Hemolytic Uremic Syndrome Patients Research Articles

Humoral immune response to Shiga Toxin 2 (Stx2) among Brazilian urban children with hemolytic uremic syndrome and healthy controls.

BackgroundShiga toxin (Stx)-producing Escherichia coli (STEC) infection is associated with hemolytic uremic syndrome (HUS), the main cause of acute renal failure in early childhood. Stx is essential in the pathogenesis of HUS, which has been mostly related to Stx2-producing isolates. Very limited data exist on the immune response to STEC in the Brazilian population. In this study, the prevalence of immunoglobulin G (IgG) antibodies to Stx2 was investigated in sera of children diagnosed with HUS and of healthy children in the city of São Paulo, Brazil.MethodsIgG-antibody reactivity to Stx2 was determined by immunoblotting (WB) and enzyme-linked immunosorbent assay (ELISA) in sera from 13 children with HUS aged 8 months to 6 years and 54 healthy urban children aged 5 months to 7 years.ResultsA positive immune response to the A and B subunits of Stx2 was observed in 46.1% HUS patients and in 16.6% healthy individuals by WB. All HUS patients and 62.9% healthy children showed IgG antibodies to the Stx2 A subunit. The frequency of antibodies to both subunits or only to the A subunit of Stx2 was significantly higher in HUS patients than controls (p < 0.05). Also, the mean OD value obtained by ELISA was higher in that group. Considering children’s age, the frequency of reactivity to either the A subunit or both subunits of Stx2 was considerably higher in HUS children up to three years old compared to controls in the same age range. Moreover, in almost 37% of healthy children, no immune response to Stx2 was detected independently of the child’s age.ConclusionsThe seroepidemiolgy of anti-Stx2 antibodies was described for the first time in healthy children and children with HUS in Brazil. The percentage of individuals showing antibodies against Stx2 was higher among HUS patients than controls, and in spite of the low number of notified HUS cases, STEC strains are circulating in our settings. In addition, the results obtained also corroborated previous data on the increased sensitivity and specificity of WB compared to toxin-based enzyme immunoassays.

Characterization of enterohemorrhagic Escherichia coli O111 and O157 strains isolated from outbreak patients in Japan.

In April and May 2011, there was a serious food-poisoning outbreak in Japan caused by enterohemorrhagic Escherichia coli (EHEC) strains O111:H8 and O157:H7 from raw beef dishes at branches of a barbecue restaurant. This outbreak involved 181 infected patients, including 34 hemolytic-uremic syndrome (HUS) cases (19%). Among the 34 HUS patients, 21 developed acute encephalopathy (AE) and 5 died. Patient stool specimens yielded E. coli O111 and O157 strains. We also detected both EHEC O111 stx2 and stx-negative E. coli O111 strains in a stock of meat block from the restaurant. Pulsed-field gel electrophoresis (PFGE) and multilocus variable-number tandem-repeat analysis (MLVA) showed that the stx-negative E. coli O111 isolates were closely related to EHEC O111 stx2 isolates. Although the EHEC O157 strains had diverse stx gene profiles (stx1, stx2, and stx1 stx2), the PFGE and MLVA analyses indicated that these isolates originated from a single clone. Deletion of the Stx2-converting prophage from the EHEC O111 stx2 isolates was frequently observed during in vitro growth, suggesting that strain conversion from an EHEC O111 stx2 to an stx-negative strain may have occurred during infection.

Role of Complement in Enterohemorrhagic Escherichia coli–Induced Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in childhood, is mainly caused by infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC). Besides its cytotoxic activity, Stx has been shown to interact with the complement system. Complement breakdown products have been found in serum of HUS patients suggesting complement activation and in vitro studies have demonstrated that Stx2 directly activates complement leading to formation of terminal complement complex. Furthermore, Stx2 has been found to bind to factor H (FH) resulting in a reduced cofactor activity on the cell surface. Binding of Stx2 has also been shown for other members of the FH family, namely FH-like protein 1 and FH-related protein 1. Both proteins also compete with FH for Stx binding, so that in the presence of FHR-1 less FH is bound to Stx and therefore more is available for endothelial cell protection. In addition, Stx2 has been demonstrated to downregulate the membrane-bound regulator CD59 on the surface of glomerular endothelial and tubulus epithelial cells on protein and at the mRNA level. In conclusion, Stx modulates complement regulator proteins leading to an impaired control and thus to enhanced complement activation. Its implication in the pathogenesis of EHEC-induced HUS in vivo and whether complement blockage might be a therapeutic option still has to be elucidated.

