Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3 / Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

Objetivo analizar y describir las concentraciones de eculizumab y el bloqueo del complemento en los pacientes con síndrome hemolítico urémico atípico (SHUa) y glomerulopatía C3, y definir un margen terapéutico donde se alcance una alta probabilidad de conseguir eficacia terapéutica. Métodos estudio observacional, ambispectivo y multicéntrico que incluyó pacientes adultos y pediátricos diagnosticados de SHUa y glomerulopatía C3 desde septiembre de 2020 hasta octubre de 2022 en 5 hospitales de España. Eculizumab se administró a las dosis recomendadas por la ficha técnica. Se determinaron las concentraciones pre y posdosis de eculizumab, así como del bloqueo de la vía clásica del complemento (CH50). Se recogieron variables sociodemográficas, analíticas y clínicas, y se calcularon los parámetros farmacocinéticos. Para establecer el punto de corte de las concentraciones de eculizumab que predecían el bloqueo del complemento se realizó un análisis de curvas ROC (Receiver Operating Characteristic). Se utilizó el test de Kruskal-Wallis para contrastar las diferencias en distintos parámetros según las concentraciones de eculizumab. Resultados se incluyeron 25 pacientes, 19 adultos (76,0%) y 6 pediátricos (24,0%), con edades medianas de 43,4 (RIC 35,7-48,8) y 10,1 (RIC 9,6-11,3) años, respectivamente. De ellos, 22 (88,0%) pacientes fueron diagnosticados con SHUa y 3 (12,0%) con glomerulopatía C3. Se determinaron un total de 111 concentraciones de eculizumab. Las concentraciones predosis y posdosis medias detectadas durante la fase de mantenimiento fueron 243,8 (SD 240,6) μg/ml y 747,4 (SD 444,3) μg/ml, respectivamente (AU)

Objective The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. Methods Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. Results Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined (AU)

Eculizumab in severe Shiga toxin-mediated haemolytic uraemic syndrome.

Shiga toxin (Stx)-producing Escherichia coli-mediated haemolytic uraemic syndrome is a primary thrombotic microangiopathy, typified by the development of microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure. It is a leading cause of acute renal failure in paediatrics, with a second peak in prevalence in adults over the age of 60. Presentations of Stx-producing E. coli-mediated haemolytic uraemic syndrome in young adults are rare. We present the case of a previously well female in her early 30s presenting with Stx-producing E. coli-mediated haemolytic uraemic syndrome with severe renal and neurological manifestations. Eculizumab was administered due to the severity of presentation and disease trajectory refractory to initial supportive therapy. A significant clinical and biochemical improvement was observed following eculizumab.

A novel Shiga toxin 2a neutralizing antibody therapeutic with low immunogenicity and high efficacy.

Shiga toxin-producing Escherichia coli infections are difficult to treat due to the risk of antibiotic-induced stress upregulating the production of toxins, medical treatment is consequently limited to supportive care to prevent the development of hemolytic uremic syndrome (HUS). Here, we introduce a potentially therapeutic humanized mouse monoclonal antibody (Hu-mAb 2-5) targeting Stx2a, the most common Shiga toxin subtype identified from outbreaks. We demonstrate that Hu-mAb 2-5 has low immunogenicity in healthy adults ex vivo and high neutralizing efficacy in vivo, protecting mice from mortality and HUS-related tissue damage.

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.

BACKGROUND: Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear. METHODS: Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied. FINDINGS: Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype. CONCLUSIONS: This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease. FUNDING: This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

Eculizumab use in patients with pneumococcal-associated hemolytic uremic syndrome and kidney outcomes.

