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Background: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed., Methods: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens., Results: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m 2 in all patients., Conclusions: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Haemolytic Uraemic Syndrome (HUS) is a rare medical condition characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. Neurological complications are documented but rarely involve the cerebellum. We present a unique case of a 23-month-old male with HUS triggered by Escherichia coli-O157 (E.coli-O157) infection leading to an isolated cerebellar stroke.The patient initially presented with fever, bloody stools, and seizures. Confirmation of E.coli-O157 infection was obtained, and MRI revealed an isolated cerebellar stroke. Treatment included supportive care, anticoagulation for a right atrial thrombus, with gradual improvement observed.This case highlights the unusual occurrence of isolated cerebellar stroke in HUS patients, emphasising the importance of promptly recognizing manifestations of the central nervous system and the necessity for a multidisciplinary approach. Finally, a comprehensive literature review was conducted to identify cases of HUS patients with cerebellar involvement., (© 2024. The Author(s).)

Background: Hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury in children. HUS is known as an acute disease followed by complete recovery, but patients may present with kidney abnormalities after long periods of time. This study evaluates the long-term outcome of Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) in pediatric patients, 10 years after the acute phase of disease to identify risk factors for long-term sequelae., Methods: Over a 6-year period, 619 patients under 18 years of age with HUS (490 STEC-positive, 79%) were registered in Austria and Germany. Long-term follow-up data of 138 STEC-HUS-patients were available after 10 years for analysis., Results: A total of 66% (n = 91, 95% CI 0.57-0.73) of patients fully recovered showing no sequelae after 10 years. An additional 34% (n = 47, 95% CI 0.27-0.43) presented either with decreased glomerular filtration rate (24%), proteinuria (23%), hypertension (17%), or neurological symptoms (3%). Thirty had sequelae 1 year after STEC-HUS, and the rest presented abnormalities unprecedented at the 2-year (n = 2), 3-year (n = 3), 5-year (n = 3), or 10-year (n = 9) follow-up. A total of 17 patients (36.2%) without kidney abnormalities at the 1-year follow-up presented with either proteinuria, hypertension, or decreased eGFR in subsequent follow-up visits. Patients needing extracorporeal treatments during the acute phase were at higher risk of presenting symptoms after 10 years (p < 0.05)., Conclusions: Patients with STEC-HUS should undergo regular follow-up, for a minimum of 10 years following their index presentation, due to the risk of long-term sequelae of their disease. An initial critical illness, marked by need of kidney replacement therapy or plasma treatment may help predict poor long-term outcome., (© 2024. The Author(s).)

Background: Mirror syndrome is a rare disease characterized by "triple edema", while Hemolytic Uremic Syndrome (PHUS) is a serious disease that occurs within a short period of time after the end of pregnancy, with a low prevalence and poor prognosis, and it is even rarer for both to occur in the same patient., Methods: We report a case of mirror syndrome combined with PHUS and analyze the clinical data to improve the understanding of the disease., Results: The patient presented clinically with "triple edema" and was diagnosed with mirror image syndrome. After cesarean section, the patient developed cardiac insufficiency, renal insufficiency, hemolysis, and other symptoms and was diagnosed as PHUS. After active treatment, the maternal prognosis was good., Conclusions: Mirror syndrome and PHUS are both clinically rare diseases with poor long-term prognosis if not diagnosed and treated in a timely manner; therefore, awareness of the diseases, early and accurate diagnosis and timely and correct treatment should be improved.

Background: Hemolytic uremic syndrome (HUS) is a serious cause of acute kidney injury in children. There is a suggestion that coronavirus disease 2019 (COVID-19) may be a trigger for HUS. In this study, we present a pediatric case diagnosed with HUS associated with COVID-19, which progressed to end-stage kidney disease., Case: A previously healthy 13-year-old girl with fever and vomiting was referred to our hospital. Laboratory investigations revealed direct Coombs-negative hemolytic anemia, thrombocytopenia and renal impairment accompanied by COVID-19 infection. Although anemia and thrombocytopenia showed improvement on the seventh day after admission, the renal impairment persisted. The histopathological findings of a renal biopsy were compatible with both HUS and COVID-19. One month later, the patient had a recurrence of HUS, again testing positive for COVID-19. Kidney function improved with plasma exchange therapy. Eculizumab treatment was recommenced after COVID-19 PCR became negative. Anemia and thrombocytopenia did not recur with eculizumab, while renal impairment persisted. Eculizumab was discontinued after three months when genetic analysis for HUS was negative. Subsequently, the patient was diagnosed with end-stage kidney disease., Conclusions: COVID-19 can be associated with HUS relapses, leading to chronic kidney disease. Further studies should investigate the mechanism of HUS associated with COVID-19., Competing Interests: The authors declare that there is no conflict of interest.

