Typical HUS Research Articles

An unusual case of adult-onset still’s disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome

BackgroundAtypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still’s disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing.Case presentationA 42 years old man was admitted with suspected adult-onset Still’s disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still’s disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml).ConclusionOur case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.

Multifaktorska etiologija atipičnog hemolitičko uremijskog sindroma - prikaz slučaja

Abstract: Introduction: Hemolytic uremic syndromes are characterized by the simultaneous occurrence of hemolytic anemia, microangiopathy, thrombocytopenia, and acute renal insufficiency. In terms of the clinical prodrome, they can be classified as typical, which is more common and occurs in 90% of cases, often preceded by diarrheal syndrome induced by enterohemorrhagic Escherichia coli. Alternatively, there is an atypical and rarer form associated with pneumococcal infection, dysregulation of the alternative complement pathway, and cases involving the use of cyclosporine. Hemolytic anemia is confirmed in laboratory analyses (presence of fragmented red blood cells, decreased hemoglobin, undetectable haptoglobin values, and elevated LDH values), along with thrombocytopenia and an increase in nitrogenous substances (urea and creatinine). Case report: The report details the case of an 18-month-old girl who experienced acute renal insufficiency subsequent to a respiratory infection. Ten days preceding admission, the patient exhibited nasal discharge, and during the seven days leading up to hospitalization, she presented with fever. Furthermore, two days prior to admission, the onset of persistent vomiting and abdominal pain occurred. Suspected of bowel intussusception, the patient underwent a surgical assessment where acute surgical pathology was ruled out. The absence of urination, coupled with heightened urea and creatinine levels, prompted consideration of hemolytic-uremic syndrome, later confirmed as atypical during hospitalization. This was grounded in the clinical presentation, devoid of diarrhea syndrome but marked by nasal discharge over the preceding ten days. The administration of fresh frozen plasma yielded no improvement, and there were decreased values of the C3 complement component, H factor, and reduced ADAMTS13 activity. The lack of verotoxins from enterohemorrhagic Escherichia coli further supported the diagnosis of atypical hemolytic-uremic syndrome. After the first dose of eculizumab, a terminal complement C5 component inhibitor, the girl recovered renal function and established diuresis. Conclusion: The prompt diagnosis of atypical hemolytic-uremic syndrome is challenging due to nonspecific symptoms like nasal discharge, vomiting, fatigue, and abdominal pain. Laboratory analyses, lacking specific criteria, make it difficult to conclusively identify aHUS at the disease's onset. In Serbia, pneumococcal immunization is recommended as a preventive measure, administered through a conjugated vaccine in three doses starting from the second month of life. Rapid and accurate differentiation between typical and atypical HUS is crucial for effective treatment and prognosis. Typical HUS requires hemodialysis and plasmapheresis, whereas atypical HUS is managed with plasmapheresis, immunosuppressive therapy, and eculizumab. Administering eculizumab heightens the risk of meningococcal infection by inhibiting the C5 complement component. Therefore, it is crucial not to disregard the importance of meningococcal immunization.

Atypical hemolytic-uremic syndrome in children

Background: Atypical hemolytic-uremic syndrome (aHUS) is a rare progressive form of systemic thrombotic microangiopathy (TMA), which develops due to uncontrolled activation of the alternative pathway of the complement system and is characterized by a predominant lesion of the vessels of the renal microcirculatory bed.Clinical cases description: The article describes two clinical cases of aHUS, which demonstrate the difficulties of differential diagnosis of typical and atypical HUS at the initial stages of the disease.Conclusion: Given the lack of clear laboratory criteria of aHUS, it is necessary to carry out a complex and consistent differential diagnosis of various TMA options, the exclusion of which makes it possible to make a correct diagnosis more accurately.

