Atypical Hemolytic Uremic Syndrome Research Articles

Application of eculizumab, a terminal complement inhibitor, in the management of atypical hemolytic uremic syndrome in a 14-month-old Chinese pediatric patient: a case report

Eculizumab, a recombined humanized monoclonal antibody which possesses high affinity for the complement protein C5, is a therapeutic agent utilized in the treatment of atypical hemolytic uremic syndrome (aHUS) by inhibiting the terminal complement complex C5b-9. In a pediatric patient with aHUS of 14 months, the administration of eculizumab therapy was accompanied by the inclusion of meningococcal vaccine as part of the national immunization program. Notably, no other antibiotics were administered prior to or during the course of eculizumab treatment. Moreover, there were no occurrences of infusion reactions or meningococcal infections observed throughout the course of treatment. Due to the presence of anti-factor H antibodies and insufficient recovery, glucocorticoids and eculizumab were administered at week 0 and week 1, followed by the initiation of mycophenolate mofetil (MMF) at a dosage of 250 mg (approximately 548 mg/m2) per day starting from Day 10. Due to the recovered of complement antibody after 8 doses of eculizumab, the therapeutic interval was extended from once every 3 weeks to once a month since 9th administration. We experienced and successfully treated a rare case of aHUS with eculizumab in a 14-month-old Chinese pediatric patient.

Bronchopleural fistula management in a pediatric patient requiring extracorporeal membrane oxygenation.

Bronchopleural fistula (BPF) is a connection between the bronchus and pleural cavity. It is associated with high morbidity and mortality and management of BPF has not been well described in the pediatric population. We describe a 2-year-old girl who presented with fever and increased work of breathing, found to have atypical hemolytic uremic syndrome and Streptococcus necrotizing pneumonia with development of persistent air leak due to bronchopleural fistulas requiring extracorporeal membrane oxygenation (ECMO). Three endobronchial valves were placed with successful resolution of bronchopleural fistulas. She required tracheostomy for chronic respiratory failure and endobronchial valves were eventually removed. Approximately 3.5 months after discharge to acute care rehabilitation, tracheostomy was successfully decannulated. This case highlights the successful use of endobronchial valves for resolution of BPF while on ECMO as well as the importance of further studies on optimal candidates, timing and duration of intervention in addition to sequelae of endobronchial valve placement.

The potential for therapeutic drug monitoring of belatacept and other biologicals in solid organ transplantation.

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.

Kidney Transplantation in Patients With aHUS: A Comparison of Eculizumab Prophylaxis Versus Rescue Therapy.

Guidelines advise eculizumab prophylaxis for most kidney transplant recipients with atypical hemolytic uremic syndrome (aHUS). However, recurrence rates may be overestimated, and starting eculizumab at relapse ("rescue therapy") may prevent graft loss. Randomized controlled trials have not compared the efficacy, safety, and costs of different treatment strategies. We performed a comparative study, including a previously described Dutch cohort treated with rescue therapy and a UK cohort using eculizumab prophylaxis. In the Netherlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2021 in the Radboud University Medical Center (n = 30) and enriched this cohort with 8 patients who received rescue therapy in other centers. The UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplanted between 2013 and 2017 with prophylactic eculizumab. We included 38 Dutch patients and 35 UK patients. Characteristics were comparable, although the UK cohort included more patients with a complement factor H SCR20 mutation or hybrid gene (31% versus 5%; P < 0.01), and more Dutch patients received living donor kidneys (66% versus 20%; P < 0.001). Follow-up was comparable (the Dutch patients 70.8 mo, range, 10-134; UK patients 55.4 mo, range, 2-95). Eighteen (47%) Dutch patients received rescue therapy. Death-censored graft survival was not significantly different (the Dutch patients 1 y, 3 y, and 6 y: 97.4%, 91.2%, and 87.1%, respectively; UK patients 1 y, 3 y, and 6 y: 97.1%, 88.2%, and 65.6%, respectively, log-rank P = 0.189). In a population characterized by low prevalence of "very high risk" genes, who were predominantly transplanted using an endothelial protective regime, death-censored graft survival with eculizumab rescue therapy was not inferior to prophylaxis.

A Rare Case of Atypical Hemolytic Uremic Syndrome Presenting as Chronic Interstitial Nephritis

A Rare Case of Atypical Hemolytic Uremic Syndrome Presenting as Chronic Interstitial Nephritis

Anti-C5 monoclonal antibody treatment showing pathological resolution of complement-mediated atypical hemolytic uremic syndrome: a case report

BackgroundNo reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies.Case presentationA 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening.ConclusionsThis is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.

