在放射性肾损伤纤维性修复中的分子病理机制

目的 为探讨纤溶本科原激活物抑制因子-1（PAI-1）在放射性肾损伤纤维怀修复中的作用和意义，揭示其发病的分子病理机制。方法 24只雄性健康的Wistar大鼠以30Gy ^60Coγ线单次双肾局部照射，于照射后4个不同时相点活杀，取肾组织进行常规病理学观察及原位分子杂交，观察PAI-1 mRNA表达的变化。结果 纤维化的肾组织PAI-1表达较正常对照组增高，与纤维化程度呈正相关。结论 PAI-1可能在肾放射性损伤后纤维性修复的发生及发展中起重要的作用。     

纤溶酶原激活物抑制因子-1在放射性肾纤维化中的作用及意义

【目的】为探讨纤溶酶原激活物抑制因子-1(PAI-1)在肾损伤后纤维化中的作用和意义,揭示其发病的分子病理机制。【方法】雄性健康的Wistar大鼠以30Gy^60Coγ／线单次双肾局部照射,于照射后4个不同时相点活杀,取肾组织进行常规病理学观察及原位分子杂交,观察PAI-1 mRNA表达的变化。【结果】纤维化的肾组织PAI-1表达较正常对照组增高,与纤维化程度呈正相关。【结论】PAI-1可能在肾损伤后纤维化的发生及发展中起重要的作用。     

手术治疗对改善左肾静脉狭窄大鼠肾组织淤血性损伤的作用

目的：探讨手术治疗改善左肾静脉狭窄大鼠肾组织纤维化损伤和氧化应激状况的效果，为临床手术治疗左肾静脉受压综合征提供实验依据。 方法：将大鼠分为4组，假手术组、模型7周组、模型12周组和手术治疗组。采用左肾静脉不全结扎的方法建立大鼠左肾静脉狭窄模型，治疗组7周后解除狭窄，于二次手术5周后处死动物。肾组织行病理学检查。肾皮质制备匀浆检测丙二醛含量和超氧化物歧化酶活性。RT-PCR法和免疫组化法分别检测肾皮质TGF-β1、PAI-1mRNA和蛋白的表达。 结果：模型7周组和模型12周组左肾皮质MDA含量较假手术组显著增高，SOD活性显著降低，左肾皮质TGF-β1、PAI-1mRNA和蛋白的表达增加，出现病理学损伤。其中模型12周组变化程度更显著。手术治疗可降低MDA含量，提高SOD的活性，减少TGF-β1与PAI-1mRNA和蛋白的表达，减轻组织病理学损伤。 结论：左肾静脉狭窄大鼠肾组织氧自由基生成增多，抗氧化能力下降。促纤维化因子TGF-β1与PAI-1表达水平上调。出现组织纤维化。病变随狭窄时间的延长而加重，手术治疗可改善氧化应激状况，减轻组织纤维化损伤。     

手术治疗对改善左肾静脉狭窄大鼠肾组织淤血性损伤的作用

目的:探讨手术治疗改善左肾静脉狭窄大鼠肾组织淤血性损伤的效果。方法:将大鼠分为4组,假手术组、模型7周组、模型12周组和手术治疗组。肾皮质匀浆检测丙二醛(MDA)含量和超氧化物歧化酶(SOD)活性,检测肾皮质转化生长因子-β1(TGF-β1)、纤溶酶原激活物抑制剂-1(PAI-1)mRNA的表达。结果:模型组左肾皮质MDA含量增高,SOD活性降低,TGF-β1、PAI-1表达增加。手术治疗可降低MDA含量,提高SOD的活性,减少TGF-β1、PAI-1的表达。结论:左肾静脉狭窄大鼠肾组织氧自由基生成增多,抗氧化能力下降,促纤维化因子表达水平上调。手术治疗可改善氧化应激状况,减轻组织纤维化损伤。     