Background: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that is characterized by quotidian fevers, arthritis, and an evanescent rash. Occurrence of concurrent thrombotic microangiopathy (TMA) in AOSD is rare. The treatment aspects of TMA in AOSD are actively being debated., Methods: Medline search using MeSH terms and snowballing yielded a total of 29 articles with co-occurrence of AOSD and thrombotic thrombocytopenic purpura (TTP) including our own. Pooled data were synthesized for descriptive analysis., Results: Median age was 35 years with a majority of females (68.96%). A majority of these studies/patients were either Asian (34.48%) or Caucasian (31.03%). Concurrent TMA at the time of AOSD diagnosis was seen in 65.51% patients. Only 3/29 patients had ADAMTS13 level less than 10%, consistent with TTP and 3/29 were diagnosed with hemolytic uremic syndrome (HUS). The remainder were diagnosed clinically. Complication rate was high, and 15/29 (51.72%) patients died or had permanent neurological/renal/vision/gangrenous complications. Median and mean ferritin peak was observed to be higher (7458 and 12 349, respectively) in patients who either died/had partial remission, compared to those who had complete response (3257 and 10 899, respectively), p = .829., Conclusions: A majority of patients with AOSD-associated TMA either died or had permanent complications. TMA was diagnosed alongside AOSD in 65% patients, while the rest developed TMA during the course of their disease. Blurred vision may precede TMA and could help risk-stratify high-risk AOSD patients clinically. Glycosylated ferritin remains low several weeks to months after disease remission and may be used to monitor severity of disease process. Further studies are necessary to confirm the existing vascular endothelial growth factor hypothesis in AOSD-associated TMA., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/aim: Therapeutic plasma exchange (TPE) is an extracorporeal treatment method that removes large molecular weight substances from plasma. In our study, we aimed to retrospectively examine the indications and procedural methods of the patients who had undergone TPE, and the complications that occurred during the procedure., Materials and Methods: Forty-one patients who were monitored in thePICU of Gazi Yaşargil Training and Research Hospital and had indications for TPE between 2017 and 2021 were included in the study. Laboratory parameters were checked before and after the TPE procedure. In addition to these, patients' diagnosis, weight, type of procedure and type of device, where the procedure was performed, duration of the procedure, amount of blood and plasma processed, complications, number of procedures, and death during the procedure or independent of the procedure were evaluated., Results: The median age was 93.0 (14.0-167.0) months. Hemolytic uremic syndrome (HUS) was the most common TPE indication with nine patients. The most common complication related to TPE was fever (11 patients), while no complication was observed in 18 patients.When laboratory results were evaluated according to American Society for Apheresis (ASFA) categories, a significant improvement was observed in the values of platelet, AST, ALT, LDH, urea, and creatinine in ASFA1 after TPE. No significant improvement was observed in ASFA2 (p > 0.05). In ASFA3, a significant improvement was observed in INR, AST, ALT, LDH, total bilirubin, creatinine, pH, and lactate values after TPE (p < 0.05). Five patients died from ASFA1, one from ASFA2, and three patients from ASFA3., Conclusion: Since significant adjustments are observed in clinical and laboratory values in sepsis-MOF, which is in the ASFA3 category, we believe that it should be evaluated in the ASFA2 or ASFA1 category in the early treatment of these diseases. In addition, we think that MIS-C cases, which have not been in any category according to ASFA, should be included in the ASFA2 or ASFA3 category, considering our TPE results., (© TÜBİTAK.)

Background: Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury., Methods: Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann-Whitney test, multiple groups were compared using the Kruskal-Wallis test followed by Dunn's procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables., Results: HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis., Conclusions: Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS., (© 2024. The Author(s).)

Background: Some data have recognized an association between shorter prodromal phase and severe episode of Shiga toxin-producing Escherichia coli-related hemolytic uremic syndrome (STEC-HUS). Our aims were to confirm such association and analyze characteristics of STEC-HUS patients according to duration of the prodromal phase., Methods: Patients treated from 2000 to 2022 were compared according to the presence of severe (> 10 days of dialysis and/or extra-renal complications) or non-severe disease. Association between prodromal phase duration and disease severity was assessed by ROC curve and by classifying the cohort in 3 groups according to time to diagnosis., Results: Non-severe (n = 145) and severe (n = 71) cases were compared. The latter had shorter prodromal phase, higher leukocyte count, hemoglobin, lactic dehydrogenase, liver enzymes, C-reactive protein, urea and creatinine, and lower albumin and sodium; only prodromal phase duration (p = 0.02) and leukocyte count (p = 0.02) remained significant in multivariate analysis. By ROC curve analysis, time to diagnosis resulted in a poor predictor of outcomes (AUC = 0.27). Since prodromal phase duration was 5 days (IQR 3-7), we divided the cohort into Groups A (1-2 days), B (3-7 days), and C (≥ 8 days). Rates of severe disease were 75.8%, 29.6%, and 11.4%, respectively. Taking Group B as reference, Group A patients had higher risk of complications (p = 0.00001; OR 7.4, 95% CI: 2.98-18.7) while Group C ones had significantly less risk (p = 0.02; OR 0.3, 95% CI: 0.1-0.91)., Conclusions: This study found that duration of prodromal phase is an independent predictor of complicated STEC-HUS and confirms that shorter prodromal phase is associated with worse prognosis. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Clostridium septicum (C. septicum) is a zoonotic bacillus found in 2.8% of healthy human stools. In humans, it can cause serious infections such as bacteremia, myonecrosis, and encephalitis by spreading through the bloodstream. Reports of Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome complicated by C. septicum superinfection are rare, likely because colonic microangiopathic lesions by Shiga toxin-producing Escherichia Coli facilitate bacterial dissemination. Only 13 cases of Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome with C. septicum superinfection have been reported to date, according to our litterature review, with a 50% mortality rate. The lack of clinico-laboratory clues suggesting this condition makes the diagnosis challenging. For these reasons C. septicum superinfection usually goes undiagnosed in patients with Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome, and results in unfavorable outcomes. In this paper, we describe the case of a 5-year-old girl admitted for Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome who developed C. septicum coinfection leading to a fatal outcome. We carried out a review of the available literature on C. septicum infection complicating Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome and we compared the clinical features of the observed cases with those of an historical cohort of uncomplicated Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome. The mechanisms of superinfection are still unclear and clinical features are indistinguishable from those of uncomplicated Shiga toxin-producing Escherichia Coli-related hemolytic-uremic syndrome. However, rapid deterioration of clinical conditions and evidence of neurological involvement, associated with abnormal radiological findings, require immediate management. Although therapeutic approaches have not been directly compared, neurosurgical treatment of amenable lesions may improve the clinical outcome of patients with C. septicum-hemolytic-uremic syndrome., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

