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1.
Clin J Am Soc Nephrol ; 16(9): 1355-1364, 2021 09.
Article in English | MEDLINE | ID: mdl-34497111

ABSTRACT

BACKGROUND AND OBJECTIVES: In contrast to shigatoxin-associated Escherichia coli (STEC) causing hemolytic uremic syndrome, STEC-unrelated infections associated with thrombotic microangiopathy are less characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective study in a four-hospital institution of 530 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period studied STEC-unrelated infections' epidemiology and major outcomes (death, acute dialysis, and major cardiovascular events). RESULTS: STEC-unrelated infection was present in 145 of 530 (27%) patients, thrombotic microangiopathies without infection were present in 350 of 530 (66%) patients, and STEC causing hemolytic and uremic syndrome was present in 35 of 530 (7%) patients. They (versus thrombotic microangiopathy without infection) were associated with age >60 years (36% versus 18%), men (53% versus 27%), altered consciousness (32% versus 11%), mean BP <65 mm Hg (21% versus 4%), lower hemoglobin and platelet count, and AKI (72% versus 49%). They were associated with more than one pathogen in 36 of 145 (25%) patients (either isolated [14%] or combined [86%] to other causes of thrombotic microangiopathy); however, no significant clinical or biologic differences were noted between the two groups. They were more frequently due to bacteria (enterobacteria [41%], Staphylococcus aureus [11%], and Streptococcus pneumonia [3%]) than viruses (Epstein-Barr [20%], cytomegalovirus [18%], influenza [3%], hepatitis C [1%], HIV [1%], and rotavirus [1%]). STEC-unrelated infections were independent risk factors for in-hospital death (odds ratio, 2.22; 95% confidence interval, 1.18 to 4.29), major cardiovascular event (odds ratio, 3.43; 95% confidence interval, 1.82 to 6.69), and acute dialysis (odds ratio, 3.48; 95% confidence interval, 1.78 to 7.03). Bacteria (versus other pathogens), and among bacteria, enterobacteria, presence of more than one bacteria, and E. coli without shigatoxin were risk factors for acute dialysis. CONCLUSIONS: Infections are frequent thrombotic microangiopathy triggers or causes, and they are mostly unrelated to STEC. Infections convey a higher risk of death and major complications. The most frequent pathogens were enterobacteria, S. aureus, Epstein-Barr virus, and cytomegalovirus. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN17511120.mp3.


Subject(s)
Infections/complications , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/microbiology , Adult , Female , Humans , Infections/epidemiology , Male , Middle Aged , Retrospective Studies , Risk Factors
2.
Intern Med ; 58(23): 3479-3482, 2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31327837

ABSTRACT

A 62-year-old woman with no previous history developed a Capnocytophaga canimorsus infection followed by thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC). She was treated with antibiotics and plasma exchange (PE) and recovered. C. canimorsus sepsis sometimes causes not only DIC but also TMA. The mortality of TMA is extremely high, so we should not hesitate to perform PE when a patient shows TMA symptoms.


Subject(s)
Capnocytophaga , Disseminated Intravascular Coagulation/microbiology , Gram-Negative Bacterial Infections/complications , Thrombotic Microangiopathies/microbiology , Anti-Bacterial Agents/therapeutic use , Bites and Stings , Disseminated Intravascular Coagulation/drug therapy , Female , Gram-Negative Bacterial Infections/drug therapy , Humans , Immunocompetence , Middle Aged , Plasma Exchange/adverse effects , Sepsis/diagnosis
3.
Am J Med Sci ; 356(5): 492-498, 2018 11.
Article in English | MEDLINE | ID: mdl-30177262

ABSTRACT

Thrombotic microangiopathy (TMA) may result from a variety of clinical conditions, including thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome and complement-mediated hemolytic uremic syndrome. Thrombocytopenic purpura is diagnosed when ADAMTS13 is <10%, while a diagnosis of Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome is made with the evidence of infection by Shiga toxin-producing Escherichia coli. Diagnosis of complement-mediated hemolytic uremic syndrome is not dependent on a specific laboratory test and is a diagnosis of exclusion. TMA is a rare disease and finding individuals that have more than 1 concurrent etiology leading to TMA is even more rare. Here we describe the presentation and management of an individual with CFHR1 deletion-associated TMA also found to have a positive stool Shiga toxin. We discuss the significance of Shiga toxin in serving as a trigger for development of TMA in an individual predisposed to development of TMA due to presence of a homozygous deletion in CFHR1.


