Diarrhea-associated Hemolytic Uremic Syndrome Research Articles

Preclinical diagnostics hemolytic-uremic syndrome in a child. Clinical observation

Hemolytic — uremic syndrome (HUS) is one of the most severe conditions in pediatric practice. Acute kidney failure (AKF), which is a component of HUS, requires the earliest diagnosis and emergency medical care. Most of the young patients suffer from diarrhea-associated (D+) HUS, so ultrasound marks of kidney injury very important for young patients with severe hemocolitis. In this article we present the observation of preclinical diagnostics AKF the child 2 years and 11 month old with hemocolitis, when HUS’s marks (such as structure’s changes of the renal parenchyma and critical changes of renal hemodynamics) were detected before clinical manifestation AKF. This observation is illustrated with echograms and accompanied by a brief review of the literature.

Hydration in hemolytic uremic syndrome.

Diarrhea-associated hemolytic uremic syndrome is preceded by gastroenteritis due to Shiga toxin-producing Escherichia coli. Support measures are recommended, specifically, fluid restriction to avoid cardiopulmonary overload. However, in the prodromal period or with established hemolytic uremic syndrome, volume expansion with isotonic fluids is safe and effective, and reduces the need for dialysis, the length of hospital and intensive care stay, neurological events, and hyponatremia. Therefore, when nephrological monitoring is available and/or short-term access to a tertiary care hospital is guaranteed, it is suggested to hydrate patients with no signs of cardiopulmonary overload, regardless of their renal function, with initial volume expansion. Afterwards, if an adequate urine output is achieved, the patient should not be dialyzed (except if they have a medically intractable metabolic/electrolyte disorder) and hydration should be continued with an isotonic solution containing 5 % dextrose for adequate hydration and urine output.

Successful use of steroids in the management of two patients of diarrhea-associated adult hemolytic uremic syndrome

Successful use of steroids in the management of two patients of diarrhea-associated adult hemolytic uremic syndrome

Fluid restriction versus volume expansion in children with diarrhea-associated HUS: a retrospective observational study.

Fifty percent of patients with typical diarrhea-associated hemolytic uremic syndrome (D+HUS) require kidney replacement therapy (KRT). In these patients, dehydration worsens disease prognosis. We evaluated dialysis requirement, presence of seizures, and mortality rate among patients diagnosed with D+HUS treated with volume expansion (VE) versus fluid restriction (FR). Thirty-five patients with D+HUS were enrolled; 16 received VE and 19 were historical patients who received conventional FR. Upon admission or during treatment, neither group presented evidence of fluid overload. The VE group received higher volumes of saline (VE 27ml/kg [10-30] over a 3-h period vs. FR 0ml), had higher urine output after 12h (VE vs. FR: OR 6.2 [1.2-41.6], P = 0.03), and required less dialysis (VE 2 [12.5%, CI 95% 0-29] vs. FR 9 [47.4%, CI 95% 24-70], P = 0.035). The VE group had an absolute risk reduction of 0.34 (CI 95% 0.07-0.63); hence, three patients treated with VE were required to avoid one KRT. VE also corrected initial hyponatremia and maintained serum sodium within normal ranges. No statistical differences were observed regarding number of patients with seizures (P = 0.08) or mortality (P = 1.0). VE markedly reduces the number of patients requiring KRT and keeps serum sodium within a normal range. We propose to initially hydrate every patient with D+HUS and without signs of fluid overload, with 10ml/kg/h 0.9% saline solution IV, over a 3-h period. Afterwards, if urine output is ≥ 0.5ml/kg/h, it is recommended to not dialyze and continue IV hydration schedule with isotonic (D5) saline solution, according to their needs.

Диарея-ассоциированный гемолитико-уремический синдром у детей

Диарея-ассоциированный гемолитико-уремический синдром у детей

Pregnancy-Associated Atypical Hemolytic Uremic Syndrome: A Systematic Review.