Case presentation: a severe case of cobalamin c deficiency presenting with nephrotic syndrome, malignant hypertension and hemolytic anemia

BackgroundThe etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare.Case PresentationWe describe a 7-month-old male patient presenting with fatigue and edema. His first laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria and further examinations reveals hemolysis in peripheric blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported nephrotic syndrome diagnosis. The patient’s condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement.Discussion/ConclusionThis case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again.

Kidney involvement in rare hereditary diseases

Various rare inherited disorders can be associated with kidney involvement, including glomerulopathies, tubulopathies, multiple cysts, congenital anomalies of the kidneys and urinary tract, urolithiasis, malignant and benign tumors. Genetic nephropathy should be always considered in children, adolescents and young patients with the kidneys or urinary tract disorders and/or patients with positive family anamnesis. Extrarenal manifestations can be a valuable clue for diagnosis of certain hereditary diseases, e.g. neurosensory deafness in Alport syndrome or photofobia in nephropathic cystinosis. Diagnosis of monogenic inherited diseases should be verified by genetic testing. Specific drugs are available for treatment of certain hereditary diseases involving kidney, e.g. Fabry disease, cystinosis, primary hyperoxaluria I type and atypical hemolytic uremic syndrome.

Clinical characteristics and genetic profile of complement system in renal thrombotic microangiopathy in patients with severe forms of arterial hypertension

Background. The spectrum of diseases characterized by the development of renal thrombotic microangiopathy (TMA) encompasses the malignant hypertension (MHT). TMA in MHT has conventionally been regarded as a variation of secondary TMA, the treatment of which is restricted to the stabilization of blood pressure levels, a measure that frequently fails to prevent the rapid progression to end-stage renal disease in patients. Nevertheless, there exists a rationale to suggest that, in certain instances, endothelial damage in MHT might be rooted in the dysregulation of the complement system (CS), thereby presenting potential opportunities for the implementation of complement-blocking therapy. Aim. To study clinical manifestations and genetic profile of CS in patients with morphologically confirmed renal TMA combined with severe AH. Materials and methods. 28 patients with morphologically verified renal TMA and severe AH were enrolled to the study. Patients with signs of microangiopathic hemolysis and thrombocytopenia were not included in the study due to possible compliance with the criteria for atypical hemolytic uremic syndrome (aHUS). The prevalence of rare genetic defects (GD) of the CS was assessed by molecular genetic analysis (search for mutations in the clinically significant part of the human genome – exome) by next-generation sequencing technology (NGS). Results. GD of CS were detected in a quarter of patients. Rare genetic variants classified as “likely pathogenic” including defects in CFI, C3, CD46, CFHR4, CFHR5 genes were detected in five cases. Two patients were found to have chromosomal deletions containing CFH-related proteins genes (CFHR1, CFHR3). Conclusion. Rare variants of CS genes linked to aHUS were found in 25% of patients with renal TMA, the genesis of which was originally thought to be secondary and attributed to MHT, with partial or complete absence of hematological manifestations of microangiopathic pathology. The key to confirming TMA associated with MHT, particularly in the absence of microangiopathic hemolysis and thrombocytopenia, elucidating its nature, and potentially effective complement-blocking therapy in patients with GD of CS, appears to be a genetic study of CS combined with a morphological study of a renal biopsy.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H(CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS– real-world data

BackgroundThe complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs.MethodsThis multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab.ResultsMean age (range) at ravulizumab initiation was 41 years (19–78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3–120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment.ConclusionsThis is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function.

Idiopathic Atypical Hemolytic Uremic Syndrome: A Case Report

Thrombotic microangiopathies (TMAs) are a spectrum of disorders characterized by hemolytic anemia, thrombocytopenia, and formation of microthrombi in blood vessels, resulting in tissue injury due to compromised blood flow. This classical presentation of TMA is characterized by varying degrees of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic damage to the brain, kidneys, heart, lungs and GI tract. TMA can be classified into different types based upon the etiology and pathogenesis like thrombotic thrombocytopenic purpura (TTP), Complement mediated TMA (atypical Hemolytic uremic syndrome [aHUS]), infection associated TMA (shiga toxin producing E.coli, streptococcus pneumoniae) secondary to systemic causes like malignancy, autoimmune diseases and medications. In this article, we discuss a case of a female diagnosed with aHUS with acute kidney injury complicated by hypertension and severe anemia. As aHUS is known to be associated with high mortality and morbidity, prompt recognition of aHUS is crucial for efficient treatment. Here we have discussed the clinical presentation, histopathological hallmarks, and the diagnostic approach for TMA.