G358 The performance of the new SLICC criteria for the classification of SLE in children

AimsThe Systemic Lupus International Collaborating Clinics (SLICC) have recently suggested a new set of criteria for the classification of SLE. We aimed to compare the sensitivity and specificities of the...

Incidence and index of severity of hemolytic uremic syndrome in a 26 year period in Fukushima Prefecture, Japan

There have been a number of reports on large outbreaks of hemolytic uremic syndrome (HUS), but there have been no long-term studies of sporadic HUS in Japan. This study therefore investigated the epidemiology and prognosis of HUS in Fukushima Prefecture over a 26 year period. The medical records of 26 patients with HUS between 1987 and 2012 were collected. These children were divided into two groups: those with HUS following an episode of gastroenteritis, often with bloody diarrhea (D + HUS; n = 24) and those with HUS not associated with prodromal diarrhea (D-HUS; n = 2). The D + HUS group was further subdivided into group A (11 patients requiring dialysis) and group B (13 patients not requiring dialysis). The epidemiological and clinical data, as well as prognosis, were retrospectively investigated for each group. Approximately 90% of HUS patients belonged to the D + HUS group. In this group, the mean number of patients per year from 1987 to 1999, and from 2000 to 2012 was 0.92 ± 0.95, and 1.08 ± 0.86, respectively. On admission, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), blood urea nitrogen (BUN), serum creatinine and serum fibrinogen degradation product (FDP) levels in group A were all higher than in group B. Serum albumin level and estimated glomerular filtration rate (eGFR) in group A were lower than in group B. At 6 months after the onset of HUS in the D + HUS group, renal function was normal. The frequency of HUS was constant from 1987 to 2012 in Fukushima. and serum LDH, ALT, BUN, creatinine, and FDP levels as well as eGFR might be risk factors for dialysis in D + HUS children.

Oral administration of Shiga toxin-producing Escherichia coli induces intestinal and systemic specific immune response in mice

Hemolytic uremic syndrome (HUS) is the major complication of gastrointestinal infections with enterohemorrhagic Escherichia coli (EHEC) and is mediated by the production of Shiga toxins (Stx). Although it has been previously reported that not only HUS patients but healthy children have anti-Stx antibodies, very little is known about how these infections impact on mucosal immune system to generate a specific immune response. This work aimed to evaluate the immune responses elicited after a single oral dose of EHEC in a mouse model of HUS at weaning. We found sequential activation of T and B lymphocytes together with an increased percentage of IgA-bearing B cells in Peyer's patches and mesenteric lymph nodes. We also found fecal anti-EHEC IgA and serum anti-Stx2 IgG in EHEC-inoculated mice. Besides, these mice were partially protected against an intravenous challenge with Stx2. These data demonstrate that one episode of EHEC infection is enough to induce activation in the gut-associated lymphoid tissue, especially the B cell compartment, and lead to the production of specific IgA in mucosal tissue and the generation of systemic protection against Stx2 in a percentage of intragastrically inoculated mice. These data also support the epidemiologic observation that a second episode of HUS is very rare.

L-arginine/NO pathway is altered in children with haemolytic-uraemic syndrome (HUS).

The haemolytic uraemic syndrome (HUS) is the most frequent cause of acute renal failure in childhood. We investigated L-arginine/NO pathway in 12 children with typical HUS and 12 age-matched healthy control subjects. Nitrite and nitrate, the major NO metabolites in plasma and urine, asymmetric dimethylarginine (ADMA) in plasma and urine, and dimethylamine (DMA) in urine were determined by GC-MS and GC-MS/MS techniques. Urinary measurements were corrected for creatinine excretion. Plasma nitrate was significantly higher in HUS patients compared to healthy controls (P = 0.021), whereas urine nitrate was borderline lower in HUS patients compared to healthy controls (P = 0.24). ADMA plasma concentrations were insignificantly lower, but urine ADMA levels were significantly lower in the HUS patients (P = 0.019). Urinary DMA was not significantly elevated. In HUS patients, nitrate (R = 0.91) but not nitrite, L-arginine, or ADMA concentrations in plasma correlated with free haemoglobin concentration. Our results suggest that both NO production and ADMA synthesis are decreased in children with typical HUS. We hypothesize that in the circulation of children with HUS a vicious circle between the L-arginine/NO pathway and free haemoglobin-mediated oxidative stress exists. Disruption of this vicious circle by drugs that release NO and/or sulphydryl groups-containing drugs may offer new therapeutic options in HUS.