To evaluate disease presentation, diagnosis, treatment, and clinical outcomes in pregnancy-associated atypical hemolytic uremic syndrome (aHUS). We searched PubMed, MEDLINE, Cochrane Library, ClinicalTrials.gov, Web of Science, EMBASE and Google Scholar, from inception until March 2018. We included English-language articles describing aHUS in pregnancy or postpartum. The diagnosis of aHUS was characterized by hemolysis, thrombocytopenia, and renal failure and was distinguished from typical diarrhea-associated hemolytic uremic syndrome. Patients were excluded if individual data could not be obtained, the diagnosis was unclear, or an alternative etiology was more likely, such as thrombotic thrombocytopenic purpura or Shiga toxin-producing Escherichia coli. Reports were appraised by two reviewers, with disagreements adjudicated by a third reviewer. The search identified 796 articles. After review of titles, abstracts, and full text, we identified 48 reports describing 60 unique cases of pregnancy-associated aHUS, with 66 pregnancies. Twelve cases involved pregnancy in women with known aHUS, and 54 cases involved first-episode pregnancy-associated aHUS. Women with known aHUS, particularly those with baseline creatinine at or above 1.5 mg/dL, had a high rate of adverse pregnancy outcomes. For first-episode pregnancy-associated aHUS, diagnosis most often occurred postpartum (94%), after a cesarean delivery (70%), in nulliparous women (58%). Preceding obstetric complications were common and included fetal death, preeclampsia, and hemorrhage. Diagnosis was usually made clinically, based on the triad of microangiopathic hemolysis, thrombocytopenia, and renal failure. Additional testing included renal biopsy, complement genetic testing, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) testing. Treatment modalities included corticosteroids, plasma exchange, dialysis, and eculizumab. More women with first-episode pregnancy-associated aHUS achieved disease remission when treated with eculizumab, compared with those not treated with eculizumab (88% vs 57%, P=.02). Pregnancy-associated aHUS usually presents in the postpartum period, often after a pregnancy complication, and eculizumab is effective for achieving disease remission. PROSPERO, CRD42019129266.

Contribution and Interaction of Shiga Toxin Genes to Escherichia coli O157:H7 Virulence.

Escherichia coli O157:H7 is the predominant cause of diarrhea-associated hemolytic uremic syndrome (HUS) worldwide. Its cardinal virulence traits are Shiga toxins, which are encoded by stx genes, the most common of which are stx1a, stx2a, and stx2c. The toxins these genes encode differ in their in vitro and experimental phenotypes, but the human population-level impact of these differences is poorly understood. Using Shiga toxin-encoding bacteriophage insertion typing and real-time polymerase chain reaction, we genotyped isolates from 936 E. coli O157:H7 cases and verified HUS status via chart review. We compared the HUS risk between isolates with stx2a and those with stx2a and another gene and estimated additive interaction of the stx genes. Adjusted for age and symptoms, the HUS incidence of E. coli O157:H7 containing stx2a alone was 4.4% greater (95% confidence interval (CI) −0.3%, 9.1%) than when it occurred with stx1a. When stx1a and stx2a occur together, the risk of HUS was 27.1% lower (95% CI −87.8%, −2.3%) than would be expected if interaction were not present. At the population level, temporal or geographic shifts toward these genotypes should be monitored, and stx genotype may be an important consideration in clinically predicting HUS among E. coli O157:H7 cases.

Ultrasound Evidence of Acute Appendicitis in a Patient with Hemolytic Uremic Syndrome

Introduction: Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Children with HUS often present with gastrointestinal complaints, including abdominal pain, vomiting, and diarrhea. This presentation can mimic other gastrointestinal illnesses, including appendicitis, which further adds to the known diagnostic challenge. Case Report: We report an 8-year-old male who presents with abdominal pain and diarrhea-associated HUS. Kidney ultrasound obtained for acute kidney failure showed incidental findings of dilated appendix which were confirmed on a follow-up appendix ultrasound. Patient lacked the typical findings of acute appendicitis such as fever, abdominal tenderness or rigidity. We observed the patient without medical or surgical treatment for acute appendicitis as ultrasound findings were attributed to HUS, and the patient’s abdominal pain and HUS resolved without any intervention. Conclusion: Self-limited appendiceal inflammation may be seen in diarrhea-associated HUS, and the diagnostic utility of appendix ultrasound to evaluate for acute appendicitis may be limited in a patient with HUS and abdominal pain.

Roles of Shiga Toxins in Immunopathology.

Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.

Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort.

Hemolytic uremic syndrome due to Shiga toxin-producing E. coli (STEC-HUS) is the main cause of acute kidney injury in young children. Most fully recover kidney function; however, some develop long-term sequelae. We aimed to determine whether kidney injury 1year after HUS onset is associated with long-term kidney outcome in pediatric STEC-HUS. A retrospective population-based study of children < 15years with STEC-HUS between 1992 and 2012 was performed. Mixed effects logistic regression was used to investigate associations between kidney injury at 1year and long-term kidney outcome. Ninety-eight STEC-HUS cases were reported. Of 96 patients who survived acute phase, 84 were evaluated at 1-year follow-up of whom 42 (44% of survivors) showed ≥ 1 signs of kidney injury. Data from 81 patients were collected after median follow-up of 8.7 (IQR 3.5-12.7) years. At last follow-up, 42 (44% of survivors) had ≥ 1 signs of kidney injury including decreased estimated glomerular filtration rate (eGFR) < 90mL/min/1.73m2 (n = 30), proteinuria (n = 17), or hypertension (n = 5). Among 42 patients with kidney injuries at 1-year follow-up, only 22 (52%) still had kidney disease at last follow-up. Conversely, of 33 patients without kidney injury at 1-year and available long-term outcome data, 11 (33%) had proteinuria or decreased GFR at last follow-up. There was no statistically significant association between kidney injury at 1year and long-term kidney outcome. Since kidney sequelae may appear at variable time intervals after acute HUS, all patients need lifelong follow-up to detect early signs of chronic kidney disease and propose measures to slow progression.

