Diarrhea-associated Hemolytic Uremic Syndrome Research Articles

Clostridium septicum myonecrosis complicating diarrhea-associated hemolytic uremic syndrome

We report the case of a 19-month-old male child with diarrhea-associated hemolytic uremic syndrome (HUS) who developed swelling of the right arm at the site of a peripherally inserted central venous catheter (PICC), fever, and later, ecchymosis. Wound cultures at the time of surgical debridement grew Clostridium septicum. The child subsequently required amputation of the right arm and prolonged therapy with parenteral penicillin and clindamycin. Clostridium septicum infections in children with HUS have been associated with a high rate of mortality. Along with colon cancer, diarrhea-associated HUS comprises a clinical entity which appears to predispose to atraumatic C. septicum infection, where acidic and anaerobic conditions in the diseased colon favor C. septicum invasion. Though not well recognized among pediatric nephrologists, C. septicum infection constitutes a severe, albeit rare, complication of diarrhea-associated HUS, but one in which a high index of suspicion is warranted as aggressive surgical and antibiotic therapy may be life-saving.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Although emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. In both situations, early intervention can significantly improve the dismal prognosis. However, the lack of a uniform AKI definition and the paucity of early, predictive biomarkers have impaired our ability diagnose AKI early to institute potentially effective therapies in a timely manner. Fortunately, recent data has validated a multidimensional AKI classification system for children. In addition, the application of innovative technologies has identified candidates that are emerging as early biomarkers of both AKI and CKD. These include neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from large cohorts and from multiple clinical situations are currently in progress, facilitated by the development of commercial tools for the reproducible measurement of these biomarkers across different laboratories.

Albuminuria and Estimated GFR 5 Years After Escherichia coli O157 Hemolytic Uremic Syndrome: An Update

Knowledge of the long-term prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) is important for patient counseling and follow-up. Estimates in the literature are highly variable, and previous studies did not use a healthy control group to establish outcomes attributable to HUS. Prospective cohort study. 19 children who recovered from HUS after contamination of their municipal water supply by Escherichia coli O157:H7. Outcomes of children who recovered from HUS were compared with a control group of 64 children who were healthy at the time of the outbreak. Both groups were similar in their demographics and follow-up testing. Proteinuria, blood pressure, glomerular filtration rate (GFR) estimated by using serum creatinine or cystatin C level, and biochemical measures 5 years after the outbreak. More children who recovered from HUS showed microalbuminuria than controls (20% versus 3%; relative risk, 6.0; 95% confidence interval, 1.1 to 32.8). There were no differences between groups in blood pressure or GFR when estimated by using serum creatinine level. GFR estimated by using cystatin C level was lower after HUS compared with controls (100 versus 110 mL/min/1.73 m(2); P = 0.02), but no child had a GFR less than 80 mL/min/1.73 m(2). Other results, including fasting glucose, albumin, and C-reactive protein levels, did not differ between groups. Although the homogenous nature of this outbreak is a strength, long-term results may generalize less well to patients with other strains of toxigenic E coli or in other settings. The prognosis of patients with HUS in this cohort was better than in other studies. Ongoing follow-up will clarify the clinical relevance of microalbuminuria and mild decreases in GFR 5 years after HUS recovery.

Pathogenesis of Thrombotic Microangiopathies

Profound thrombocytopenia and microangiopathic hemolytic anemia characterize thrombotic microangiopathy, which includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP has at least three types: congenital or familial, idiopathic, and nonidiopathic. The congenital and idiopathic TTP syndromes are caused primarily by deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity. HUS is similar to TTP, but is associated with acute renal failure. Diarrhea-associated HUS accounts for more than 90% of cases and is usually caused by infection with Shiga-toxin-producing Escherichia coli (O157:H7). Diarrhea-negative HUS is associated with complement dysregulation in up to 50% of cases, caused by mutations in complement factor H, membrane cofactor protein, factor I or factor B, or by autoantibodies against factor H. The incomplete penetrance of mutations in either ADAMTS13 or complement regulatory genes suggests that precipitating events or triggers may be required to cause thrombotic microangiopathy in many patients.