BACKGROUND: Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) is a rare and severe disease. Only a few reports have been published about eculizumab use in P-HUS. METHODS: We analyzed demographic, clinical, and laboratory data of patients with P-HUS from our center. RESULTS: The cohort consisted of 4 females and 3 males. All patients had pneumonia. Four were given eculizumab (days 1-3). The eculizumab group required a shorter duration of dialysis and mechanical ventilation (medians 20 vs. 28.5 and 30 vs 38.5 days, respectively) compared with the non-eculizumab group, but this was still much longer than normally reported; the thrombocytopenia resolution was similar in both groups (medians 10 vs. 8 days). Chronic kidney disease (CKD) was correlated with the duration of dialysis and mechanical ventilation duration at 1 year (r = 0.797, P = 0.032 and r = 0.765, P = 0.045) and last follow-up (r = 0.807, P = 0.028 and r = 0.814, P = 0.026, respectively); our scoring system showed even stronger correlations (r = 0.872, P = 0.011 and r = 0.901, P = 0.0057, respectively). The eculizumab group showed slightly better 1-year and last follow-up CKD stage (2.75 vs. 3, P = 0.879 and 2.5 vs. 3.67, P = 0.517). CONCLUSIONS: Despite the fact that the eculizumab group showed better outcomes, eculizumab does not seem to improve the course of P-HUS compared with previous reports. Kidney outcomes are strongly correlated with the duration of dialysis and mechanical ventilation duration. A higher resolution version of the Graphical abstract is available as Supplementary information.

HUS with mutations in CFH and STEC infection treated with eculizumab in a 4-year-old girl.

BACKGROUND: Hemolytic uremic syndrome secondary to Shiga-toxin-producing Escherichia coli infection (STEC-HUS) generally shows a favorable outcome. Few cases develop extra-renal complications, since neurological involvement is an important cause of morbidity and mortality. The role of complement in STEC-HUS has been recently highlighted, and the use of eculizumab in severe cases has been communicated. HUS results from environmental and genetic factors, but the simultaneous occurrence of STEC and complement mutations remains undetermined. METHODS: A pediatric case with severe STEC-HUS carrying CFH mutations, with favorable response to eculizumab is analyzed. RESULTS: STEC-HUS was diagnosed in a 4-year-old girl with classic HUS, including low C3. Peritoneal dialysis was started due to hypertension, oligoanuria, and pleural effusion. She evolved with generalized tonic-clonic seizures and required mechanical ventilation. MRI reported multiple supra- and infratentorial ischemic lesions with laminar/striatal cortical necrosis and leukoencephalopathy. After two eculizumab doses, a significative stabilization in diuresis, blood pressure, creatinine, and C3 was achieved. At the third week, episodes of massive digestive bleeding and a life-threatening condition required a colectomy thus preserving the ileocecal valve. Due to atypical evolution, a genetic study was considered, identifying two heterozygous variants (CFH S1191L/V1197A). CONCLUSION: STEC-HUS in patients with a genetic predisposition has been previously reported, but the low frequency of occurrence makes it a rare disease. As in the present case, patients with atypical course might benefit from genetic analysis to evaluate early eculizumab initiation and to better understand its phenotype. A higher resolution version of the Graphical abstract is available as Supplementary information.

Targeting the innate repair receptor axis via erythropoietin or pyroglutamate helix B surface peptide attenuates hemolytic-uremic syndrome in mice.

Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.

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.

Why antibiotics should not be used to treat Shiga toxin-producing Escherichia coli infections.

PURPOSE OF REVIEW: There has been much debate about treating Shiga toxin-producing Escherichia coli (STEC) infections with antibiotics. No data convincingly demonstrate that antibiotics are better than no antibiotic treatment at all, and many studies suggest antibiotics increase the risk of developing the hemolytic uremic syndrome (HUS). This topic is timely, because emerging technology enables rapid identification of STEC-infected patients, and we anticipate questions about management will increase. This review is designed to familiarize readers with the series of observations that underlie our recommendations. RECENT FINDINGS: The long debate over antibiotics in STEC infections appears resolved by gradually accruing information that show that antibiotics do not benefit infected patients. In fact, they are associated with an increased likelihood of developing HUS. A meta-analysis published in 2016 demonstrated that low risk of bias studies find a clear association between antibiotic use and development of HUS. Subsequent publications do not refute these findings. SUMMARY: In high-income countries, antibiotics should not routinely be given to patients with acute diarrhea unless testing demonstrates a pathogen for which antibiotics are indicated, and STEC infection has been excluded. Future work to prevent HUS should focus on preventing primary infections, and mitigating extraintestinal consequences of STEC gut infections.

