Treatment Of Hemolytic Uremic Syndrome Research Articles

Research Advances on the Pathogenesis and Treatment of Hemolytic Uremic Syndrome --Review

Hemolytic uremic syndrome (HUS) is clinically rare, with high mortality and case fatality rates. In recent years, the research on HUS has been intensified and the pathophysiological mechanism has been continuously improved. At present, the main mechanism of pathogenesis is the excessive activation of complement alternative pathways mediated by complement-related gene mutations or the existence of antibodies. The treatment methods and strategies are also constantly updated, mainly including complement-blocking drugs such as Eculizumab, Lavalizumab, and Ravulizumab. In this review, the new developments in the pathogenesis and treatment of HUS is summarized, and provide references for the clinical treatment of HUS.

Case Report: Tackling Complement Hyperactivation With Eculizumab in Atypical Hemolytic Uremic Syndrome Triggered by COVID-19

Hemolytic uremic syndrome (HUS) is a rare life-threatening disease of unrestrained complement system dysregulation, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure in genetically predisposed individuals. In this report, we describe two cases of SARS-CoV-2–associated HUS treated with eculizumab, a C5-blocking monoclonal antibody reported to be remarkably effective in the treatment of HUS. Detailed biochemical and genetic complement system analysis is reported, and the prompt clinical response after C5 pharmacological blockade is documented. Our report provides the rationale and supports the use of terminal complement pathway inhibition for the treatment of SARS-CoV-2–associated HUS.

Impact of a multidisciplinary team for the management of thrombotic microangiopathy.

BackgroundThrombotic microangiopathy (TMA) is an important complication associated with several diseases that are rare and life-threatening. TMA is common to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP is defined by a severe deficiency of ADAMTS13, and early treatment is associated with good prognosis. The diagnosis of HUS can be difficult due to the potential multiple etiologies, and the best treatment option in most cases is not well-established yet. The implementation of a multidisciplinary team (MDT) could decrease the time to diagnosis and treatment for HUS and may improve the outcomes of these patients.ObjectiveTo determine the impact of MDT on morbidity and mortality [death or chronic renal replacement therapy (CRRT) requirements], incidence and response time [(RT) defined as the period between hospital admission and the first day of direct therapy administration], length of stay at an intensive care unit (ICU-LOS) and total hospitalization (T-LOS) were also assessed.MethodsWe compared a pre-MDT implementation period (from January/2008 to May/2016) versus post-MDT period (from May/2016 to December/2016). The screening TMA diagnosis was made according the following criteria: hemolytic anemia, thrombocytopenia and acute renal damage and without ADAMTS13 deficiency. An online chat was implemented to provide instant medical information.ResultsTwenty-eight patients were included. The incidence changed from 2.3 cases/pre-MDT: (all cases: n = 18) to 10 cases/year post-MDT (all cases: n = 10). Two patients died in pre-MDT and post- MDT (11% versus 20%, P = 0.60). From pre-MDT, the number of patients who required CRRT by post-MDT decreased from 7 (39%) to 0, P = 0.03. Similarly, RT, ICU-LOS and T-LOS [median(p25-p75)] decreased from 10 (2–12) days to 0.5 (0–1.5) days, P = 0.04, from 16 (9–30) days to 10 (4–13) days, P = 0.01 and from 33 (22–53) days to 16 (12–32) days, P < 0.01, respectively.ConclusionMDT implementation was associated with a greater number of patients who meet TMA criteria. A decrease in the RT and T-LOS periods were observed and associated with better outcomes in these patients.

Hemolytic uremic syndrome associated with methylmalonic acidemia

Methylmalonic acidemia(MMA) is one of the most common diseases of autosomal recessive inherited organic acid metabolic disorder, which can cause multiple organ involvement.It can be found in infants or even in the neonatal period and be manifested as feeding difficulty, repeated vomiting, convulsions, abnormal muscle tension, mental retardation, hemolytic uremic syndrome(HUS), etc.In which HUS caused by MMA is better and better known by pediatricians when treating renal diseases while the diagnosis rate is increasing year by year.This article reviews the epidemiology, etiology, pathogenesis, clinical manifestations and treatment of HUS associated with MMA. Key words: Methymalonicacademia; Hemolytic uremic syndrome; Hydroxocobalamin

