急性肝衰竭时肾功能障碍发生机理的探讨

本实验研究了半乳糖胺所致急性肝衰时内毒素血症和肾功能障碍的关系以及丹参的防治作用。实验结果表明、半乳糖胺所致肝衰的动物均伴有内毒素血症的发生、肾功能明显异常(Pcr,BUN升高,Ccr,UV,U_(Na)V降低,FE_(H2O),FE_(Na)增高)。经丹参治疗后内毒素血症明显减轻,肾功能也随之明显改善,从而提示内毒素血症和肾功能障碍密切相关。本实验结果证明,内毒素血症在肝肾综合征的发生,发展中是一个重要致病因素;丹参对肝肾综合征具有明显的防治作用。此外,半乳精胺所致肝衰竭模型同时也可用于肝肾综合征发病机理与防治的研究。     

Effect of anticoagulation upon nephron obstruction in experimental acute ischaemic renal failure. A morphological study

Ischaemic-reperfusion injury as a model of acute renal failure (ARF) results in increased macromolecular permeability, tubular obstruction, and renal oedema. To investigate the role for coagulation in this model, anticoagulated and saline-pretreated rats were subjected to 60 min unilateral renal artery occlusion (RAO). After 15 min of reflow, specimens were collected for electron and light microscopic examination. Morphometry was employed to study podocyte changes and Bowman's space dilatation as measures of increased permeability and tubular obstruction, respectively. After 15 min of reflow, Bowman's space increased significantly and the podocytes were markedly widened and flattened. Rats pretreated with heparin or warfarin showed less widening of Bowman's space than saline-treated rats, whereas no significant difference was seen regarding the podocyte changes. In saline-treated rats, fibrin-positive material was seen in the tubules but not in the urine sediments collected after 90 min of reflow, either due to fibrinolysis or poor urinary elimination. The results suggest that anticoagulation does not preclude the glomerular sieving of macromolecules, but seems to reduce tubular obstruction, probably by preventing conversion of filtered fibrinogen into fibrin.     

虫草肾康胶囊防治肾综合征出血热急性肾功能衰竭的临床观察

目的观察虫草肾康胶囊对肾综合征出血热（ＨＦＲＳ）急性肾功能衰竭（肾衰）的防治作用。方法将１５０例ＨＦＲＳ患者随机分为治疗组（７６例）和对照组（７４例）。两组均按不同病期给予病毒唑抗病毒,及以平衡盐液为主的综合治疗,治疗组加用虫草肾康胶囊（２７ｇ／次,每日３次）,用至多尿期结束。结果治疗组少尿发生率为１３０％（６／４６）,少尿持续２７±１６天,多尿持续６８±２９天,尿蛋白平均５１±２３天消失,血清肌酐（Ｓｃｒ）平均１０９±６２天恢复正常;在治疗５天、１０天时,治疗组血与尿β２微球蛋白水平均显著低于对照组;治疗组严重并发症发生率为１８４％（１４／７６）,治愈率为９４７％（７２／７６）,对照组分别为３３８％（２５／７４）、８７８％（６５／７４）。两组以上各项除治愈率外,余差异均有显著意义（Ｐ＜０．０１或Ｐ＜０．０５）。结论虫草肾康胶囊可减少ＨＦＲＳ急性肾衰的发生率,缩短急性肾衰的病程,从而降低患者的透析需要率,减少并发症,提高治愈率,且使用安全、方便,值得临床推广应用。     

Expression of epidermal growth factor and its receptor in rabbits with ischaemic acute renal failure

Urinary immunoreactive epidermal growth factor (EGF) levels decrease, and renal immunoreactive EGF levels increase in rats with ischaemic acute renal failure (ARF). We investigated the immunohistochemical localization of EGF and EGF receptor in rabbits with ischaemic ARF to clarify the significance of renal EGF. Male New Zealand White rabbits underwent right nephrectomy prior to a 60 min renal artery clamp. At 3, 6, 24, 48, 72 and 96 h after ischaemia, serum urea nitrogen and serum creatinine were determined. Guinea pig anti-rabbit EGF antibody and monoclonal anti-EGF receptor antibody were used for the primary incubation. EGF was immunolocalized to the ascending limb of Henle and the distal convoluted tubule in the normal right kidneys. However, in the post ischaemic left kidneys at 6, 24, 48 and 72 h, immunoreactivity of EGF was associated with proximal tubules. In the normal kidneys, antibody to EGF receptor reacted with distal tubules and collecting ducts. In the ischaemic kidneys, EGF receptor was localized in the basolateral membrane in the proximal tubules. The expression of EGF and EGF receptor in renal tubules may play an important role in repair following ischaemic renal damage.     