A healthy 9-years-old boy was brought to the Emergency Department for widespread abdominal pain associated with bloody diarrhoea and significant tenesmus, in the absence of fever. Blood tests were compatible with an acute gastroenteritis, even though microbiological tests on stools resulted negative. Given the haemorrhagic dysentery, the boy was hospitalized to start empiric antibiotic therapy and intravenous rehydration. Abdominal ultrasound showed a thickening of colonic walls, mimicking an inflammatory intestinal disease at the onset (subsequently denied by gastro-colonoscopy). Seven days after the onset of symptoms, blood tests revealed microangiopathic anaemia with negative Coombs test, associated with thrombocytopenia. Urine dipstick revealed haematuria and proteinuria in nephritic range. No contraction of diuresis or alteration of renal function were observed (being creatinine values always within the normal range). Laboratory tests were consistent with the diagnosis of Haemolytic Uremic Syndrome (Hus) at the onset. Approximately 1% of paediatric patients with bloody diarrhoea can develop Hus. Positivity for Escherichia coli is not always evident in the stools. Thus, the triad of haemolytic anaemia, thrombocytopenia and renal failure could be present in only 60% of Hus at the onset. The finding of haematuria and/or proteinuria on the urine dipstick may be indicative of early kidney damage, allowing for careful monitoring and a rehydration program that can prevent progression of kidney damage and extrarenal complications.

Background: Long-term kidney outcomes of non-dialyzed children with Shiga-toxin Escherichia Coli hemolytic uremic syndrome (STEC-HUS) have been scantily studied. Therefore, we aimed to evaluate kidney outcomes and prognostic markers in these patients., Methods: Non-dialyzed STEC-HUS patients followed for at least 5 years were included. They were grouped and compared according to kidney status at last visit: complete recovery (CR) or chronic kidney disease (CKD). Predictors of CKD evaluated at diagnosis were sex, age, leukocytes, hematocrit, hemoglobin (Hb), and serum creatinine (sCr). Peak sCr and time of follow-up were also analyzed., Results: A total of 122 patients (62 female, median age at diagnosis 1.6 years) with a median follow-up of 11.3 years were included. At last visit, 82 (67%) had CR, 36 (30%) had CKD stage 1, and 4 (3%) had stage 2. No patient developed CKD stage 3-5. Median time to CKD was 5 years (IQR 3.1-8.76 years). Of the 122 patients, 18% evolved to CKD in the first 5 years, increasing to 28% at 10 and 33% at 20 years of follow-up. Serum Cr at diagnosis and peak sCr were significantly higher in patients with CKD than in those with CR., Conclusions: One third of non-dialyzed STEC-HUS patients evolved to CKD after a median time of 5 years. However, CKD may appear even after 15 years of CR. Serum Cr was significantly higher among patients who evolved to CKD. These data reinforce that all non-dialyzed patients should be followed until adulthood. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (STEC-HUS). Understanding its prognostic factors is essential for immediate interventions. We examined early-phase unfavorable prognostic factors among patients with STEC-HUS using a nationwide database., Material and Methods: This is a retrospective cohort study to analyze practice patterns and identify prognostic factors among patients with STEC-HUS. We used the Diagnosis Procedure Combination Database, which includes approximately half of the acute-care hospitalized patients in Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. The composite unfavorable outcome included in-hospital death, mechanical ventilation, dialysis, and rehabilitation at discharge. Unfavorable prognostic factors were assessed using a multivariable logistic regression model., Results: We included 615 patients with STEC-HUS (median age, 7 years). Of them, 30 (4.9%) patients had acute encephalopathy and 24 (3.9%) died within 3 months of admission. Unfavorable composite outcome was observed in 124 (20.2%) patients. Significant unfavorable prognostic factors were age of 18 years or older, methylprednisolone pulse therapy, antiepileptic drug administration, and respiratory support within 2 days of admission., Discussion: Patients requiring early steroid pulse therapy, antiepileptic drugs, and respiratory support were considered to be in poor general condition; such patients should receive aggressive intervention to avoid worse outcomes., Competing Interests: Conflicts of interest All authors declare that they do not have any conflicts of interests directly associated with the study., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Shiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15-20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis., Methods: We will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction., Discussion: HUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection., Trial Registration: ClinicalTrials.gov NCT05219110 . Registered on February 1, 2022., (© 2023. The Author(s).)