超声辐照携TIMP-1siRNA微泡对大鼠肝纤维化的影响

目的 探讨携TIMP-1 siRNA的造影剂微泡在超声辐照条件下对肝纤维化大鼠组织学改变的影响。方法二甲基亚硝胺建立肝纤维化模型，6周后分组并静脉质粒注射，2天后观察肝、肾、肺、脑、心肌组织内基因荧光表达；12天后检测肝组织内TIMP-1 mRNA、蛋白表达及胶原纤维变化。结果2天后，超声照射微泡组基因荧光表达明显增强，较其他组织差异显著，P〈0．001；12天后，其TIMP-1 mRNA及蛋白表达、胶原含量均较单质粒组及对照组减低，P〈0．001。结论超声辐照携TIMP-1 siRNA超声微泡有将目的基因定位释放作用，TIMP-1 siRNA转染肝纤维化大鼠可改善肝纤维化结构，为肝纤维化的基因治疗提供了新的思路及方法。     

巨噬细胞诱导肾间质纤维化机制研究进展

肾间质纤维化是指胶原分子在肾间质的累积,是慢性肾脏病的最终病理结局和共同死亡通路。肾间质纤维化发生、发展涉及多种细胞及分子,包括巨噬细胞、肌成纤维细胞、生长因子、基质金属蛋白酶或基质金属蛋白酶抑制物等。巨噬细胞在肾间质纤维化的进程中起重要作用,巨噬细胞的异质性可促进肾纤维化,且对肾脏损伤修复有重要作用。M1型活化巨噬细胞有促炎及促纤维化的作用,M2型活化巨噬细胞可能发挥抗纤维化及促进组织修复作用。本文就巨噬细胞诱导肾间质纤维化机制的研究进展作一综述。     

骨髓间充质干细胞移植治疗大鼠急性放射性肺损伤

背景：针对放射性肺损伤,临床上除了糖皮质激素及抗生素等对症处理外,尚缺乏有效的治疗手段。近年来研究表明,骨髓间充质干细胞表现出强大的组织修复能力。目的：观察骨髓间充质干细胞对大鼠放射性肺损伤的治疗作用,并初步探讨其作用机制。方法：体外分离、培养并鉴定雄性SD大鼠骨髓间充质干细胞。应用直线加速器照射60只雌性SD大鼠胸部,建立大鼠放射性肺损伤模型,随机分为骨髓间充质干细胞治疗组和生理盐水对照组。骨髓间充质干细胞治疗组经大鼠尾静脉输注骨髓间充质干细胞2×109L-1,生理盐水对照组注射等量生理盐水,分别于照射后1,2,4,6周时进行相关指标检测。结果与结论：照射后第1,2,4周时,骨髓间充质干细胞治疗组大鼠肺系数明显低于生理盐水对照组（P〈0.05）。镜下见骨髓间充质干细胞治疗组大鼠肺组织炎症渗出较少,肺泡、肺泡壁结构基本完整,纤维化程度等均明显轻于生理盐水对照组。照射2周时骨髓间充质干细胞治疗组血清转化生长因子β1、羟脯氨酸水平显著低于生理盐水对照组（P〈0.05）。照射2,4,6周时骨髓间充质干细胞治疗组肺组织超氧化物歧化酶活力显著高于生理盐水对照组（P〈0.05）,照射4,6周时骨髓间充质干细胞治疗组丙二醛含量显著低于生理盐水对照组（P〈0.05）。照射6周时骨髓间充质干细胞治疗组的肺表面活性物质B表达显著高于生理盐水对照组。PCR方法检测肺、肝脏、胰腺、肾脏等器官组织均有不同程度的Sry基因表达,尤以肺显著。结果表明骨髓间充质干细胞可以迁移到放射性损伤的肺组织,促进放射性肺损伤组织的修复,其治疗机制可能与抑制炎症反应、抗氧化、减轻肺组织纤维化等有关。     

霉酚酸酯对UUO大鼠肾间质TGF-β_1、PAI-1表达的影响

目的:通过霉酚酸酯(MMF)干预单侧输尿管梗阻(UUO)模型大鼠,动态观察转化生长因子-β1(TGF-β1)、纤溶酶原激活抑制物-1(PAI-1)在梗阻侧肾组织中的表达,探讨MMF延缓肾间质纤维化进展的机制。方法:将54只大鼠随机分为假手术组、单侧输尿管结扎手术组和霉酚酸酯组。采用UUO模型,在     

