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Significance Statement: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment., Background: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority., Methods: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement., Results: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported., Conclusions: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae., Clinical Trials Registrations: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 )., (Copyright © 2023 by the American Society of Nephrology.)

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403., (© 2021 by The American Society of Hematology.)

Background and Objectives: In contrast to the improvement in our understanding of the pathogenesis and presentation of autosomal recessive polycystic kidney disease (ARPKD), data regarding the issue of kidney and liver transplantation in patients with ARPKD remain particularly scarce. Here, we report the results and outcome of renal and/or liver transplantation in a series of patients with ARPKD., Methods: Fourteen ARPKD patients (age: 3-25 years) who underwent renal transplantation with or without liver transplantation were retrospectively identified in five French nephrology departments. The patients' medical charts were reviewed and relevant data were collected., Results: The clinical and radiological presentation of the 14 patients was highly variable illustrating the heterogeneity of ARPKD. Six patients underwent kidney and/or liver transplantation in adulthood. First renal graft survival was 92, 78 and 14% at 1, 5 and 10 years after renal transplantation, respectively. Mortality rate was relatively high (3/14; 21%) in these young patients and was directly related to infectious complications (recurrent angiocholitis) of severe Caroli's disease (dilatation of intra- and/or extra-hepatic bile ducts), a typical feature of ARPKD., Conclusions: Our data suggest that ARPKD patients evaluated for renal transplantation should be carefully screened for severe Caroli's disease. Even though the limited number of patients included in our study precludes any definite recommendation, pre-emptive liver transplantation may be a therapeutic option in ARPKD patients with severe Caroli's disease evaluated for renal transplantation.

Background and Objectives: Neurologic involvement is the most threatening complication of diarrhea-associated hemolytic uremic syndrome (D+HUS)., Design, Setting, Participants, & Measurements: We report a retrospective multicenter series of 52 patients with severe initial neurologic involvement that occurred in the course of D+HUS., Results: Verotoxigenic Escherichia coli infection was documented in 24. All except two patients had acute renal failure that required peritoneal dialysis, hemodialysis, or both techniques. A first group of eight patients remained with normal consciousness; five of them had protracted seizures. A second group of 23 patients had stuporous coma; five of these had protracted severe seizures, and 18 had a neurologic defect including pyramidal syndrome, hemiplegia or hemiparesia, and extrapyramidal syndrome. A third group of 21 patients had severe coma. Plasma exchanges were undertaken in 25 patients, 11 of whom were treated within 24 hours after the first neurologic sign; four died, two survived with severe sequelae, and five were alive without neurologic defect. Magnetic resonance imaging (MRI) for 29 patients showed that (1) every structure of the central nervous system was susceptible to involvement; (2) no correlation seemed to exist between special profile of localization on early MRI and the final prognosis; and (3) MRI did not exhibit any focal lesions in three patients. The overall prognosis of the series was marked by the death of nine patients and severe sequelae in 13., Conclusions: Neurologic involvement is associated with a severe renal disease but does not lead systematically to death or severe disability.