Background: Complement-mediated HUS (CM-HUS) and paroxysmal nocturnal hemoglobinuria (PNH) are rare hematologic disorders that cause dysregulation and hyperactivation of the complement system. Historically, treatment of CM-HUS involved plasma exchange (PLEX), often with limited benefit and variable tolerance. Conversely, PNH was treated with supportive care or hemopoietic stem cell transplant. Within the last decade, monoclonal antibody therapies that block terminal complement pathway activation, have emerged as less invasive and more efficacious options for management of both disorders. This manuscript seeks to discuss a relevant clinical case of CM-HUS and the evolving landscape of complement inhibitor therapies for CM-HUS and PNH., Areas of Uncertainty: Eculizumab, the first humanized anti-C5 monoclonal antibody, has been the standard of care in treating CM-HUS and PNH for over a decade. Although eculizumab has remained an effective agent, the variability in ease and frequency of administration has remained an obstacle for patients. The development of novel complement inhibitor therapies with longer half-lives, has allowed for changes in frequency and route of administration, thus improving patient QOL. However, there are limited prospective clinical trial data given disease rarity, and limited information on variable infusion frequency and length of treatment., Therapeutic Advances: Recently, there has been a push to formulate complement inhibitors that improve QOL while maintaining efficacy. Ravulizumab, a derivative of eculizumab, was developed to allow for less frequent administration, while remaining efficacious. In addition, the novel oral and subcutaneous therapies, danicopan and crovalimab, respectively, along with pegcetacoplan are currently undergoing active clinical trials, and poised to further reduce treatment burden., Conclusion: Complement inhibitor therapies have changed the treatment landscape for CM-HUS and PNH. With a significant emphasis on patient QOL, novel therapies continue to emerge and require an in-depth review of their appropriate use and efficacy in these rare disorders., Clinical Case: A 47-year-old woman with hypertension and hyperlipidemia presented with shortness of breath and was found to have hypertensive emergency in the setting of acute renal failure. Her serum creatinine was 13.9 mg/dL; elevated from 1.43 mg/dL 2 years before. The differential diagnosis for her acute kidney injury (AKI) included infectious, autoimmune, and hematologic processes. Infectious work-up was negative. ADAMTS13 activity level was not low at 72.9%, ruling out thrombotic thrombocytopenic purpura (TTP). Patient underwent a renal biopsy, which revealed acute on chronic thrombotic microangiopathy (TMA). A trial of eculizumab was initiated with concurrent hemodialysis. The diagnosis of CM-HUS was later confirmed by a heterozygous mutation in complement factor I (CFI), resulting in increased membrane attack complex (MAC) cascade activation. The patient was maintained on biweekly eculizumab and was eventually transitioned to ravulizumab infusions as an outpatient. Her renal failure did not recover, and the patient remains on hemodialysis while awaiting kidney transplantation., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In developing nations, limitations in diagnostic facilities act as a barrier for differentiation of hemolytic uremic syndrome (HUS) based on the etiology. A sick-looking 18-month-old boy presented to our hospital in Bhubaneswar, India, with clinical signs and symptoms of left lobar pneumonia, abnormal hematological and renal parameters, no growth in blood culture, a negative direct antiglobulin test (DAT) result, and low complement levels. A rapid deterioration in his clinical condition necessitated intensive care support, blood transfusion, and renal replacement therapy (peritoneal dialysis and hemodialysis). Because his health care team suspected atypical HUS, therapeutic plasma exchange (TPE) was initiated as soon as possible. In the absence of a lectin panel, minor cross-matching confirmed T-antigen exposure. With a diagnosis of HUS induced by Streptococcus pneumoniae (sp-HUS), TPE was stopped immediately, and washed blood components were administered. Despite the aforementioned measures, the boy died of HUS on day 20 after presentation. This case emphasized the role of minor cross-matching in the detecting of polyagglutination in resolving the diagnostic dilemma of sp-HUS., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the emergency room, patients with anemia and thrombocytopenia are common. Although these findings can often be explained by the medical situation, thrombotic microangiopathy is an important differential diagnosis. In this case, occlusion of the smallest vessels consequently leads to functional impairment of the affected organs. Patients generally present with symptoms of organ dysfunction, e.g., in the kidney or brain. Characteristically, Coombs-negative fragmentation of erythrocytes with hemolysis occurs in the area of the occluded vessels. Lactate dehydrogenase levels are elevated, and platelets and haptoglobin are reduced. Differential diagnoses beyond thrombotic microangiopathy that should be considered are numerous and diverse in their pathophysiology. Rapid workup is needed, because sometimes a specific treatment must be initiated rapidly. For example, thrombotic thrombocytopenic purpura leads to death in about 90% of patients if left untreated. However, by reconstitution of the underlying deficiency of the so-called ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) by plasma separation, survival can be ensured in most cases. Complement-mediated hemolytic uremic syndrome should also be considered and, if suspected, treated with complement inhibition. In many cases, however, thrombotic microangiopathy reflects a disorder elsewhere and may be a manifestation of severe hypertension or a coagulation disorder, such as disseminated intravascular coagulation or antiphospholipid syndrome. It can also be observed as a consequence of drug therapies or metabolic derangement. Systemic workup is therefore necessary for rapid clarification of differential diagnoses., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Shiga-toxin associated-hemolytic uremic syndrome (STEC-HUS) is a severe cause of acute kidney injury (AKI) in children. Although most children recover, about 5% die and 30% develop chronic renal morbidity. HUS pathophysiology includes activated neutrophils damaging vascular endothelial cells. Therapeutic immunomodulation of activated neutrophils may alter the progression of disease. We present 3 pediatric patients treated with the selective cytopheretic device (SCD)., Methods: We describe a 12 y.o. (patient 1) and two 2 y.o. twins (patients 2 and 3) with STEC-HUS requiring continuous renal replacement therapy (CRRT) who were enrolled in two separate studies of the SCD., Results: Patient 1 presented with STEC-HUS causing AKI and multisystem organ failure and received 7 days of SCD and CRRT treatment. After SCD initiation, the patient had gradual recovery of multi-organ dysfunction, with normal kidney and hematologic parameters at 60-day follow-up. Patients 2 and 3 presented with STEC-HUS with AKI requiring dialysis. Each received 24 h of SCD therapy. Thereafter, both gradually improved, with normalization (patient 2) and near-normalization (patient 3) of kidney function at 60-day follow-up., Conclusion: Immunomodulatory treatment with the SCD was associated with improvements in multisystem stigmata of STEC-HUS-induced AKI and was well-tolerated without any device-related adverse events., (© 2023 S. Karger AG, Basel.)