雷米普利对糖尿病大鼠肾脏保护作用的影响及其机制研究

目的观察雷米普利对糖尿病大鼠肾脏病理学变化及肾组织中Megsin、血浆纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)和胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)表达的影响,探讨其肾保护机制。方法取健康雄性SD大鼠48只,其中12只作为正常对照组(A组),余均一次性腹腔注射链脲佐菌素建立糖尿病大鼠模型(血糖≥16.7 mmol/L),将建模成功的24只随机均分为雷米普利干预组[C组,雷米普利1 mg/(kg·d)灌胃]和糖尿病组(B组,等量注射用水灌胃)。12周后,收集各组大鼠血、尿及肾组织标本,比较各组体重、24 h尿量、血糖、肾重与体重比、尿蛋白定量和肌酐清除率,观察各组肾组织病理学变化,并采用免疫组织化学染色及Western blot法测定各组大鼠肾组织Megsin、PAI-1及IGF-1蛋白的表达。结果与A组比较,B、C组体重减轻,24 h尿量、血糖明显增加,肾重与体重比、24 h尿蛋白定量、肌酐清除率明显升高,差异均有统计学意义(P0.05);C组24 h尿蛋白定量、肌酐清除率较B组显著降低(P0.05)。A组肾脏无明显病理改变;B组肾脏病理改变明显,系膜区增宽、PAS染色阳性物质增多,肾组织Megsin、PAI-1、IGF-1蛋白表达明显高于A组(P0.05);C组肾脏病理变化较B组轻,肾组织Megsin、PAI-1及IGF-1蛋白表达较B组下降但仍高于A组,差异均有统计学意义(P0.05)。结论雷米普利能减轻糖尿病大鼠肾脏病理学变化,并下调Megsin、PAI-1、IGF-1在肾小球中的表达,具有肾保护作用。     

不同剂量贞清方对糖尿病肾病大鼠肾的保护作用

目的:观察贞清方对糖尿病肾病(diabetic nephropathy,DN)大鼠凝血纤溶系统的调节作用,并探讨其作用与剂量的关系。方法:将Wistar大鼠随机分为正常组、模型组、贞清方高剂量组和贞清方低剂量组。除正常组外,均用腹腔注射链脲佐菌素(streptozotocin,STZ)的方法建立糖尿病模型。检测喂养1个月及注射STZ后1周各组大鼠的血胰岛素(fasting serum lisulin,FINS)水平,喂养1个月、注射STZ后1周、给药4周及给药8周后的血糖(fasting blood glucose,FBG)、血脂(TC、TG)水平、给药8周后的各组大鼠血浆血栓素B_2(thromboxane B_2,TXB_2)、组织型纤溶酶原激活物(tissue plasminogen activator,t-PA)和纤溶酶原激活物抑制物-1(plasminogen activator inhibitor type-1,PAI-1)含量及各组大鼠尿微量白蛋白(UAE)、血肌酐(SCr)和尿肌酐(UCr)的改变,并计算内生肌酐清除率(CCr)。称量大鼠体重后处死,称量肾重,并计算肾重指数(kidney index,KI)、将肾组织进行HE染色、过碘酸希夫(PAS)染色观察肾病变,并用免疫组织化学及Western印迹检测肾组织PAI-1的蛋白表达水平及用聚合酶链反应(PCR)检测肾皮质PAI-1的mRNA的表达变化。结果:模型组大鼠各时期的FIN,FBG,TC,TG均显著高于正常组(P0.05),与正常组相比,模型组血浆KI,TXB_2,PAI-1,UAE,CCr也明显升高(P0.05),肾组织PAI-1蛋白表达及mRNA水平明显上调(P0.05),而治疗组以上指标均低于模型组(P0.05),且贞清方高剂量组低于贞清方低剂量组。结论:贞清方可明显降低血糖,血脂;升高t-PA的水平,降低血浆PAI-1,TXB_2含量,减少糖尿病大鼠肾组织PAI-1的蛋白和mRNA的表达量,且贞清方对糖尿病大鼠肾的保护作用呈剂量依赖性。     

