血栓性微血管病的新进展

血栓性微血管病(thrombotic microangiopathies)的主要病理特征是微血管血栓形成.以此为特征的血栓性微血管病包括两个疾病:血栓性血小板减少性紫癜(thrombocytic thrombocytopenic purpura,TTP)以及溶血性尿毒症综合征(hemolytic uremic syndrome,HUS).TTP最早于1924年由Moschcowitz报道,TTP的微血栓呈全身性分布.HUS最早于1955年由Gasser等人报道,HUS的微血栓主要分布于肾.血栓性微血管病的发病机制在最近已获不少进展.     

溶血性尿毒症综合征一例的护理要点

溶血性尿毒症综合征(HUS)首先由Gasser于1955年报道,主要临床特征是微血管病性溶血性贫血,急性肾功能不全和血小板减少。典型的HUS住院见于婴儿和儿童,肾功能损害突出,原因是志贺毒素导致血管内皮细胞损伤[1]。我科于2012年5月收治1例HUS患     

维生素E治疗溶血尿毒综合征

有报道指出,前列腺环素的缺乏是溶血尿毒综合征(HUS)的发病机制之一。有人观察到HUS患者的血浆不同于正常人,它不能刺激小鼠主动脉环产生前列腺环素,表明HUS患者血浆中缺乏一种刺激前列腺环素生成的因子。最近研究揭示HUS患者血中存在一种前列腺环素合成酶的抑制物。某种脂类过氧化物可     

血栓性微血管病肾损害

血栓性微血管病（thrombotic microangiopathy，TMA）是一组急性临床病理综合征，其主要特征是微血管病性溶血性贫血、血小板下降以及微血管内血栓形成。肾脏受累时多引起急性肾衰竭。经典的TMA包括溶血尿毒综合征（HUS）和血栓性血小板减少性紫癜（TTP），其它还有恶性高血压、硬皮病肾危相、妊娠相关肾病等。尽管病因和发病机制多样，最终均可导致微血管内皮细胞损伤，诱发微血栓形成。     

溶血尿毒综合征有关问题的研究进展

溶血尿毒综合征（HUS）以内皮细胞受损继而血小板性血栓形成、微血管性溶血、肾功能损伤为特点，可以由许多种因素诱发。近年来HUS的病因、诊断和治疗取得显著进展，同时也存在一些争议。本文结合国内外研究进展，就HUS分类、感染导致HUS、补体调节异常HUS以及治疗方面的有关问题展开讨论。     

血浆置换与血液透析串联治疗血栓性血小板减少性紫癜及溶血尿毒综合征

血栓性血小板减少性紫癜（TTP）及溶血尿毒综合征（HUS）均属于以血栓性微血管病为主的综合征，传统血浆置换（PE）治疗副反应发生率较高。2003年以来我们采用血浆置换与血液透析串联（PE＋HD）的方法并结合药物，治疗了4例TTP及HUS患者，取得了较好效果。     

肾移植术后的溶血性尿毒综合征

溶血性尿毒综合征(HUS)是移植肾功能障碍的一个少见原因,治疗困难、预后不良。肾移植术后的HUS包括原发HUS的复发和新发HUS两类,后者主要为药物(免疫抑制剂环孢素A和他克莫司、抗血小板药物氯吡格雷等)引起。新发HUS的主要高危因素是感染、急性排斥反应和免疫抑制剂浓度过高。治疗方法主要有:停用诱发药物、调整免疫抑制方案、血浆置换、输注新鲜冰冻血浆和抗凝治疗等。     

非典型溶血尿毒综合征的研究进展

正溶血尿毒综合征(HUS)是一种以微血管性溶血性贫血、血小板减少以及急性肾衰竭为主要临床特征的疾病,其根据病因不同分为典型HUS和非典型HUS(aHUS)。典型HUS是由以大肠杆菌O157:H7为主的产志贺毒素细菌引起,因此又被称为腹泻相关HUS,起初aHUS也因此被定义为非腹泻相关型HUS。但自2016年起,根据最新的国际分类,aHUS特指补体替代途径调控异常所引起的血栓性微     

溶血性尿毒症性综合征的血液透析治疗

溶血性尿毒症性综合征（HUS）最早见于1955年Gasser的报道,主要临床特征是微血管性溶血性贫血,急性肾功能不全和血小板减少。HUS在成人及小儿均可发病,但主要多见于小儿,是导致儿童急性肾衰竭的一个重要原因。成人HUS预后较差,多遗留慢性肾衰竭,需长期透析治疗。     

