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BACKGROUND: Chronic kidney-related sequelae after STEC-HUS occur in 20-40% of patients. Hyperuricemia (HU) may cause acute and chronic toxicity involving the kidneys. We retrospectively assessed if there was an association between the presence of HU during the acute illness and that of kidney-related sequelae in children with STEC-HUS. METHODS: Children with STEC-HUS who had clinical and laboratory data at 2 years of follow-up were included in this case-control study. Univariate and multivariate analyses were performed between patients with (cases) or without (controls) kidney-related sequelae to identify factors associated with outcomes, including different measures of serum uric acid (sUA) (baseline level, peak, and duration of HU). HU was defined as sUA > 8 mg/dL. RESULTS: Of 86 patients included, 77.9% had HU. Patients with sequelae (n = 41) had a higher prevalence of HU (41/41 vs. 26/45, p < 0.01), higher baseline leukocyte count, serum creatinine (sCr), and sUA levels as well as lower sodium than controls. During hospitalization, cases also had higher sCr peak, sUA peak and duration of HU, requirement and duration of dialysis, extrarenal complications, and hypertension. By multivariate analysis, after adjusting for length of dialysis, only duration of HU (p = 0.0005; OR 1.7, 95% CI 1.27-2.36) remained as an independent predictor of sequelae, with a best cutoff of 5.5 days (AUC 0.95, specificity 80%, sensitivity 100%). CONCLUSIONS: The presence of HU is a common finding in children with STEC-HUS and its duration during the acute stage was associated with kidney-related sequelae, regardless of the duration of dialysis. A higher resolution version of the Graphical abstract is available as Supplementary Information.

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BACKGROUND: The efficacy of recombinant human erythropoietin (rHuEPO) in sparing red blood cell (RBC) transfusions in children with hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) is uncertain. METHODS: We conducted a pilot randomized controlled open trial between December 2018 and January 2021. Children were randomized to the intervention (subcutaneous rHuEPO 50 U/kg three times weekly until discharge + RBC transfusion if hemoglobin ≤ 7 g/dL and/or hemodynamic instability) or to the control arm (RBC transfusion if hemoglobin ≤ 7 g/dL and/or hemodynamic instability). Primary outcome was the number of RBC transfusions received during hospitalization. Secondary outcomes were to explore whether baseline EPO levels were adequate to the degree of anemia, to correlate selected acute phase parameters with the number of RBC transfusions, and to assess possible adverse events. RESULTS: Twelve patients per arm were included; they were comparable at recruitment and throughout the disease course. Median number of RBC transfusions was similar between groups (1.5, p = 0.76). Most patients had baseline EPO levels adequate to the degree of anemia, which did not correlate with the number of transfusions (r = 0.19, p = 0.44). Conversely, baseline (r = 0.73, p = 0.032) and maximum lactic dehydrogenase levels (r = 0.78, p = 0.003), creatinine peak (r = 0.71, p = 0.03) and dialysis duration (r = 0.7, p = 0.04) correlated significantly with RBC requirements. No side effects were recorded. CONCLUSION: In children with STEC-HUS, the administration of rHuEPO did not reduce the number of RBC transfusions. Larger studies addressing higher doses and similar severity of kidney failure at rHuEPO initiation (e.g. at start of dialysis) are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03776851. A higher resolution version of the Graphical abstract is available as Supplementary information.

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Introduction: Neurologic involvement in hemolytic uremic syndrome related to Shiga toxin­producing Escherichia coli (STEC-HUS) is the main cause of death. In last years has been demonstrated that activation of complement alternative pathway also contributes to organ damage. This finding led to the recognition of decreased C3 levels at admission as a marker of poor prognosis as well as the evaluation of the use of eculizumab in cases with neurologic compromise. Objective: to report a patient with STEC-HUS and hypocomplementemia with neurological involvement treated with eculizumab. Clinical case: A 17-month-old male was admitted due to seizures and anuria for last 24 h with a history of 48 h of bloody diarrhea. He presented a laboratory profile compatible with STEC-HUS and severe hyponatremia, results of brain tomography were normal. Also there was complement activation: C3 73 mg/dl (normal > 90 mg/dL) and C5b-9 778.9 ng/ml (normal 135.8-385.3 ng/ml). Initial treatment includes normal saline solution and anticonvulsants drugs, sodium correction and peritoneal dialysis. On third day of hospitalization, because of progression of the neurologic involvement a dose of eculizumab (300 mg) was given, showing at 24 h a markedly neurologic improvement along with and increasing platelet count and a descending lactic dehydrogenase levels. He was discharged after 14 days in a good condition. Later a STEC O157:H7 infection was confirmed and he also normalized the C3 level. Conclusion: This case shows that decreased C3 level at admission was associated to neurologic involvement and suggests that eculizumab might be a favorable therapeutic option.