血清抗AT1、α1、β1和M2受体自身抗体与慢性肾功能不全的相关研究

目的：探讨抗血管紧张素Ⅱ受体1型（AT1-受体）、α1-肾上腺素受体（α1受体）、M2胆碱能受体（M2-受体）、β1岛肾上腺素受体（β1受体）自身抗体是否与慢性肾功能不全发病有关。方法：以合成的受体多肽片段为抗原，应用酶联免疫吸附测定（ELISA）技术检测。结果：慢性肾炎并肾功能不全组抗AT1、α1、β1和M2受体抗体阳性率分别为46．96％、43．93％、50．00％、40．90％，高血压合并肾损害分别为46．40％、46．40％、67．90％、46．4％，明显高于高血压无肾损害组和正常对照组（P〈0．01）。结论：抗G蛋白偶联型受体自身抗体可能与慢性肾功能不全发病有关。     

Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC

In this study, we analyzed the immunohistochemical and molecular profiles of an unusual RCC showed coexistent absence of INI1 and BRG1 expression, rhabdoid morphology, and poor prognosis. Histologically, the tumor had rhabdoid features, which were demonstrated by large round to polygonal cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm varying from abundant to scanty. Immunohistochemically, the tumor were positive for BRM, PBRM1, ARID1A, CD10, CKpan, Vimentin, carbonic anhydrase IX (CA-IX), and P504S (AMACR) but negative for INI1, BRG1, HMB45, melan A, CK7, CD117, Ksp-cadherin, TFEB, TFE3, and Cathepsin K. We detected all three exons status of the VHL gene of the tumor and observed 1 somatic mutations in 1st exon. Chromosome 3p deletion, coupled with polysomy of chromosome 3 was also found. Based on these findings, it is further indicated that in some cases, rhabdoid RCC may arise from clear cell RCC. SWI/SNF chromatin remodeling complex may be an attractive candidate for being the “second hit” in RCCs and may play an important role during tumor progression. The role of SWI/SNF complex in rhabdoid RCC should be further studied on a larger number of cases.     

中毒性急性肾衰早期肾近曲小管上皮细胞细胞骨架的改变

目的 :了解中毒性急性肾衰 (ARF)早期肾近曲小管上皮细胞 (PTC)细胞骨架微丝和微管的改变 ,并探讨其改变的机制。方法 :采用皮下注射氯化汞建立中毒性ARF模型 ,用免疫组化和电镜法观察中毒 6h和 12hPTC细胞骨架微丝和微管的改变 ,并用高效液相色谱法测试细胞内ATP水平。结果 :免疫组化显示微丝随着中毒时间的延长 ,PTC刷状缘损伤逐渐加重 ,胞浆内有片状肌动蛋白分布 ;电镜示中毒 6h微绒毛变成球形小体 ,中毒 12h微绒毛部分缺失 ;免疫组化微管示中毒 6hPTC严重受损 ,着色变浅、不规则 ,中毒 12h着色部分恢复 ;细胞内ATP水平随着中毒时间延长而逐渐下降。结论 :中毒性ARF时 ,PTC细胞骨架微丝和微管发生变化 ,微丝的改变可能与细胞内ATP水平相关。     

Intra- and extrarenal vascular changes in the acute renal failure of the rat caused by mercury chloride