Management of diarrhea-associated hemolytic uremic syndrome in children

Most cases of diarrhea-associated hemolytic uremic syndrome (D+HUS) are caused by Shiga toxin-producing bacteria. Shiga toxin-producing Escherichia coli (STEC) O157:H7 has the strongest association worldwide with HUS. A massive outbreak of E. coli O157:H7 infections in Sakai, Osaka, Japan, in 1996 raised public and medical awareness of STEC. However, most cases are sporadic or occur in small clusters. Indeed, more than 100 sporadic or small cluster cases of D+HUS occur every year in Japan. The use of antibiotics in patients with definite or possible enteric STEC infections is controversial; however, there has been no randomized controlled trial to date showing the effectiveness of antibiotics for the prevention of the development of HUS. Thus, most investigators in western countries believe that antibiotics should not be administered to patients with such infections, and the management of HUS remains supportive. There are no specific therapies to ameliorate the course of the disease, and vascular injury leading to HUS is likely to be well under way by the time infected patients seek medical attention for diarrhea. The best way to prevent HUS is to prevent primary infection by Shiga toxin-producing bacteria.

Recurrent hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is an uncommon cause of acute renal failure. Diarrhea-associated (D+) HUS, usually seen in children, is a common variety of HUS. HUS that is not associated with diarrhea (D−) is caused by a heterogeneous group of disorders. We report here a case of recurrent HUS (D−) in an adult female with hypocomplementemia.

Recurrent pleural effusion during peritoneal dialysis: question

A 3-year old girl with a body weight of 15 kg was admitted to our pediatric intensive care unit with acute renal failure. She was the first of a twin pregnancy, born at a gestational age of 28 weeks with a birth weight of 1140 g. There had been no significant neonatal complications. The present history began 5 days before admission with diarrhea and vomiting. She was admitted to a local hospital with signs of severe dehydration and progressive renal failure, which persisted after aggressive fluid therapy. Hemolytic uremic syndrome (HUS) was suspected and she was referred to our hospital. On admission, hemoglobin level was 5.5 mmol/L (9.2 g/dL), serum LDH 4459 U/l and platelets 55×10/L with schistocytes on blood smear. While faeces culture was negative for E. coli 0157, there was a positive PCR for E. coli 0157 on peripheral white blood cells. Complement studies showed no evidence for atypical HUS/thrombotic microangiopathy. Serum creatinine was 458 μmol/L (5.2 mg/dL) and urea 33.1 mmol/L (92.7 mg/dL) in the anuric child. Under the diagnosis of a diarrhea-associated HUS, a Tenckhoff catheter was placed and peritoneal dialysis (PD) begun with a dwell volume of 15 mL/kg of Gambro-Trio (Gambro BCT Europe NV/SA, Zaventem, Belgium) containing 1.9% glucose. Ultrafiltration was 20 mL per hour on day 1. Despite this therapy, the patient remained ventilator-dependent and needed increasing amounts of supplemental oxygen. In order to increase ultrafiltration, the glucose concentration was increased to 2.5% with good effect (ultrafiltration rate 41 mL per hour). A large pleural effusion was noted on the right side (Fig. 1) and about 200 mL of a clear transudate (RBC 5–10/field, WBC 5–10/field, protein concentration 0.594 g/L) was aspirated. Despite this intervention, her respiratory situation deteriorated rapidly and she developed a severe acute respiratory distress syndrome (ARDS). This required highlevel ventilatory support with mean airway pressure values of up to 30 cmH2O. Mechanical ventilation was complicated by subcutaneous and mediastinal emphysema and recurrent pneumothoraces (Fig. 2). During this period, peritoneal dialysis was continued with dwell volumes between 8 and 20 mL/kg and transiently combined with continuous veno-venous hemodiafiltration. When her respiratory situation improved and the ventilator settings could be reduced, leakage of clear fluid of around 150 mL per day was noted from an incision site of a previous thorax-drain on the right side.

The Operon Encoding SubAB, a Novel Cytotoxin, Is Present in Shiga toxin-producingEscherichia coliIsolates from the United States

Diarrhea-associated hemolytic uremic syndrome (D+HUS) is thought to result from endothelial cell damage following gastrointestinal infection with Shiga toxin-producing Escherichia coli (STEC) ([10][1]); Shiga toxin (Stx) is regarded as the main virulence factor causing these microangiopathic

Absence of renal sequelae after childhood Escherichia coli O157:H7 gastroenteritis