243.2: Pediatric Kidney Transplantation in Argentina: Is Delayed Graft Function a Problem? Results of a Multicenter Study

Introduction: Delayed graft function (DGF) is a manifestation of acute kidney injury occurring after kidney transplantation (KTx). Incidence of DGF in pediatric KTx recipients is variable (10% to 25%) due to different definitions of DGF and different subgroups of kidney donors. It is associated with an increased risk of graft loss in adult KTx. Several factors related to donor, recipient, and organ procurement/transplantation procedures may increase the risk of DGF. The aim of our study was to evaluate the cumulative incidence of DGF in a children who received a kidney graft from a brain-dead donor, its impact on patient and graft survival, and to identify predictive risk factors of DGF. Methods: A retrospective multicenter study was conducted including recipients under 18 years of age who underwent KTx from a brain-dead donor between January 1, 2015 and December 31, 2017. DGF was defined as the need for dialysis within the first week after KTx. Data were obtained from the clinical records of the patients and from the Registry and Management System of Argentina (SINTRA) and were analyzed using MedCalc® Statistical Software version 20.014; 2021. Results: We analyzed 239 KTx performed at 17 centers. Of the recipients 54.4% were male, median age at Tx was 13.7 yr (r: 2.8 -17.9), weight 30 kg (r: 7 - 82), BMI 17 Kg/m2 (r: 11 - 36). Etiology of ESRD: CAKUT 30%, glomerular diseases with risk of recurrence 24.3%, typical HUS 3.8%, others 29.7%, and unknown 12.2%. Pre-emptive KTx was performed in 18.8% of patients, 39.7% were receiving hemodialysis, and 41.5% peritoneal dialysis. Median of time on dialysis was 2.62 yr (r: 0.12 - 9.8). Of the donors 70.7% were male, median age was 17.6 yr (r: 2.8 - 55), BMI 23 Kg/m2 (r: 17 - 35), BMI ratio donor/recipient 1.35, and pre-ablation serum creatinine 0.82 mg/dl (r: 0.6 - 2.6). Cause of death was trauma in 57%, vascular in 24%, and others in 19%. Cold ischemia time was 16.6 hours (r: 4.2 - 42), HLA mismatches ≼ 3: 54% and > 3: 46 %. Multiple-organ donor in 84.5%. Overall, 59 patients (24.7%) developed DGF. Patients without DGF had better graft survival at 1 (96% vs 78%) and 3 yrs of follow-up (89% vs 73%) p= 0.001. There were no significant differences in patient survival between both groups at the 3-year follow-up (95% vs 91%). Incidence of early AR (90 days post Tx) was higher in patients with DGF (34.5% vs 10.6%) p= 0.0001. In univariate analysis risk factors for DGF were: age at Tx > 13.7 yr, male gender, glomerular disease with risk of recurrence, hemodialysis as prior to KTx, and time on dialysis > 1 yr. In multivariate analysis independent risk factors for DGF were: time on dialysis > 1 yr (OR 9.2 - 95% CI 2.1 - 39) and age at KTx > 13.7 yr (OR 1.09 - 95% CI 1.01 - 1.18). Conclusion: In our cohort, cumulative incidence of DGF was higher than that reported by other authors. Patients with DGF had worse graft survival than those without DGF. Shortening the time on dialysis seems to be a modifiable factor to reduce DGF.

Recurrent hemolytic uremic syndrome caused by DGKE gene mutation: a case report

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury without any association with preceding diarrhea. Dysregulation of the complement system is the most common cause of aHUS, and monoclonal humanized anti-C5 antibodies are now recommended as the first-line treatment for aHUS. However, if the complement pathway is not the cause of aHUS, C5 inhibitors are ineffective. In this study, we report the second reported case of aHUS caused by DGKE mutations in Republic of Korea. The patient was an 11-month-old infant who presented with prodromal diarrhea similar to typical HUS, self-remitted with conservative management unlike complement-mediated aHUS but recurred with fever. While infantile aHUS often implies genetic dysregulation of the complement system, other rare genetic causes, such as DGKE mutation, need to be considered before deciding long-term treatment with C5 inhibitors.

