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Background The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Methods Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, [alpha]FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Results Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. Conclusions In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well., Author(s): Dineke Westra[sup.1] , Elena B. Volokhina[sup.1] , Renate G. van der Molen[sup.2] , Thea J. A. M. van der Velden[sup.1] , Annelies Jeronimus-Klaasen[sup.1] , Joop Goertz[sup.2] , Valentina Gracchi[sup.3] [...]

Background The hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy leading to acute kidney injury in children. In most cases it is triggered by an infection caused by Shiga-like toxin-producing Escherichia coli (STEC). Endothelial damage plays a central role in the pathogenesis of disease. Hemophilia A is a genetic disorder leading to factor VIII (FVIII) deficiency, an important factor in the coagulation system. Case Here we describe a hemophilia A patient who developed HUS due to a STEC O26 infection. The patient developed not only acute kidney injury, but also severe gastrointestinal and neurological complications. Increased amounts of recombinant FVIII (rFVIII) had to be administered during the acute phase of the disease to reach acceptable blood levels of FVIII, in order to control the hemorrhagic colitis and to prevent severe neurological complications. Conclusion The patient's treatment schedule of rFVIII during the HUS period was a serious challenge, and we cannot exclude that it contributed to the severity of the HUS by enhancing the thrombotic microangiopathic process. The role of factor VIII administration in the severe outcome of this disease is discussed. Keywords Factor VIII * Hemolytic uremic syndrome * Hemophilia * Neurological complications * STEC O26, Introduction The hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA), is one of the most common causes of acute kidney injury in children between 2 and 5 years of age [...]

Background Mutations in complement factor H (CFH), factor I(CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H ([alpha]FH) with or without a homozygous deletion in CFH-related protein 1 and 3 ([DELTA]CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS). Methods Different mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome. Results In 47% of the study participants, potentially pathogenic genetic anomalies were found (5 x CFH,4 x MCP, and 4 x C3, 3 x CFI, 2 x CFB,6 x [alpha]FH, of which five had [DELTA]CFHR1/ 3); four patients carried combined genetic defects or a mutation, together with [alpha]FH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant. Conclusions Performing adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options. Keywords Atypical HUS * Complement regulation * Plasma therapy * Dialysis * Transplantation. Clinical outcome, Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure secondary to thrombotic microangiopathy [1]. It is distinguished from typical or [...]

Reliable reference values of enzymatically assayed serum creatinine categorized in small age intervals are lacking in young children. The aim of this study was to determine reference values for serum creatinine during the first year of life and study the influence of gender, weight and height on these values. Serum creatinine determinations between 2003 and 2008 were retrieved from the hospital database. Strict exclusion criteria ensured the selection of patients without kidney damage. Correlation analysis was performed to evaluate the relation between height, weight and serum creatinine; the Mann-Whitney test was used to evaluate the relation between gender and serum creatinine. A broken stick model was designed to predict normal serum creatinine values. Mean serum creatinine values were found to decrease rapidly from 55 [micro]mol/L on day 1 to 22 [micro]mol/L in the second month of life; they then stabilized at 20 [micro]mol/L until the seventh month, followed by a slight increase. No significant relation was found between serum creatinine and gender, weight and height. We present here reference values of serum creatinine in infants not at risk of decreased renal function. The absence of a relationship with gender, weight and height confirms that height-based equations to estimate glomerular filtration rate are less useful in patients of this age group. Keywords Creatinine * Enzymatic * Infants * Reference values, Introduction Screening for renal disease or monitoring of renal function should be based on an adequate estimation of the glomerular filtration rate (GFR). The most commonly used marker to estimate [...]

Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. Methods: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. Results: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m2 at last follow-up. Conclusions: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. [ABSTRACT FROM AUTHOR]

Background Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease with frequent progression to end-stage renal disease and a high recurrence after kidney transplantation. Eculizumab, a humanized monoclonal antibody that binds to complement protein C5, may be beneficial in the treatment of aHUS. Case-diagnosis/treatment A 6-year-old girl developed aHUS with only slightly elevated C3d (4.4%), no mutations in complement factors, and no antibodies against factor H. Plasma exchange treatment was successful initially, until aHUS recurred. After reinitiating plasma exchange, normalization of the platelet count and improvement of hemolysis occurred, but renal function worsened. Renal function then improved dramatically promptly after the switch to eculizumab. Conclusions This case demonstrates that platelet count is not always a reliable marker for improvement of aHUS and that eculizumab can prevent dialysis in plasma-resistant aHUS patients. Keywords Eculizumab. Atypical hemolytic uremic syndrome. Acute kidney failure. Child, Introduction Hemolytic uremic syndrome (HUS) is a severe disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. In children, over 90% of HUS is caused [...]