Subject(s)
Base Sequence/drug effects , Complement C3b Inactivator Proteins/genetics , Sequence Deletion/drug effects , Shiga Toxin/adverse effects , Thrombotic Microangiopathies/genetics , Adult , Complement C3b Inactivator Proteins/metabolism , Female , Homozygote , Humans , Thrombotic Microangiopathies/microbiology
4.
Transfusion ; 58(10): 2426-2429, 2018 10.
Article in English | MEDLINE | ID: mdl-30222856

ABSTRACT

BACKGROUND: The Gram-negative bacillus Capnocytophaga canimorsus may cause a severe illness resembling thrombotic thrombocytopenic purpura (TTP). The pathogenesis and optimal therapy of this secondary thrombotic microangiopathy (TMA) remain uncertain. CASE REPORT: A 63-year-old Caucasian man was admitted with suspicion for TTP, but blood cultures grew C. canimorsus. Initial investigations revealed severe thrombocytopenia, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity level of less than 1%, and strongly elevated D-dimer and lactate dehydrogenase levels. He made a full recovery with antibiotics and plasma infusion for 3 days. Plasmapheresis was not performed. Retrospective determination of serial ADAMTS13 activity levels revealed that ADAMTS13 activity had already increased to 25% at the start of plasma infusion. CONCLUSION: This case highlights that a C. canimorsus sepsis may cause a secondary TMA with a severe ADAMTS13 deficiency. It also illustrates that the adjunctive role of plasma exchange or plasma infusion is doubtful as ADAMTS13 activity levels increased with antibiotics alone.


Subject(s)
ADAMTS13 Protein/deficiency , Anti-Bacterial Agents/therapeutic use , Capnocytophaga , Sepsis/microbiology , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/microbiology , Humans , Male , Middle Aged , Sepsis/complications , Thrombotic Microangiopathies/etiology , Treatment Outcome
5.
Am J Physiol Renal Physiol ; 314(3): F454-F461, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29167171

ABSTRACT

Hemolytic uremic syndrome (HUS) is major global health care issue as it is the leading cause of acute kidney injury in children. It is a triad of acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. In recent years, major advances in our understanding of complement-driven inherited rare forms of HUS have been achieved. However, in children 90% of cases of HUS are associated with a Shiga toxin-producing enteric pathogen. The precise pathological mechanisms in this setting are yet to be elucidated. The purpose of this review is to discuss advances in our understanding of the pathophysiology underlying HUS and identify the key questions yet to be answered by the scientific community.


Subject(s)
Acute Kidney Injury/etiology , Atypical Hemolytic Uremic Syndrome/etiology , Complement Activation , Complement System Proteins/immunology , Escherichia coli Infections/microbiology , Shiga-Toxigenic Escherichia coli/pathogenicity , Thrombotic Microangiopathies/etiology , Acute Kidney Injury/genetics , Acute Kidney Injury/immunology , Acute Kidney Injury/microbiology , Animals , Atypical Hemolytic Uremic Syndrome/genetics , Atypical Hemolytic Uremic Syndrome/immunology , Atypical Hemolytic Uremic Syndrome/microbiology , Complement Activation/genetics , Complement System Proteins/genetics , Genetic Predisposition to Disease , Humans , Phenotype , Prognosis , Risk Factors , Thrombotic Microangiopathies/genetics , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/microbiology
6.
Pediatr Nephrol ; 32(7): 1263-1268, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28343354

ABSTRACT

BACKGROUND: Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children, with the majority of cases caused by an infection with Shiga toxin-producing Escherichia coli (STEC). Whereas O157 is still the predominant STEC serotype, non-O157 serotypes are increasingly associated with STEC-HUS. However, little is known about this emerging and highly diverse group of non-O157 serotypes. With supportive therapy, STEC-HUS is often self-limiting, with occurrence of chronic sequelae in just a small proportion of patients. CASE DIAGNOSIS/TREATMENT: In this case report, we describe a 16-month-old boy with a highly severe and atypical presentation of STEC-HUS. Despite the presentation with multi-organ failure and extensive involvement of central nervous system due to extensive thrombotic microangiopathy (suggestive of atypical HUS), fecal diagnostics revealed an infection with the rare serotype: shiga toxin 2d-producing STEC O80:H2. CONCLUSIONS: This report underlines the importance of STEC diagnostic tests in all children with HUS, including those with an atypical presentation, and emphasizes the importance of molecular and serotyping assays to estimate the virulence of an STEC strain.