Although a quarter of children who survive diarrhea-associated hemolytic uremic syndrome develop long-term renal sequelae, the prognosis of acute, self-limited Escherichia coli O157:H7 gastroenteritis has never been previously studied. Four years after a drinking water outbreak of E. coli O157:H7, we examined the risk of high blood pressure (>95th percentile expected for age, sex, and height), reduced kidney function, and microalbuminuria among previously healthy children and adolescents. Of the 951 participants, 313 were asymptomatic during the outbreak, 305 had moderate symptoms of acute gastroenteritis, and 333 had severe symptoms that necessitated medical attention. An additional 23 children who developed hemolytic uremic syndrome during the outbreak were excluded from this analysis. There were no differences in mean systolic blood pressure between those who had no, moderate, or severe symptoms of acute gastroenteritis during the outbreak (109, 110, and 107 mm Hg). Similarly, there were no group differences in diastolic blood pressure, estimated glomerular filtration rate, or random urine albumin to creatinine ratio (P ranged from 0.14 to 0.52), or in the adjusted relative risk of high blood pressure, a glomerular filtration rate <80 ml/min per 1.73 m(2), or microalbuminuria (P ranged from 0.23 to 0.89). Patients who presented to medical attention with gastroenteritis during this E. coli O157:H7 outbreak had an absence of renal sequelae 4 years later. With no existing data to support screening after self-limited E. coli O157:H7 gastroenteritis, we recommend that only those children who develop recognized features of hemolytic uremic syndrome be followed for long-term renal health.

Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury

Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure. Neutrophil gelatinase-associated lipocalcin (NGAL) is an early indicator of kidney injury. To determine if urinary NGAL excretion is a biomarker of severe renal injury and predicts the need for dialysis in D+HUS. Patients were randomly selected from among participants in the SYNSORB Pk trial. Urine samples were collected daily if available during the first week of hospitalization. NGAL levels were determined by ELISA. 34 children, age 5.9+/-3.9 yr, were studied; ten (29%) required dialysis. Patients were categorized based on urinary NGAL concentration within five days of hospitalization - <200 ng/ml and >or=200 ng/ml. Twenty patients (58%) had increased urinary NGAL excretion. The severity of D+HUS at enrollment was similar in the two groups. However, children with increased urinary NGAL levels had higher peak BUN and creatinine concentrations (P<0.01) and required dialysis more often, 9/20 versus 1/14 (P=0.024) compared to children with normal excretion. The majority of patients with D+HUS have renal tubular epithelial injury, as evidenced by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five days of hospitalization may be an adjunctive marker that defines less severe renal involvement.

Procalcitonin in Children with Escherichia coli O157:H7 Associated Hemolytic Uremic Syndrome

Shiga toxin producing Escherichia coli (STEC) are noninvasive enteric pathogens that may cause hemorrhagic colitis (HC) and diarrhea-associated hemolytic uremic syndrome (D+ HUS). We hypothesized that development of D+ HUS is associated with increased serum procalcitonin (PCT) levels. PCT was measured by an immunoluminometric assay in 113 patients. Concentrations of PCT were different in normal controls, disease control groups (rotavirus enteritis, HC due to non-STEC pathogens, chronic renal failure), and children with uncomplicated O157:H7 HC or D+ HUS. Children with D+ HUS showed higher PCT levels than those with uncomplicated O157:H7 HC, and increased concentrations were noted in cases requiring peritoneal dialysis. Severely increased concentrations were observed in children with D+ HUS on d 5 or 6 after the onset of enteritis, whereas serial measurements in those with uncomplicated O157:H7 HC remained within the normal range throughout the first week of illness. PCT was correlated with serum concentrations of lipopolysaccharide (LPS)-binding protein and serum levels of alanine aminotransferase. Using two separate sets of real-time PCR primers, we were unable to detect elevated PCT mRNA transcripts in nonadherent undifferentiated (monocytic) or differentiated (macrophage-like) THP-1 cells stimulated with purified Shiga toxin-1 and/or LPS. Our data show that serum levels of PCT are associated with the severity of illness in children with D+ HUS. Further studies are needed to determine the role of PCT in the pathogenesis of thrombotic microangiopathy associated to childhood D+ HUS.