MO194: A Rare Case of Secondary Haemolytic Uremic Syndrome after ANTI-SARS-COV-2 Vaccination

Abstract BACKGROUND AND AIMS Haemolytic uremic syndrome (HUS) is a rare disease characterized by macroangiopathic haemolytic anaemia, thrombocytopaenia and severe AKI, belonging to the thrombotic microangiopathies (TMAs). It is divided into typical and atypical HUS: the first one occurs most frequently in children within the first 5 years of life and it is associated with Shiga-like toxin producing Escherichiacoli infection; the second one (aHUS) is less common (10%) and it is due to complement abnormalities with coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs or pregnancy. There is an increasing interest in SARS-CoV-2 infection as new trigger for complement activation. Nine cases of aHUS were recently associated with COVID-19, most of them occurring within 1 month from the infection. Available data suggest that SARS-CoV-2 is a potential trigger for aHUS: it can induce an over inflammatory state and to activate coagulation and complement pathway. Likewise, mRNA-based vaccines against COVID-19 inducing the expression of SARS-CoV-2 spike protein to stimulate immune recognition and antibody response could be a suitable trigger for HUS. METHOD We report the case of a 17-year-old woman, who presented at our emergency department with fever, dyspnoea, acute kidney injury AKI III with anuria, hypertension, severe anaemia, no diarrhoea, severe thrombocytopaenia and myocarditis, about 2 weeks after the first administration of SARS-CoV-2 vaccine (Comirnaty) and recent exposition to SARS-CoV-2 positive individual. SARS-CoV-2 nasal PCR swab was negative (as well as successive ones) and she was immediately admitted to paediatric intensive care unit and treated with transfusions and haemodialysis. Laboratory exams suggested a thrombotic microangiopathy with normal ADAMTS-13 activity and no E. coli infection. She underwent a renal biopsy that confirmed our hypothesis of aHUS: wrinkled capillaries, subendothelial expansion, mesangiolysis and rare thrombi in capillaries lumen. Arterioles had intimal proliferation with mucoid oedema who gave rise to onionskin like lesion that obliterates lumens. One glomerulus showed extracapillary proliferation (crescent), and there was interstitial lymphomonocytic inflammatory infiltration in the nearby. Also signs of acute tubular injury and atrophy were reported. Positive stain to fibrinogen in the arterioles at immunohistology was noted. She immediately performed genetic exams for aHUS-related complement mutations and she started immunosuppression with corticosteroids and eculizumab infusions. After 2 months of eculizumab, she was still oliguric, requiring renal replacement therapy. Genetic analysis showed no mutations. Therefore, she was examined for other genetic causes of thrombotic microangiopathies. RESULTS Finally, came to light that she had high levels of homocysteine, and she was diagnosed with secondary HUS associated with cobalamin C deficiency, which manifests with methylmalonic aciduria and homocystinuria due to a recessive mutation in the MMACHC gene, causing a cobalamin C type deficiency, which is the common functional variant of vitamin B12. After metabolic therapy with hydroxocobalamin, she gradually recovered diuresis and partially renal function without need for replacement therapy. CONCLUSION Reports from immunization programs show as myocarditis and thrombotic thrombocytopaenia are considered among main serious complications caused by COVID-19 vaccines, representing 12.6 cases per million doses and 0.73 cases per 100 000, respectively. This interesting case probably supports data about the role of mRNA-based anti-SARS-CoV-2 vaccines like a precipitant factor for TMAs. Moreover, our patient turned out to be an extremely rare case of HUS secondary to cobalamin C deficiency, that is generally diagnosed in early infancy and show typically neurological symptoms (absent in our case). Probably, the mRNA-based vaccine acted like ‘a second hit’, but existing predisposition should always be investigated including also the less frequent forms.

Task force for the diagnosis of thrombotic microangiopathy / Força-tarefa para o diagnóstico de microangiopatia trombótica

Background: Thrombotic microangiopathy triggers microangiopathic hemolytic anemia, thrombocytopenia, and organic injuries. It is a rare and serious condition that demands specific approaches and strategies to recognize it promptly, especially in critically ill patients. The task force could be an effective model. Methods: An evaluative study of the impact of a task force in establishing a routine for the diagnosis of TMA in ICUs. A standard flowchart was used for 90 consecutive days and a low platelet count was the driver for the collection of epidemiological and laboratory data. Suspicion of typical HUS was proven after analyzing haptoglobin, LDH, creatinine, ADAMTS-13 enzyme, and Shiga toxin levels. Meetings were also held with ICU personnel and the self-explanatory flowchart was fine tuned. Results: There were 490 patients (55.9% male and 44.1% female) aged 59.5 ± 21.13 years. Forty-two percent of patients in the sample had thrombocytopenia. Out of the 42 patients, five (1.02%) had TTP, three (0.6%) were presumed to have atypical HUS, and none had typical HUS. The task force remained in touch with researchers to assess diagnoses and three other suspected cases of atypical HUS underwent specific treatment.Discussion: Only 1.62% of the sampled patients had TMA. Despite its complexity, the task force model is useful in situations in which higher technology is the norm. Conclusion: The use of a task force has proven to be effective in establishing a diagnostic practice for a health condition deemed rare or exceedingly rare.