Since the appearance of the first case of coronavirus disease 2019 (COVID-19) a pandemic has emerged affecting millions of individuals worldwide. Although the main clinical manifestations are respiratory, an increase in neurological conditions, specifically acute cerebrovascular disease, has been detected. We present cerebrovascular disease case incidence in hospitalized patients with SARS-CoV-2 infection. Patients were confirmed by microbiological/serological testing, or on chest CT semiology. Available data on co-morbidity, laboratory parameters, treatment administered, neuroimaging, neuropathological studies and clinical evolution during hospitalization, measured by the modified Rankin scale, were analysed. A bivariate study was also designed to identify differences between ischaemic and haemorrhagic subtypes. A statistical model of binary logistic regression and sensitivity analysis was designed to study the influence of independent variables over prognosis. In our centre, there were 1683 admissions of patients with COVID-19 over 50 days, of which 23 (1.4%) developed cerebrovascular disease. Within this group of patients, cerebral and chest CT scans were performed in all cases, and MRI in six (26.1%). Histological samples were obtained in 6/23 cases (two brain biopsies, and four arterial thrombi). Seventeen patients were classified as cerebral ischaemia (73.9%, with two arterial dissections), five as intracerebral haemorrhage (21.7%), and one leukoencephalopathy of posterior reversible encephalopathy type. Haemorrhagic patients had higher ferritin levels at the time of stroke (1554.3 versus 519.2, P = 0.004). Ischaemic strokes were unexpectedly frequent in the vertebrobasilar territory (6/17, 35.3%). In the haemorrhagic group, a characteristic radiological pattern was identified showing subarachnoid haemorrhage, parieto-occipital leukoencephalopathy, microbleeds and single or multiple focal haematomas. Brain biopsies performed showed signs of thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis. The functional prognosis during the hospital period was unfavourable in 73.9% (17/23 modified Rankin scale 4-6), and age was the main predictive variable (odds ratio = 1.5; 95% confidence interval 1.012-2.225; P = 0.043). Our series shows cerebrovascular disease incidence of 1.4% in patients with COVID-19 with high morbidity and mortality. We describe pathological and radiological data consistent with thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition. [ABSTRACT FROM AUTHOR]

Background: Hemolytic uremic syndrome (HUS), a common subtype of thrombotic microangiopathy (TMA), is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Shiga toxin-producing Escherichia coli infection is the most common cause of post-diarrheal HUS. Kidney and central nervous system are the primary target organs.Case Presentation: A 64-year-old male presented with HUS following bloody diarrhea. Nephrotic-range proteinuria and hypoalbuminemia were present at the acute stage and renal histology revealed common TMA features. Neurological involvement presented as confusion and impaired cognitive function. Cranial magnetic resonance imaging demonstrated bilateral T2 hyperintensities in the brainstem and insula. The patient received plasma exchange and supportive care. Both the renal and neurological impairments were completely recovered 3 months after the onset.Conclusion: We report an adult patient presenting with nephrotic-range proteinuria and central nervous system involvement at the acute phase of post-diarrheal HUS. The reversibility of the organ damages might predict a favorable outcome. [ABSTRACT FROM AUTHOR]

Background. Acute kidney injury (AKI) occurs in up to 30% of pediatric intensive care unit (PICU) patients and is associated with a high mortality rate. Objectives. The objective of the study was to evaluate factors associated with the outcome and to identify the prognostic factors in children receiving continuous renal replacement therapy (CRRT). Material and methods. This was a retrospective, single-center study, including 46 patients. Results. Logistic regression analysis demonstrated significant effects on patient survival exerted by the percentage of fluid overload (FO%) (odds ratio (OR): 1.030; p = 0.044). In the group of patients with FO% <25%, the mortality was 33.3%, and in the FO% .25% group, the mortality was 67.9% (p < 0.001). The probability of death without multi-organ failure (MOF) was 13%, while with MOF it was 74%. There was no difference in the duration of hospitalization between the CRRT patients (mean: 21.9 days) and the general population of children hospitalized in PICU in the same period (n = 3,255; mean: 25.4 days); however, a significant difference was noted in mortality between the 2 groups of patients (54% vs 6.5%; p < 0.001). Conclusions. The mortality of PICU CRRT patients is more than 8-fold higher than the mortality of the total PICU population. Coexisting MOF increases the mortality almost 6 times. The mortality of children with FO% =25% was more than 2-fold higher than the mortality of children with FO% <25%. [ABSTRACT FROM AUTHOR]