Summary Histologic evidence of intrarenal vasomotor changes were observed in the rat in the course of acute renal failure caused by the injection of HgCl₂. Male Wistar rats injected s.c. with 2.5 or 4.7 mg HgCl₂ per kg b.wt. developed fibrinoid damage in the media segments of preglomerular renal vessels, mostly in the arcuate and interlobular arteries. The lesions were patchy and irregularly scattered throughout the kidneys. 24 h post-injection the lesions were very rare and of only mild degree, whereas they were fully developed and regularly seen 48 h post-injection. A high percentage of similar changes was found in certain extrarenal vascular areas especially in the mesentery and pancreas. The damaged vascular segments were usually dilated. The results of various trichrome stains and histochemical reactions suggested edema of vascular smooth muscle cells and imbibition of the media by blood plasma substances, sometimes reaching the degree of fibrinoid necrosis. These findings were confirmed by electron microscopy. The imbibition of the smooth muscle cells by blood plasma material was clearly evidenced by the demonstration of intracellular fibrin precipitations. In connection with the degeneration of smooth muscle cells, accumulations of crystal-like fibrin formations could often be shown. Subendothelial fibrin formations were not observed. 96 h after the 2.5 mg injection the changes were already regressing, but edema of the vascular wall and signs of disturbed vasotonia persisted for several days. The maximum of the vascular changes usually coincided with the maximum of azotemia and the formation of debris cylinders in the renal tubules. However, no clear relationship was recognizable in individual cases between vascular damage, extent of tubular necrosis and renal function. The pathogenesis of the vascular changes is obscure, but neurogenic factors, increased release of catecholamines and/or vasoactive agents of renal origin in connection with other factors might play a decisive role. Arterial hypertension was absent. It is assumed that the structural damage of the vascular media is mainly brought about by prolonged or recurring vasospasms, or by alternating spasm and vasodilatation with local ischemia and increased tension of the vascular wall in the dilated segments. The altered function and structure of the vascular wall might, to a certain extent, contribute to renal insufficiency.Part of this work has been communicated at the 59, meeting of the German Society of Pathology, Kiel, May 20–24, 1975 (Verh. Dtsch. Ges. Path. 59, 454 (1975)) and at the Hacettepe University of Ankara (Turkey), June 22, 1976     

Intra- and extrarenal vascular changes in the acute renal failure of the rat caused by high-dose folic acid injection

Summary Male Wistar rats were investigated 9, 24 and 48 h and 4 and 8 days after a single s.c. injection of 500 mg folic acid (FA)/kg b.wt. dissolved in 0.3 M NaHCO₃. Temporary acute renal failure (ARF) developed after the injection. In the early stage of ARF most renal tubules appeared to be obstructed mainly by intratubular FA-precipitates. Necrosis of tubular epithelium developed at the same time. Its maximum extent was reached 48 h post-injection, particularly in the partes rectae of the proximal tubules. By this time the FA-precipitates had already diminished and were predominantly localized in the ascending thick limb of Henle's loop. Signs of intrarenal vasomotor changes and structural lesions of the vascular wall were also found. The most impressive finding was the development of fibrinoid medial lesions, mostly in the arcuate and interlobar arteries. The smooth muscle cells (SMC) of these generally dilated vascular segments appeared to be edematous and had imbibed blood plasma material, some had become necrotic. In many of these damaged cells intracellular fibrin (or fibrinogen) precipitates were seen. Subendothelial fibrin deposits were not detected. The vascular lesions were patchy and irregularly scattered throughout the kidneys but were also found in the pancreas, mesentery, heart, occasionally in the brain, and, in one rat, also in the liver. They occurred as early as 9 h post-injection but reached their greatest renal and extrarenal extent 48 h post-injection when azotemia, electrolyte disturbances and tubular damage were likewise at a maximum. Systemic arterial blood pressure was not elevated. The fibrinoid lesions were decreased 4 days post-injection and had completely disappeared (with one exception) 8 days post-injection. Residual damage and reactive changes, however, seemed to persist for some time. The regression of the vascular lesions was accompanied by regeneration of the tubular epithelium and marked improvement of renal function. FA-precipitation, tubular necrosis, vascular lesions and renal insufficiency were largely prevented or at least diminished by further alkalinization of the injection solution (using 1 M NaHCO₃ as solvent). It is concluded that the intratubular precipitation of FA in the main experiment resulted in functional tubular obstruction which induced considerable vasomotor changes, and thereby vascular lesions and circulatory disturbances — probably independent from the juxtaglomerular apparatus. The circulatory disturbances might be of special importance in the maintenance of FA-induced ARF. A temporary impairment of renal autoregulation might be considered since this autoregulation depends on the functional integrity of the renal vessels.Dr. Dieker is senior nephrologist at the Kreiskrankenhaus Siegen, Haus Hüttental     

Important role for fibronectin-EIIIA during renal tubular repair and cellular recovery in uranyl acetate-induced acute renal failure of rats

