIRI groups at the same time points after the surgeries (P>0.05). Renal blood flow in all regions were lower in SSG group on day one compared with those on days three and seven after the surgeries, but there was no significant difference (P>0.05) except the value ofβwith significant difference (P<0.05). Just as the same, no significant differences were found while comparing the serum parameters of renal function and tubular necrosis score of pathological evaluation on days one, three and seven after the surgeries (P>0.05). The renal blood flow in the cortex, the outer medulla and the inner medulla were significant lower on day one compared with those on days three and seven after the surgeries in CIRI group and renal cortical blood flow was significant lower compared with those of SSG group on day one after surgeries (P<0.01). The reduction of renal blood flow was mainly due to the decreaced value ofβ. The regional blood flow in cortex, outer medulla and inner medulla of CIRI group were still significant lower compared with those of SSG group(P<0.01) on days three after the surgeries, but the renal cortical blood flow rose progressively while renal outer and inner medullary blood flow remained relatively unchanged. The regional blood flow in cortex, outer medulla and inner medulla of CIRI group further increased and returned to normal compared with those of SSG group on days seven after the surgeries (no significant difference, P>0.05). Accordingly, the values of the parameters of serum renal function and pathological score of tubular necrosis were significantly higher than those of SSG group on day one (P<0.01), and was gradually decreased on days three but still significantly higher than those of SSG group on day one (P<0.01) and returned to normal on days seven with no significant difference between SSG group and CIRI group (P>0.05). The values of parameters of serum renal function and tubular necrosis score were no significant correlation with the parameters of A in all renal regions (P>0.05), while they have negative correlation with the values of parametersβand A×βin all renal regions, especially those in cortical region. Conclusion: CEUS can display the different perfusion pattern and quantify the blood flow in renal cortex, outer medulla and inner medulla in a real-time status, and confirmed that renal blood flow in cortex and medulla were significantly decreased in rats after cold ischemia - reperfusion injury. At the same time, renal cortical blood flow was preferentially increased than those in renal medullary regions during the recovery phase and renal blood flow varied with the values of signal velocity (β) after renal cold ischemia-reperfusion injury. Bothβand A×βwere sensitive parameters in detecting the microcirculation disturbances after renal cold ischemia-reperfusion injury.
Part two Evaluation of renal haemodynamics of acute renal allograft rejection in rat models with CEUS
Objective: We investigated the changes of regional renal haemodynamics of acute renal allograft rejection (AR) consecutively and comprehensively in rat models in the early stages by CEUS with the pathological evaluation. The aim of this study was to investigate the regularities of intrarenal hemodynamics in different renal regions during AR occurence and the value of CEUS in the diagnosis of AR in the early stages. Methods: Eighteen male rats of orthotopic kidney transplantation were collected in both isograft group (Lewis→Lewis, n=9) and allogrft group (F344→Lewis, n=9) into CEUS examinations. Every three rats were performed CEUS examinations on days one, three and seven, respectively. The methods of CEUS examination and quantitative test of serum renal function were just as the same as those mentioned in part one. Renal tissue fixed by formalin and sectioned later for conventional HE staining, special staining (masson trichrome, periodic acid Schiff and methenamine silver staining) and ultrastructural observation under transmission electron microscope. The diagnoses of acute renal allograft rejection were made according to Banff 2007 criteria. Correlations between renal hemodynamics parameters and serum renal function parameters or Banff classification of acute rejection were analyzed statistically. Results: Prominent reduction of renal blood flow in cortex, outer medulla and inner medulla were seen on day one after transplantation in both isograft and allograft groups. Comparisons of parameter A、βas well as A×βshowed no significant differences between isograft and allograft groups (P>0.05). Renal cortical blood flow began to improve on days three and increased significantly on days seven after transplantation in isograft group. Significant differences were found while comparing the value of parametersβand A×βin days seven with those in days one and three (P<0.01), but no significant differences while comparing the value of parameter A among days one, three and seven in isograft group (P>0.05). Renal blood flow in cortex, outer medulla and inner medulla further decreased from days three by presenting as the reduction of the value of parameters A、βand A×βand showed significant difference comparing the values on days seven with those on days one and three (P<0.01) in allograft group. Comparison with those in isograft group, significant reduction was found with the value of parameters A,βas well as A×βin cortical and outer medulla and parameter A×βin inner medulla on days three (P<0.05) which exacerbated on days seven (P<0.01) in allograft