Background: Shiga toxin 2 from enterohemorrhagic Escherichia coli is the etiologic agent of bloody diarrhea, hemolytic uremic syndrome and derived encephalopathies that may result to death in patients. Being a Gram negative bacterium, lipopolysaccharide is also released. Particularly, the hippocampus has been found affected in patients intoxicated with Shiga toxin 2. In the current work, the deleterious effects of Shiga toxin 2 and lipopolysaccharide are investigated in detail in hippocampal cells for the first time in a translational murine model, providing conclusive evidences on how these toxins may damage in the observed clinic cases. Methods: Male NIH mice (25 g) were injected intravenously with saline solution, lipopolysaccharide, Shiga toxin 2 or a combination of Shiga toxin 2 with lipopolysaccharide. Brain water content assay was made to determine brain edema. Another set of animals were intracardially perfused with a fixative solution and their brains were subjected to immunofluorescence with lectins to determine the microvasculature profile, and anti-GFAP, anti-NeuN, anti-MBP and anti-Iba1 to study reactive astrocytes, neuronal damage, myelin dysarrangements and microglial state respectively. Finally, the Thiobarbituric Acid Reactive Substances Assay was made to determine lipid peroxidation. In all assays, statistical significance was performed using the One-way analysis of variance followed by Bonferroni post hoc test. Results: Systemic sublethal administration of Shiga toxin 2 increased the expressions of astrocytic GFAP and microglial Iba1, and decreased the expressions of endothelial glycocalyx, NeuN neurons from CA1 pyramidal layer and oligodendrocytic MBP myelin sheath from the fimbria of the hippocampus. In addition, increased interstitial fluids and Thiobarbituric Acid Reactive Substances-derived lipid peroxidation were also found. The observed outcomes were enhanced when sublethal administration of Shiga toxin 2 was co-administered together with lipopolysaccharide. Conclusion: Systemic sublethal administration of Shiga toxin 2 produced a deterioration of the cells that integrate the vascular unit displaying astrocytic and microglial reactive profiles, while edema and lipid peroxidation were also observed. The contribution of lipopolysaccharide to pathogenicity caused by Shiga toxin 2 resulted to enhance the observed hippocampal damage. [ABSTRACT FROM AUTHOR]

Background/Aim: As continuous renal replacement therapy (CRRT) has emerged as a standard therapy in pediatric intensive care units (PICU), many related issues that may have an impact on circuit survival have gained in importance. Objective of the study was an evaluation of factors associated with circuit survival, including anticoagulation (ACG). Methods: Retrospective study that included 40 patients, who in total received 7636 hours of CRRT during 150 sessions (84 filters, 4260 hours with heparin anticoagulation (Hep-ACG); 66 filters, 3376 hours with regional citrate anticoagulation (RCA)). Results: The Kaplan-Meier analysis of the total circuit survival time depending on the type of ACG did not demonstrate a significant difference between Hep-ACG and RCA. The percentage of clotted filters was significantly higher in case of smaller filters (HF20: 58.8%; ST60:29.5%; ST100: 15.8%), and their lifetime was significantly lower regardless of ACG (the mean and median lifetime for HF20: 38.7/27.0 h; for ST60: 54.1/72.0 h., for ST100: 62.1/72.0 h, respectively). Conclusions: Irrespectively of filter size, filter clotting occurs within the first 24 hours after the initiation of CRRT. Most commonly, clotting affects small filters, and their lifetime is significantly shorter as compared to larger filters regardless of the type of the ACG. [ABSTRACT FROM AUTHOR]