Introduction: A better understanding of hemolytic-uremic syndrome (HUS) pathophysiology significantly changed its treatment and prognosis. The aim of this study is to characterize the clinical features, severity, management, and outcomes of HUS patients., Materials and Methods: Retrospective study of HUS patients admitted to a Pediatric Nephrology Unit between 1996 and 2020. Demographic and clinical data regarding etiology, severity, treatment strategies, and patient outcome were collected., Results: Twenty-nine patients with HUS were admitted to our unit, but four were excluded. Median age at diagnosis was two years (2 months - 17 years). Clinical manifestations included diarrhea, vomiting, oliguria, hypertension, and fever. During the acute phase, 14 patients (56%) required renal replacement therapy. Infectious etiology was identified in seven patients (five Escherichia coli and two Streptococcus pneumoniae). Since 2015, 2/7 patients were diagnosed with complement pathway dysregulation HUS and there were no cases of infectious etiology detected. Six of these patients received eculizumab. The global median follow-up was 6.5 years [3 months-19.8 years]. One patient died, seven had chronic kidney disease, four of whom underwent kidney transplantation, one relapsed, and seven had no sequelae., Conclusion: These results reflect the lack of infectious outbreaks in Portugal and the improvement on etiological identification since genetic testing was introduced. The majority of patients developed sequels and mortality was similar to that of other countries. HUS patients should be managed in centers with intensive care and pediatric nephrology with capacity for diagnosis, etiological investigation, and adequate treatment. Long-term follow-up is essential.

Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (STEC-HUS) is a clinical syndrome involving hemolytic anemia (with fragmented red blood cells), low levels of platelets in the blood (thrombocytopenia), and acute kidney injury (AKI). It is the major infectious cause of AKI in children. In severe cases, neurological complications and even death may occur. Treating STEC-HUS is challenging, as patients often already have organ injuries when they seek medical treatment. Early diagnosis is of great significance for improving prognosis and reducing mortality and sequelae. In this review, we first briefly summarize the diagnostics for STEC-HUS, including history taking, clinical manifestations, fecal and serological detection methods for STEC, and complement activation monitoring. We also summarize preventive and therapeutic strategies for STEC-HUS, such as vaccines, volume expansion, renal replacement therapy (RRT), antibiotics, plasma exchange, antibodies and inhibitors that interfere with receptor binding, and the intracellular trafficking of the Shiga toxin.

Hemolytic uremic syndrome is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. Most cases are caused by Shiga-toxin-producing bacteria, especially Escherichia coli. Transmission occurs through ground beef and unpasteurized milk. STEC-HUS is the main cause of acute renal failure in children. Management remains supportive. Immediate outcome is most often. Atypical HUS represents about 5% of cases, has a relapsing course with more than half of the patients progressing to end-stage kidney failure. Most cases are due to variants in complement regulators of the alternative pathway. Complement inhibitors, such as eculizumab, have considerably improved the prognosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To explore the clinical characteristics, treatment protocol and prognosis of children with anti-complement factor H (CFH) autoantibody (Ab)-associated hemolytic uremic syndrome (HUS)., Methods: Clinical data of 8 patients with anti-CFH Ab-associated HUS who were admitted to Shandong Provincial Hospital from January 2011 to December 2020 were collected retrospectively., Results: The age at disease onset ranged between 5.83 and 13.5 years, with a male: female ratio of 1.67:1. The time of onset was distributed from May to June and November to December. Digestive and upper respiratory tract infections were common prodromal infections. Positivity for anti-CFH Ab and reduced C3 levels were observed among all patients. Heterozygous mutation of the CHFR5 gene (c.669del A) and homozygous loss of the CFHR1 gene [loss2(EXON:2-6)] were found in two patients. All patients received early treatment with plasma exchange and corticosteroid therapy. Six patients were given immunosuppressive agents (cyclophosphamide and/or mycophenolate mofetil) for persistent proteinuria. The follow-up period was 12-114 months. Four of 8 patients achieved complete remission, 3 achieved partial remission, and 1 died. Relapse occurred in two patients., Conclusion: Children with anti-CFH Ab-associated HUS were mainly school-aged and predominantly male, with onset times of summer and winter. Digestive and upper respiratory tract infections were common prodromal infections. Plasma exchange combined with methylprednisolone pulse therapy in the acute phase and cyclophosphamide or mycophenolate mofetil treatment for maintenance can be utilized in children with anti-CFH Ab-associated HUS if eculizumab is not available.

Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified., Competing Interests: Declaration of interests MM declares no conflicts of interest related to this topic but has served as site principal investigator for use of lumasiran for primary hyperoxaluria type 1 by Alnylam Pharmaceuticals. SES has received research funding from Alexion Pharmaceuticals to test pre-clinical complement agents in murine models of complement-mediated disease. RJHS directs the Molecular Otolaryngology and Renal Research Laboratories (Iowa City, IA, USA) where genetic and complement testing for atypical HUS and the TMAs is done. AB declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Complement-mediated hemolytic uremic syndrome (CM-HUS) following chemotherapy for pediatric acute lymphoid neoplasms has rarely been reported. We report the case of an 8-year-old boy with T-lymphoblastic lymphoma (T-LBL) who developed CM-HUS with complement factor H (CFH) mutations (S1191L, V1197A) during induction therapy. Safe administration of chemotherapy after CM-HUS recovery was challenging. By closely monitoring hemolytic and renal parameters during the 2-year treatment period, we observed four episodes of microangiopathic hemolytic anemia (MAHA) with hypocomplementemia and low haptoglobin but no renal dysfunction or thrombocytopenia. Here, we describe the MAHA and CM-HUS episodes in the hopes of elucidating the complex pathophysiology of disorders associated with CFH mutation., (© 2022. Japanese Society of Hematology.)