АТИПИЧНЫЙ ГЕМОЛИТИКО-УРЕМИЧЕСКИЙ СИНДРОМ У ДЕТЕЙ В РЕСПУБЛИКЕ БЕЛАРУСЬ: ПЕРВЫЙ ОПЫТ КОМПЛЕМЕНТБЛОКИРУЮЩЕЙ ТЕРАПИИ

Atypical hemolytic uremic syndrome (aHUS) is one of the most complex and severe forms of thrombotic microangiopathy with an unfavorable outcome in its natural course. The purpose of this research was to study the epidemiology, demographics, course and outcomes of aHUS in comparison with patients with typical hemolytic uremic syndrome (tHUS) as well as to conduct a personal analysis of all cases of aHUS and evaluate the response to therapy, including comple-ment-blocking with Eculizumab. Materials and methods used: the study was longitudinal, obser-vational and included all 349 cases of HUS in children in Belarus in 2015-2023. A comparative analysis of demographic and clinical data, laboratory results and outcomes was performed in pa-tients with HUS hospitalized at the Center for Pediatric Nephrology and Renal Replacement Therapy of the Republic of Belarus (Minsk, Belarus). Results: of 349 HUS cases, the proportion of aHUS was 3,7% (13). Children with aHUS were older (4,6 (1,6; 6,7) v. 2,7 (1,7; 4,8) y/o with tHUS) due to the portion of patients older than 5 y/o (46%). In aHUS, severe central nervous system disorders were more often observed (62% v. 14%, p=0,002), the development of critical conditions requiring transfer to mechanical ventilation (39% v. 9%, p=0,006), prolonged anuria with the need for dialysis therapy in 100% of cases and severe adverse outcomes (death or end-stage renal disease) during natural course (66,0% v. 2,7%, p&lt;0,001). The most common trigger for aHUS was acute intestinal infections in 54% of cases. A genetic study was performed in 9 (69%) children with aHUS and in 8 (89%) of them the CFHR3/CFHR1 deletions were detected: in 4 cases (3 hetero- and a single homozygous) and heterozygous pathogenic and probably patho-genic gene mutations, CFHR5 in 2 cases, CFH in a single case and combined CD46 and CFI in a single case as well. Antibodies to complement factor H were detected in 5 patients, 3 of which had a CFHR3/CFHR1 deletion. Therapy with a biosimilar of the original Eculizumab showed its effectiveness in aHUS: in 3 (100%) children it was possible to prevent the return of the disease in the kidney graft, in single patient who did not receive prophylaxis it was able to block the recur-rence of aHUS in the transplanted kidney while preserving its function, in 3 (100%) patients with late administration of treatment the urine output was restored after prolonged anuria (24, 33 and 59 days); in a single child with the antibody variant of aHUS, with early administration of the drug, renal function was preserved. No complications of complement blocking therapy were not-ed. Conclusions: the introduction into clinical practice of a biosimilar of the original Eculizumab in children in Belarus has significantly improved the outcomes and prognosis of the disease.

A Case of Carfilzomib-Induced Atypical Hemolytic Uremic Syndrome

A Case of Carfilzomib-Induced Atypical Hemolytic Uremic Syndrome

Eculizumab for adult patients with atypical haemolytic-uraemic syndrome: full dataset analysis of Japanese post-marketing surveillance.