Peripheral nervous system manifestations of Shiga toxin-producing E. coli-induced haemolytic uremic syndrome in children

BackgroundThe 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 presentationHere, 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.ConclusionsPNS 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.

Threatening Blindness in a Child With Typical Hemolytic Uremic Syndrome

BackgroundHemolytic uremic syndrome (HUS) is the most common cause of acute kidney failure in children younger than five years. Central nervous system involvement occurs in 15% of patients, with clinical manifestations including confusion, coma, seizures, stroke, and cortical blindness. Ocular involvement in children with HUS is rare, but retinal and choroidal hemorrhages as well as ischemic retinopathy due to thrombotic microangiopathic lesions have been documented. Patient DescriptionWe describe a 26-month-old girl with typical HUS who experienced severe visual loss likely resulting from cytotoxic injury of both lateral geniculate nuclei with bilateral damage to optic pathways coupled with macular thrombotic microangiopathic lesions. Her vision recovered completely within a month in conjunction with the normalization of her imaging studies. ConclusionsAlthough this child's vision was severely impaired, the prognosis for this mixed visual impairment of peripheral and central origin was excellent with a full recovery.

Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics.

Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.

Retrospective and Systematic Analysis of Causes and Outcomes of Thrombotic Microangiopathies in Routine Clinical Practice: An 11-Year Study.

Background: Thrombotic microangiopathies (TMAs) are highly suspected in patients showing mechanical hemolytic anemia, thrombocytopenia, and haptoglobin consumption. Primary [thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome] and secondary TMA are considered. Even if ADAMTS13 measurements and alternative complement pathway explorations have greatly improved the ability to identify primary TMA, their diagnosis remains difficult, and their frequency relative to that of secondary TMA is undetermined. The objectives of the present study were, therefore, to describe the etiologies, management, and the outcomes of patients presenting with TMA in real-life clinical practice.Methods: We conducted a retrospective study between 01/01/2008 and 31/12/2018 that included all consecutive patients presenting with biological TMA syndrome at admission or developing during hospitalization. Patients were identified from the laboratory databases, and their medical files were reviewed to confirm TMA diagnosis, to determine etiology, and to analyze their therapeutic management and outcomes.Results: During this period, 239 patients with a full TMA biological syndrome were identified, and the TMA diagnosis was finally confirmed in 216 (90.4%) after the cases were reviewed. Primary TMAs (thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome) were diagnosed in 20 of 216 patients (9.3%). Typical HUS was diagnosed in eight patients (3.7%), and the most frequent secondary TMAs were HELLP syndrome (79/216, 36.6%) and active malignancies (30/219, 13.9%). ADAMTS13 measurements and alternative complement pathway analyses were performed in a minority of patients. Multiple factors identified as TMA triggers were present in most patients, in 55% of patients with primary TMA, vs. 44.7% of patients with secondary TMA (p = 0.377). Death occurred in 57 patients (23.4%) during follow-up, and dialysis was required in 51 patients (23.6%). Active malignancies [odds ratio (OR) 13.7], transplantation (OR 4.43), male sex (OR 2.89), and older age (OR 1.07) were significantly associated with death.Conclusion: Secondary TMAs represent many TMA causes in patients presenting a full TMA biological syndrome during routine clinical practice. Multiple factors favoring TMA are present in about half of primary or secondary TMA. ADAMTS13 and complement pathway were poorly explored in our cohort. The risk of death is particularly high in patients with malignancies as compared with patients with other TMA.