Novel Sequence Variation Affects GPIbα in Post-diarrheal Hemolytic Uremic Syndrome

Background: Hemolytic uremic syndrome (HUS) is one of the major causes of renal failure in children. In most cases the disease is caused by infection with Shiga toxin- producing Escherichia coli (STEC) and preceded by diarrhea. Only in 15% of cases STEC infection leads to HUS. Genetic predisposition of a patient to develop HUS after STEC infection might play a role, but very few reports on this subject are available. We describe a novel missense mutation in the GP1BA gene encoding platelet-receptor glycoprotein Ibα (GPIbα) in a severely affected HUS patient. Methods: GP1BA was screened by Sanger sequencing. Binding of recombinant GPIbα and von Willebrand factor (VWF) fragments was analyzed using surface plasmon resonance (SPR). The hematological studies using patient blood were performed. Results: The detected heterozygous mutation p.Pro46Leu is located in the proximity to one of the two GPIbα-VWF binding sites. SPR experiments show that the p.Pro46Leu leads to a small increase in GPIbα-VWF binding (p<0.001). The hemostatic parameters of patient blood after recovery from HUS show normal values. Conclusions: The described mutation affects GPIbα interaction with VWF in a mild gain-of-function manner and might have contributed to a prothrombotic state in the patient and to development of HUS.

Decreased sialylation of IgA1 O‐glycans associated with pneumococcal hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) in children is usually caused by Shiga-like toxin-producing Escherichia coli, but approximately 5% of cases are caused by invasive pneumococcal infection (P-HUS). Reported herein is the case of a 9-month-old HUS patient with pneumococcal meningitis who needed hemodialysis for 12 days. Decreased sialylation was characterized in both transferrin N-glycans and IgA1 O-glycans, analyzed in the acute phase on mass spectrometry, consistent with S. pneumonia-produced sialidases hydrolyzing both α2,3- and α2,6-linked sialic acids. The method will complement the T-antigen activation test and help to understand the molecular pathology related to P-HUS.

Evaluation Of Laboratory and Clinical Markers For Predicting Survival In TTP/HUS: A Single Center Retrospective Study