In 2011, a large outbreak of Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC) infections occurred in northern Germany, which mainly affected adults. Out of 3842 patients, 104 experienced a complicated course comprising hemolytic uremic syndrome and neurological complications, including cognitive impairment, aphasia, seizures and coma. T2 hyperintensities on magnet resonance imaging (MRI) bilateral in the thalami and in the dorsal pons were found suggestive of a metabolic toxic effect. Five of the 104 patients died because of toxic heart failure. In the present study, the post-mortem neuropathological findings of the five EHEC patients are described. Histological investigation of 13 brain regions (frontal, temporal, occipital cortex, corpora mammillaria, thalamus, frontal operculum, corona radiata, gyrus angularis, pons, medulla oblongata, cerebellar vermis and cerebellar hemisphere) showed no thrombosis, ischemic changes or fresh infarctions. Further, no changes were found in electron microscopy. In comparison with five age-matched controls, slightly increased activation of microglia and a higher neuronal expression of interleukin-1β and of Shiga toxin receptor CD77/globotriaosylceramide 3 was observed. The findings were confirmed by Western blot analyses. It is suggested that CD77/globotriaosylceramide upregulation may be a consequence to Shiga toxin exposure, whereas increased interleukin-1β expression may point to activation of inflammatory cascades. [ABSTRACT FROM AUTHOR]

Background: In May 2011 an outbreak of Shiga toxin-producing enterohaemorrhagic E. coli (STEC) O104:H4 in Northern Germany led to a high number of in-patients, suffering from post-enteritis haemolytic-uraemic syndrome (HUS) and often severe affection of the central nervous system. To our knowledge so far only neurological manifestations have been described systematically in literature. Aim: To examine psychiatric symptoms over time and search for specific symptom clusters in affected patients. Methods: 31 in-patients suffering from E. coli O104:H4 associated HUS, were examined and followed up a week during the acute hospital stay. Psychopathology was assessed by clinical interview based on the AMDP Scale, the Brief Symptom Inventory and the Clinical Global Impressions Scale. Results: At baseline mental disorder due to known physiological condition (ICD-10 F06.8) was present in 58% of the examined patients. Patients suffered from various manifestations of cognitive impairment (n = 27) and hallucinations (n = 4). Disturbances of affect (n = 28) included severe panic attacks (n = 9). Psychiatric disorder was significantly associated with higher age (p<0.0001), higher levels of C-reactive protein (p<0.05), and positive family history of heart disease (p<0.05). Even within the acute hospital stay with a median follow up of 7 days, symptoms improved markedly over time (p <0.0001). Conclusions: Aside from severe neurological symptoms the pathology in E.coli O104:H4 associated HUS frequently includes particular psychiatric disturbances. Long term follow up has to clarify whether or not these symptoms subside. [ABSTRACT FROM AUTHOR]

Objectives: Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli (STEC/EHEC) is one of the most common causes of Haemolytic Uraemic Syndrome (HUS) related to infectious haemorrhagic colitis. Nearly all recommendations on clinical management of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first to be caused by the serotype O104:H4. This EHEC strain was found to carry genetic features of Entero Aggregative E. coli (EAEC) and extended spectrum β lactamase (ESBL). We report symptoms and complications in patients at one of the most affected centres of the 2011 EHEC O104 outbreak in Northern Germany. Methods: The courses of patients admitted to our hospital due to bloody diarrhoea with suspected EHEC O104 infection were recorded prospectively. These data include the patients’ histories, clinical findings, and complications. Results: EHEC O104 infection was confirmed in 61 patients (female = 37; mean age: 44±2 years). The frequency of HUS was 59% (36/61) in our cohort. An enteric colonisation with co-pathogens was found in 57%. Thirty-one (51%) patients were treated with plasma-separation/plasmapheresis, 16 (26%) with haemodialysis, and 7 (11%) with Eculizumab. Patients receiving antibiotic treatment (n = 37; 61%) experienced no apparent change in their clinical course. Twenty-six (43%) patients suffered from neurological symptoms. One 83-year-old patient died due to comorbidities after HUS was successfully treated. Conclusions: EHEC O104:H4 infections differ markedly from earlier reports on O157:H7 induced enterocolitis in regard to epidemiology, symptomatology, and frequency of complications. We recommend a standard of practice for clinical monitoring and support the renaming of EHEC O104:H4 syndrome as “EAHEC disease”. [ABSTRACT FROM AUTHOR]