纤溶酶原激活物/Ⅰ型纤溶酶原激活物抑制物的失衡在大鼠肾脏衰老过程中的意义

目的　探讨纤溶酶原激活物 (PAs)及其抑制物 1(PAI 1)在大鼠肾脏衰老过程中的作用。方法　选用 3、12、2 4个月龄Wistar大鼠 ,采用免疫组化技术分别检测组织型纤溶酶原激活物 (t PA)、尿激酶型纤溶酶原激活物 (u PA)、PAI 1及转化生长因子 β1(TGF β1)在不同年龄大鼠肾组织中的表达。 结果　PAI 1主要表达在肾小球壁层上皮细胞、内皮细胞及系膜细胞、小血管的内皮细胞及平滑肌细胞和肾小管上皮细胞 ,并随增龄表达增强 (P <0 0 1) ;t PA主要表达在肾小球、肾小管 ,并随增龄表达减弱 (P <0 0 1) ;u PA主要表达在肾小管上皮细胞 ,亦随增龄表达减弱 (P <0 0 1) ;TGF β1主要表达在肾小球、血管周围、小管及间质 ,随增龄表达增强 (P <0 0 1)。PAI 1与TGF β1与肾小球硬化有相关性 (P <0 0 5 )。结论　PA/PAI 1表达失衡在肾脏衰老过程中可能起重要作用     

Preservation of residual renal function in dialysis patients: effects of dialysis-technique-related factors.

OBJECTIVES: Residual renal function (RRF) is of paramount importance to dialysis adequacy, morbidity, and mortality, particularly for long-term continuous ambulatory peritoneal dialysis (CAPD) patients. Residual renal function seems to be better preserved in patients on CAPD than in hemodialysis (HD) patients. We analyzed RRF in 45 patients with end-stage renal disease (ESRD), commencing either CAPD or HD, to prospectively define the time course of the decline in RRF, and to evaluate dialysis-technique-related factors such as cardiovascular stability and bioincompatibility. STUDY DESIGN: Single-center prospective investigation in parallel design with matched pairs. MATERIALS: Fifteen patients starting CAPD and 15 matched pairs of patients commencing HD were matched according to cause of renal failure and RRF. Hemodialysis patients were assigned to two dialyzer membranes differing markedly in their potential to activate complement and cells (bioincompatibility). Fifteen patients were treated exclusively with the cuprophane membrane (bioincompatible) and the other 15 patients received HD with the high-flux polysulfone membrane (biocompatible). MEASUREMENTS: Residual renal function was determined at initiation of dialytic therapy and after 6, 12, and 24 months. Dry weight (by chest x ray and diameter of the vena cava) was closely recorded throughout the study, and the number of hypotensive episodes counted. RESULTS: Residual renal function declined in both CAPD and HD patients, although this decline was faster in HD patients (2.8 mL/minute after 6 months and 3.7 mL/min after 12 months) than in CAPD patients (0.6 mL/min and 1.4 mL/min after 6 and 12 months respectively). It declined faster in patients with bioincompatible than with biocompatible HD membranes (3.6 mL/min vs 1.9 mL/min after 6 months). Eleven percent of the HD sessions were complicated by clinically relevant blood pressure reductions, but there were no differences between the two dialyzer membrane groups. None of the CAPD patients had documented hypotensive episodes. None of the study patients suffered severe illness or received nephrotoxic antibiotics or radiocontrast media. CONCLUSIONS: The better preservation of RRF in stable CAPD patients corresponded with greater cardiovascular stability compared to HD patients, independently of the membrane used. Furthermore, there was a significantly higher preservation of RRF in HD patients on polysulfone versus cuprophane membranes, indicating an additional effect of biocompatibility, such as less generation of nephrotoxic substances by the membrane. Thus, starting ESRD patients on HD prior to elective CAPD should be avoided for better preservation of RRF.     