BackgroundThrombocytopenic thrombotic purpura (TTP) and hemolytic uremic syndrome (HUS) form a group of diseases distinguishable by the development of thrombotic microangiopathy. Both are life-threatening disorders classically described by a pentad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure and altered mental status. Early initiation of plasma exchange (PEX) is vital when TTP/HUS is suspected. However, diagnostic criteria are imprecise and clinical judgment remains the primary impetus for initiation of treatment. ADAMTS13 levels have not proven to be highly specific or sensitive for diagnosis of outcomes in TTP/HUS, and the delay in laboratory reporting limits its use in the acute setting. There may be other data available that more closely correlates with prognosis. The goal of this single institution retrospective study is to assess (i) the association of easily available clinical and laboratory factors with early death in patients with clinically diagnosed TTP/HUS, and (ii) the association of these factors among survivors with the length of stay (LOS) during the initial hospitalization with TTP/HUS. Design and methodsAfter IRB approval, medical record review of adult patients at a single tertiary medical center treated with plasma exchange (PEX) for presumed TTP/HUS between 1999 and May 2013 was performed. For the 62 discrete cases identified, demographic and clinical data was obtained from the medical center and pertinent information was collected. Descriptive analysis was used to evaluate clinical symptoms and laboratory biomarkers with respect to their associations with survival. Episodes of TTP/HUS in the same patient were considered discrete if they occurred greater than 3 months apart. Survival was defined by hospital discharge without readmission for TTP/HUS or their sequelae for 3 months following discharge. The association of demographic factors (age, gender), symptoms (fever, neurologic changes, abdominal pain), and laboratory factors (hemoglobin [Hb], white blood cell count [WBC], platelet count, acute kidney injury [AKI] based on creatinine, AST, ALT, lactate dehydrogenase (LDH), indirect bilirubin, prothrombin time (PT), partial thromboplastin time (PTT), reticulocyte count) with survival during the first 3 months was studied using univariate analysis. ADAMTS13 levels were not included in analysis as the decision to treat with PEX was made in all cases prior to knowledge of any deficiency. All factors that attained a p value of, <= 0.1 were analyzed collectively using logistic regression with backward model selection. For survivors (n=49), the association with length of stay was compared with each of the above factors and was similarly studied using univariate analysis and multiple linear regression. ResultsIn our sample (n=62), median age was 48 years and 26 (42%) were male. Of these, 79% (n=49) survived to discharge and did not have relapse or known death until 3 months afterwards. Thirteen (21%) died during hospitalization or within 3 months after discharge. There were 55 TTP and 7 HUS patients included in this retrospective cohort. Acute kidney injury (AKI) was diagnosed in 44 (71%) patients. On univariate analysis, factors associated with death included: AST (p=0.009) and AKI (p=0.045) with trends noted for hemoglobin (p=0.080) and PT (p=0.078). On multiple logistic regression, association with death was observed with AKI (OR: 0.093, 95% CI 0.009 – 0.950, p= 0.04) and hemoglobin (OR: 0.65, 95% CI 0.434 – 0.975, p=0.037). Among the 49 survivors (median age 45.1, range 12-81 years; 28 (57%) were female), correlation of the LOS in hospital with all variables was assessed. On linear regression analysis, elevated white blood cell count (WBC) (p=0.027) and prolonged prothrombin time (PT) (p=0.035) were independently associated with prolonged hospitalization. ConclusionClinical and laboratory markers found to have an independent association with death are AKI and low hemoglobin. It may be possible to risk stratify patients more accurately with clinical algorithms based on this evidence even before ADAMTS13 levels are available. Increased WBC count and prolonged PT are independently associated with increased length of stay. The application of our results could therefore be used for further risk stratification in prospective studies of outcomes in patients diagnosed with TTP/HUS. Disclosures:No relevant conflicts of interest to declare.

Time To Hematologic and Renal Improvements In Atypical Hemolytic Uremic Syndrome Patients With Long Disease Duration and Chronic Kidney Disease (CKD) Treated With Eculizumab

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening, chronic, and progressive disease of thrombotic microangiopathy (TMA). Plasma exchange/plasma infusion (PE/PI) has been shown to lack efficacy in patients (pts) with aHUS. Despite PE/PI, up to 65% of pts sustain permanent renal damage, progress to end-stage renal disease, or die within 1 year (yr) of diagnosis. Among aHUS pts with long disease duration and CKD receiving chronic PE/PI, significant improvements in hematologic parameters and renal function were achieved in a clinical trial of eculizumab (Ecu). The current analysis was undertaken to gain better insight into the timing of hematologic and renal improvements in a 26-week (wk), Phase 2 trial with a long-term extension. MethodsaHUS pts ≥12 yrs of age with long disease duration and CKD receiving chronic PE/PI were enrolled. This analysis assessed the percentage of pts achieving each of the following outcomes – all for ≥2 consecutive measurements, ≥4 wks apart – at specific time points: Platelet count normalization (≥150x109/L); LDH ≤ULN; serum creatinine (Cr) decrease ≥25%; eGFR increase ≥15 mL/min/1.73 m2; and CKD improvement ≥1 Stage. Results20 pts aged ≥12 yrs receiving long-term PE/PI were enrolled and treated with Ecu in a 26-wk, single-arm, Phase 2 trial, and 19 continued in the extension study. The median time (range) from aHUS diagnosis to screening was 48.3 months (0.7–285.8), and the median time from the current manifestation of aHUS to screening was 8.6 months (1.2–45). The median duration of Ecu treatment at the time of the data cut was 114 wks. Mean baseline values were as follows: platelet – 228x109/L; Hb – 10.7 g/L; LDH – 223 U/L; Cr – 287 μmol/L; and eGFR – 30.8 mL/min/1.73 m2. 3 pts had platelet counts <150 x109/L at baseline, and 4 had LDH levels >ULN.The timing and duration of the criteria-defined hematologic and renal improvements during continued treatment with Ecu are shown in Figure 1. At wk 4, the percentage of pts achieving platelet and LDH normalization was 75% and 50%, respectively (the first assessable time point based on the criteria definition). 90% of pts had platelet count normalization by wk 8, which was sustained with ongoing Ecu treatment for the remainder of the study period. 85% of pts had LDH ≤ULN by wk 8, which increased to 95% by wk 12 (Figure 1). With ongoing Ecu treatment, 10% of pts achieved Cr decrease (≥25%) at wk 14, and 55% by wk 80. eGFR increase (≥15 mL/min/1.73 m2) was first seen at wk 18 (by 5% of pts). This proportion increased to a maximum of 40% at wk 104 with ongoing Ecu treatment. CKD improvement (≥1 Stage) was seen at wk 4 by 5% of pts. This proportion increased to 60% at wk 76 with ongoing Ecu treatment (Figure 1). Significant mean changes from baseline in eGFR were observed as early as wk 4, and were followed by time-dependent improvements through the end of the study (Figure 2). All patients were able to discontinue PE/PI. [Display omitted] [Display omitted] ConclusionsThe use of Ecu in aHUS pts with long disease duration and CKD on long-term PE/PI led to sustained normalization of hematologic values within the first month of treatment, followed by time-dependent improvements in renal function. These data demonstrate that improvement in renal function may be achieved over time in pts with long-standing aHUS and CKD, and underscore the importance of ongoing and consistent treatment with Ecu. The underlying mechanism of the observed renal function improvement over the study period (e.g., normalization of endothelial cell function) warrants further exploration. Disclosures:No relevant conflicts of interest to declare.