溶血性尿毒症综合征发病机制的研究进展

溶血性尿毒症综合征（hemo1ytic uremic syndrome,HUS）,于1955年首先由Gasser报道。它是一种以微血管性溶血性贫血、血小板减少和急性肾功能不全为临床特点的综合征。本文就近年来HUS的分类、病因及发病机制研究进展作一介绍。     

Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome

The typical form of hemolytic uremic syndrome (D+HUS) is a thrombotic microangiopathy that causes acute renal failure in children. The etiology of this disease is a toxin called Shiga-like toxin (Stx), present in certain strains of gram-negative bacteria. Vascular endothelial cell (EC) injury appears to be central in the pathogenesis of D+HUS. Thrombomodulin (TM) is a glycoprotein present in EC with anti-thrombogenic properties. The objective of this study was to investigate the effects of Stx on the surface expression of TM in EC using an in vitro culture of human glomerular microvascular endothelial cells. We also evaluated other inflammatory mediators [tumor necrosis factor- (TNF-) and lipopolysaccharide], which are known to increase Stx receptor expression and are potentially involved in the pathogenesis of D+HUS. Stx2 induced a significant decrease of TM expression in this cell type after pre-incubation with TNF-. This decrease could not be attributed to the inhibition of protein synthesis only, as cycloheximide, another inhibitor of protein synthesis, did not affect TM surface expression. These results suggest that the Stx2-induced decrease of TM expression in glomerular EC might contribute to the local procoagulant state present in D+HUS.     

Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome?

Thrombotic microangiopathy is characterized by microvascular thrombosis coupled with thrombocytopenia, hemolytic anemia, and red blood cell fragmentation. Familiar to nephrologists and hematologists alike, classically associated with thrombotic microangiopathy are the hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), the histories and presentations of which are closely intertwined. Not surprising, these two disorders are considered by many to be manifestations of the same disease process, whereas others consider HUS and TTP to be distinct clinical and pathologic entities. Herein are reviewed HUS and TTP along with recent progress shedding new light on possible shared pathophysiologic mechanisms for these two intriguing disorders.     

Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes

One of the requirements for an agent to cause hemolytic uremic syndrome (HUS) is its ability to injure endothelial cells. Shiga-like toxin (SLT) can do this. SLT is produced byEscherichia coli andShigella dysenteriae serotype 1; both have been implicated as causes of typical HUS. Endothelial cells have receptors (GB₃) for SLT and the toxin can inhibit eukaryotic protein synthesis, thereby causing cell death. Glomerular endothelial cell injury or death results in a decreased glomerular filtration rate and many of the perturbations seen in HUS. It is no longer certain that hemolysis is the result of a microangiopathy. Cell injury results in release of von Willebrand multimers; if these are ultra-large, thrombosis may ensue. There is also increasing evidence that neutrophils have a role in the pathogenesis of typical HUS.Streptococcus pneumoniae can also cause HUS and care must be taken to avoid giving plasma to patients withS. pneumoniae-associated HUS. There is compelling evidence that types of HUS are inherited by autosomal recessive and autosomal dominant modes. Patients with autosomal recessive HUS may have recurrent episodes. Mortality and morbidity rates are high for the inherited forms.     

Verotoxin (shiga toxin) sensitizes renal epithelial cells to increased heme toxicity: possible implications for the hemolytic uremic syndrome

Escherichia coli-derived verotoxins (VT; Shiga toxins) are causally related to the pathogenesis of enteropathic hemolytic uremic syndrome (HUS). Profound hemolysis is a defining feature of the disease, but it is not known whether the acute intravascular release of heme proteins contributes to HUS pathology. This study examined the biologic effects of hemin and VT by means of tubular epithelial-derived ACHN cells. Hemin at concentrations >/=200 microM caused cell rounding, spike formation, and detachment that was morphologically distinct from verocytotoxicity. VT caused apoptosis at concentrations >100 pM, as demonstrated by nuclear segmentation and poly(ADP-ribose) polymerase cleavage, whereas hemin-mediated injury of ACHN cells grown in serum-containing medium lacked attributes of programmed cell death. Pretreatment of ACHN monolayers with sublethal concentrations (1 to 10 pM) of VT for 12 to 18 h led to superadditive hemin-mediated cytotoxicity. This effect was not limited to ACHN cells, but was similarly noted in microvascular endothelial cells. Heme catabolism is regulated by (inducible) heme oxygenase-1 (HO-1). VT abrogated HO-1 expression in ACHN cells. Stimulation of cells for 6 h with CdCl(2), which markedly increased HO-1 expression before the addition of VT, blunted subsequent hemin injury. In conclusion, VT augments hemin-induced toxicity in renal tubular epithelial cells that can be reversed by prior induction of HO-1. It is proposed that VT subverts the physiologic defense against heme proteins by interfering with the regulated expression of HO-1 and that this mechanism contributes to the renal pathology in patients with Escherichia coli-associated HUS.     