Recurrence of Diabetes After Diarrhea-Associated Hemolytic Uremic Syndrome

We read with interest the article by Suri et al. (1). In this article, we find a systematic review and meta-analysis of articles assessing diabetes during diarrhea-associated hemolytic uremic syndrome (D+HUS). The 21 included studies describe 49 children who developed diabetes during acute D+HUS. Long-term outcome was reported for 44 of 49 children: 13 of 34 survivors were left with persistent diabetes requiring insulin; 11 had persistent diabetes from the outset, while 2 …

Platelet Activation in Hemolytic Uremic Syndrome

Platelet consumption in platelet-fibrin aggregates leading to thrombocytopenia and small vessel obstruction are major features of the hemolytic uremic syndrome (HUS). Although thrombocytopenia has been correlated to poor prognosis, the mechanisms by which thrombocytopenia develops in HUS have not been completely elucidated. However, plausible explanations have been platelet contact with thrombogenic surfaces and/or direct contact with an aggregating agent. This article summarizes several mechanisms of platelet activation, interactions with leukocytes, chemokine release, complement activation, and antimicrobial defense. Specific mechanisms are outlined by which platelets may be activated, leading to thrombocytopenia during HUS. In diarrhea-associated HUS Shiga toxin has been shown to injure the endothelium, thus exposing the subendothelium, releasing tissue factor, and rendering the vessel wall prothrombotic. Shiga toxin also binds to and activates platelets. The toxin may activate endothelial cells and platelets simultaneously. In atypical HUS the alternative complement pathway is activated because of mutations in complement regulatory proteins. Mutated factor H does not bind to endothelium and platelets efficiently, enabling complement activation on these cells. In thrombotic thrombocytopenic purpura, intravascular platelet clotting occurs due to dysfunction of the von Willebrand factor (VWF) -cleaving protease ADAMTS13. Thrombi are formed by binding of platelets to ultralarge VWF multimers.

Urinary Podocyte mRNA Excretion in Children with D+HUS: A Potential Marker of Long-Term Outcome

Background. Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure and may lead to podocyte loss. Objective. To determine if the urinary mRNA excretion of podocyte proteins is detectable in children with D+HUS and if it is a biomarker of a poor long-term outcome. Methods. Patients were randomly selected from participants in the SYNSORB Pk® trial. Urine samples were collected daily during the first week of hospitalization. Specimens were also obtained in healthy volunteers. Synaptopodin and nephrin mRNA levels were measured using real-time PCR. Results. Fifteen children, aged 4.9±2.8 years, were studied. Patients were categorized based on urinary mRNA levels into normal (marker:GAPDH≤mean + SD) or high (marker:GAPDH>mean + SD) in controls. Twelve patients (80%) had increased urinary podocyte mRNA excretion; 11 (73%) had high synaptopodin and 5 (33%) had high nephrin mRNA levels. Follow-up data were available in 13/15 patients, all of whom had normal blood pressure, urinalysis, and serum creatinine concentration. Conclusion. The isolation of podocyte mRNA from routine urine samples is feasible in children with D+HUS. Most patients have podocyturia based on synaptopodin and nephrin mRNA excretion. Larger studies with extended follow-up are required to determine the relationship of these biomarkers to long-term renal prognosis in D+HUS.

Hemolytic uremic syndrome–associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers

Shiga toxin 1 (Stx-1) and Stx-2 produced by enterohemorrhagic Escherichia coli cause the diarrhea-associated hemolytic uremic syndrome (HUS). This type of HUS is characterized by obstruction of the glomeruli and renal microvasculature by platelet-fibrin thrombi, acute renal failure, thrombocytopenia, microvascular hemolytic anemia, and plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range. We investigated the mechanism of initial platelet accumulation on Stx-stimulated endothelial cells. Stx-1 or Stx-2 (1-10 nM) stimulated the rapid secretion of unusually large (UL) VWF multimeric strings from human umbilical vein endothelial cells (HUVECs) or human glomerular microvascular endothelial cells (GMVECs). Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings. Nanomolar concentrations (1-10 nM) of the Shiga toxins were as effective in inducing the formation of ULVWF-platelet strings as millimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS13 was delayed by 3 to 10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2 compared with 20 mM histamine. Stx-induced formation of ULVWF strings, and impairment of ULVWF-platelet string cleavage by ADAMTS13, may promote initial platelet adhesion above glomerular endothelial cells. These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS.

ADAMTS13 and VWF: not just for TTP anymore?