Introducción: En compromiso neurológico en el síndrome urémico hemolítico producido por Eschericha coli productor de Shiga toxina (STEC-SUH) es la primera causa de mortalidad. En los últimos años se ha demostrado que también contribuye al daño de órgano la activación de la vía alterna del complemento. Este hallazgo dio lugar al reconocimiento del descenso de C3 como marcador de mal pronóstico así como a la evaluación del uso de eculizumab ante compromiso neurológico severo. Objetivo: Comunicar un paciente con STEC-SUH e hipocomplementemia con compromiso neurológico tratado con eculizumab. Caso clínico: Varón de 17 meses que ingresa por síndrome convulsivo y 24 horas de anuria con antecedente de diarrea con sangre de 48 horas de evolución. Presentaba al ingreso laboratorio compatible con STEC-HUS e hiponatremia severa, con tomografía de cerebro normal. Además presentaba activación del complemento: C3 73 mg/dl (normal > 90 mg/dL) y C5b-9 778,9 ng/ml (normal 135,8-385,3 ng/ml). Se administró solución fisiológica y anticonvulsivantes, se corrigió la natremia y comenzó diálisis peritoneal. Al tercer día, por progresión del compromiso neurológico, se administró eculizumab (300 mg) experimentando una notable recuperación neurológica a las 24 horas junto a aumento de plaquetas y descenso de láctico deshidrogenasa. El paciente fue dado de alta luego de 14 días en buen estado general. Posteriormente se confirmó aislamiento de STEC O157:H7 y normalización de C3. Conclusión: este caso demuestra que el descenso de C3 al ingreso se asoció con daño neurológico y sugiere que la administración de eculizumab podría ser una alternativa terapéutica favorable.

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OBJECTIVES: This study aimed to evaluate practice patterns during prodromal phase of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS). METHODS: Trajectories of children from first symptoms until STEC-HUS admitted consecutively at our center (period 2000-2017) were retrospectively reviewed. Early recommended practices include identification of STEC infections, antibiotics and antiperistaltic avoidance, and administration of anticipatory intravenous fluids; therefore, implementation and changes over time (before and after 2011) of such interventions were assessed. In addition, early management was correlated with acute disease outcomes. RESULTS: Of 172 patients, 98 (57%) had early consults, 75 of them visit the pediatric emergency department. Those seen with watery diarrhea (n = 74) were managed as outpatients, whereas 27 of the 45 assisted with bloody diarrhea were hospitalized for diagnosis other than STEC-HUS. Stool cultures were performed in 13.4% (23/172), 18% (31/172) received antibiotics, and 12.8% (22/172) received endovenous fluids; none received antiperistaltic agents. Shiga toxin-producing E. coli infection was proven in 4% (7/172) before HUS. Rate of cultured patients and treated with intravenous fluids remained unchanged over time (P = 0.13 and P = 0.48, respectively), whereas antibiotic prescription decreased from 42.8% to 16.6% (P = 0.005). Main acute outcomes (need for dialysis, pancreatic compromise, central nervous system involvement, and death) were similar (P > 0.05) regardless of whether they received antibiotics or intravenous fluids. CONCLUSIONS: During the diarrheal phase, 57% of patients consulted; three-quarters of them consulted to the pediatric emergency department. Shiga toxin-producing E. coli detection was poor, antibiotic use remained high, and anticipatory volume expansion was underused. These findings outline the critical need to improve the early management of STEC-HUS.

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BACKGROUND: Hyperuricemia might induce additional renal damage in children with hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS). A few case reports have shown rasburicase to be effective in decreasing serum uric acid (UA) and improving renal function. However, there is only one report on the use of rasburicase in a child with STEC-HUS, which shows satisfactory results. We describe here the safety and efficacy of rasburicase in nine additional cases. CASE-DIAGNOSIS/TREATMENT: Data from 9 children (5 females, median age 2 years) who received rasburicase were reviewed. At admission, 6 were dehydrated and 3 euvolemic. Dehydrated patients received saline solution and afterwards, as well as for those initially euvolemic, we aimed to keep a neutral fluid balance. Despite this, urine output did not increase. Baseline creatinine was 3.35 mg/dL (1.47-9.1) and UA 11.4 mg/dL (8.3-19.2). A single dose of rasburicase (0.2 mg/kg) was given 6-8 h after admission, which reduced UA levels to 1.8 mg/dL (0.3-5, p = 0.009) on the next day. However, renal parameters worsen and dialysis had to be initiated. Then, while still on dialysis, a UA rebound occurred in all cases reaching a peak of 8.9 mg/dL (4.5-13.8). Just after a steady increase in urine output, a sustained decline in UA levels concomitantly occurred with an improvement in renal function. At discharge, all patients reached normal UA levels. No side effects were recorded. CONCLUSIONS: Administration of rasburicase in children with STEC-HUS was safe but failed to provide any significant benefit despite fall in serum UA levels.