Coronavirus Disease-2019 in Children with Primary Kidney Disease: A Case series.

Underlying comorbid illness is a known risk factor for severe coronavirus disease-2019 (COVID-19). Clinical course of COVID-19 in children with primary kidney disease is not well understood. We present the clinical profile and management of COVID-19 in three children at a COVID hospital in India. These children had nephrotic syndrome, hemolytic uremic syndrome, and chronic kidney disease, respectively. The first two were immunosuppressed, mandating to stop their immunosuppressive medications temporarily. Both had mild course of illness. Third child presented with respiratory distress requiring oxygen support, falling into moderate disease. Renal functions were normal in all of them. They all responded well to oral azithromycin and supportive management. None of them received chloroquine, corticosteroids, or monoclonal antibodies. All three recovered without complications.

Fenoldopam and renal hemodynamics in shiga toxin-related hemolytic uremic syndrome.

BACKGROUND: Fenoldopam, a vasodilating agent, may represent a potential therapeutic opportunity to increase renal perfusion in those conditions where renal hemodynamics are severely impaired by vascular sub-occlusion, as, indeed, is the case in thrombotic microangiopathies. METHODS: The renal resistance index (RRI) was measured, on and off fenoldopam, in 27 children with STEC-HUS. RESULTS: A 12% decrease in RRI was observed on fenoldopam compared to off treatment without changes in the systemic hemodynamics and with no side effects. CONCLUSIONS: If confirmed in larger series, fenoldopam may become an important addition to supportive care to reduce ischemic damage in STEC-HUS and improve long-term outcomes.

Hemolytic uremic syndrome following complicated appendicitis in a child: what is the missing link?

We herein describe an 18-month-old boy who underwent initially successful surgical and antibiotic treatment of complicated appendicitis with postoperative occurrence of hemolytic uremic syndrome (HUS). This complication was due to Shiga toxin-producing Escherichia coli (STEC) found secondarily in rectal swabs but not in the peritoneal cavity. The literature indicates that a causal link may exist between these two entities, and HUS could be considered an iatrogenic complication of appendicitis management due to a multimodal stress effect in non-symptomatic STEC carriers.

Ockham's razor defeated: about two atypical cases of hemolytic uremic syndrome.

BACKGROUND: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxin-producing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes. CASES PRESENTATION: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery. CONCLUSIONS: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or co-occurrence of several rare conditions.

Rasburicase improves the outcome of acute kidney injury from typical hemolytic uremic syndrome.

BACKGROUND: Typical hemolytic uremic syndrome (HUS) causes acute kidney injury (AKI) and serious sequelae of chronic kidney disease (CKD) in some. Hyperuricemia is a common finding in typical HUS that may contribute to kidney damage. We explored whether aggressive management of hyperuricemia with rasburicase could improve outcomes in AKI patients with typical HUS. METHODS: We retrospectively analyzed medical records of children with typical HUS admitted to a tertiary center between 2005 and 2017. We compared clinical outcomes of hospitalization and 1-year post-discharge between those with rasburicase treatment (n = 13) and those without (controls, n = 29). RESULTS: With rasburicase treatment, hyperuricemia corrected more rapidly (median 36 vs. 120 h, p < 0.001), and hospital stays were shorter (median 9 vs. 12 days, p = 0.003) than in the controls. There was no difference in dialysis requirement. At 1-year post-discharge, the proportion of patients with impaired kidney function (estimated glomerular filtration rate < 90 mL/min/1.73 m2) was lower in the rasburicase group (7.7% vs. 41.4%, p = 0.036) than in the controls. Hypertension and proteinuria tended to be more common in the controls than in the rasburicase group. Collectively, long-term renal sequelae of impaired kidney function, proteinuria, or hypertension at a 1-year follow-up was less common in the rasburicase group than in the controls (7.7% vs. 62.1%; p = 0.001). CONCLUSIONS: Children with typical HUS treated with rasburicase had shorter hospital stays and less long-term sequelae at 1-year post-discharge than those who were not treated with rasburicase. These results support the use of rasburicase to prevent CKD in pediatric patients with typical HUS-associated AKI. Graphical Abstract.