Eculizumab has been approved for atypical haemolytic-uraemic syndrome (aHUS) in Japan since 2013. Post-marketing surveillance enrolled patients with aHUS who received ≥ 1 dose of eculizumab to assess eculizumab safety and effectiveness. We evaluated serious adverse events and effectiveness endpoints, i.e., haematologic normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, and complete thrombotic microangiopathy (TMA) response in adult patients with aHUS without otherunderlying diseases. In addition, the difference of baseline characteristics between patients who did and did not meet effectiveness endpoints was examined. In this safety and effectiveness analysis, 79 adult patients were included; median age was 54.0years, median treatment duration was 30weeks. Total exposure time of eculizumab was 75.51 patient-years, and 94 serious adverse events were reported in 39 patients. No unexpected safety signals were identified in this population. Mean platelet count, lactate dehydrogenase and estimated glomerular filtration rate significantly improved after 7daysof treatment. Complete TMA response, haematologic normalization and the improvement of sCr levels were met by 35.3%, 40.4% and 51.3% of patients, respectively. Median treatment duration was shorter in patients who did not achieve complete TMA response (6weeks) than in patients who did (114weeks). Multivariate analysis suggested that the time from the most recent TMA episodeto start ofeculizumab treatment was negatively associated with kidney function improvement. No unexpected safety signals of eculizumab were identified in Japanese patients with aHUS in a real-world setting. Renal outcomes were negatively associated with the time from the most recent TMA episodeto the initiation of eculizumab treatment.

Биоаналог экулизумаба в лечении атипичного гемолитико-уремического синдрома, связанного с беременностью: ретроспективное сравнительное исследование

To compare the efficacy and safety profile of the original and biosimilar eculizumab in the treatment of pregnancy associated atypical hemolytic uremic syndrome (p-aHUS).

#2262 Renal outcomes of postpartum atypical hemolytic uremic syndrome treated with plasma exchange

Abstract Background and Aims Postpartum acute kidney injury (AKI) with features of thrombotic microangiopathy (TMA) are particularly challenging and complex cases. Causes include Preeclampsia (PE), hemolysis, elevated liver enzymes and low platelet count syndrome (HELLP) and atypical hemolytic uremic syndrome (aHUS). In a limited resource setting, it is difficult to diagnose such cases with more than standard blood tests. Therapeutic Plasma exchange (TPE) is the only available option for treatment in the absence of complement inhibitors. This study evaluates renal outcomes in patients with aHUS treated with plasma exchange. Method This is a single centre observational study conducted in a Tertiary Obstetric Intensive Care unit. The data of women who were admitted with postpartum AKI from January 2021 to October 2023 was retrospectively collected and analyzed. We used the following criteria to diagnose postpartum atypical HUS (Serum creatinine ≥1.9 mg/dL, Lactate dehydrogenase (LDH) ≥1832 U/L, or serum creatinine ≥1.9 mg/dL in combination with LDH ≥600 U/L) [1]. Inclusion criteria include women older than 18 yrs with microangiopathic hemolytic anaemia, schistocytes on peripheral blood film, negative direct antiglobulin test (DAT) and platelet count &amp;lt;100 /mm3.Lack of improvement of kidney functions and hemolysis 72 hours after delivery. Patients with sepsis, disseminated intravascular coagulopathy (DIC), postpartum hemorrhage (PPH) and chronic kidney disease were excluded. We identified 10 patients with postpartum aHUS. Peak creatinine, LDH, AST and Nadir platelet count and hemoglobin were recorded. Patients were followed up in the nephrology outpatient clinic. Results Fifty-two patients developed postpartum AKI in the study period. Ten patients (19%) were diagnosed with aHUS according to the above-mentioned criteria. Mean age was 24.5 ± 6.9 yrs. Median peak creatinine 5.1 (2.6-7) mg/dl, LDH 1950 (612-4000) U/L, AST 246 (150-699) U/L. Median nadir hemoglobin 7.25 (6-8.2) g/dl and platelets 57 (41-95)/mm3. All 10 patients received 3 to 6 sessions of TPE guided by platelets and LDH levels. All patients required at least 3 sessions of hemodialysis. Eight patients received TPE with plasma filter and 2 had centrifugal TPE (due to lack of plasma filters). Two patients died during ICU admission. Two months after discharge 4 (50%) patients had partial recovery of kidney functions average creatinine (3.5 ± 0.8) mg/dl and four (50%) remained dialysis dependent. Six of these patients had kidney biopsies, three biopsies showed a picture of thrombotic microangiopathy and two showed thrombotic microangiopathy with renal cortical necrosis. The other patient was lost to follow up. Conclusion It is difficult to diagnose and treat aHUS in a resource limited setting. The available treatment with therapeutic plasma exchange has poor renal outcomes.