This review tells the story of my personal experience with thrombotic thrombocytopenic purpura (TTP). It begins with my first encounter with TTP 50 years ago when 2 sisters presented 2 years apart, both pregnant and both died. At that time, I knew nothing about hereditary TTP (hTTP), the risks of pregnancy, or effective treatments. In 1991, a year after I moved to Oklahoma, therapeutic plasma exchange (TPE) was established as an effective treatment. With the availability of effective treatment, the number of patients presenting with suspected TTP soared. The diagnosis of TTP was imprecise. I worked with the Oklahoma Blood Institute (OBI) to understand the management of TTP. Because the OBI provided all TPE procedures for most of Oklahoma, we saw all consecutive patients within a defined geographic area who were identified at a uniform time early in the course of their TTP, without selection or referral bias. It was an inception cohort; this became the Oklahoma TTP Registry. In 2001, we began a very successful collaboration with the University of Bern, Switzerland, to measure ADAMTS13 activity in all of our patients. From our patients, we learned that acquired, autoimmune TTP (iTTP) is a chronic disease with risks for cognitive impairment and depression. Recognition in 2012 of three sisters with hTTP was reminiscent of the beginning of my story. hTTP has risks for multiple severe morbidities, beginning at birth and especially during pregnancy. Future management of both iTTP and hTTP will be more effective and more convenient., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Hemolytic uremic syndrome (HUS) is a systemic thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and variable kidney involvement. Extrarenal thrombotic microangiopathy occurs in central nervous system (CNS), colon, and other organ systems, but ocular involvement is rarely recognized. This study aimed to analyze frequency and severity of ocular involvement in STEC-HUS, and the relationship between ocular involvement and disease severity, with emphasis on CNS, kidney, and colonic disease., Methods: Prospective, longitudinal, observational study., Inclusion Criteria: STEC-HUS patients September 2014-January 2019. Funduscopic examination (FE) was performed within 48 h of admission. We evaluated severity of CNS disease, kidney involvement, and presence of hemorrhagic colitis (HC)., Results: Ninety-nine patients were included (female 52), mean age 39.4 months (DE: 29.8; range 9-132). Thirteen patients (13.1%) had abnormal FE, 10 showing variable degrees of hemorrhagic exudates and 2 with typical Purtscher-like retinopathy. Other findings included tortuous vascularity, cotton wool spots, and transient retinal edema. CNS involvement was present in 16/99 patients, severe in 12 (75%). Abnormal FE occurred in 5/12 (31%) patients with severe CNS involvement vs. 8/87 (9.2%) with mild, moderate, or no CNS disease (p = 0.0191). Abnormal FE was present in 2/33 (6%) patients without dialysis vs. 11/66 (16.6%) requiring dialysis (p = 0.20). Finally, there were FE abnormalities in 6/20 patients with HC vs. 7/79 without HC (p = 0.012)., Conclusions: FE abnormalities were present in 13% of HUS patients. Abnormal FE significantly associated with more severe disease, including severe CNS involvement and HC. We suggest FE should be performed in severe HUS, especially in cases with severe CNS disease. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Patients with Hemolytic Uremic Syndrome (HUS) face late diagnosis and lack of appropriate treatment because of a lack of knowledge and experience in this field. A prerequisite for such knowledge is the development of research infrastructures such as a registry system. Therefore, this study aimed to develop and describe the HUS registry in accordance with the Iranian health system and implement its software system., Methods: We first interviewed 10 pediatric nephrologists and after analyzing the interviews, we identified the features and requirements and the data related to HUS. Then, during two rounds of the Delphi technique (the first round with 23 participants and the second round with 18 participants), the model of this registry was finalized based on the agreement of at least 75% of specialists. At the next step, based on the agreed requirements, IRI.HUS.Reg (Iranian Hemolytic Uremic Syndrome Registry) software was developed and implemented in a pediatric hospital., Results: We classified 369 meaning units of interviews in 41 codes and 7 final themes including purposes of the registry (10 codes), inclusion criteria (7 codes), data collection method (4 codes), data quality control (6 codes), data sources (4 codes), data analysis (3 codes) and software features (7 codes). These 7 feature groups (67 subgroups) and 12 data classes (138 data elements) include demographic data, referrals, examinations, clinical signs, causes, laboratory tests, medical histories, paraclinical measures, treatments, outcomes, patient's status at discharge, and follow-up data were reviewed by the Delphi panelists, and finally, 64 features and 131 data elements were accepted by at least 78% agreement. Then, we developed and implemented a registry software system in a hospital., Conclusion: We implemented IRI.HUS.Reg based on related features, 12 data classes agreed by specialists, literature review, and comparison with other existing registries. Therefore, the data collected in this registry can be compared with other data from existing registries in other countries., (© 2022. The Author(s).)

Hemolytic uremic syndrome can be initiated by Escherichia coli infections (Shiga-toxin-producing enterohemorrhagic Escherichia coli hemolytic uremic syndrome). When hemoglobin and heme released from ruptured erythrocytes interact with the kidney cells, this can result in platelet activation, vascular inflammation and occlusion, and kidney injury. Pirschel et al. now report that in the absence of protective mechanisms against free hemoglobin and heme, heme-induced kidney injury can be exacerbated. Therapeutic strategies should therefore also target heme-mediated deleterious effects in (severely ill) patients with Shiga-toxin-producing enterohemorrhagic Escherichia coli hemolytic uremic syndrome., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Primary thrombotic microangiopathies (TMAs) are observed in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), while secondary TMAs have a wide range of etiologies. Early diagnosis and treatment of TMA are critical for patient well-being; however, distinguishing TTP from HUS on presentation is particularly challenging. Thrombocytopenia and platelet activation are central to different types of TMAs, thus limiting the utility of standard diagnostic approaches to evaluate the platelet function and hemostatic capacity. Alternative means of quantifying and monitoring changes to platelet activation and function are urgently needed. Activated platelets have been shown to interact with proteins of the complement and coagulation cascades and form part of inflammation processes engaged in TMA. Increased levels of platelet surface receptors as well as increased plasma levels of platelet-derived soluble proteins have been reported in TMAs. Elevated levels of platelet-leukocyte aggregates and platelet microparticles are also reported in different types of TMAs. Larger prospective evaluations of platelet activation markers in TMA using standardized assays, with comparison to cohorts of patients with thrombosis, coagulopathy, and thrombocytopenia, to evaluate the clinical usefulness of platelet markers in TMA are now needed. This review will summarize the current knowledge around platelet activation markers and critically evaluate their utility in diagnosis and prognosis of TMA patients.