持续性腹膜透析和血液透析对慢性肾功能衰竭多发性神经病转归的影响

目的通过电生理测试结果评估持续腹膜透析（PD）或血液透析（HD）的慢性肾功能衰竭患者周围神经病的发生率,并根据残余肾功能判断透析方式对周围神经功能的影响。方法将131例慢性肾功能衰竭患者按透析方式分为HD组（n=73）和PD组（n=58）。根据透析治疗期间肌电图的结果分别将HD组、PD组各分为MN亚组和非MN亚组。采用德国Medelec Shaphire 2MED仪对每例患者的正中神经、尺神经、腓总神经和胫神经的神经传导速度（NCV）进行电生理测定,感觉神经检测包括波幅、潜伏期和传导速度;运动神经检测则包括复合肌肉动作电位的波幅、潜伏期和传导速度。电生理检测发现至少2条神经异常结果可诊断为多发性神经病。在透析开始后的第1、6、12、18、24月检测每位患者的残余肾功能。结果 131例患者中在观察末期有78例存在感觉障碍。78例患者经肌电图检查诊断为MN者77例,其中HD组中MN患者44例（60.3%）,PD组中MN患者33例（56.9%）,2组比较差异无统计学意义（P〉0.05）。透析治疗初期HD组中的MN亚组、非MN亚组,PD组中的MN亚组、非MN亚组对残余肾功能（RRF）变化进行多重比较,差异均无统计学意义（均P〉0.05）。随着透析的进行,第12、24个月2种透析组的MN亚组RRF显著下降（P〈0.05）,非MN亚组RRF比较差异无统计学意义（P〉0.05）。结论 MN在慢性肾衰患者中是常见的并发症,发生率与治疗方法无明显关系;PD或HD治疗不能阻止慢性肾功能衰竭患者周围神经病变的发生。残留肾功能在保护慢性肾功能衰竭患者周围神经功能方面起了重要的作用。     

早期低剂量腹膜透析对尿毒症患者残存肾功能的保护及微炎症状态的影响

目的 探讨早期低剂量腹膜透析对尿毒症患者残存肾功能的保护及微炎症状态的影响.方法 将2008年3月至2011年2月收治的68例慢性肾功能衰竭患者分为两组,其中腹透组34例,接受常规药物治疗,并给予间歇性腹膜透析,每日4000～6000 ml,每周4～5 d;对照组34例,只接受常规药物治疗.所有患者每3个月行残存肾功能测定(RRF)及C-反应蛋白(CRP)检测,研究前后检测肌酐清除率(Ccr)、血钾、血红蛋白,并记录血压和24 h尿量.结果 研究结束时,早期低剂量腹膜透析组和对照组的收缩压、舒张压、血红蛋白、血钾水平差异均无统计学意义;腹透组Ccr高于对照组,但对照组较腹透组减少明显(P<0.05).前6个月两组RRF的明显下降,6个月后腹透组下降变缓,研究结束时腹透组RRF较对照组高(P<0.05).而从第3个月时腹透组CRP较对照组高(P<0.05).结论 早期使用低剂量腹膜透析可以延缓尿毒症患者残存肾功能的丢失及降低尿毒症患者微炎症状态.     

Presence of Peripheral Arterial Disease Predicts Loss of Residual Renal Function in Incident CAPD Patients

♦ Background: Accelerated cardiovascular disease (CVD), including peripheral arterial disease (PAD), is very common in patients with end-stage renal disease. Residual renal function (RRF) is a strong predictor of patient survival that is suggested to be linked to the degree of CVD. However, the relationship between PAD and decline in RRF has not previously been measured.♦ Methods: We studied incident continuous ambulatory peritoneal dialysis patients from Peking University Third Hospital. An ankle brachial index of less than 0.9 was used to diagnose PAD. Residual renal function (RRF) was determined as the mean of 24-hour urea and creatinine clearances (glomerular filtration rate). The Cox proportional hazards model was used to identify factors predicting loss of RRF.♦ Results: The study included 86 patients (age: 61 ± 14 years; men: 51%), 23 of whom had PAD at baseline. Mean follow-up was 19 months (median: 18 months; range: 6 – 30 months). In univariate analysis, baseline PAD, peritonitis during follow-up, inflammation (C-reactive protein), serum uric acid, Ca×P, and serum phosphate were all significantly associated with a greater-than-50% decrease in RRF during follow-up. In multivariate analysis, only baseline PAD, Ca×P, and peritonitis were independently associated with a decline in RRF.♦ Conclusions: Our study suggests that PAD may be a clinically important marker of CVD predicting the loss of RRF. It remains to be determined whether interventions aimed at decreasing PAD may also improve renal vascular status and thus slow the rate of RRF decline.     