ПЕРВЫЙ ОПЫТ ИСПОЛЬЗОВАНИЯ БИОАНАЛОГА ОРИГИНАЛЬНОГО ПРЕПАРАТА ЭКУЛИЗУМАБА ДЛЯ ПРОФИЛАКТИКИ ВОЗВРАТА АТИПИЧНОГО ГЕМОЛИТИКО-УРЕМИЧЕСКОГО СИНДРОМА В ПОЧЕЧНЫЙ ТРАНСПЛАНТАТ У РЕБЕНКА

The article presents a clinical case of atypical hemolytic uremic syndrome (аHUS), the debut of which proceeded under the guise of a typical HUS. After 4 months of hemodialysis, the child did not need renal replacement therapy for the next 9 months. The development of end-stage renal failure required a molecular genetic study to clarify the diagnosis. The child has mutations in the genes of the complement regulatory proteins – factor I and MCP. The risk of aHUS recurrence with these genes mutations to a renal transplant without pathogenetic prophylaxis is up to 80%. The use of the Russian biosimilar eculizumab before and after kidney transplantation allowed to prevent the activation of complement and disease recurrence to transplanted organ.

Kidney transplantation in children with CAKUT and non-CAKUT causes of chronic kidney disease: Do they have the same outcomes?

Almost half the children who undergo kidney transplantation (KTx) have congenital abnormalities of the kidney and urinary tract (CAKUT). We compared patient, graft survival, and kidney function at last follow-up between CAKUT and non-CAKUT patients after KTx. We divided the analysis into two eras: 1988-2000 and 2001-2019. Of 923 patients, 52% had CAKUT and 48% non-CAKUT chronic kidney disease (CKD). Of the latter, 341 (77%) had glomerular disease, most frequently typical HUS (32%) and primary FSGS (27%); 102 had non-glomerular disease. CAKUT patients were more often boys, younger at KTx, transplanted more frequently preemptively, but with longer time on chronic dialysis. They had less delayed graft function (DGF) and better eGFR, but higher incidence of urinary tract infection (1 year post-KTx). In both eras, 1-, 5-, and 10-year patient survival was similar in the groups, but graft survival was better in CAKUT recipients vs those with primary glomerular and primary recurrent glomerular disease: Era 1, 92.3%, 80.7%, and 63.6% vs 86.9%, 70.6%, and 49.5% (P=.02), and 76.7%, 56.6%, and 34% (P=.0003); Era 2, 96.2%, 88%, and 73.5% vs 90.3%, 76.1%, and 61% (P=.0075) and 75.4%, 54%, and 25.2% (P<.0001), respectively. Main predictors of graft loss were DGF, late acute rejection (AR), and age at KTx in CAKUT group and disease relapse, DGF, early AR, and number of HLA mismatches in recipients with glomerular disease. Graft survival was better in CAKUT patients. DGF was the main predictor of graft loss in all groups. Disease recurrence and early AR predicted graft failure in patients with glomerular disease.