Reduced expression of complement regulators CD55 and CD59 on peripheral blood cells is not involved in development of hemolytic uremic syndrome in patients with EHEC O104:H4 infection

Aims: An outbreak of Shiga Toxin 2 (Stx-2) producing enterohemorrhagic E.coli (EHEC) O104:H4 infection in May 2011 caused enterocolitis and an unprecedented high 22% rate of hemolytic uremic syndrome (HUS). The monoclonal anti-C5 antibody Eculizumab (ECU) has been used experimentally in EHEC patients with HUS but treatment efficacy is uncertain. ECU can effectively prevent hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) caused by a lack of complement-regulating CD55 and CD59 on blood cells. We hypothesized a low expression of CD55 and CD59, as seen in atypical HUS in PNH, might correlate with HUS development in EHEC patients.

Standardisation of the factor H autoantibody assay

The screening of all atypical haemolytic uraemic syndrome (aHUS) patients for factor H autoantibodies is best practice. However, there is no consensus assay for the reporting of factor H autoantibody titres. In this study, three European complement laboratories with expertise in the field of autoantibody testing address this by systematically evaluating several ELISA methods used for the detection of factor H autoantibodies. All methods tested adequately detect high titre samples. However, this study recommends the Paris method for the detection and reporting of factor H autoantibodies to be used when setting up a factor H autoantibody screen. The importance of individual sample background subtraction in these ELISA tests was established. The use of a relative or arbitrary unit index with a common positive and negative serum allowed for consistent comparison of findings from different test centres. Therefore, it is recommended that a standard arbitrary unit scale based on a titration curve from a common positive anti-serum be adopted to allow future establishment of the relative importance of particular titres of factor H autoantibodies in aHUS. Systematic assay for the presence of factor H autoantibodies in patients using the Paris method will provide the longitudinal analysis needed to fully establish the importance of factor H autoantibodies in disease. This will feed into additional research to clarify whether additional factors have a bearing on the phenotype/outcome of autoimmune aHUS.

Standardisation of the factor H autoantibody assay

The screening of all atypical haemolytic uraemic syndrome (aHUS) patients for factor H autoantibodies is best practice. However, there is no consensus assay for the reporting of factor H autoantibody titres. In this study, three European complement laboratories with expertise in the field of autoantibody testing address this by systematically evaluating several ELISA methods used for the detection of factor H autoantibodies.All methods tested adequately detect high titre samples. However, this study recommends the Paris method for the detection and reporting of factor H autoantibodies to be used when setting up a factor H autoantibody screen. The importance of individual sample background subtraction in these ELISA tests was established. The use of a relative or arbitrary unit index with a common positive and negative serum allowed for consistent comparison of findings from different test centres. Therefore, it is recommended that a standard arbitrary unit scale based on a titration curve from a common positive anti-serum be adopted to allow future establishment of the relative importance of particular titres of factor H autoantibodies in aHUS.Systematic assay for the presence of factor H autoantibodies in patients using the Paris method will provide the longitudinal analysis needed to fully establish the importance of factor H autoantibodies in disease. This will feed into additional research to clarify whether additional factors have a bearing on the phenotype/outcome of autoimmune aHUS.