group. No significant differences were seen of the values of SCr、BUN in both isograft and allograft groups on day one after transplantations (P>0.05). Statistical significant differences were seen of data SCr and BUN from days three to seven with the gradually decreased in isograft group but obvious increased in allograft group (P<0.01). Histological evaluation with HE and special staining showed different degree of tubular necrosis on days one and three in isograft group and the renal tissue returned to normal on days seven with no obvious inflammatory cell infiltration and vascularities. But inflammatory cell infiltrations were found in renal interstitial and were graded as acute cellular rejectionⅠA -ⅠB according to Banff 2007 criteria on days seven in allograft group. On days seven, more lymphocytic infiltrations were seen in renal interstitial, renal tubules and small arteries with the hypertrophy of Bowman capsule and vascular wall. Their pathological diagnoses were acute cellular rejection ofⅡ-Ⅲclassification with no evidence of humoral rejection in allograft group. The ultrastructure of renal tissue under the electron microscope showed no obvious abnormalities in isograft group. But the ultrastructure of renal tissue in allograft group showed larger clearance among tubular epithelial cells, mild hyperplasia of the capillary endothelial cells, inflammatory cell infiltration in renal interstitial and the hypertrophy of vascular smooth muscle on days three and exacerbated on days seven with markedly thickening of Bowman capsules and arterial wall after transplantations. All the values of parameters A、β、A×βin cortex, outer medulla and inner medulla showed negative correlations with those of the parameters of serum renal function and Banff classification (P<0.05), especially the value of parameter A. Conclusion: Renal blood flow in cortex and medulla regions decreased significantly in acute renal allograft rejection in rat models after transplantations. Parameters A,βand A×βwere sensitive in detecting hemodynamic abnormalities in acute renal rejection. Consecutive and dynamic monitoring the changes of renal hemodynamics can provide early diagnosis of acute rejection after transplantation.
Part three Comparative study of renal haemodynamic abnormalities of acute tubular necrosis and acute renal allograft rejection in rat models
Objective: The aim of this study was to investigate the different renal haemodynamic abnormalities of acute tubular necrosis after ischemia-reperfusion injuries and acute renal allograft rejection in the early stages and provide possible basic theory for differential diagnosis of ATN and AR after renal transplantion.
Methods: Every five rats in both SSG and CIRI groups with every three rats in both isograft and allograft groups were performed CEUS examinations on days one, three and seven, respectively. The methods of CEUS examination and quantitative test of serum renal function were just as the same as those used in experimental one and two. Analysis of variance was used in comparison among each groups.
Results: Renal cortical blood flow decreased in CIRI, Isograft and Allograft groups compared with that in SSG group on day one after sugeries, which presented as the reduction of the value of parametersβ、A×β(P<0.05) with no significant difference of parameter A (P>0.05). All the value of every parameters of renal haemodynamics in cortex showed no significant difference among CIRI, Isograft and Allograft groups on days one after the surgery (P>0.05). Renal outer medullary blood flow also decreased in Isograft and Allograft groups compared with those in CIRI and SSG group on day one after sugeries by presenting as the reduction of the value of parameters A×β(P<0.05). Renal cortical blood flow began to improve in CIRI and Isograft group on days three and increased significantly on days seven with no significant difference compared with those in SSG group (P>0.05). Renal blood flow in cortex, outer medulla and inner medulla were exacerbated and further decreased by presenting as the reduction of the value of parameters A、βand A×βand showed significant difference compared with those in the other three groups on days three (P<0.05) and on days seven (P<0.01). Accordingly, the values of the parameters of serum renal function in CIRI, Isograft and Allograft groups were significantly higher than those of SSG group on day one (P<0.01) with no significant difference among CIRI, Isograft and Allograft groups (P>0.05). The values of of the parameters of serum renal function in CIRI and Isograft groups decreased from days three and returned to normal on days seven with no signifiacant difference compared to those in SSG group (P>0.05). But The values of of the parameters of serum renal function in allogrfat group exacerbated and further increased significantly compared to those in the other three groups on days three and seven (P<0.01).
Conclusion: ATN occurred in the early phase after the surgeries and renal blood flow in cortex and medulla were significantly reduced which were due to the changes of blood flow velocity. AR occurred later than that of ATN after renal transplantation with more severe reduction of renal blood flow in cortex and medulla which was due to both reduction of blood flow velocity and vascular volume. Our studies identified that CEUS examination may be the useful methods in differential diagnosis between AR and ATN in the early stage.
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