Complement activation is associated with more severe course of diarrhea-associated hemolytic uremic syndrome, a preliminary study.

Diarrhea-associated hemolytic uremic syndrome is characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury secondary to enteric infection, typically Shiga toxin-producing Escherichia coli. Shiga toxin 2 is able to activate alternative complement pathways; therefore, the aim of the study was to analyze C3 as a predictor of clinical courses in patients with diarrhea-associated hemolytic uremic syndrome. We hypothesized that the patients with increased complement activation at admission suffered from a more severe course. We retrospectively analyzed data of 33 pediatric patients between 1999 and 2015 in the Czech Republic. We tested the association of a C3 concentration with biochemical parameters and the clinical data reflecting the severity of the disease. We found significant correlation between the initial C3 and the duration of renal replacement therapy (r = - 0.62, p = 0.0001) and the initial glomerular filtration rate (r = 0.36, p = 0.026). Patients with C3 < 0.825g/L needed renal replacement therapy and also had significantly more renal complications (p = 0.015).Conclusion: Based on our study, decreased C3 concentrations can be used as one of the risk factors that can help predict the need for acute dialysis and a more severe course of disease in children with diarrhea-associated hemolytic uremic syndrome. What is Known: • Shiga toxin modulates the function of complement regulatory proteins and thus contributes to complement activation in patients with diarrhea-associated hemolytic uremic syndrome. • Risk factors that can predict the need for acute renal replacement therapy and poor outcome in patients with diarrhea-associated hemolytic uremic syndrome are mainly the combination of oligoanuria, dehydration, leukocytosis, high hematocrit > 23%, and neurological involvement. What is New: • A lowered concentration of C3 at the time of initial presentation of diarrhea-associated hemolytic uremic syndrome was associated with more severe renal failure and the need for renal replacement therapy along with the development of more extra renal complications. • Decreased C3 at admission can predict complicated course of diarrhea-associated hemolytic uremic syndrome.

ПОРАЖЕНИЕ ПОЧЕК У ДЕТЕЙ С ТЯЖЕЛЫМИ ФОРМАМИ ОСТРЫХ КИШЕЧНЫХ ИНФЕКЦИЙ

Introduction. Acute intestinal infections and diarrhea-associated hemolytic-uremic syndrome (HUS) are the main cause of acute renal failure in children. Objective: to establish the frequency of development of acute renal failure in children hospitalized in the intensive care unit of an infectious hospital with severe forms of acute intestinal infections. Material and methods. A retrospective comparative statistical analysis of 123 case histories of children with acute intestinal infections who were undergoing treatment in the intensive care unit of the Grodno Regional Infectious Disease Clinical Hospital was conducted. Patients were divided into 3 groups: 1 group (n = 84) - children with acute intestinal infections and lack of clinical and laboratory signs of impaired renal function; 2 group (n = 27) - children with acute intestinal infections and prerenal acute renal failure (reduced diuresis, increased urea and / or serum creatinine, normalized against the background of ongoing rehydration therapy during the day); 3 group (n = 12) - children with acute intestinal infections and renal acute renal failure. Results. The age of the children was 1.0 (0.2, 2.2) year. Children prevailed up to a year – 49,6%, from one to five years – 42,3%, over 8 years – 8,1%. Oligouria was recorded in 28.5% of children, anuria in 3.3%. A statistically significant difference in levels of urea and creatinine in groups (p˂0,05) was established. The highest rates were observed in patients of the 3 group. In 9 of them (75%), a typical HUS associated with infectious diarrhea was diagnosed. Conclusion. In 21,9% of children with acute intestinal infections, prerenal acute renal failure was diagnosed, in 9,8% - renal. The main cause of renal acute renal failure in children with severe forms of acute intestinal infections is a typical HUS associated with the infectious etiology of diarrhea.