Quantitative MRI shows cerebral microstructural damage in hemolytic–uremic syndrome patients with severe neurological symptoms but no changes in conventional MRI

Severe neurological symptoms in Shiga toxin-producing Escherichia coli infection associated hemolytic-uremic syndrome (STEC-HUS) are often accompanied by none or only mild alterations of cerebral magnetic resonance imaging (MRI). This study aims to analyze if quantitative MRI is able to reveal cerebral pathological alterations invisible for conventional MRI. In nine patients with STEC-HUS associated severe neurological symptoms but inconspicuous cerebral MRI findings maps of the parameters T2 relaxation time, relative proton density (PD), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were generated. Quantitative values of these parameters were measured at the basal ganglia, thalamus, and white matter of the frontal and parietal lobe and compared to those of nine age- and sex-matched controls. Significant T2 prolongation (p < 0.01) was found in the basal ganglia of all patients compared to controls. PD and ADC were not significantly altered. A significant reduction of FA in patients was seen at caput nuclei caudati (p < 0.01). Prolonged T2 relaxation time indicates cerebral microstructural damages in these patients despite their inconspicuous MRI findings. T2 relaxometry could be used as a complementary tool for the assessment of metabolic-toxic brain syndromes.

Investigation of Encephalopathy Caused by Shiga Toxin 2c-Producing Escherichia coli Infection in Mice

A large outbreak of Shiga toxin (Stx)-producing enteroaggregative Escherichia coli (EAEC) O104:H4 occurred in northern Germany. From this outbreak, at least 900 patients developed hemolytic uremic syndrome (HUS), resulting in more than 50 deaths. Thirty percent of the HUS patients showed encephalopathy. We previously established a mouse model with encephalopathy associated with blood brain barrier (BBB) damage after oral infection with the Shiga toxin (Stx) 2c-producing Escherichia coli O157: H- strain E32511 (E32511). In this model, we detected high expression of the Stx receptor synthase enzyme, glycosphingolipid globotriaosylceramide (Gb3) synthase, in endothelial cells (ECs) and neurons in the reticular formation of the medulla oblongata by in situ hybridization. Caspase-3 was activated in neurons in the reticular formation of the medulla oblongata and the anterior horn of the spinal cord. Astrocytes (ASTs) were activated in the medulla oblongata and spinal cord, and a decrease in aquaporin 4 around the ECs suggested that BBB integrity was compromised directly by Stx2c or through the activation of ASTs. We also report the effectiveness of azithromycin (AZM) in our model. Moreover, AZM strongly inhibited the release of Stx2c from E32511 in vitro.

Impact of graft loss among kidney diseases with a high risk of post-transplant recurrence in the paediatric population

Some kidney diseases tend to recur in the renal allograft after transplantation. We studied the risk of graft loss among primary renal diseases known for their high risk of recurrence and compared it with that of patients with hypoplasia and/or dysplasia. Within the European Society of Paediatric Nephrology and European Renal Association and European Dialysis and Transplant Association (ESPN/ERA-EDTA) registry, we studied children from 33 countries who received a kidney transplant before the age of 20 between 1990 and 2009. Patients were censored after 5 years of follow-up and cumulative incidence competing risk analysis was used to calculate survival curves. Patients with focal and segmental glomerulosclerosis (FSGS), haemolytic uraemic syndrome (HUS), membranoproliferative glomerulonephritis Type I or II (MPGN), IgA nephropathy or Henoch Schönlein Purpura (HSP/IgA) or systemic lupus erythomatosus (SLE) underwent pre-emptive transplantation significantly less often than patients with hypoplasia and/or dysplasia. The rate of living donation was lower among patients with FSGS and SLE than in patients with hypoplasia and/or dysplasia. In comparison with hypoplasia and/or dysplasia patients with a risk of 14.4%, the 5-year risk of graft loss was significantly increased in patients with FSGS (25.7%) and MPGN (32.4%) while it was not significantly increased in children with HUS (18.9%), HSP/IgA (16.3%) or SLE (20.3%). One-year graft survival strongly improved among HUS patients from 17.1% in 1995-1999 to 3.6% in 2005-2009 and was not accompanied by a decrease in the number of transplantations. The risk of graft loss is increased among specific causes of renal failure with a high risk of post-transplant recurrence. It seems likely that, due to anticipation of such risk, physicians perform less pre-emptive transplantation and provide fewer grafts from living related donors in patients with these conditions. Improved risk stratification by physicians, resulting in the identification of patients with HUS at higher or lower risk of recurrence, might explain the much improved graft survival rates.