缺血后处理对缺血再灌注损伤大鼠肾脏HIF-1α的影响

目的 观察缺血后处理对缺血再灌注损伤（IRI）大鼠肾脏缺氧诱导因子-1α（HIF-1α）表达的影响。方法 将72只成年SD大鼠随机分为假手术组（S组）、缺血再灌注组（IR组）、缺血后处理组（IPO组），每组24只。S组结扎右肾动脉，暴露左肾45min后关闭腹腔；IR组结扎右肾动脉并完全阻断左侧肾动脉45min后恢复血流；IPO组在IR模型的基础上，恢复血流前给予反复10次20s供血20s缺血处理。每组分别在造模后0．5h、1h、3h、6h、12h、24h、48h、72h留取血和肾组织标本，检测血肌酐和血尿素氮，并对肾组织行免疫组化染色和单言评分；Western blot检测HIF-1α的表达强度。结果 HIF-1α主要在小管上皮细胞中表达，肾小球中未发现阳性染色。各组HIF-1α表达情况：与S组相比IR组HIF-1α在1h表达开始显著升高，6h达到高峰，12h开始下降。而IPO组HIF-1α在3h表达开始升高，6h达到高峰，且高峰水平显著高于IR组，24h后HIF-1α开始下降，48h其表达水平与IR组差异无显著性。结论 缺血后处理能增加缺血再灌注损伤大鼠肾脏HIF-1α表达并延长其表达高峰时间，从而减轻缺血缺氧对肾脏的损伤。     

Effect of Biocompatible Peritoneal Dialysis Solution on Residual Renal Function: A Systematic Review of Randomized Controlled Trials

♦ Introduction: Residual renal function (RRF) plays an important role in outcome of peritoneal dialysis (PD) including mortality. It is, therefore, important to provide a strategy for the preservation of RRF. The objective of this study was to evaluate relative protective effects of new glucose-based multicompartmental PD solution (PDS), which is well known to be more biocompatible than glucose-based conventional PDS, on RRF compared to conventional PDS by performing a systematic review (SR) of randomized controlled trials.♦ Methods: We searched studies presented up to January 2014 in MEDLINE, EMBASE, the COCHRANE library, and local databases. Three independent reviewers reviewed and extracted prespecified data from each study. The random effects model, a more conservative analysis model, was used to combine trials and to perform stratified analyses based on the duration of follow-up. Study quality was assessed using the Cochrane Handbook for risk of bias. Eleven articles with 1,034 patients were identified for the SR.♦ Results: The heterogeneity of the studies under 12 months was very high, and the heterogeneity decreased substantially when we stratified studies by the duration of follow-up. The mean difference of the studies after 12 months was 0.46 mL/min/1.73 m² (95% confidence interval = 0.25 to + 0.67).♦ Conclusion: New PDS showed the effect to preserve and improve RRF for long-term use compared to conventional PDS, even though it did not show a significant difference to preserve RRF for short-term use.     

替米沙坦对非糖尿病腹膜透析患者胰岛素抵抗及残余肾功能的影响

目的观察替米沙坦对非糖尿病腹膜透析患者胰岛素抵抗的影响,并探讨其能否延缓残余肾功能（RRF）的丢失。方法选取病情稳定的持续不卧床非糖尿病腹膜透析患者42例为研究对象,将其随机分为替米沙坦组和对照组各21例。其中对照组给予血管紧张素转换酶抑制剂及血管紧张素受体阻断剂以外的降压药;替米沙坦组给予替米沙坦片80mg／d,观察时间1年,定期检测两组空腹血糖、空腹胰岛素、总Kt／V、总肌酐清除率（Ccr）、血红蛋白（Hb）、甲状旁腺素（iPTH）、高敏C反应蛋白（hs—CRP）,计算稳态模型胰岛素抵抗指数（HOMA—IR）及残余肾功能（RRF）。结果研究结束时,两组Hb均明显升高,iPTH均明显下降,总Kt／V则无显著改变。组间比较,hs—CRP值替米沙坦组显著低于对照组,其他上述指标无显著性差异。对照组HOMA—IR较研究前有所下降,但无显著性差异（P〉0．05）,替米沙坦组HOMA—IR较对照组显著下降（3．24±1．41VS．4．37±1．93,P〈0．05）,两组患者RRF均显著下降,但替米沙坦组较对照组RRF下降延缓[（3．25±1．31vs．2．35±1．20）ml／min,P〈0．05]。结论替米沙坦能改善非糖尿病腹膜透析患者胰岛素抵抗,并延缓残余肾功能的丢失。     