Comment on Nolasco et al, page [4199][1] Shiga toxin stimulates VWF release from endothelial cells and impairs ADAMTS13-mediated VWF proteolysis, demonstrating potential roles for VWF and ADAMTS13 in hemolytic-uremic syndrome (HUS) pathogenesis. Acute diarrhea-associated hemolytic uremic syndrome

Hemolytic Uremic Syndrome Risk andEscherichia coliO157:H7

We reviewed medical records of 238 hospitalized patients with Escherichia coli O157:H7 diarrhea to identify risk factors for progression to diarrhea-associated hemolytic uremic syndrome (HUS). Data indicated that young age, long duration of diarrhea, elevated leukocyte count, and proteinuria were associated with HUS.

Diabetes During Diarrhea-Associated Hemolytic Uremic Syndrome

To quantify the incidence of diabetes during the acute phase of diarrhea-associated hemolytic uremic syndrome (D + HUS) and to identify features associated with its development. A systematic review and meta-analysis of articles assessing diabetes during D + HUS was conducted. Relevant citations were identified from Medline, Embase, and Institute for Scientific Information Citation Index databases. Bibliographies of relevant articles were hand searched. All articles were independently reviewed for inclusion and data abstraction by two authors. Twenty-one studies from six countries were included. Only 2 studies reported a standard definition of diabetes; 14 defined diabetes as hyperglycemia requiring insulin. The incidence of diabetes during the acute phase of D + HUS could be quantified in a subset of 1,139 children from 13 studies (1966-1998, age 0.2-16 years) and ranged from 0 to 15%, with a pooled incidence of 3.2% (95% CI 1.3-5.1, random-effects model, significant heterogeneity among studies, P = 0.007). Children who developed diabetes were more likely to have severe disease (e.g., presence of coma or seizures, need for dialysis) and had higher mortality than those without diabetes. Twenty-three percent of those who developed diabetes acutely died, and 38% of survivors required long-term insulin (median follow-up 12 months). Recurrence of diabetes was possible up to 60 months after initial recovery. Children with D + HUS should be observed for diabetes during their acute illness. Consideration should be given to long-term screening of D + HUS survivors for diabetes.

Hemolytic‐uremic syndrome in a dog

A 3-year-old, spayed, female Boxer was presented because of acute onset of anorexia, vomiting, and hemorrhagic diarrhea. Microangiopathic hemolytic anemia with intravascular hemolysis, thrombocytopenia, and acute renal failure were detected. The dog was treated with fluids, antiemetics, antibiotics, and diuretics. Despite supportive therapy, the dog's condition worsened, and the owners elected euthanasia. Necropsy revealed disseminated petechiae on the parietal peritoneum and serosal surfaces of the intestinal tract. The histologic lesions were consistent with severe arteritis and microvascular thrombosis involving only the renal and intestinal arterioles. The final diagnosis was hemolytic-uremic syndrome (HUS), a rarely described disorder in dogs. The clinical presentation of primarily gastrointestinal clinical signs was similar to that of typical or diarrhea-associated HUS (D+ HUS) in humans (mainly children), which is caused by gastrointestinal proliferation of verocytotoxin-producing Escherichia coli. Bacterial toxins can be adsorbed and cause endothelial injury, activation of hemostasis, and thrombosis, with lesions confined primarily to the kidneys. Although rare, HUS should be considered in the differential diagnosis of dogs with microangiopathic hemolytic anemia.

Hemolytic Uremic Syndrome in Children

The term hemolytic uremic syndrome (HUS) describes a heterogenous group of diseases characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Diarrhea-associated HUS (D+ HUS) accounts for 90 % of cases in childhood, and it is one of the most frequent causes of acute renal failure in children less than five years of age leading to a significant degree of morbidity and mortality. The first step in the pathogenesis of D+HUS is the local inflammation of the intestinal epithelium and endothelium due to Shigatoxin (Stx) producing E. coli infection. This leads to intestinal hemorrhagie, loss of barrier functions, and generation of inflammatory cytokines. Together with TNFα and E.coli derived lipopolysaccharide Stx may act synergistically to damage vascular endothelium. Vascular endothelial injury and its consequences may lead to permanent damage of the kidney, brain, heart, pancreas, and necrosis of intestine. In contrast to D+HUS, the atypical HUS is not associated with diarrhea. Familial and recurrent form of HUS may be associated with low C3 complement levels and/or genetic mutations in factor H. The main purpose of this article is to review the epidemiological, pathogenetic, and clinical features, current treatment strategies, and outcome of D+ HUS with a brief focus on atypical HUS. Keywords: hemolytic uremic syndrome, childhood, clinical manifestations, pathogenesis, treatment, prognosis