Dynamic evolution of kidney function in patients with STEC-hemolytic uremic syndrome followed for more than 15 years: unexpected changes.

BACKGROUND: Most studies regarding kidney outcomes in patients with Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS) focus on kidney status at last assessment. We aimed to describe patterns of changes in kidney function during follow-up and investigate associations between kidney function at 1st, 5th, and 10th year after onset and long-term kidney outcomes. METHODS: Data of patients with STEC-HUS followed for at least 15 years were analyzed. Kidney function patterns were constructed considering kidney status at 1st, 5th, 10th, and ≥ 15 years and defined as (1) progressive, if patients changed from complete recovery to any chronic kidney disease (CKD) stage or if CKD worsened; (2) improvement, if they shifted from any CKD stage to complete recovery or to a milder stage; and (3) stable, if remained unchanged. RESULTS: Of 152 patients included, after 1 year of follow-up, 47% had complete recovery, 22% CKD1, and 32% CKD2-5. At last assessment, 46% had complete recovery, 34% CKD1, and 19% CKD2-5. Despite percentages seeming similar, patients differed: 48% were stable, 27% improved, and 25% worsened. Further, 62% of patients with CKD2-4 in the 1st year normalized their glomerular filtration rate (GFR) thereafter. Comparison of kidney function between 1st, 5th, and 10th year to last assessment shows a stable pattern in 48, 59, and 69% respectively. CONCLUSIONS: Changes in kidney function showed a dynamic and complex behavior, with patients moving from one group to another. Consistently, kidney function neither at the 1st, 5th, or 10th year was representative of final outcome. Unexpectedly, two-thirds of patients with CKD2-4 after 1 year achieved normal eGFR later during follow-up.

Hyperuricemia: an unrecognized risk factor for kidney-related sequelae in children with hemolytic uremic syndrome.

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.

Eliglustat prevents Shiga toxin 2 cytotoxic effects in human renal tubular epithelial cells.

BACKGROUND: Shiga toxin-producing Escherichia coli is responsible for post-diarrheal (D+) hemolytic uremic syndrome (HUS), which is a cause of acute renal failure in children. The glycolipid globotriaosylceramide (Gb3) is the main receptor for Shiga toxin (Stx) in kidney target cells. Eliglustat (EG) is a specific and potent inhibitor of glucosylceramide synthase, first step of glycosphingolipid biosynthesis, actually used for the treatment of Gaucher's disease. The aim of the present work was to evaluate the efficiency of EG in preventing the damage caused by Stx2 in human renal epithelial cells. METHODS: Human renal tubular epithelial cell (HRTEC) primary cultures were pre-treated with different dilutions of EG followed by co-incubation with EG and Stx2 at different times, and cell viability, proliferation, apoptosis, tubulogenesis, and Gb3 expression were assessed. RESULTS: In HRTEC, pre-treatments with 50 nmol/L EG for 24 h, or 500 nmol/L EG for 6 h, reduced Gb3 expression and totally prevented the effects of Stx2 on cell viability, proliferation, and apoptosis. EG treatment also allowed the development of tubulogenesis in 3D-HRTEC exposed to Stx2. CONCLUSIONS: EG could be a potential therapeutic drug for the prevention of acute kidney injury caused by Stx2. IMPACT: For the first time, we have demonstrated that Eliglustat prevents Shiga toxin 2 cytotoxic effects on human renal epithelia, by reducing the expression of the toxin receptor globotriaosylceramide. The present work also shows that Eliglustat prevents Shiga toxin 2 effects on tubulogenesis of renal epithelial cells. Eliglustat, actually used for the treatment of patients with Gaucher's disease, could be a therapeutic strategy to prevent the renal damage caused by Shiga toxin.

Erythropoietin in children with hemolytic uremic syndrome: a pilot randomized controlled trial.

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.

Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli infection in Argentina: update of serotypes and genotypes and their relationship with severity of the disease.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) infection is the most common cause of hemolytic uremic syndrome (HUS). Only few studies correlated serotypes and stx genotypes with disease severity. This study aimed to update STEC serotypes, stx genotypes, and virulence factors (eae and ehxA) in a cohort of patients with STEC-HUS and investigate whether they influence the severity of disease. METHODS: In this multicentric study, children hospitalized between 2005 and 2016 with STEC-HUS confirmed by the National Reference Laboratory were included. Serotypes (O157, O145, O121, and others), stx genotypes (stx1a, stx2a, stx2c, stx2d, and others), and virulence factors were analyzed, and their association with dialysis requirement (>10 days); severe neurological, cardiovascular, and/or bowel involvement; and death was assessed. RESULTS: The records of 280 patients were reviewed; 160 females, median age 21 months (IQR18m). STEC O157 was isolated in 206 (73.6%) patients, O145 in 47 (16.8%), O121 in 15 (5.4%), and other serotypes in 12 (4.2%). The stx2a/2c genotype was carried by 179 (63.9%) strains, stx2a by 94 (33.6%), stx1a/stx2a by five (1.8%), and stx1a only by two (0.7%). All strains except six harbored eae and ehxA genes. Fifty-nine (21.1%) patients had severe neurological involvement, 29 (10.4%) severe bowel injury, 14 (5%) cardiovascular involvement, 53 (18.9%) required > 10 days of dialysis, and 12 (4.3%) died. Neither serotypes nor stx genotypes detected were significantly linked to severity. CONCLUSIONS: Serotype O157 and virulence stx2a/2c, eae, ehxA genotype are prevalent in Argentina, and no relationship was found between severity and serotypes and genotypes of STEC detected.