Hemolytic uremic syndrome (HUS) is clinically rare, with high mortality and case fatality rates. In recent years, the research on HUS has been intensified and the pathophysiological mechanism has been continuously improved. At present, the main mechanism of pathogenesis is the excessive activation of complement alternative pathways mediated by complement-related gene mutations or the existence of antibodies. The treatment methods and strategies are also constantly updated, mainly including complement-blocking drugs such as Eculizumab, Lavalizumab, and Ravulizumab. In this review, the new developments in the pathogenesis and treatment of HUS is summarized, and provide references for the clinical treatment of HUS.

Background: Oxaliplatin-based chemotherapy represents a standard of care in the treatment of metastatic colorectal cancer. We report a rare case of fulminant oxaliplatin-induced thrombotic microangiopathy, clinically suggestive of hemolytic-uremic syndrome, occurring in a female patient with a prolonged history of exposure to oxaliplatin for the treatment of metastatic colon cancer., Case Presentation: A 73-year-old Caucasian female with a treatment history including several lines of chemotherapy for the management of metastatic colon cancer was reinitiated on chemotherapy with oxaliplatin, fluorouracil, and leucovorin with bevacizumab for disease progression. She presented to the emergency department with malaise, headache, vomiting, and decreased urine output appearing a few hours after chemotherapy administration. Clinical symptoms and laboratory findings were suggestive of thrombotic microangiopathy, with a triad of microangiopathic hemolytic anemia, pronounced thrombocytopenia, and acute renal failure. The predominance of the severe renal failure was evocative of hemolytic-uremic syndrome. The rapid development of the thrombotic microangiopathy was linked to exposure to oxaliplatin. The patient was promptly managed with daily plasma exchange and high-dose corticosteroids, platelet, and red blood cell transfusions in conjunction with intermittent hemodialysis, and she recovered progressively., Conclusion: Our case confirms the risk of hemolytic-uremic syndrome as a rare and life-threatening complication of oxaliplatin-based chemotherapy. A dose-dependent, drug-induced toxicity mechanism is suggested. Physicians need to maintain a high level of clinical suspicion to diagnose and treat this acute life-threatening disorder., (© 2022. The Author(s).)

Background: The role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial., Objectives: To evaluate the association between treatment (antibiotics, antidiarrheal agents, and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development., Patients and Methods: We performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used., Results: 7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics., Conclusions: Antibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided., Competing Interests: The authors have declared that no competing interests exist.

Thrombotic microangiopathy (TMA) is the broad definition for thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage. Two important categories are thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic-uremic syndrome (CM-HUS). Pregnancy and the immediate postpartum period are associated with TMAs specific to pregnancy in rare situations. These include pregnancy-induced hypertension, preeclampsia, and hemolysis, elevated liver enzymes, and low platelets. TTP and CM-HUS may present in pregnancy. However, the diagnosis may not be immediately obvious as they share characteristics of pregnancy-related TMAs. Within this review, we discuss investigations, differential diagnosis of TMAs in pregnancy, and management. The importance is a risk of maternal mortality but also poor fetal outcomes in relation to TTP and CM-HUS. Treatment of these disorders at presentation in pregnancy is discussed to achieve remission and prolong fetal viability if possible. In subsequent pregnancies, a treatment pathway is presented that has been associated with successful maternal and fetal outcomes. Critical to this is a multidisciplinary approach involving obstetricians, the fetal medicine unit, and neonatologists., (Copyright © 2021 by The American Society of Hematology.)

Introduction: Anti-Compliment Factor H antibody hemolytic uremic syndrome (AFH-HUS) is a common cause of paediatric atypical HUS in India. We wanted to study the outcome of patients receiving less than recommended plasma exchange (PLEX) but adequate immunosuppression, with respect to hypertension, preservation of renal function and proteinuria., Methods: A retrospective study was performed in 15 children admitted from 2016 to 2018 with AFH-HUS. Follow up details including physical examination, hematological parameters, renal function test and urine examination performed at 3, 6, and 12 months were noted. Risk stratification and staging for chronic kidney disease (CKD) were done according to the Kidney Disease Improving Global Outcomes (KDOQI) guidelines. Standard statistical tests which were appropriate were used., Results: Mean age of our study cohort was 7.8 ± 1.9 years. 14 children had hypertension. Mean nadir hemoglobin was 5.8 ± 1.0 g/dL and platelet = 58 ± 37.7 × 109 cells/L. Median anti factor H (AFH) level was 316 AU/mL (150 to 452). Hemodialysis was required in 7 children. Fourteen children received PLEX with a mean of 11 ± 6 cycles. Thirteen children received 6 cycles of intravenous cyclophosphamide. After six months, therapy was switched to mycophenolate mofetil in 4 children, steroids alone in 2 children and 9 children with azathioprine. On follow-up, risk of CKD reduced from 80% at 3 months to 26% at 12 months (P = .01). Only 40% patients had CKD stage 2 at the end of 12 months (mean eGFR = 95.0 ± 19.4 mL/min/1.73m2)., Conclusion: The adequate number of PLEX needed in AFH-HUS needs further studies. Till such reports come, PLEX in recommended strategies or lesser, if not available, with immunosuppression in AFH-HUS can decrease progression to CKD. DOI: 10.52547/ijkd.6507.