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Identifying those children with complicated forms of diarrhea-associated hemolytic uremic syndrome (D+HUS) on admission can optimize their management. Recently, the blood urea nitrogen to serum creatinine ratio (BCR) at admission has been proposed as a novel and accurate predictor of complicated clinical outcome in D+HUS; therefore, we performed this retrospective study aimed to validate such observation in a larger series of patients. A complicated course was defined as developing one or more of the following: severe neurological or bowel injury, pancreatitis, cardiac or pulmonary involvement, hemodynamic instability, hemorrhage, and death. Data from 161 children were reviewed, 50 of them with a complicated disease including five deaths. Those with worse evolution presented a lower admission BCR than those with good outcome (22.5 vs. 30.8; p = 0.005). BCR at admission showed a limited ability to identify children at risk of a complicated course, with an AUC of 0.63 (95% CI 0.58-0.71) and an optimal cutoff point of ≤ 26.7, which achieves a sensitivity of 70% (95% CI 55.2-81.7) and a specificity of 56.7% (95% CI 47-66). CONCLUSION: 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.

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Introducción. La hipercalciuria idiopática (HI) predispone al desarrollo de infección del tracto urinario (ITU); sin embargo, hay escasa información local sobre dicha asociación. Nuestros objetivos fueron estimar la prevalencia de HI en niños con ITU y evaluar si esta difería según la presencia o no de reflujo vesicoureteral (RVU). Complementariamente, analizamos la asociación entre HI y la ingesta de sal. Población y métodos. Determinamos la calciuria a pacientes menores de 18 años con ITU estudiada (ecografía y cistouretrografía miccional) y ausencia de causas secundarias de hipercalciuria. Consideramos HI al cociente calcio/creatinina > 0,8; 0,6; 0,5 y 0,2 en niños de 0-6 meses, 7-12 meses, 12-24 meses y en los mayores de 2 años, respectivamente; e ingesta elevada de sodio, al cociente sodio/potasio urinario > 2,5. Resultados. En 136 pacientes (87 niñas, mediana de edad 3 años), la prevalencia de HI fue de 20%. Los pacientes con (n= 54) y sin (n= 82) RVU fueron similares en género, peso, talla, edad al diagnóstico y al momento del estudio, características clínicas (hematuria, nefrolitiasis, dolor cólico y recurrencia de ITU), antecedentes familiares de nefrolitiasis y en la prevalencia de HI (26% vs. 16%, p= 0,24). Los niños hipercalciúricos presentaron ingesta elevada de sodio más frecuentemente que los normocalciúricos (76% vs. 46%, p= 0,007). Conclusiones. La prevalencia de HI en niños con ITU fue alta (20%) y no difirió entre los pacientes con y sin RVU. Sería recomendable la búsqueda de HI en los niños con ITU, independientemente de la presencia o no de RVU.

Introduction. Idiopathic hypercalciuria (IH) predisposes to urinary tract infections (UTIs); however, there is scarce local information regarding such association. Our objectives were to estimate IH prevalence in children with UTI and to assess whether there were differences in relation to the presence or absence of vesicoureteral reflux (VUR). Additionally, the association between IH and salt intake was studied. Population and Methods. Calciuria was determined in patients younger than 18 years old on whom UTI had been studied (ultrasound and voiding cystourethrogram), and who had no secondary causes of hypercalciuria. IH was defined as a calcium to creatinine ratio of >0.8, 0.6, 0.5 and 0.2 in children aged 0 to 6 months old, 7 to12 months old, 12 to 24 months old and older than 2 years old, respectively; and a high sodium intake with a urinary sodium to potassium ratio of >2.5. Results. IH prevalence among 136 patients (87 girls, median age: 3 years old) was 20%. Patients with VUR (n= 54) and without VUR (n= 82) had similar characteristics in terms of sex, weight, height, age at diagnosis and age at the time of the study, and clinical features (hematuria, nephrolithiasis, colicky pain, and recurrent UTI), family history of kidney stone formation, and IH prevalence (26% versus 16%, p= 0.24). A high sodium intake was more frequently observed in children with hypercalciuria than in those with normal urine calcium levels (76% versus 46%, p= 0.007). Conclusions. IH prevalence in children with UTI was high (20%), with no differences observed between patients with and without VUR. As a recommendation, the presence of IH should be detected in children with UTI, regardless of VUR presence or absence.