Effect of X‐ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats

Concurrent chemoradiation with irinotecan hydrochloride (CPT‐11) is accepted for cancer treatment. However, the effects of X‐ray irradiation on chemotherapeutics in the plasma remain unclear. We evaluated the pharmacokinetics of CPT‐11 in rats after exposure to X‐ray irradiation and examined the changes of protein and mRNA expression of CES1 and CYP3A1. The X‐ray irradiation with 1 Gy and 5 Gy was delivered to the whole body of rats. CPT‐11 at 30 and 60 mg/kg, respectively, was intravenously infused 24 h after irradiation. CPT‐11 was determined by RP‐HPLC in plasma. ELISA and PCR were used to analyze the protein and mRNA expression of CES1 and CYP3A1, respectively. Compared with control rats, the X‐ray irradiation decreased the AUC of CPT‐11 (30 mg/kg) by 15.6% at 1 Gy and 39.0% at 5 Gy and increased the CL by 60.0% at 5 Gy. The X‐ray irradiation could also decrease the AUC of CPT‐11 (60 mg/kg) and increase the CL. In addition, the protein and mRNA expression of CES1 and CYP3A1 were increased significantly in rats after irradiation. This study found significant changes in the pharmacokinetics of CPT‐11 in rats after exposure to X‐ray irradiation, and they might be due to significant increases in the expressions of CYP3A1 and CES1. The pharmacokinetics of CPT‐11 should be rechecked, and the optimal CPT‐11 dose should be reevaluated during concurrent chemoradiation therapy.     

Influence of residual renal function on dietary protein and caloric intake in patients on incremental peritoneal dialysis.

OBJECTIVE: To evaluate protein and caloric intake in peritoneal dialysis (PD) patients on an incremental dialysis schedule, in an attempt to discriminate the influence of residual renal function (RRF) on these nutritional parameters. DESIGN: Prospective observational study. PATIENTS: Nine patients who had significant RRF at the beginning of PD therapy, which permitted a schedule of incremental PD (i.e., the number of peritoneal exchanges was increased as the RRF fell) in order to maintain the sum of renal and peritoneal clearance (weekly Kt/V urea) at approximately 2. METHODS: The mean adequacy parameters (urine and peritoneal Kt/V urea and creatinine clearance) along with the mean dietary energy (DEI) and protein intake (DPI) estimated by 3-day diet histories, were determined 6 and 9 months after the beginning of PD, when patients had RRF (period 1), and 6 and 9 months after the loss of RRF (period 2). The mean data obtained in both periods were compared. The best determinants for the changes in DEI and DPI after the loss of RRF were also investigated. RESULTS: Mean total Kt/V urea was very similar in both periods (2.16+/-0.32 vs 2.15+/-0.18), although creatinine clearance decreased significantly after the loss of RRF (74.41+/-12.28 L/week/1.73 m2 vs 56.78+/-11.77 L/week/1.73 m2, p = 0.0001). Absolute and normalized DPI values for actual body weight decreased after the loss of RRF (68.21+/-11.87 g/kg vs 59.27+/-13.66 g/kg, p = 0.02; and 1.17+/-0.32 g/kg/day vs 0.97+/-0.32 g/kg/day, p = 0.01). Although the energy delivered by peritoneal glucose uptake increased significantly after the loss of RRF, the mean total energy intake (DEI plus peritoneal glucose uptake) was very similar in both periods (2141+/-339 kcal/day vs 2010+/-303 kcal/day, p = 0.13). However, the mean total energy intake normalized for actual body weight decreased significantly after the loss of RRF (37.5+/-10.1 kcal/kg/day vs 32.8+/-8.9 kcal/kg/day, p = 0.02). The changes in DEI and DPI between periods 1 and 2 correlated negatively with the difference of the energy delivered by peritoneal glucose uptake (r = 0.65, p = 0.05, and r = 0.88, p = 0.001, respectively). The magnitude of DPI changes between both periods correlated significantly with the magnitude of urinary Kt/V urea changes (r = 0.77, p = 0.01). However, there was no correlation between the changes in DPI and the changes in total Kt/V urea, total or renal creatinine clearance, or the length of time on PD. CONCLUSIONS: The loss of RRF led to a reduction in dietary caloric and protein intake. The magnitude of the reduction in the DPI was strongly correlated with the increase in the energy delivered by peritoneal glucose uptake and with the decrease in the urinary Kt/V urea, but not with the total Kt/V urea.