Lack of specific binding of Shiga-like toxin (verocytotoxin) and non-specific interaction of Shiga-like toxin 2 antibody with human polymorphonuclear leucocytes.

BACKGROUND: After gastrointestinal infection with Shiga-like toxin (Stx) producing Escherichia coli, the toxin is transported from the intestine to the renal microvascular endothelium. This is the main target for Stx in humans. Previous studies indicated that polymorphonuclear leucocytes (PMN) could serve as carriers for Stx in the systemic circulation. As at a later stage we could not confirm these data, we performed new studies. METHODS: The binding of Stx1 to PMN was determined in vitro (isolated human PMN and whole blood) and in vivo (injection in mice). The specificity of binding of an antibody against Stx2 to PMN from patients with haemolytic uraemic syndrome (HUS) was determined. This was compared with binding to PMN from healthy controls, and patients after haemodialysis (HD) or on peritoneal dialysis (PD). Furthermore, PMN were incubated with Stx to study possible activation. RESULTS: No specific binding of Stx1 to PMN could be detected. After intravenous injection of the toxin in mice, it was not associated with PMN. The binding of an antibody against Stx2 to PMN was detected in both patients with HUS and patients after HD, but not in patients on PD. Stx was not able to activate PMN. CONCLUSIONS: PMN are not acting as transporter for Stx in the pathogenesis of HUS. The interaction of a Stx antibody with PMN from HUS patients is not specific as it can also be observed in patients after HD (possibly due to activation of the PMN). Therefore, binding of Stx antibody to PMN is not reliable as a diagnostic tool for HUS.     

Pathophysiology and management of thrombotic microangiopathies

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia, and thrombocytopenia in which endothelial dysfunction appears to be an important factor in the sequence of events leading to microvascular thrombosis. They are termed thrombotic microangiopathies (TMA). Differentiation of the several primary forms of TMA is crucial to predict disease outcome and to establish the most appropriate therapeutic approach. Typical verotoxin-associated HUS, mostly due to E.coli O157:H7 infection, is associated with prodromal diarrhea followed by acute renal failure, and considered a disease with a good outcome. Antibiotics are not necessary and antimotility agents are contraindicated. No specific therapies aimed at preventing or limiting the microangiopathic process have been proved to affect the course of the disease in children. Atypic HUS covers two clinical conditions: one characterized by severe gastrointestinal prodromes, acute onset anuria, and neurological involvement, and associated to high mortality rate; the second form without diarrhea prodromes but with progressive renal function deterioration and neurological involvement that resembles TTP. Supportive therapy is required in the diarrhea-associated form, while more specific therapies are needed in the latter form. Neurological symptoms usually dominate the clinical picture of acute TTP. Infusion or exchange of fresh frozen plasma have dramatically changed the outcome of a disease that in the sixties was almost invariably fatal. Relapsing episodes of TTP are being reported increasingly often because more patients recover from the initial acute episode thanks to improved treatments. Plasma infusion has been extensively used for this form of TTP, and remission of relapsing episodes documented in most cases. Plasma-resistant HUS or TTP have invariably a poor outcome if alternative treatments are not effective. Bilateral nephrectomy may be an effective rescue therapy for patients who failed to respond to plasma. Familial HUS/TTP is a form of TMA with recessive or dominant inheritance of unknown pathogenesis. The outcome is usually poor. In summary, a general consensus has been achieved that therapies (i.e. plasma exchange or infusion) aimed at stopping the microangiopathic process should always be tried in TTP and in adult and/or atypical forms of HUS to minimize the risk of death or long-term sequela. This approach is seldom effective in secondary forms whose outcome mainly depends on the prognosis of the underlying condition, and is not risk-effective in typical childhood HUS, that usually recovers spontaneously.     

Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome

The epidemic form of hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children and is characterized by a prodromal phase of sometimes bloody diarrhea. The role of verocytotoxin (VT)-producing Escherichia coli has been strongly implicated. Although antibodies against VT have been detected in the serum of patients with HUS, VT itself has never been detected in circulating blood. In this study, VT-2 was detected in the systemic circulation in 9 of 10 patients with the epidemic form of HUS. In those cases, VT-2 was bound exclusively to polymorphonuclear leukocytes (PMN). The detection of VT-2 bound to PMN was associated with the presence of diarrhea at the time the blood samples were obtained. The one patient for whom VT was not detected presented with atypical HUS. For 5 of the 10 patients with HUS who were studied, the time course of VT binding was analyzed; binding decreased in four patients. The finding of VT bound to PMN in the systemic circulation of patients with HUS is important for a clearer understanding of the pathogenesis of HUS and suggests new approaches for treatment in the future.     

Prostacyclin in diarrhoea-associated haemolytic uraemic syndrome

The role of prostacyclin (PGI₂) in the pathogenesis of haemolytic uraemic syndrome (HUS) is controversial. In part, confusion has been caused by failure to distinguish between two main sub-types of the syndrome: extrinsic, diarrhoea-associated HUS (D+ HUS), usually caused by infection with verocytotoxin-producingEscherichia coli orShigella dysenteriae, and the heterogeneous group of non-prodromal forms where intrinsic factors predominate (D– HUS). This paper critically reviews data confined to D+ HUS. Two methods have been used to assess PGI₂ synthesis; the generation of PGI₂ from endothelium in the presence of HUS plasma in vitro and the measurement of stable metabolites in body fluids. No concensus could be reached with regard to the former. The reported increase of PGI₂ stable metabolites in plasma may represent reduced clearance or increased carriage by plasma lipids. Apparent differences between studies of urinary excretion of PGI₂ metabolites may reflect the way excretion was expressed. If the metabolite concentration is factored for urinary creatinine, it appears that renal excretion and thus renal synthesis of PGI₂ is reduced. However, these are insufficient data on which to attribute the pathogenesis of D+ HUS to disordered PGI₂ metabolism.Presented at the Festschrift for Professor R. H. R. White on March 6, 1992, Birmingham, UK     

Does hemolytic uremic syndrome differ from thrombotic thrombocytopenic purpura?

Both hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are characterized by thrombotic microangiopathy (TMA), affecting mainly the kidney and brain, respectively. Diagnosis of HUS or TTP has been complicated by the fact that these disorders share several clinical characteristics, and by the dearth of knowledge regarding the pathogenesis of TMA. Advances in the identification of pathogenic features--deficiency of the metalloprotease ADAMTS13 in TTP and association of mutated complement proteins with atypical HUS--have gone some way towards improving clinicians' ability to distinguish between the two diseases. Here, we pose the following question: is it important to patient management that HUS be distinguished from TTP? By discussing what is known about the pathogenesis, clinical features and treatment of these two conditions we address this question, and propose a new nomenclature for TMA.     

Protective role of nitric oxide in mice with Shiga toxin-induced hemolytic uremic syndrome

BACKGROUND: Nitric oxide (NO) is an endogenous vasodilator and platelet inhibitor. An enhanced NO production has been detected in patients with hemolytic uremic syndrome (HUS), although its implication in HUS pathogenesis has not been clarified. METHODS: A mouse model of Shiga toxin 2 (Stx2)-induced HUS was used to study the role of NO in the development of the disease. Modulation of l-arginine-NO pathway was achieved by oral administration of NO synthase (NOS) substrate or inhibitors, and renal damage, mortality and platelet activity were evaluated. The involvement of platelets was studied by means of a specific anti-platelet antibody. RESULTS: Inhibition of NO generation by the NOS inhibitor L-NAME enhanced Stx2-mediated renal damage and lethality; this effect was prevented by the addition of l-arginine. The worsening effect of L-NAME involved enhanced Stx2-mediated platelet activation, and it was completely prevented by platelet depletion. CONCLUSIONS: NO exerts a protective role in the early pathogenesis of HUS, and its inhibition potentiates renal damage and mortality through a mechanism involving enhanced platelet activation.