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Introducción. La hipercalciuria idiopática (HI) predispone al desarrollo de infección del tracto urinario (ITU); sin embargo, hay escasa información local sobre dicha asociación. Nuestros objetivos fueron estimar la prevalencia de HI en niños con ITU y evaluar si esta difería según la presencia o no de reflujo vesicoureteral (RVU). Complementariamente, analizamos la asociación entre HI y la ingesta de sal. Población y métodos. Determinamos la calciuria a pacientes menores de 18 años con ITU estudiada (ecografía y cistouretrografía miccional) y ausencia de causas secundarias de hipercalciuria. Consideramos HI al cociente calcio/creatinina > 0,8; 0,6; 0,5 y 0,2 en niños de 0-6 meses, 7-12 meses, 12-24 meses y en los mayores de 2 años, respectivamente; e ingesta elevada de sodio, al cociente sodio/potasio urinario > 2,5. Resultados. En 136 pacientes (87 niñas, mediana de edad 3 años), la prevalencia de HI fue de 20%. Los pacientes con (n= 54) y sin (n= 82) RVU fueron similares en género, peso, talla, edad al diagnóstico y al momento del estudio, características clínicas (hematuria, nefrolitiasis, dolor cólico y recurrencia de ITU), antecedentes familiares de nefrolitiasis y en la prevalencia de HI (26% vs. 16%, p= 0,24). Los niños hipercalciúricos presentaron ingesta elevada de sodio más frecuentemente que los normocalciúricos (76% vs. 46%, p= 0,007). Conclusiones. La prevalencia de HI en niños con ITU fue alta (20%) y no difirió entre los pacientes con y sin RVU. Sería recomendable la búsqueda de HI en los niños con ITU, independientemente de la presencia o no de RVU.(AU)

Introduction. Idiopathic hypercalciuria (IH) predisposes to urinary tract infections (UTIs); however, there is scarce local information regarding such association. Our objectives were to estimate IH prevalence in children with UTI and to assess whether there were differences in relation to the presence or absence of vesicoureteral reflux (VUR). Additionally, the association between IH and salt intake was studied. Population and Methods. Calciuria was determined in patients younger than 18 years old on whom UTI had been studied (ultrasound and voiding cystourethrogram), and who had no secondary causes of hypercalciuria. IH was defined as a calcium to creatinine ratio of >0.8, 0.6, 0.5 and 0.2 in children aged 0 to 6 months old, 7 to12 months old, 12 to 24 months old and older than 2 years old, respectively; and a high sodium intake with a urinary sodium to potassium ratio of >2.5. Results. IH prevalence among 136 patients (87 girls, median age: 3 years old) was 20%. Patients with VUR (n= 54) and without VUR (n= 82) had similar characteristics in terms of sex, weight, height, age at diagnosis and age at the time of the study, and clinical features (hematuria, nephrolithiasis, colicky pain, and recurrent UTI), family history of kidney stone formation, and IH prevalence (26% versus 16%, p= 0.24). A high sodium intake was more frequently observed in children with hypercalciuria than in those with normal urine calcium levels (76% versus 46%, p= 0.007). Conclusions. IH prevalence in children with UTI was high (20%), with no differences observed between patients with and without VUR. As a recommendation, the presence of IH should be detected in children with UTI, regardless of VUR presence or absence.(AU)

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INTRODUCTION: Idiopathic hypercalciuria (IH) predisposes to urinary tract infections (UTIs); however, there is scarce local information regarding such association. Our objectives were to estimate IH prevalence in children with UTI and to assess whether there were differences in relation to the presence or absence of vesicoureteral reflux (VUR). Additionally, the association between IH and salt intake was studied. POPULATION AND METHODS: Calciuria was determined in patients younger than 18 years old on whom UTI had been studied (ultrasound and voiding cystourethrogram), and who had no secondary causes of hypercalciuria. IH was defined as a calcium to creatinine ratio of >0.8, 0.6, 0.5 and 0.2 in children aged 0 to 6 months old, 7 to12 months old, 12 to 24 months old and older than 2 years old, respectively; and a high sodium intake with a urinary sodium to potassium ratio of >2.5. RESULTS: IH prevalence among 136 patients (87 girls, median age: 3 years old) was 20%. Patients with VUR (n= 54) and without VUR (n= 82) had similar characteristics in terms of sex, weight, height, age at diagnosis and age at the time of the study, and clinical features (hematuria, nephrolithiasis, colicky pain, and recurrent UTI), family history of kidney stone formation, and IH prevalence (26% versus 16%, p= 0.24). A high sodium intake was more frequently observed in children with hypercalciuria than in those with normal urine calcium levels (76% versus 46%, p= 0.007). CONCLUSIONS: IH prevalence in children with UTI was high (20%), with no differences observed between patients with and without VUR. As a recommendation, the presence of IH should be detected in children with UTI, regardless of VUR presence or absence.

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