#1028 Experience with ravulizumab in atypical hemolytic uremic syndrome

Abstract Background and Aims The arrival of eculizumab revolutionized the treatment of Atypical Hemolytic Uremic Syndrome (aHUS). Ravulizumab also offers C5 inhibition, but with 3-4 times longer half- life. We describe the experience with ravulizumab in patients with aHUS in two scenarios: 1. Switching from another C5 inhibitor in stable patients; 2. Direct initiation of therapy with ravulizumab (naïve). Method We present 9 patients with an average age of 42 ± 13 years and weight of 81 ± 12.4 kg. The switch to ravulizumab was initiated 2 weeks after the last dose of eculizumab in switch patients, while in naïve patients it was initiated after excluding other causes of aHUS. The initial dose was 2700 mg, followed by a second dose of 3300 mg after 2 weeks, and subsequently every 2 months. Analytical variables of renal function, hematological parameters, and complement were collected. Results Switch : 6 patients (50% females), 4/6 were transplant recipients (3 on prophylactic treatment). Regarding renal function, 5/6 patients had a complete response with eculizumab (creatinine 1.33 ± 0.32 mg/dL, eGFR 59.5 ± 34.3 mL/min/1.73 m2, proteinuria 115 ± 91.5 mg/g), and all of them had a complete hematological response. After the switch, all patients maintained a complete hematological response, stability of renal function, and serum complement levels. Naïve : 3 cases (2 males); 2/3 required hemodialysis (HD) at presentation. The renal response was complete in two patients and partial in the third (who discontinued HD after 90 days and currently remains stable with stage G3b chronic kidney disease). All three patients had a complete hematological response. Only 3 adverse effects were documented (arthralgia, headache, and rhinitis), with no cases of infection. Conclusion The use of ravulizumab is effective both in maintaining a complete response after switching from eculizumab and as a first-line therapy. The safety profile is comparable, with the main difference being the dosing regimen, as ravulizumab requires fewer administrations and leads to a reduction in direct and indirect costs.

#1231 Atypical uremic hemolytic syndrome diagnosis, therapeutic management, control and follow-up in pregnancy: about a case

Abstract Background and Aims Atypical hemolytic uremic syndrome (aHUS) is a clinical entity characterized by non immune hemolytic anemia, thrombopenia, and renal failure in which the lesions are mediated by a process of thrombotic microangiopathy, mutations in its genes that lead to uncontrolled activation. of C5 and formation of the membrane attack complex. Its correct diagnosis allows prescribing treatment based on eculizumab, a C5 inhibitor. The clinical case of a patient with aHUS is presented, who three months after diagnosis, becomes pregnant. The objective is to highlight the importance of early differential diagnosis for the early establishment of effective treatment of this pathology, as well as management during pregnancy, childbirth and the postpartum period. The pathophysiology, diagnosis and genetic study are updated, as well as the therapeutic management of aHUS. Case Reports 27 year old women with no personal or family history of interest. She went to the emergency room in the full pandemic by SARSCov2 due to choluric urine along with fever of 38, myalgias and generalized arthralgias. At that time, PCR positive SARSCov2, deterioration of renal function was noted with Creatinine of 1.8 mg/dl (previous normal), LDH 1954 u/l, Platelets 21000, Hemoglobin 14.4 g/dl without schistocytes in smear, albumin/creatinine ratios 8700 and intense hematuria. It was interpreted as thrombotic thrombocytopenic purpura receiving corticosteroids, rituximab and plasmapheresis. After 48 hours, thrombopenia persists, schistocytes appear in smears and renal function deteriorates creatinine to 2.8 mg/dl. ADAMS 13 is received at normal values, considering at this time a diagnosis of aHUS, the previous treatment is interrupted and a dose of eculizumab 900 mg is received, doses of 900 per week are scheduled for 4 weeks in the fifth week 1200 mg and from Then on biweekly dose 1200 mg of eculizumab. At the third week of treatment, renal function has already normalized, hemolysis data have disappeared, Htcro and platelets have returned to normal. Proteinuria and hematuria disappears which has been maintained up to now. Good tolerance to treatment without any incidence, presenting a positive pregnancy test at three months. During pregnancy treatment with eculizumab is maintained. We continued with the biweekly regimen with 1200 mg of eculizumab until delivery. Labor is induced at week 37 receiving a extra dose of 1200 mg in the first 24 hours of delivery and continuing with 4 doses of 1200 mg once a week. Afterwards the dose is changed to a biweekly dose without modifying it throughout lactation until it ends. The reason is to avoid complement deregulation in the context of pregnancy and therefore ensure blockade. Subsequently it is done Switch to ravulizumab when breastfeeding begins as follows: A loading dose of 2700 mg (according to the interval of patient's weight) 15 days after the last dose of eculizumab. The maintenance dose is 3300 mg every 8 weeks starting 2 weeks after the loading dose. Normal kidney function has been maintained. She presented on debut positive serology for parvovirus B19, receiving treatment with Immunoglobulins and PCR SARSCov2 was positive prescribing treatment with remdesivir. Vitus (CMV, HBV, HCV and HIV) serology was negative and autoimmune study as well as study of complement and proteinogram were negative or within normal limits. No data suggestive of a neoplastic process. Genetic study has been detected a pathogenic variant associated with aHUS. Conclusion We found a heterozygous carrier patient in genetic study, who developed aHUS during a Sars-cov2 infection, which could have been a trigger for its clinical expression. The clinical course of this case highlights how crucial it is to identify atypical hemolytic uremic syndrome. The early initiation of eculizumab improves the prognosis and quality of life, with pregnancy becoming increasingly more likely and therapy with eculizumab does not have safety problems in this regard, although pregnant patients with aHUS should be closely monitored close during pregnancy and postpartum.