Hemolytic uremic syndrome in children~-- a concise review

The hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, micro-angiopathic hemolytic anemia and acute renal failure. This review provides a comprehensive overview of the existing literature on the epidemiology, etiology, pathogenesis, clinical presentation, diagnosi s and management of HUS. The ongoing controversy regarding the role of antibiotics during the acute enteric phase of the classical HUS and the challenges involved in the management of the atypical diseases are highlighted. The most common cause of HUS is systemic uptake of toxins, and develops in 5-10% of children exposed to verocytotoxin-producing Escherichia coli O157:H7. Children below the age of 5 years are the most susceptible hosts and the main route of spread is by fecal-oral transmission. Other infective agents and complement genetic abnormalities are responsible for 10% of cases, referred to as atypical HUS. The characteristic pathologic findings in HUS are renal endoth elial swelling, thrombi in the arterioles and capillaries, and su bendothelial fibrin deposits. After 30 years of discovering Shiga toxins and over 15 years after associating it with the development of HUS, there are neither specific predictive factors to ident ify the most susceptible patients after an infection with E. coli 0157:H7 nor specific treatment for HUS once it has become esta blished. Treatment of HUS is mainly supportive. The introduction of specific toxin neutralizing agents has proven disappointing in clinical practice. Recent trials of E. coli O157:H7 O-specific conjugated polysaccharide vaccines app ear promising in preventing the development of HUS.

Role of bacteriophages in STEC infections: new implications for the design of prophylactic and treatment approaches.

Shiga toxin (Stx) is considered the main virulence factor in Shiga toxin-producing Escherichia coli (STEC) infections. Previously we reported the expression of biologically active Stx by eukaryotic cells in vitro and in vivo following transfection with plasmids encoding Stx under control of the native bacterial promoter (1,2). Since stx genes are present in the genome of lysogenic bacteriophages, here we evaluated the relevance of bacteriophages during STEC infection. We used the non-pathogenic E. coli C600 strain carrying a lysogenic 933W mutant bacteriophage in which the stx operon was replaced by a gene encoding the green fluorescent protein (GFP). Tracking GFP expression using an In Vivo Imaging System (IVIS), we detected fluorescence in liver, kidney, and intestine of mice infected with the recombinant E. coli strain after treatment with ciprofloxacin, which induces the lytic replication and release of bacteriophages. In addition, we showed that chitosan, a linear polysaccharide composed of d-glucosamine residues and with a number of commercial and biomedical uses, had strong anti-bacteriophage effects, as demonstrated at in vitro and in vivo conditions. These findings bring promising perspectives for the prevention and treatment of haemolytic uremic syndrome (HUS) cases.

Role of bacteriophages in STEC infections: new implications for the design of prophylactic and treatment approaches

Shiga toxin (Stx) is considered the main virulence factor in Shiga toxin-producing Escherichia coli (STEC) infections. Previously we reported the expression of biologically active Stx by eukaryotic cells in vitro and in vivo following transfection with plasmids encoding Stx under control of the native bacterial promoter. Since stx genes are present in the genome of lysogenic bacteriophages, here we evaluated the relevance of bacteriophages during STEC infection. We used the non-pathogenic E. coli K12 strain carrying a lysogenic 933W mutant bacteriophage in which the stx operon was replaced by a gene encoding the green fluorescent protein (GFP). Tracking GFP expression using an In Vivo Imaging System (IVIS), we detected fluorescence in liver, kidney, and intestine of mice infected with the recombinant E. coli strain after treatment with ciprofloxacin, which induces the lytic replication and release of bacteriophages. In addition, we showed that chitosan, a linear polysaccharide composed of D-glucosamine residues and with a number of commercial and biomedical uses, had strong anti-bacteriophage effects, as demonstrated in vitro and in vivo. These findings bring promising perspectives for the prevention and treatment of hemolytic uremic syndrome (HUS) cases.

Role of bacteriophages in STEC infections: new implications for the design of prophylactic and treatment approaches

Shiga toxin (Stx) is considered the main virulence factor in Shiga toxin-producing Escherichia coli (STEC) infections. Previously we reported the expression of biologically active Stx by eukaryotic cells in vitro and in vivo following transfection with plasmids encoding Stx under control of the native bacterial promoter. Since stx genes are present in the genome of lysogenic bacteriophages, here we evaluated the relevance of bacteriophages during STEC infection. We used the non-pathogenic E. coli K12 strain carrying a lysogenic 933W mutant bacteriophage in which the stx operon was replaced by a gene encoding the green fluorescent protein (GFP). Tracking GFP expression using an In Vivo Imaging System (IVIS), we detected fluorescence in liver, kidney, and intestine of mice infected with the recombinant E. coli strain after treatment with ciprofloxacin, which induces the lytic replication and release of bacteriophages. In addition, we showed that chitosan, a linear polysaccharide composed of D-glucosamine residues and with a number of commercial and biomedical uses, had strong anti-bacteriophage effects, as demonstrated in vitro and in vivo . These findings bring promising perspectives for the prevention and treatment of hemolytic uremic syndrome (HUS) cases.