Ciprofloxacin reduces the risk of hemolytic uremic syndrome in patients with Escherichia coli O104:H4-associated diarrhea

Whether antibiotic treatment in patients with enterohemorrhagic Escherichia coli (EHEC)-associated diarrhea influences the risk of hemolytic uremic syndrome (HUS) has still to be elucidated. During the EHEC epidemic which occurred in northern Germany in spring 2011, 24 patients with E. coli O104:H4 infection were treated at our hospitals, 19 of whom developed HUS. The use of antibiotics before and after the onset of HUS was documented, and the outcome in patients with and without antibiotic treatment was evaluated. Of the 24 patients with EHEC-associated diarrhea, seven received antibiotics before any signs of HUS were present (ciprofloxacin, cefotaxime, amoxicillin and/or metronidazole). Four of these seven patients (57 %) and 15 of the 17 patients (88 %) who were treated without antibiotics developed HUS (p = 0.12). Microbiological testing showed all E. coli O104:H4 to be extended-spectrum beta lactamase producers and thus susceptible only to fluoroquinolones, aminoglycosides and carbapenems. Two of the five patients (40 %) treated with ciprofloxacin and 17 of the 19 patients (89 %) treated without ciprofloxacin developed HUS (p = 0.043). In our E. coli O104:H4-infected patients, treatment of diarrhea with antibiotics did not increase the risk of HUS. Significantly fewer patients treated with ciprofloxacin developed HUS than patients who did not receive ciprofloxacin.

End-stage kidney disease due to haemolytic uraemic syndrome – outcomes in 241 consecutive ANZDATA registry cases

BackgroundThe aim of this study was to investigate the characteristics and outcomes of patients receiving renal replacement therapy for end-stage kidney disease (ESKD) secondary to haemolytic uraemic syndrome (HUS).MethodsThe study included all patients with ESKD who commenced renal replacement therapy in Australia and New Zealand between 15/5/1963 and 31/12/2010, using data from the ANZDATA Registry. HUS ESKD patients were compared with matched controls with an alternative primary renal disease using propensity scores based on age, gender and treatment era.ResultsOf the 58422 patients included in the study, 241 (0.4%) had ESKD secondary to HUS. HUS ESKD was independently associated with younger age, female gender and European race. Compared with matched controls, HUS ESKD was not associated with mortality on renal replacement therapy (adjusted hazard ratio [HR] 1.14, 95% CI 0.87-1.50, p = 0.34) or dialysis (HR 1.34, 95% CI 0.93-1.93, p = 0.12), but did independently predict recovery of renal function (HR 54.01, 95% CI 1.45-11.1, p = 0.008). 130 (54%) HUS patients received 166 renal allografts. Overall renal allograft survival rates were significantly lower for patients with HUS ESKD at 1 year (73% vs 91%), 5 years (62% vs 85%) and 10 years (49% vs 73%). HUS ESKD was an independent predictor of renal allograft failure (HR 2.59, 95% CI 1.70-3.95, p < 0.001). Sixteen (12%) HUS patients experienced failure of 22 renal allografts due to recurrent HUS. HUS ESKD was not independently associated with the risk of death following renal transplantation (HR 0.92, 95% CI 0.35-2.44, p = 0.87).ConclusionsHUS is an uncommon cause of ESKD, which is associated with comparable patient survival on dialysis, an increased probability of renal function recovery, comparable patient survival post-renal transplant and a heightened risk of renal transplant graft failure compared with matched ESKD controls.

Eculizumab Is an Effective Treatment for Atypical Hemolytic Uremic Syndrome in Patients with or without Identified Genetic Complement Mutations or Complement Factor H Auto-Antibodies.