#243 Characteristics and safety in patients with atypical haemolytic uraemic syndrome switching to ravulizumab from eculizumab: a global registry analysis

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS) is a progressive rare disease caused by complement dysregulation that can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, was designed via targeted modification of eculizumab to enhance antibody recycling and attenuate target-mediated drug disposition to achieve an extended half-life. Ravulizumab was first approved for the treatment of aHUS in 2019. Real-world evidence with ravulizumab in patients with aHUS is limited. This analysis aimed to assess real-world safety outcomes in patients with aHUS who switched to ravulizumab from eculizumab using data from the Global aHUS Registry. Method The Global aHUS Registry is a multicentre study (NCT01522183) collecting retrospective and prospective data on patients with aHUS since 2012, making it the largest registry of real-world data for this patient population. Safety outcomes (including serious and non-serious adverse events [AEs], meningococcal infections and deaths) were assessed in patients with aHUS who switched to ravulizumab from eculizumab up to 3 July 2023. Results Overall, 60 patients were included in the analysis population and evaluated for baseline demographics and characteristics, and safety outcomes. Most patients were female (70%) and the median (range) age at ravulizumab initiation was 34 (2–72) years (Table 1). In total, 27 patients (45%) had pathogenic complement variants and 19 (32%) had a kidney transplantation prior to ravulizumab initiation. Among extrarenal manifestations (experienced at any time during observation), the most common were gastrointestinal (n = 29 [48%]), central nervous system (n = 19 [32%]) and cardiovascular (n = 15 [25%]). The median (range) time on treatment was 21 (2–40) months for ravulizumab and 62 (11–155) months for eculizumab. No new events of thrombotic microangiopathy, dialysis or kidney transplantation were reported during ravulizumab treatment. One patient who was on chronic dialysis under eculizumab switched to ravulizumab; the patient returned to eculizumab (per local guidelines) for a planned kidney transplantation with the intention to switch back to ravulizumab post-transplantation (data not yet available). In total, 20 AEs were reported in 13 patients, of which none were unexpected (Table 2). Three serious AEs were reported in three patients (1 event each of squamous cell carcinoma, atrial fibrillation, SARS-CoV-2 infection). Ten AEs occurred in eight patients who received a kidney transplantation before ravulizumab initiation. Treatment-related AEs occurred in two patients while on ravulizumab: one infusion reaction event in one patient was assessed to be probably related to ravulizumab by the investigator (the event resolved within 24 hours and the patient continued treatment); one patient experienced headaches and fatigue while on ravulizumab, which resolved after switching back to eculizumab. The most common AEs were infection (n = 7 events), including SARS-CoV-2 infection (n = 4), influenza (n = 1), infection without focus (n = 1) and pulmonary nodular infiltration (n = 1); all infections were resolved except for one event of SARS-CoV-2 infection that was ongoing/persistent. No meningococcal infections or deaths were reported during ravulizumab treatment. Conclusion This analysis from the Global aHUS Registry reports the largest real-world safety dataset from patients with aHUS treated with ravulizumab. No unexpected AEs, meningococcal infections or deaths were reported during ravulizumab treatment. These data provide evidence for the long-term safety of ravulizumab in patients with aHUS who switched from eculizumab and reinforce the positive benefit–risk profile of ravulizumab.