Lessons Learned From Outbreaks of Shiga Toxin Producing Escherichia coli.

In 2011, a large outbreak caused by a Shiga toxin producing E. coli (STEC) occurred in Northern Germany, with a satellite outbreak in Western France, including the highest number of hemolytic uremic syndrome (HUS) cases ever encountered during a STEC outbreak. The outbreak strain was characterized as an enteroaggregative E. coli of serotype O104:H4 expressing a phage-encoded Shiga toxin 2. The majority of STEC infections and HUS cases were observed in adults, with a preponderance of the female gender. The outbreak imposed huge challenges on clinicians, microbiologists, and epidemiologists but also provided important new insight for the understanding of STEC infection. Thus, novel therapeutic strategies in the treatment of HUS in adults and for decolonization of long-term STEC carriers were evaluated. This review highlights the unusual features of the recent O104:H4 outbreak and focuses on emerging new strategies in diagnostics and treatment of acute STEC-related disease, as well as STEC long-term carriage.

Application of plasma exchange in the treatment of hemolytic uremic syndrome

Objective To investigate the significance of plasma exchange (PE) treatment on children with hemolytic uremic syndrome (HUS).Methods From Jan 2008 to Dec 2010,16 patients diagnosed with HUS were included in this study,and PE was carried out on them.Frozen plasma was taken as replacement fluid,and the treatment time was 2 to 3 hours per time.Results All the 16 patients after PE treatment were survived without any apparent complications.The condition obviously alleviated after initial treatment.In 12 to 72hours,the icterus disappeared,serum creatinine [ ( 385.0 ± 189.4 ) μmol/L vs ( 100.0 ± 19.3 ) μmol/L ] and lactate dehydrogenase [ (799.3 ± 289.8 ) U/L vs (300.0 ± 100.4) U/L ] declined obviously ( P ＜ 0.05 ) and platelet count [ (45.0 ± 18.8 ) × 109/L vs ( 120.0 ± 20.0 ) × 109/L ],hemoglobin [ ( 59.3 ± 15.3 ) g/L vs ( 120.0 ± 18.3) g/L] rised( P ＜ 0.05 ).In the end,symptoms disappeared in 15 patients,laboratory examination returned to normal in 14 cases.Hospitalization time was 15 to 57 days.Conclusion PE can effectively relieve the illness and remove plasma pathogenic substances,block the pathological process of HUS and supply useful ingredients.Recommend PE as the fhst option in the treatment of HUS. Key words: Plasma exchange; Hemolytic uremic syndrome; Children

Extensive hemispheric diffusion restriction in haemolytic uremic syndrome

Haemolytic uremic syndrome (HUS) is a rare multi-organ disease affecting predominantly children between 1 and 4 years of age with an incidence of 1 per 50,000. It is caused by verotoxin-producing enterohaemorrhagic Escherichia coli (EHEC) infection. Neurological symptoms are reported in 20–50% of cases and represent the major cause of morbidity and mortality in patients with HUS. The neurological symptoms vary widely and may include visual disturbances, seizures, alteration of consciousness, hemiparesis, and brainstem symptoms. 1 Toldo I. Manara R. Cogo P. et al. Diffusion-weighted imaging findings in hemolytic uremic syndrome with central nervous system involvement. J Child Neurol. 2009; 24: 247-250 Crossref PubMed Scopus (13) Google Scholar The pathogenesis of the central nervous involvement is not fully understood. Putative mechanisms include thrombotic microangiopathy of cerebral arterioles, haemorrhage due to secondary coagulopathy, direct verotoxin neurotoxicity, and metabolic derangements. 1 Toldo I. Manara R. Cogo P. et al. Diffusion-weighted imaging findings in hemolytic uremic syndrome with central nervous system involvement. J Child Neurol. 2009; 24: 247-250 Crossref PubMed Scopus (13) Google Scholar , 2 Eriksson K.J. Boyd S.G. Tasker R.C. Acute neurology and neurophysiology of haemolytic-uraemic syndrome. Arch Dis Child. 2001; 84: 434-435 Crossref PubMed Scopus (59) Google Scholar , 3 Kaplan B.S. Meyers K.E. Schulman S.L. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998; 9: 1126-1133 PubMed Google Scholar , 4 Upadhyaya K. Barwick K. Fishaut M. et al. The importance of nonrenal involvement in hemolytic-uremic syndrome. Pediatrics. 1980; 65: 115-120 PubMed Google Scholar We report the case of child with typical HUS. Details of the clinical course and treatment have been reported by Lapeyraque et al. 5 Lapeyraque A.L. Malina M. Fremeaux-Bacchi V. et al. Complement blockade in severe Shiga-toxin-associated HUS. N Engl J Med. May 2011; PubMed Google Scholar