ADAMTS-13 level in children with severe diarrhea-associated hemolytic uremic syndrome: Unmasking new association.

Severe deficiency of ADAMTS-13 leads to thrombotic thrombocytopenic purpura. Few studies have reported reduced activity of ADAMTS-13 in patients with atypical and typical hemolytic uremic syndrome (HUS). We hypothesized that ADAMTS-13 deficiency might play a role in the pathogenesis of severe HUS. This study aimed to evaluate the ADAMTS-13 level in severe typical HUS. This prospective case-control study was carried out in the Pediatric Nephrology Unit and Clinical Pathology Department, Faculty of Medicine, Zagazig University from February 2013 to February 2014. The study included 15 consecutive children with typical HUS as well as 15 healthy children as a control group. Routine laboratory investigations were performed. Assessment of serum ADAMTS-13 level was performed using the Quantikine human ADAMTS-13 ELISA kit. Data were analyzed using Statistical Package for Social Sciences version 16. Nonparametric values were expressed as median and range, and the median of two groups was tested by Mann-Whitney test. The serum ADAMTS-13 level was significantly lower in HUS patients when compared to the control group (P < 0.05). There were significant negative correlations between ADAMTS-13 level and duration on dialysis, as well as serum urea and creatinine. Furthermore, there were significant positive correlations between serum ADAMTS-13 level and both hemoglobin level and platelet count. Our study suggests that the ADAMTS-13 level was decreased in children with severe typical HUS and its deficiency correlated with disease severity.

Soluble CD40 Ligand and Oxidative Response Are Reciprocally Stimulated during Shiga Toxin-Associated Hemolytic Uremic Syndrome.

Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces platelet activation, contributing to thrombus formation. Moreover, activated platelets release soluble CD40 ligand (sCD40L), which in turn contributes to oxidative imbalance, triggering the release of reactive oxidative species (ROS) on various cellular types. The aim of this work was to determine if the interaction between the oxidative response and platelet-derived sCD40L, as consequence of Stx-induced endothelium damage, participates in the pathogenic mechanism during HUS. Activated human glomerular endothelial cells (HGEC) by Stx2 induced platelets to adhere to them. Although platelet adhesion did not contribute to endothelial damage, high levels of sCD40L were released to the medium. The release of sCD40L by activated platelets was inhibited by antioxidant treatment. Furthermore, we found increased levels of sCD40L in plasma from HUS patients, which were also able to trigger the respiratory burst in monocytes in a sCD40L-dependent manner. Thus, we concluded that platelet-derived sCD40L and the oxidative response are reciprocally stimulated during Stx2-associated HUS. This process may contribute to the evolution of glomerular occlusion and the microangiopathic lesions.

Blood urea nitrogen to serum creatinine ratio as a prognostic factor in diarrhea-associated hemolytic uremic syndrome: a validation study.

In this validation study, the BCR at admission provided a limited value to predict severe forms of D+HUS. What is Known: • BCR at admission has been proposed as an accurate predictor of complicated clinical course in children with D+HUS. What is New: • In a larger series of children with D+HUS, we were unable to confirm the usefulness of the admission BCR to early identify those at risk of complicated forms of the disease. • Further research is warranted to improve the optimal detection of these high-risk patients.

Neurological Involvement in Pediatric Hemolytic Uremic Syndrome: A Symptom-Oriented Analysis.

Background Neurological involvement is common in hemolytic uremic syndrome (HUS), but each neurological symptom may be due to a variety of factors. Objective We aimed to evaluate predisposing factors to the neurological symptoms in HUS. Materials and Methods The 10-year follow-up data on HUS patients were retrospectively analyzed. Statistical comparisons were made across subgroups based on age and neurological symptoms. Results The neurological involvement rate was 37.5%. The female-to-male ratio increased in patients with neurological involvement (3.8 vs. 1.37). Regarding all HUS patients, hemoglobin levels were higher in patients with paresis. The rate of paresis was twofold higher in patients with a hemoglobin level above 11 g/dL (p &lt; 0.05). In diarrhea-associated HUS patients, D-dimer and C-reactive protein levels were higher in patients with paresis, and leukocyte counts were higher in patients with seizures. Patients with altered consciousness had higher creatinine levels. The survival rate was significantly lower in patients with a reticulocyte percentage of less than 2% (50 vs. 100%). Conclusion Results of our study indicate that neurological involvement depends on overall findings in HUS. A symptom-oriented approach, which is different from that employed in previous studies, reveals some clues to the pathogenesis and management of these patients.