AbstractAbstract 2085 Introduction:Atypical hemolytic uremic syndrome (aHUS) is a rare chronic disorder characterized by persistent uncontrolled complement activation that results in life-threatening systemic thrombotic microangiopathy (TMA). In an estimated 50%–70% of patients (pts) with aHUS, uncontrolled complement activation can be attributed to identified genetic mutation(s) in complement regulatory factors and/or the presence of complement factor H auto-antibodies (CFH auto-Abs); newly identified complement mutations continue to be reported in the medical literature. For the 30%–50% of pts who currently have no identified genetic mutation/CFH auto-Abs, the overall risk of end-stage renal disease or death is high and similar to that observed in pts with known genetic mutation(s)/CFH auto-Abs, supporting the need for immediate management of disease in all aHUS pts regardless of mutation/CFH auto-Ab status. Eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, is the only approved treatment for aHUS. Chronic eculizumab treatment has been proven to inhibit systemic TMA via terminal complement inhibition, improve renal function, and reduce or eliminate the need for plasma exchange/infusion (PE/PI) and dialysis. Furthermore, earlier eculizumab treatment has been associated with greater clinical improvement. The purpose of this analysis was to evaluate the relative efficacy of eculizumab in aHUS pts with or without identified genetic complement mutation(s)/CFH auto-Abs based on data from 3 clinical studies. Methods:This report summarizes a subgroup analysis of efficacy outcomes based on the presence or absence of identified genetic mutation(s)/CFH auto-Abs in 3 aHUS studies: 2 controlled, prospective studies (pts aged ≥12 y), and 1 retrospective study (pts aged <18 y). Results:Across the 3 studies, 24%–41% of pts had no identified genetic complement mutation or detectable CFH auto-Abs. The efficacy of eculizumab was similar regardless of mutation/CFH auto-Ab status (Table). Conclusions:Across 3 studies investigating the efficacy of eculizumab treatment in aHUS pts, our analysis shows that improvements in hematologic, renal, and supportive care interventions (PE/PI, dialysis) outcomes were similar in pts with or without identified genetic complement mutation(s)/CFH auto-Abs. Given that (1) genetic testing often requires several months to complete, (2) uncontrolled complement activation places aHUS pts at risk of life-threatening systemic TMA events and organ damage, and (3) earlier intervention with eculizumab is associated with greater clinical improvement, we conclude that the results of this analysis provide a rationale for initiating eculizumab as first-line therapy at the time of clinical diagnosis of aHUS, without the availability of genetic testing resultsTableEfficacy of eculizumab in pts with or without an identified genetic complement mutation and/or CFH auto-AbsParameterPts with Long Duration of Disease (Median Eculizumab Duration 114 Weeks) (N=20)Pts with Progressing TMA (Median Eculizumab Duration 100 Weeks) (N=17)Pediatric Pts (Retrospective Study)a (N=17)Identified mutationb n=13No identified mutationc n=7Identified mutationb n=13No identified mutation n=4I entified mutation n=10No identified mutation n=7TMA event-free status,d n (%)13 (100)6 (86)12 (92)3 (75)7 (70)5 (71)Platelet count ≥150×109/L, n (%)12 (92)6 (86)12 (92)3 (75)10 (100)6 (86)Hematological normalization,f n (%)12 (92)6 (86)12 (92)3 (75)4 (40)3 (43)Serum creatinine decrease ≥25%, n (%)7 (54)4 (57)11 (85)2 (50)4 (40)4 (57)eGFR increase ≥15 mL/min/1.73 m2, n (%)5 (38)3 (43)8 (62)2 (50)5 (50)3 (43)eGFR increase, mL/min/1.73 m2, mean (SE)8.0 (2.1)g2.0 (9.5)37.7 (10.0)35.7 (20.0)eNANAeGFR, estimated glomerular filtration rate; NA, not available; SE, standard error.aVariable follow-up duration.bIdentified genetic mutations includes CFH auto-Abs.cA pt with a CFHR1-3 deletion has been included under no identified mutation for this analysis.dNo decrease in platelet count of >25%, no PE/PI, and no new dialysis ≥12 consecutive weeks.eData from pt who discontinued after 1 dose due to an exclusion criteria is not included.fPlatelet count ≥150×109/L and lactate dehydrogenase ≤ upper limit of normal for ≥4 weeks.gFor the 1 pt receiving transplant during study, post-transplant data are excluded. Disclosures:Goodship:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.