Subject(s)
Escherichia coli Infections/microbiology , Hemolytic-Uremic Syndrome/microbiology , Multiple Organ Failure/microbiology , Shiga Toxin 2/toxicity , Shiga-Toxigenic Escherichia coli/pathogenicity , Thrombotic Microangiopathies/microbiology , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Biopsy , Blood Culture , Ceftriaxone/therapeutic use , Escherichia coli Infections/blood , Escherichia coli Infections/complications , Escherichia coli Infections/drug therapy , Hemolytic-Uremic Syndrome/blood , Hemolytic-Uremic Syndrome/complications , Hemolytic-Uremic Syndrome/drug therapy , Humans , Infant , Liver/pathology , Magnetic Resonance Imaging , Male , Midazolam/therapeutic use , Multiple Organ Failure/blood , Multiple Organ Failure/complications , Multiple Organ Failure/drug therapy , Real-Time Polymerase Chain Reaction , Resuscitation , Serotyping/methods , Shiga Toxin 2/isolation & purification , Shiga-Toxigenic Escherichia coli/isolation & purification , Shiga-Toxigenic Escherichia coli/metabolism , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/complications , Thrombotic Microangiopathies/drug therapy , Virulence
7.
Medicine (Baltimore) ; 95(27): e4104, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27399110

ABSTRACT

UNLABELLED: To describe a case of complete remission of thrombotic microangiopathy after treatment with eculizumab in a patient with non-Shiga toxin-associated bacterial enteritis. CASE REPORT: Medical/surgical intensive care unit (ICU) of a university teaching hospital.A 62-year-old man presented to a local hospital with mucous and bloody stool persisting for 1 month and worsening abdominal pain for 2 weeks. He had thrombocytopenia and renal dysfunction and was admitted with a diagnosis of sepsis due to intraabdominal infection. However, he did not respond to antimicrobial therapy, and after 7 days he was transferred to the Chiba University Hospital ICU.Antimicrobial therapy was continued, and continuous hemodiafiltration was initiated on ICU day 3, but the patient's condition deteriorated and he became anuric. Plasma exchange (PE) was initiated on ICU day 11, but anuria and thrombocytopenia persisted. Intravenous eculizumab therapy was initiated on day 26 and resulted in quick recovery of urine output and platelet count and successful discontinuation of renal support.The diagnosis of thrombotic microangiopathy was established by the presence of schistocytes on the peripheral blood smear on ICU day 9. A plasma sample collected prior to initiation of PE showed a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs member 13 (ADAMTS13) activity level of >10% (25.1%). The absence of both Shiga-toxin producing E coli in feces and anti-Shiga-toxin antibody in blood led to suspicion of atypical hemolytic uremic syndrome (aHUS). Genetic test identified a nonsynonymous mutation (p.Ala311Val) in the membrane cofactor protein gene (MCP).Although the pathological significance is currently unknown, this mutation may have been the cause of adult-onset aHUS in our patient. In this case, eculizumab was successfully introduced and discontinued, and the patient remained relapse-free after 1 year of follow-up. The duration of eculizumab therapy for patients with aHUS should be determined on a case-by-case basis and possibly according to the causative genetic mutation, even though discontinuation of eculizumab therapy once initiated is not generally recommended.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/microbiology , Hemodiafiltration , Humans , Male , Middle Aged , Plasma Exchange , Platelet Count
9.
Semin Thromb Hemost ; 40(4): 444-64, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24911558

ABSTRACT

Thrombotic microangiopathy (TMA) is a rare but severe disorder characterized by endothelial cell activation and thrombus formation. It manifests with the triad of hemolytic anemia, thrombocytopenia, and organ failure. Prompt diagnosis and treatment initiation are crucial for long-term outcome. TMA often manifests subsequent to infectious events, of which (enterohemorrhagic) Escherichia coli is the most frequently reported. TMA also occurs on the background of genetic/autoimmune defects in the complement system (atypical hemolytic uremic syndrome [aHUS]) and underlying conditions, such as pregnancy, transplantation, drugs, other glomerulopathies, vasculitides, or metabolic defects. Complement activation or defects in its regulation have now been described in an increasing number of acquired diseases with TMA. Coinciding with this expanding spectrum of complement-mediated diseases, the question arises which patients might benefit from a complement-targeted therapy. Success of therapy depends on the individual contribution of complement activation in disease pathogenesis. The advent of eculizumab, a monoclonal antibody that blocks terminal complement activation, has markedly improved outcome and quality of life in patients with aHUS. This review discusses the contribution of complement and highlights its complex interaction with inflammation, coagulation, and the endothelium. Treatment experiences focusing on eculizumab therapy are discussed in detail across the emerging spectrum of complement-mediated thrombotic microangiopathies.