Epidemiology and outcome of acute kidney injury in children, a single center study

Background: Information on the epidemiology of Acute Kidney Injury (AKI) in children is scarce. We performed a single center retrospective cohort study to analyze the incidence of AKI, the male/female ratio, the underlying etiology, and age at presentation. We also aimed to assess outcome measured by mortality, duration of PICU stay, and development of Chronic Kidney Disease (CKD).Methods: Records were searched for children presenting with or developing AKI between 1st January 2008 and 1st January 2015. AKI was classified according to the pediatric Rifle criteria while the cause of AKI was defined as the major underlying disease.Results: Of the 28,295 children admitted, 167 episodes of AKI were identified, equaling 5.9 cases per 1000 children. Patients classified as Failure at presentation according to pRifle criteria where significantly more likely to need dialysis (27/50, 54%) compared to those presenting with Injury (12/57, 21.1%) or Risk (6/60, 10 %). Diarrhea-associated Hemolytic Uremic Syndrome (D+HUS) was the most frequent cause (20.3 %) peaking during the summer months, followed by cardiac surgery (13.7%), medication-related nephrotoxicity (13.2%), and acute Glomerulonephritis (12%). The median age of children admitted with AKI was 6.1 years (range 0.1–17) and 50.8% of cases were male. Twenty five (15%) children died while 27 (16.1%) developed CKD.Conclusions: Pediatric AKI poses a significant problem and strategies aimed at prevention, early detection, treatment, and adequate follow-up are needed. D+HUS is the most common underlying cause and effective surveillance of Enterohemorrhagic E. coli infections in association with additional measures is highly recommended.

Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome, a preliminary study.

A BUN-to-serum Creatinine ratio can accurately identify children with D+HUS at risk for a complicated course and poor outcome. What is Known: • Oliguria is a predictor of poor long-term outcome in D+HUS What is New: • BUN-to-serum Creatinine ratio at admission is an entirely novel and accurate predictor of poor outcome and complicated clinical outcome in D+HUS • Early detection of the high risk group in D+HUS enabling early treatment and adequate monitoring.

Clinical characteristics and long-term outcome of diarrhea-associated hemolytic uremic syndrome: a single center experience.

To clarify the clinical characteristics and long-term outcomes of patients with diarrhea-associated hemolytic uremic syndrome (D + HUS) with a particular focus on time course. We retrospectively analyzed the medical records of 61 patients with D + HUS who were admitted to Kobe University Hospital between 1995 and 2015. The onset of D + HUS was defined as day 1 of diarrhea. The age of onset was 4.1 (1.5-13.4) years, and the period between onset and diagnosis of D + HUS was 5 (3-18) days. The platelet count was lowest on day 7 (4-24), and the lactase dehydrogenase level was maximal on day 8 (4-25). Twenty-three patients required dialysis for 13 (2-37) days, starting at day 5-9. Seventeen patients showed central nervous system (CNS) symptoms at day 4-18. They were followed up for 3.7 (0-18.4) years. At the final follow-up, estimated glomerular filtration rate was 113.7 (57.9-159.9) ml/min/1.73m2 with five patients having chronic kidney disease. Three patients developed CNS sequelae. The time to diagnosis was significantly shorter in the group of patients receiving dialysis than without dialysis (p = 0.018) and in the group with CNS complications than without (p = 0.013). CNS complications were often apparent after blood examination results improved. Moreover, a shorter period between the onset of diarrhea and a diagnosis of D + HUS indicated a more severe clinical course or long-term sequelae, and it should be considered as a risk factor for poor prognosis.

Compromiso cerebrovascular agudo en síndrome hemolítico urémico: descripción de dos casos pediátricos

To report two pediatric cases of D+HUS with severe neurological involvement due to cerebrovascular disease, and review available literature. Two previously healthy 15- and 21-month-old children debuted with seizures and impairment of consciousness within the first week of a D+HUS. Both presented hypertension, severe acute renal failure, and focal motor deficit. One child showed significant improvement in neurologic status after five sessions of plasmapheresis. Brain magnetic resonance showed in the first child multiple bilateral infarcts of small vessels and lesions of white matter. In the second patient, large bilateral infarcts on both middle cerebral arteries territories were identified. One year after the acute event, both children showed functional impairment; The first patient evolved with language delay and spastic hemiparesis; the second patient with spastic quadriparesis, epilepsy with poor seizure control and marked functional impairment. Although most of the children with D+HUS and brain involvement do not have long-term sequelae, cerebrovascular disease in the acute period causes permanent damage, and in addition to the management of electrolyte disturbances, hypertension, and renal failure, therapies directed at specific pathophysiological mechanisms that trigger vascular compromise may improve prognosis.