Acute peritoneal dialysis, complications and outcomes in 389 children with STEC-HUS: a multicenter experience.

BACKGROUND: Management of acute kidney injury (AKI) in children with hemolytic uremic syndrome induced by a Shiga toxin-producing Escherichia coli infection (STEC-HUS) is supportive; however, 40 to 60% of cases need kidney replacement therapy (KRT). The aim of this study was to analyze procedure complications, especially peritonitis, and clinical outcomes in children with AKI secondary to STEC-HUS treated with acute PD. METHODS: This is a multicenter retrospective study conducted among thirty-seven Argentinian centers. We reviewed medical records of 389 children with STEC-HUS hospitalized between January 2015 and February 2019 that required PD. RESULTS: Complications associated with PD were catheter malfunction (n = 93, 24%), peritonitis (n = 75, 19%), fluid leaks (n = 45, 11.5%), bleeding events (n = 23, 6%), and hyperglycemia (n = 8, 2%). In the multivariate analysis, the use of antibiotic prophylaxis was independently associated with a decreased risk of peritonitis (hazard ratio 0.49, IC 95% 0.29-0.81; p = 0.001), and open-surgery catheter insertion was independently associated with a higher risk (hazard ratio 2.8, IC 95% 1.21-6.82; p = 0.001). Discontinuation of PD due to peritonitis, severe leak, or mechanical complications occurred in 3.8% of patients. No patient needed to be transitioned to other modality of KRT due to inefficacy of the technique. Mortality during the acute phase occurred in 2.8% patients due to extrarenal complications (neurological and cardiac involvement), not related to PD. CONCLUSIONS: Acute PD was a safe and effective method to manage AKI in children with STEC-HUS. Prophylactic antibiotics prior to insertion of the PD catheter should be considered to decrease the incidence of peritonitis.

Prodromal Phase of Hemolytic Uremic Syndrome Related to Shiga Toxin-Producing Escherichia coli: The Wasted Time.

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.

Correction to: C3 levels and neurologic involvement in hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli.

The original version of the letter unfortunately contained a mistake.

Rasburicase in hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli: a report of nine cases.

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.

C3 levels and acute outcomes in Shiga toxin-related hemolytic uremic syndrome.

BACKGROUND: The correlation between complement activation and severity of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) has been examined in few studies, with conflicting results. We investigated whether C3 levels on admission are associated with worse acute outcomes. METHODS: Demographic, clinical, and laboratory variables were compared between dialyzed and non-dialyzed patients and between those with or without extrarenal complications. Univariate and multivariate analyses were performed; odds ratio (OR) and 95% confidence interval (95%CI) were calculated. C3 concentrations were correlated with dialysis length (Spearman test) and ROC curves with area under the curves (AUC) were calculated to identify C3 concentrations able to discriminate patients with dialysis requirements and complicated course. RESULTS: Among 49 children, 33 had normal and 16 had decreased C3 concentrations. Higher hemoglobin, lactic dehydrogenase, urea and creatinine and lower albumin, sodium, and C3 and C4 concentrations at admission were associated with dialysis requirement; only creatinine remained significant (p = 0.03, OR 2.1, 95%CI 1.34-2.7) by multivariate analysis. Patients with a complicated course presented higher leukocyte count, hemoglobin and lactic dehydrogenase and lower albumin, sodium, and C3 and C4. In the multivariate analysis, leukocyte count (p = 0.02, OR 2.6, 95%CI 1.4-4.3) and C3 concentration (p = 0.039, OR 1.7, 95%CI 1.1-2.73) were independently associated with a complicated disease. C3 levels correlated with dialysis length (r = - 0.42, p = 0.002); nevertheless, they were unable to discriminate dialysis requirement (AUC = 0.25, 95%CI 0.11-0.38) and extrarenal complications (AUC = 0.24, 95%CI 0.11-0.4). CONCLUSIONS: Our study suggests that decreased C3 levels at admission are associated with a more complicated STEC-HUS episode.

Correction to: C3 levels and acute outcomes in Shiga toxin-related hemolytic uremic syndrome.

Due to an unfortunate error during the processing of the article, the spelling of the second author name was incorrect.

Prognostic value of urinary TGF-ß1 in hemolytic uremic syndrome: A pilot study.