Description of the First Cases with ADAMTS13 Mutations in Hungary

INTRODUCTIONLow ADAMTS13 activity is associated with an increased risk of thrombotic thrombocytopenic purpura (TTP). This may be caused by the presence of inhibitory autoantibody (immune-mediated TTP) or genetic deficiency of the enzyme. The latter condition is also known as Upshaw-Schulman syndrome (USS), the extremely rare congenital form of TTP. The clinical picture typically presents during infancy or early childhood but an increasing number of late-onset cases are detected. OBJECTIVEClinical and laboratory characterization of the first 5 Hungarian cases with ADAMTS13 mutations. PATIENTSDuring the last 4 years, 5 cases with ADAMTS13 gene mutations were recognized in Hungary. All were adults, 4 females and 1 male. Two patients (Pts) showed an immune-mediated TTP like clinical picture, while 3 Pts were examined in conjunction with their pregnancies. The first Pt was an 18 years old girl, initially presenting with stroke and isolated cerebral vasculitis. She responded promptly to plasma exchange (PE) combined with immunosuppressive treatment (ISU) and acetylsalicylate (AS). However, severe headache with progressively decreasing platelet (PLT) count into the low normal range and repeatedly deficient ADAMTS13 activity returned after one week of PE cessation necessitating further treatment. ISU was stopped when cerebral vasculitis was excluded. There were several, plasma (PE/infusion) responsive severe headache+bradycardia episodes without hematologic manifestation in the follow-up period. The first TTP episode of the only male Pt occurred at age of 25 and the later clinical course highly resembled autoimmune relapsing (intermittent type) TTP. The Pt received several series of PEs, ISU, even splenectomy, before having the correct diagnosis. Interestingly, this Pt had unclassified HUS in the childhood. The 3rd case was a 40 years old woman with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) needing an immediate cesarean section (CS) in the 25th week of gestation. She achieved a spontaneous remission and remained symptom-free. The fourth Pt a 29 years old female had typical HUS at 3 years of age. Her kidney function slowly declined without HUS flares to end-stage kidney failure necessitating kidney transplantation. She had deep venous thrombosis (DVT) and intrauterine fetal death at 20 weeks of gestation. The workup showed decreased but not severely deficient ADAMTS13 activity. She received AS + low molecular weight heparin (LMWH) and increasing dose of plasma treatment starting at the 10th week of gestation of her next pregnancy. CS was done due to progressive hypertension and worsening placental circulation at the 30th week of gestation. The last Pt was a 41-year-old pregnant woman with recurrent abortions in her history. She received AS and LMWH only. The pregnancy was terminated by CS due to severe vaginal bleeding at the 30th week of gestation. RESULTSPts 1 and 2 with TTP clinical phenotype and Pt 3 with HELLP syndrome had deficient ADAMTS13 activity (0-0-8%, respectively). The activity was decreased but not deficient in Pts 4 and 5 (13-35%). All deficient Pts were compound heterozygous for ADAMTS13 mutations: c.3178C>T and c.4143-4144dupA (Pt1), c.1016_1017delCA and c.3199T>A (Pt2), c.1261C>T and c.3283C>T (Pt3). Three of these mutations were described in patients with USS, 1 in Pts with DVT, whereas 2 mutations are novel. By family study, we could demonstrate the association of c.1261C>T mutation described in DVT and one USS Pts with reduced ADAMTS13 activity. The two non-deficient cases were heterozygous for one of the following mutations: c.3178C>T and c.2839C>T. The previous was identified in late-onset USS, the latter has not yet been described, its association with reduced ADAMTS13 activity was also proven by family study. CONCLUSIONSClinical and molecular characterization of the first 5 Hungarian cases with ADAMTS13 mutations was presented. Compound heterozygous, damaging ADAMTS13 mutations with deficient plasma ADAMTS13 activity were associated with serious clinical consequences. In case of thrombotic microangiopathy in young patients with stroke, or HELLP syndrome, complete workup for ADAMTS13 activity and inhibitors is necessary, and genetic analysis should be considered. Three new ADAMTS13 mutations (c.1016_1017delCA, c.3199T>A , c.2839C>T) were identified and shown to be associated with decreased plasma ADAMTS13 activity. DisclosuresKremer Hovinga:Ablynx: Other: Member of Advisory Board; Shire: Other: Member of Advisory Board, Research Funding. Masszi:AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Pfizer: Consultancy.

Carfilzomib-Associated Cardiomyopathy: Atypical Haemolytic Uraemic Syndrome or Drug-Induced Cardiomyopathy?

Background: Atypical haemolytic uraemic syndrome (aHUS) is primarily a disorder of complement regulation with renal, gastrointestinal, hepatic and neurological manifestations. Cardiac manifestations have been described, primarily in a paediatric population with typical HUS. This abstract reports a case of adult aHUS with cardiac involvement, following carfilzomib (a proteasome inhibitor) administration for myeloma.

Shiga toxin during pregnancy and breastfeeding: Can human milk protect children from typical HUS?

Shiga toxin during pregnancy and breastfeeding: Can human milk protect children from typical HUS?

Typical Hus: Evidence of Acute Phase Complement Activation from a Daycare Outbreak.

The clinical manifestations of typical hemolytic uremic syndrome (HUS) encompass a wide spectrum. Despite the potentially severe sequelae from this syndrome, treatment approaches remain supportive. We present the clinical course of a child who contracted Shiga toxin-positive E. coli (STEC) from a daycare center during an outbreak. Utilizing the modified Ham test which is a rapid, serum-based functional assay used to detect activation of the alternative pathway of complement as observed in atypical HUS, patient sera revealed evidence of increased complement activation in the acute phase of the syndrome but not after resolution. Further, this complement activation was attenuated by eculizumab in vitro, an effect that was replicated in vitro utilizing Shiga toxin as a stimulus of complement activation in normal serum. Our report suggests that complement blockade may be effective in the treatment of STEC-HUS when initiated early in the disease. Given the epidemic nature of the disease that limits the feasibility of randomized clinical trials, further studies are needed to determine the value of early eculizumab treatment in STEC-HUS.