Therapeutic Apheresis in the Treatment of Hemolytic Uremic Syndrome in View of Pathophysiological Aspects

Hemolytic-uremic syndrome (HUS) is a disease that can lead to acute kidney injury and often to other serious sequelae, including death. The disease is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In view of the different courses of HUS, a minimum of three different pathogenetic types leading to HUS can be subdivided as follows: HUS caused by infection, idiopathic HUS (non-Shiga toxin HUS), and HUS in systemic diseases and after toxin exposure. The etiology and pathogenesis of HUS are not completely understood and its therapy is complicated. After the introduction of therapeutic apheresis as a supportive therapy in HUS, several authors reported successful treatment in more than 87% of treated patients. The supportive therapy is indicated basically in severe courses of HUS and is superior to available therapy interventions.

Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome

This guideline for the investigation and initial treatment of atypical hemolytic uremic syndrome (HUS) is intended to offer an approach based on opinion, as evidence is lacking. It builds on the current ability to identify the etiology of specific diagnostic sub-groups of HUS. HUS in children is mostly due to infection, enterohemorrhagic Escherichia coli (EHEC), Shigella dysenteriae type 1 in some geographic regions, and invasive Streptococcus pneumoniae. These sub-groups are relatively straightforward to diagnose. Their management, which is outside the remit of this guideline, is related to control of infection where that is necessary and supportive measures for the anemia and acute renal failure. A thorough investigation of the remainder of childhood HUS cases, commonly referred to as "atypical" HUS, will reveal a risk factor for the syndrome in approximately 60% of cases. Disorders of complement regulation are, numerically, the most important. The outcome for children with atypical HUS is poor, and, because of the rarity of these disorders, clinical experience is scanty. Some cases of complement dysfunction appear to respond to plasma therapy. The therapeutic part of this guideline is the consensus of the contributing authors and is based on limited information from uncontrolled studies. The guideline proposes urgent and empirical plasmapheresis replacement with whole plasma fraction for the first month after diagnosis. This should only be undertaken in specialized pediatric nephrology centers where appropriate medical and nursing skills are available. The guideline includes defined terminology and audit points so that the early clinical effectiveness of the strategy can be evaluated.

Advances in the treatment of hemolytic uremic syndrome in children

溶血尿毒综合征(HUS)是以微血管病性溶血性贫血、急性肾功能衰竭和血小板减少为主要特征的临床综合征.该文综述r国内外关于HUS的治疗方案,目前公认的有效措施包括急性期对于肾功能衰竭的综合治疗、预防并发症的发牛、必要时予血浆置换或血浆输注以及早期透析(血液透析或腹膜透析)等.对于小典型HUS,治疗的重点在于纠正补体调节因子的缺陷.急性期后则应根据不同的临床表现给予相应的治疗,早期限制蛋白质摄入和长期应刚血管紧张素转换酶抑制剂是延缓.肾损害进程、改善预后的主要方法。

Human protein C concentrate in the treatment of hemolytic uremic syndrome

Human protein C concentrate in the treatment of hemolytic uremic syndrome

Human protein C concentrate in the treatment of hemolytic uremic syndrome

Human protein C (PC) concentrate may anticipate thrombotic microangiopathy and facilitate fibrinolysis in the severe hemolytic uremic syndrome (HUS). We report the effects of PC in six HUS patients. HUS is characterized by a simultaneous occurrence of hemolytic anemia, thrombocytopenia and acute renal failure. Postdiarrheal HUS is often based on an infection with EHEC producing Shiga toxins. Our current pathogenetic understanding is that Shiga toxins cause endothelial injury, leading to thrombotic microangiopathy. There is still a 5% rate of mortality particularly caused by cerebral involvement.