Subject(s)
Complement System Proteins/immunology , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antiphospholipid Syndrome , Atypical Hemolytic Uremic Syndrome/immunology , Autoimmune Diseases , Bone Marrow Transplantation , Complement Activation , Diacylglycerol Kinase/immunology , Enterohemorrhagic Escherichia coli , Escherichia coli Infections/complications , Female , Homeostasis , Humans , Inflammation , Kidney Transplantation , Male , Pregnancy , Pregnancy Complications , Quality of Life , Recurrence , Stem Cell Transplantation , Thrombotic Microangiopathies/microbiology , Treatment Outcome
10.
Blood Coagul Fibrinolysis ; 25(7): 765-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24614430

ABSTRACT

We report a case of Streptococcus pneumonia sepsis-associated disseminated intravascular coagulation (DIC) with features of acute renal failure and microvascular thrombosis characterized by skin purpura and bilateral foot necrosis. The persistence of laboratory features of microangiopathic hemolytic anemia despite aggressive correction of DIC-associated coagulopathy suggests the possibility of an additional concomitant microangiopathic process. Here, we discuss the management and diagnostic approach, particularly highlighting the difficulties in making a definitive diagnosis. Although unconfirmed, our differentials include the concomitant process of sepsis-induced DIC occurring together with an indeterminate form of plasmapheresis and plasma exchange-responsive thrombotic microangiopathy, processes which are previously believed to be mutually exclusive.


Subject(s)
Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/therapy , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/therapy , Bacteremia/blood , Bacteremia/diagnosis , Bacteremia/microbiology , Bacteremia/therapy , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/microbiology , Humans , Male , Middle Aged , Pneumococcal Infections/blood , Pneumococcal Infections/diagnosis , Pneumococcal Infections/therapy , Streptococcus pneumoniae/isolation & purification , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/microbiology
11.
Clin Nephrol ; 81(4): 302-6, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23320969

ABSTRACT

We report 3 cases of Clostridium difficile-associated hemolytic uremic syndrome (HUS) with biopsy proven renal thrombotic microangiopathy. Two patients with acute renal failure were kidney transplants recipients whereas the third patient developed renal failure in the native kidneys. The presentation was preceded by acute diarrhea and stool. Clostridium difficile toxin was detected in all the 3 patients. Stool studies were negative for Escherichia coli, Shigella dysenteriae and other enteric pathogens. The diagnosis of Clostridium difficile-associated hemolytic uremic syndrome was suspected due to presence of thrombocytopenia, microangiopathic hemolytic anemia and biopsy proven renal thrombotic microangiopathy without another clinically apparent cause. This case series suggest that Clostridium difficile infection may cause renal failure due to thrombotic microangiopathy (TMA) and should be considered in the differential diagnosis of diarrhea-associated HUS.


Subject(s)
Enterocolitis, Pseudomembranous/complications , Hemolytic-Uremic Syndrome/microbiology , Thrombotic Microangiopathies/microbiology , Adult , Biopsy , Clostridioides difficile/isolation & purification , Diagnosis, Differential , Enterocolitis, Pseudomembranous/drug therapy , Female , Hemolytic-Uremic Syndrome/drug therapy , Humans , Kidney Transplantation , Middle Aged , Renal Dialysis , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/drug therapy
12.
Blood ; 116(18): 3653-9, 2010 Nov 04.
Article in English | MEDLINE | ID: mdl-20644116

ABSTRACT

Diarrhea-associated hemolytic uremic syndrome (D+HUS) is the most common cause of acute renal failure among children. Renal damage in D+HUS is caused by Shiga toxin (Stx), which is elaborated by Shigella dysenteriae and certain strains of Escherichia coli, in North America principally E coli O157:H7. Recent studies demonstrate that Stx also induces von Willebrand factor (VWF) secretion by human endothelial cells and causes thrombotic thrombocytopenic purpura, a disease with similarities to D+HUS, in Adamts13(-/-) mice. Stx occurs in 2 variants, Stx1 and Stx2, each of which is composed of 1 catalytically active A subunit that is responsible for cytotoxicity, and 5 identical B subunits that mediate binding to cell-surface globo-triaosylceramide. We now report that B subunits from Stx1 or Stx2 can stimulate the acute secretion of VWF in the absence of the cytotoxic A subunit. This rapid effect requires binding and clustering of globotriaosylceramide, and depends on plasma membrane cholesterol and caveolin-1 but not clathrin. Furthermore, similar to Stx2 holotoxin, the isolated Stx2B subunits induce thrombotic microangiopathy in Adamts13(-/-) mice. These results demonstrate the existence of a novel Stx B-induced lipid raft-dependent signaling pathway in endothelial cells that may be responsible for some of the biological effects attributed previously to the cytotoxic Stx A subunit.


Subject(s)
Endothelial Cells/metabolism , Metalloendopeptidases/genetics , Shiga Toxins/adverse effects , Shiga Toxins/metabolism , Shigella dysenteriae/metabolism , Thrombotic Microangiopathies/etiology , von Willebrand Factor/metabolism , ADAMTS13 Protein , Animals , Caveolin 1/genetics , Caveolin 1/metabolism , Cell Line , Cholera Toxin/metabolism , Cholesterol/metabolism , Clathrin/metabolism , Gene Deletion , Gene Knockdown Techniques , Humans , Mice , Mice, Inbred C57BL , Thrombotic Microangiopathies/microbiology , Trihexosylceramides/metabolism
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