Prophylactic Eculizumab Use in Kidney Transplantation: A Review of the Literature and Report of a Case with Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a very rare disease, which presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Progression to end-stage renal disease (ESRD) from acute kidney injury is observed in 60% of aHUS cases. The prognosis of aHUS patients who undergo kidney transplantation (Ktx) is generally poor, but these patients should be treated prophylactically with eculizumab to prevent recurrence after transplantation. An 18-year-old man was referred to our center with a history of rapid progression to ESRD with unknown etiology. He had anemia, thrombocytopenia, high levels of LDH, and indirect bilirubin and creatinine on initial laboratory results. Our diagnosis was aHUS due to initial results, normal level of ADAMTS activity, and lack of predisposing factors seen in typical HUS. We planned to perform genetic analysis for the patient and the donor candidate (mother). The variations found on exon 7 of the CFH gene had not been reported previously. According to PolyPhen analysis, this mutation was reported as a potential cause for aHUS. We decided to perform Ktx under eculizumab prophylaxis. Weekly administration of prophylaxis was extended to 1 month. The graft functioned immediately after Ktx. The patient has completed his first year uneventfully in our follow-up, with a creatinine 0.79 mg/dl at his last control visit. We found favorable results of an aHUS case successfully treated with kidney transplantation combined with short-term prophylactic eculizumab therapy.

Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network

Despite the severity of HUS and the fact that it represents a leading cause of acute kidney injury in children, the general epidemiology of HUS is all but well documented. The present study provides updated, population-based, purely epidemiological information on HUS in childhood from a large and densely populated area of northern Italy (9.6 million inhabitants, 1.6 million children). We systematically reviewed the files concerning patients with STEC-HUS and atypical HUS (aHUS) over a 10-year observation period (January 2003-December 2012). We included all incident cases with a documented first episode of HUS before the age of 18 years. We identified 101 cases of HUS during the 10 years. The overall mean annual incidence was 6.3 cases/million children aged <18 years (range 1.9-11.9), and 15.7/million of age-related population (MARP) among subjects aged <5 years; aHUS accounted for 11.9 % of the cases (mean incidence 0.75/MARP). The overall case fatality rate was 4.0 % (3.4 % STEC-HUS, 8.3 % aHUS). Given the public health impact of HUS, this study provides recent, population-based epidemiological data useful for healthcare planning and particularly for estimating the financial burden that healthcare providers might have to face in treating HUS, whose incidence rate seems to increase in Northern Italy. • HUS is a rare disease, but it represents the leading cause of acute kidney injury in children worldwide. • STEC-HUS (also called typical, D + HUS) is more common compared to atypical HUS, but recent, population-based epidemiological data (incidence) are scanty. What is New: • Comprehensive, population-based epidemiological data concerning both typical and atypical HUS based on a long observational period.

Arterial hypertension in children with hemolytic uremic syndrome after kidney transplantation.

The development of arterial hypertension after KTX is a well-known complication. HUS is a systemic disease associated with arterial hypertension during long-term follow-up. Our goal was to report on the severity of arterial hypertension after KTX in patients with typical and atypical HUS. We analyzed the course of 197 patients with HUS, of which 22 (n = 10 with typical HUS; n = 12 with atypical HUS) developed ESRF and received KTX as renal replacement therapy. We analyzed data from 1766 casual BP and 85 24-h ABPM measurements. In addition, we evaluated the used antihypertensive strategy. Comparison between the two patient groups revealed that patients with atypical HUS had significantly higher casual SBP-SDS and DBP-SDS values after KTX despite similar intensity of antihypertensive treatment. These data were supported by analysis of ABPM profiles showing comparable results for the interval 1-5 yr after KTX. Patients with atypical HUS had a greater severity of arterial hypertension despite similar treatment strategies and intensity of treatment. Our observation, even though in a small cohort, supports recent genetic studies showing arterial hypertension closely associated with HUS-causing mutations in patients with atypical HUS.