The longest known interval between commencement of intravenous infusion of gabexate mesilate and the development of a hand cyst

A 4-year-old Japanese girl received a continuous infusion of gabexate mesilate (200 mg/25 ml 5% glucose) for 6 days via a peripheral vein for the treatment of hemolytic uremic syndrome. After administration, pigmentation was seen at the needle entry point on her right hand. Six years later, an elastic, hard subcutaneous mass was noted around this pigmentation. The tumor was encapsulated and partially adherent to the tendon of the extensor digitorum muscle. Histological examination revealed a membranous structure consisting of fibrous tissue containing many inflammatory cells. This was considered to be a side effect of gabexate mesilate.

Potential therapeutic agents for the prevention and treatment of haemolytic uraemic syndrome in shiga toxin producing Escherichia coli infection.

Shiga toxin producing Escherichia coli (STEC) cause a wide spectrum of disease ranging from asymptomatic carriage through to haemorrhagic colitis and the haemolytic uraemic syndrome. There are no current therapeutic interventions available in clinical practice that can prevent the development of haemolytic uraemic syndrome. A number of newly developed agents offer the potential for the treatment of STEC-associated disease. Three different classes of agent designed to bind and inactivate shiga toxin have now been developed. Synthetic toxin binders, recombinant bacteria and monoclonal antibodies provide potentially potent agents that could prevent the development of haemolytic uraemic syndrome. These agents have been shown in animal models of STEC disease to be effective. A recent clinical trial of one synthetic toxin binder showed no benefit in established haemolytic uraemic syndrome. More potent toxin binders, however, have since been developed and await human clinical trials. It is likely to be important that these agents are administered early in the course of disease in order to have maximum efficacy. Although rapid diagnostic techniques are available for the diagnosis of STEC disease, they still rely on stool culture. Clinicians need to maintain a high level of suspicion of STEC disease as the diagnosis is often made on epidemiological and clinical grounds. This will allow potential cases to be identified early and treated appropriately.

Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection.

Hemolytic-uremic syndrome (HUS) is a serious complication predominantly associated with infection by enterohemorrhagic Escherichia coli (EHEC), such as E. coli O157:H7. EHEC can produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2), both of which are exotoxins comprised of active (A) and binding (B) subunits. In piglets and mice, Stx can induce fatal neurological symptoms. Polyclonal Stx2 antiserum can prevent these effects in piglets infected with the Stx2-producing E. coli O157:H7 strain 86-24. Human monoclonal antibodies (HuMAbs) against Stx2 were developed as potential passive immunotherapeutic reagents for the prevention and/or treatment of HUS. Transgenic mice bearing unrearranged human immunoglobulin (Ig) heavy and kappa light chain loci (HuMAb___Mouse) were immunized with formalin-inactivated Stx2. Thirty-seven stable hybridomas secreting Stx2-specific HuMAbs were isolated: 33 IgG1kappa A-subunit-specific and 3 IgG1kappa and 1 IgG3kappa B-subunit-specific antibodies. Six IgG1kappa A-subunit-specific (1G3, 2F10, 3E9, 4H9, 5A4, and 5C12) and two IgG1kappa B-subunit-specific (5H8 and 6G3) HuMAbs demonstrated neutralization of > 95% activity of 1 ng of Stx2 in the presence of 0.04 microg of HuMAb in vitro and significant prolongation of survival of mice given 50 microg of HuMAb intraperitoneally (i.p.) and 25 ng of Stx2 intravenously. When administered i.p. to gnotobiotic piglets 6 or 12 h after infection with E. coli O157:H7 strain 86-24, HuMAbs 2F10, 3E9, 5H8, and 5C12 prolonged survival and prevented development of fatal neurological signs and cerebral lesions. The Stx2-neutralizing ability of these HuMAbs could potentially be used clinically to passively protect against HUS development in individuals infected with Stx-producing bacteria, including E. coli O157:H7.

The pathogenesis and treatment of hemolytic uremic syndrome.

Journal of the American Society of Nephrology : JASN 9(6):p 1126-1133, June 1998. | DOI: 10.1681/ASN.V961126