BACKGROUND: Transforming growth factor ß1 (TGF-ß1) is the main profibrotic cytokine. Its urinary excretion reflects intrarenal production; thus, we conjectured that it is elevated during hemolytic uremic syndrome related to Shiga-toxin-producing Escherichia coli (STEC-HUS). In this pilot study, we explored the ability of baseline TGF-ß1 excretion (exposure variable) to predict renal prognosis at 6 months (outcome variable). In a secondary investigation, we compared changes in cytokine levels during the study period between patients with opposite renal outcomes. METHODS: Urinary TGF-ß1 concentrations were measured prospectively in 24 children with STEC-HUS on admission, and at 15, 30, 60, 90, and 180 days. Normal values were obtained from 20 healthy subjects. RESULTS: Baseline TGF-ß1 concentrations predicted renal outcomes with an area under the curve of 1 (95%CI 0.85-1; sensitivity 100%, specificity 100%) with the best cutoff level >293.7 pg/mg uCr. All patients with high TGF-ß1 levels developed persistent renal impairment, unlike none with low concentrations (4/4 vs. 20/0 respectively, P = 0.0001). The latter had higher cytokine levels (P < 0.05) at each time point without reaching normal concentrations (<45 pg/mg uCr). CONCLUSIONS: Baseline urinary TGF-ß1 levels accurately predicted short-term renal outcomes in STEC-HUS children, and cytokine excretion during the first 6 months after diagnosis was higher among those with worse evolution. Larger studies are needed to validate these findings.

[Prevalence of Arterial Hypertension in a neonatal intensive care unit]. / Prevalencia de Hipertensión Arterial en una unidad de cuidados intensivos neonatales.

INTRODUCTION: The prevalence of neonatal hypertension in neonatal intensive care units (NICU) ranges between 3 and 9%. However, there is no current data on Latin America. OBJECTIVE: To estimate the prevalence of neonatal hypertension and to assess its association with causes previously related to this condi tion. PATIENTS AND METHOD: cross-sectional study. All patients admitted to the NICU during one year were included, excluding those transferred to the cardiovascular NICU. The following maternal and neonatal variables were registered: maternal arterial hypertension, type of delivery, gestational age, age, sex, birth weight, Apgar score, history of pulmonary maturation with corticosteroids, and umbilical vessel catheterization as well as the reason for admission to the NICU, medications, and complications during hospitalization. Blood pressure was measured with an automated oscillometric device, defining neonatal hypertension according to standards in gestational age. Prevalence was ex pressed as percentage (confidence interval 95%, CI95%). Descriptive data were reported as median (range) and frequency of presentation (percentage). Finally, we used the Wilcoxon, Chi2 o Fisher exact test to identify factors related to NH as applicable (p < 0.05). RESULTS: 169 patients were in cluded (60% males). Gestational age was 38 weeks (range 26-42 weeks), 38% were preterm. Birth weight was 3000 g (range 545-4950 g) and 32% presented low birth weight. Eight patients presented hypertension during hospitalization (4.7% prevalence, CI95% 2.4-9). The presence of hypertension was associated with prematurity (p = 0.0003), low birth weight (p = 0.01), prenatal corticosteroid treatment (p = 0.002), umbilical catheterization (p = 0.03), administration of ὅ 2 nephrotoxic drugs (p = 0.02), caffeine treatment (p = 0.0001), acute kidney injury (p = 0.02), and intracranial hyper tension (p = 0.04). Only one patient required antihypertensive pharmacologic treatment and in all cases, hypertension was resolved during follow-up. CONCLUSION: Prevalence of neonatal hypertension in our NICU was 4.7% and in all cases occurred in preterm newborns with previously recognized factors associated with this condition.

Hyponatremia: a new predictor of mortality in patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome.

OBJECTIVES: (1) Evaluate mortality rate in patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, (2) determine the leading causes of death, and (3) identify predictors of mortality at hospital admission. METHODS: We conducted a multicentric, observational, retrospective, cross-sectional study. It included patients under 18 years old with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome hospitalized between January 2005 and June 2016. Clinical and laboratory data were obtained from the Argentine National Epidemiological Surveillance System of Hemolytic Uremic Syndrome. Clinical and laboratory variables were compared between deceased and non-deceased patients. Univariate and multivariate analyses were performed. ROC curves and area under the curve were obtained. RESULTS: Seventeen (3.65%) out of the 466 patients died, being central nervous system involvement the main cause of death. Predictors of death were central nervous system involvement, the number of days since the beginning of diarrhea to hospitalization, hyponatremia, high hemoglobin, high leukocyte counts, and low bicarbonate concentration on admission. In the multivariate analysis, central nervous system involvement, sodium concentration, and hemoglobin were independent predictors. The best cut off for sodium was ≤ 128 meq/l and for hemoglobin ≥ 10.8 g/dl. CONCLUSIONS: Mortality was low in children with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, being central nervous system involvement the main cause of death. The best mortality predictors found were central nervous system involvement, hemoglobin, and sodium concentration. Hyponatremia may be a new Shiga toxin-producing Escherichia coli hemolytic uremic syndrome mortality predictor.

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

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.