The present study was designed to identify the source and kinetics of an alternatively spliced "embryonic" cellular fibronectin EIIIA (cFn-EIIIA) in relation to regenerating renal tubules in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. Damage of the proximal tubules was found as early as day 2 after induction of ARF, peaked at day 5, and was almost substituted by epithelial relining by day 7. Immunohistochemistry showed de novo deposition of cFn-EIIIA in peritubular regions as early as day 2, then on the tubular basement membrane (TBM) after day 4. 1 Integrin, the receptor for Fn, was mainly found at the basal side of tubules in the normal control and increased in the interstitium after induction of ARF, but the staining pattern gradually returned to the control after day 7. Immunoelectron microscopy revealed that cFn-EIIIA was produced initially by the peritubular endothelium and later by fibroblastic cells and was deposited to the TBM, on which regenerating tubules proliferated, probably with cFn-EIIIA production. 1 Integrin was expressed in cFn-EIIIA-producing cells, especially in regenerating tubular cells, suggesting that cFn-EIIIA signal transduction affects regenerating tubules. Transforming growth factor (TGF)-1 was found in some damaged proximal tubules and interstitial cells after induction of ARF and later in the regenerating tubules. CFn-EIIIA and 1 integrin mRNA levels were upregulated as early as day 2. TGF-1 mRNA level significantly increased after day 3, suggesting a modulatory role for TGF-1 on cFn-EIIIA production, but not by day 2. Our data suggest that cFn-EIIIA production by the endothelium during the very early response to tubular injury and by fibroblastic cells and regenerating tubules may play an important role in the cellular recovery of UA-induced ARF in rats.     

急性肝衰竭小鼠线粒体分裂蛋白DRP1在肝脏和大脑皮层的表达变化

目的:观察C57小鼠急性肝衰竭(acute liver failure,ALF)过程中线粒体分裂蛋白(dynamic-related protein 1,DRP1)在肝脏和大脑皮层中的变化及与肝衰竭的相关性。方法:C57/BL小鼠,随机分为对照组、ALF1d、4 d、7 d组。腹膜腔内注射硫代乙酰胺(TAA)建立ALF模型,利用高架十字和旷场实验测定行为学,取血清检测谷氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平;之后取肝组织,HE染色观察肝组织的病理变化;用Western Blot和RT-q PCR检测DRP1在肝脏和大脑皮层中蛋白及mRNA水平的表达变化。结果:(1)行为学结果显示:ALF各组小鼠自发活动及探索行为均明显降低(P0.05);(2)肝功检测ALF组ALT、AST表达水平明显升高(P0.05);(3)肝组织病理学检查ALF组1 d时肝细胞出现大面积坏死,7 d时肝细胞坏死较1 d、4 d缓解;(4)Western Blot检测DRP1在ALF全肝组织和肝线粒体中明显降低(P0.05);而在大脑皮层全组织蛋白中明显升高(P0.05),但在提取的线粒体中则无明显改变(P0.05);(5)RT-q PCR检测DRP1在肝组织中ALF各组中表达明显降低(P0.05);而在大脑皮层组织中1 d时表达增多,持续到4 d,在7 d时恢复(P0.05)。结论:DRP1在急性肝衰竭小鼠的肝脏和大脑皮层中对线粒体形态学发挥着重要的作用。     

Ki67反义多肽核酸抑制肾癌生长的体外及动物实验研究

为研究肿瘤增殖基因Ki67反义多肽核酸(AS-PNAs)对人肾癌细胞的体内外抑制作用.将AS-PNAs(10.0μmol/L)转染人肾癌786-0细胞,采用免疫组化、Western印迹技术检测Ki67表达;3H-TdR掺入试验检测细胞增殖;免疫组化TUNEL法检测细胞凋亡。裸鼠移植瘤内注射AS-PNAs(10.0μmol/L)连续4d后,第3、6、12天处死小鼠,取瘤组织检测肿瘤体积、Ki67表达、细胞凋亡。结果发现,AS-PNAs处理组786-0细胞Ki67表达明显降低,3H-TdR掺入率明显降低,细胞凋亡率明显增加,与随机PNAs对照组比较差异均有显著性(P<0.01)。动物实验AS-PNAs处理组小鼠肿瘤体积明显缩小,Ki-67抗原表达明显降低,细胞凋亡明显增加,与对照组比较差异均有显著性(P<0.01)。Ki67基囚AS-PNAs在体外及动物体内均有抑制增殖、促进凋亡作用,是一种有前途的反义治疗药物。     

Gender and ethnic differences in the post-liver transplant outcomes of patients with autoimmune hepatitis with acute liver failure at initial presentation: a case-control study

Introduction

Autoimmune hepatitis (AIH) may initially present as acute liver failure (ALF). The outcome of liver transplantation (LT) in patients with AIH and ALF is not very well defined. We determined the outcome of LT in UNOS (United Network for Organ Sharing) status 1 adult patients with and without AIH using post-MELD (Model for End-Stage Liver Disease) UNOS data.