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., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To analyze the results of an enhanced laboratory-surveillance protocol for bloody diarrhea aimed at identifying children with Shiga toxin-producing Escherichia coli (STEC) infection early in the course of the disease toward the early identification and management of patients with hemolytic uremic syndrome (HUS)., Study Design: The study (2010-2019) involved a referral population of 2.3 million children. Stool samples of patients with bloody diarrhea were screened for Shiga toxin (Stx) genes. Positive patients were rehydrated and monitored for hemoglobinuria until diarrhea resolved or STEC-HUS was diagnosed., Results: A total of 4767 children were screened; 214 (4.5%) were positive for either Stx1 (29.0%) or Stx2 (45.3%) or both Stx1+2 (25.7%); 34 patients (15.9%) developed STEC-HUS (0.71% of bloody diarrheas). Hemoglobinuria was present in all patients with HUS. Patients with Stx2 alone showed a greater risk of STEC-HUS (23.7% vs 12.7%) and none of the patients with Stx1 alone developed HUS. During the same period of time, 95 other patients were diagnosed STEC-HUS but were not captured by the screening program (26 had nonbloody diarrhea, 11 came from areas not covered by the screening program, and 58 had not been referred to the screening program, although they did meet the inclusion criteria). At HUS presentation, serum creatinine of patients identified by screening was significantly lower compared with that of the remaining patients (median 0.9 vs 1.51 mg/dL)., Conclusions: Nearly 1% of children with bloody diarrhea developed STEC-HUS, and its diagnosis was anticipated by the screening program for Stx. The screening of bloody diarrhea for Stx is recommended, and monitoring patients carrying Stx2 with urine dipstick for hemoglobinuria is suggested to identify the renal complication as early as possible., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Neurological involvement is the most common extra-renal complication of Shiga toxin-producing E. coli-hemolytic uremic syndrome (HUS) or typical HUS. On brain magnetic resonance examination, main neurological signs encompass acute lesions of the basal ganglia and the white matter, which could usually regress after Eculizumab infusion. In contrast, peripheral nervous system (PNS) manifestations in typical HUS are very rare and, when occurring, they require a careful management of neurological sequelae and an intensive multidisciplinary neuro-rehabilitation program., Case Presentation: Here, we present two pediatric cases of severe and complicated typical HUS with PNS manifestations who required therapeutic treatment and an intensive multidisciplinary neuro-rehabilitation program. In both cases, PNS manifestations were followed by the recovery from typical HUS-related severe central neurological damage and manifested mainly with marked bilateral motor deficit and hyporeflexia/areflexia in the lower limbs. The peripheral polyneuropathy was treated with immunosuppressive therapy (methylprednisolone boluses, i.v. immunoglobulins, plasma exchange), followed by a prolonged intensive neuro-rehabilitation program. After 8 months of rehabilitation, both patients gained complete functional recovery., Conclusions: PNS manifestations during typical HUS are a rare event and potentially leading to severe disability. A timely clinical assessment is mandatory to set up a prompt therapeutic and rehabilitation program and to obtain a complete clinical and functional recovery., (© 2021. The Author(s).)

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.

Background: Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is the main cause of pediatric acute kidney injury (AKI) in Argentina. Endothelial injury is the trigger event in the microangiopathic process. The host inflammatory response to toxin and E. coli lipopolysaccharide (LPS) is involved in disease pathophysiology., Methods: This retrospective study describes pediatric STEC-HUS patients with multiorgan involvement at the initial phase of disease. A retrospective study of critically ill HUS patients with evidence of E. coli infection was conducted through a period of 15 years., Results: Forty-four patients 35.4 ± 4.1 months were admitted to the intensive care unit for 21 ± 2 days. Mechanical ventilation was required in 41 patients, early inotropic support in 37, and 28 developed septic shock. Forty-one patients required kidney replacement therapy for 12 ± 1 days. Forty-one patients showed neurological dysfunction. Dilated cardiomyopathy was demonstrated in 3 patients, left ventricular systolic dysfunction in 4, and hypertension in 17. Four patients had pulmonary hemorrhage, and acute respiratory distress syndrome in 2. Colectomy for transmural colonic necrosis was performed in 3 patients. Thirty-seven patients were treated with therapeutic plasma exchange, and 28 patients received methylprednisolone (10 mg/kg for 3 days). Of the surviving 32 patients, neurological sequelae were seen in 11 and chronic kidney failure in 5., Conclusions: Severe clinical outcome at onset suggests an amplified inflammatory response after exposure to Shiga toxin and/or E. coli LPS. STEC-HUS associated with severe neurological involvement, hemodynamic instability, and AKI requires intensive care and focused therapy.

Background: Hemolytic uremic syndrome caused by invasive pneumococcal disease (P-HUS) is rare in children and adolescents, but accompanied by high mortality in the acute phase and complicated by long-term renal sequelae. Abnormalities in the alternative complement pathway may additionally be contributing to the course of the disease but also to putative treatment options., Methods: Retrospective study to assess clinical course and laboratory data of the acute phase and outcome of children with P-HUS., Results: We report on seven children (median age 12 months, range 3-28 months) diagnosed with P-HUS. Primary organ manifestation was meningitis in four and pneumonia in three patients. All patients required dialysis which could be discontinued in five of them after a median of 25 days. In two patients, broad functional and genetic complement analysis was performed and revealed alternative pathway activation and risk haplotypes in both. Three patients were treated with the complement C5 inhibitor eculizumab. During a median follow-up time of 11.3 years, one patient died due to infectious complications after transplantation. Two patients showed no signs of renal sequelae., Conclusions: Although pathophysiology in P-HUS remains as yet incompletely understood, disordered complement regulation seems to provide a clue to additional insights for pathology, diagnosis, and even targeted treatment.