Material and methods

For each AIH patient, 3 patients with non-AIH, matched for age ±5 years and donor risk index (DRI) ±5 years, were identified; 200 patients (50 AIH, 150 non-AIH) were found eligible for the study.

Results

Patients with AIH were more likely to be female (p = 0.003), non-Caucasian (p = 0.009), have higher bilirubin (p = 0.003), longer waiting time (p = 0.01), and lower creatinine (p = 0.019). African American patients with AIH were younger (p = 0.003), had lower bilirubin (p = 0.037), and were more likely to have had a prior LT compared to Caucasians (p = 0.02). Kaplan-Meier analysis showed that 5-year post-LT survival was similar in those with and without AIH (p = 0.3). African American with AIH showed a trend for lower 5-year survival compared to Caucasians (55% vs. 80%, p = NS). Women had a better outcome, especially in those with non-AIH (p = 0.002).

Conclusions

Patients with AIH transplanted as status 1 have similar outcomes to those without AIH. Women with non-AIH-related ALF have better survival than their male counterparts.     

In vivo evaluation of the improved MCMS-0102 pacemaker with a rapid pacing mode for induction of experimental heart failure in animals

The MCMS-0102 cardiac pacemaker for rapid ventricular pacing to induce heart failure in animals has been improved in terms of miniaturization and performance. To determine the performance of the new MCMS-0102, six devices were implanted in beagle dogs, and two of these devices were reimplanted for continued pacing in a total of eight beagle dogs. The hearts were paced at 260 beats per minute for 4 weeks (P group: n = 8). The hemodynamic status of the P group was examined and compared with nonpaced dogs (NP group: n = 8). The neurohumoral status of the P group was evaluated before and after rapid pacing. Stable operation of the six devices during rapid pacing was confirmed using the telemetry system. Postmortem examinations revealed features similar to clinical heart failure characterized by massive ascites, pleural effusion, cardiomegaly, and liver congestion in all the paced dogs. Cardiac output was 1.1 ± 0.2 l/min in the NP group and 0.5 ± 0.1 l/min in the P group (P < 0.0001). The left atrial pressure and the central venous pressure of the P group and the NP group were 23 ± 6 versus 6 ± 2 mmHg (P < 0.0001) and 10 ± 3 versus 4 ± 3 mmHg (P < 0.001), respectively. In the paced dogs, plasma renin activity increased from 0.5 ± 0.4 to 8.5 ± 7.4 ng/ml/h (P < 0.05) and atrial natriuretic peptide levels increased from 69 ± 41 to 229 ± 72 pg/ml (P < 0.001). The improved MCMS-0102 was successfully implanted in beagle dogs and it succeeded in inducing the congestive heart failure model.     

Expression of CD25 is a specific and relatively sensitive marker for the Philadelphia chromosome (BCR-ABL1) translocation in pediatric B acute lymphoblastic leukemia

Background: Precursor B acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and overall, has an excellent prognosis. However, the Philadelphia chromosome translocation (Ph+), t(9;22)(q34;q11), is present in a small subset of patients and confers poor outcomes. CD25 (IL-2 receptor alpha chain) expression has been associated with Ph+ B-ALL in adults, but no similar study has been performed in pediatric B-ALL. Methods: A retrospective analysis of 221 consecutive pediatric patients with a diagnosis of B-ALL (blood and/or bone marrow) from 2009 to 2012 was performed to determine an association between Ph+ B-ALL and CD25 expression. A threshold of 25% was used to define positive cases for CD25 expression by flow cytometry. Results: There were 221 patients with a diagnosis of B-ALL ranging from 2 to 22 years (median, 6 years). Eight (3.6%) B-ALL patients were positive for the Philadelphia chromosome translocation (Ph+ B-ALL) and 213 were negative (Ph-negative B-ALL). CD25 expression was observed in 6 of 8 (75%) Ph+ B-ALL patients and 6 of 213 (2.8%) Ph-negative B-ALL patients. CD25 expression was significantly higher in Ph+ B-ALL compared to Ph-negative B-ALL, with median CD25 expression of 64% (range 0-93%) and 0.1% (range 0-91%), respectively (P ≤ 0.0002). Therefore, CD25 expression as a predictor of Ph+ B-ALL had 75% sensitivity, 97% specificity, 50% positive predictive value and 99% negative predictive value. Conclusions: CD25 expression is a specific and relatively sensitive marker for the identification of Ph+ B-ALL in the pediatric population.