Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome.

BACKGROUND AND OBJECTIVES: This study evaluated the relevance of complement factor H (CFH)-related protein (CFHR) 1 deficiency in pediatric patients with atypical hemolytic uremic syndrome (aHUS) by evaluating both the frequency of deletions in CFHR1 and the presence of complement factor H (CFH) antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 116 patients (mainly from central Europe) and 118 healthy blood donors were included from 2001 to 2012. The presence of CFHR1 gene deletions was determined in 90 pediatric patients with aHUS and 118 controls by an easy, fast, and cheap PCR assay; 100 patients with aHUS and 42 controls were tested for CFH antibodies by ELISA. Questionnaires were administered to evaluate the clinical and laboratory data. RESULTS: Homozygous deletion in CFHR1 was detected in 32% of the patients with aHUS tested, compared with 2.5% of controls (P<0.001). CFH antibodies were present in 25% of the patients and none of the controls. CFH antibodies were detected in 82% of patients with homozygous CFHR1 gene deletion and in 6% of patients without. CFH antibody-positive patients with aHUS showed a significantly lower platelet nadir at disease onset and significantly less frequent involvement of the central nervous system than did antibody-negative patients. Antibody-positive patients also received plasma therapy more often. CONCLUSION: Homozygous deletion in CFHR1 is strongly associated with occurrence of CFH antibodies in pediatric patients with aHUS. However, despite this apparent genetic disease predisposition, it cannot be considered an exclusive cause for aHUS. Initial presentation of Shiga toxin-negative HUS with severe thrombocytopenia and no central nervous system complications in pediatric patients is especially suspicious for CFH antibody aHUS.

Lyme neuroborreliosis: aetiology and diagnosis of facial palsy in children from Tyrol.

BACKGROUND: Lyme neuroborreliosis (LNB) is the second most common manifestation of Borrelia burgdorferi sensu lato (s. l.) infection in Europe. LNB is difficult to differentiate from other aetiologies of aseptic meningitis. Diagnostic criteria for LNB in children are not established. Therfore, based on the epidemiology of LNB in children from Tyrol, the aim of our study was to point out the necessity of a clear definition of pediatric LNB to avoid underdiagnosis and overtreatment. PATIENTS AND METHODS: All medical charts of patients presented with acute peripheral facial palsy from January 2002 to December 2005 were reviewed. The patients were rediagnosed according to the criteria of the German Society of Neurology (DGN). RESULTS: We identified 66 patients with peripheral facial palsy. 30 children were handled as B. burgdorferi s. l. infection. 5 patients were overtreated with antibiotic therapy. After reevaluation according to the DGN criteria 7 cases were reclassified as possible, 16 cases as probable and 7 cases as confirmed LNB. CONCLUSIONS: Utilization of the established DGN criteria for pediatric LNB might help to elucidate the propability of LNB. Prospective studies are required to establish a classification system. A diagnostic tool, based on laboratory and clinical data, should avoid overtreatment of pediatric LNB.

Inhibitor treatment by rituximab in congenital haemophilia A - Two case reports.

UNLABELLED: The development of neutralizing alloantibodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. CONCLUSION: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

Successful treatment of severe juvenile microscopic polyangiitis with rituximab.

Microscopic polyangiitis (MPA) previously called hypersensitivity angiitis is a systemic necrotizing vasculitis affecting predominantly small vessels. MPA involves multiple organ systems including the lung, the kidneys, the joints, and the skin. MPA mostly affects adults in their fourth and fifth decade of life. MPA and Wegener;s granulomatosis are grouped together as ANCA-associated vasculitis. MPA is associated with high titre of myeloperoxidase antineutrophil cytoplasmic antibodies (MPO)-ANCA. We present a 14-year-old female patient presented with MPA. She was treated with steroids and cyclophosphamide. After the complication of severe lung involvement, rituximab was administered as immune-modulating treatment. The MPA came to remission. This is the first report of a pediatric patient with MPA treated with rituximab. Rituximab might be a potential therapeutic option for relapsing ANCA associated vasculitis in childhood.

Successful implantation of a cochlear implant in a four-yr-old boy after kidney transplantation: a case report.

Sensorineural hearing loss is common in children with chronic renal insufficiency. The implantation of a CI is performed routinely in children with profound sensorineural hearing loss. A feared complication is a local infection with subsequent meningitis. Because of this risk, a successful implantation of a CI in children under immunosuppression after kidney transplantation has yet to be described. A four-yr-old boy with congenital renal dysplasia and posterior urethral valves, who was successfully transplanted with a kidney from his father at the age of two and a half yr, is presented. The boy had profound bilateral hearing loss before transplantation, most likely due to ototoxic antibiotic medication and long-term furosemide use. A hearing aid was insufficient; therefore, a CI was performed 20 months after the transplantation and no complications occurred in the 24 months of follow-up. This is the first report of a successful CI in a child after kidney transplantation.

CTX-M-1-related extended-spectrum beta-lactamases producing Escherichia coli: so far a sporadic event in Western Austria.

BACKGROUND: The present study was aimed to searching for CTX-M-type extended-spectrum beta-lactamases in community- and hospital-acquired Escherichia coli (E. coli) collected in western Austria and to investigate their clonal relatedness and their ability to spread. PATIENTS AND METHODS: All patients with E. coli positive cultures collected from a catchment population of 186,000 between January and July 2006 were enrolled into the study. CTX-M-producing E. coli were identified by antibiotic susceptibility testing and blaCTX-M multiplex PCR. Clonal relatedness was analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: In 2,042 E. coli isolates, 20 isolates (16 from urine, 4 from blood cultures) demonstrated CTX-M-1-related genes and no CTX-M-2- or CTX-M-9-related enzymes or CTX-M-15-producing strains were identified. We did not find clonal relatedness among CTX-M-1 producers isolated from the same referring center. E. coli were investigated for plasmid transfer ability of CTX-M-1-encoding genes. Plasmid digest patterns were not consistent with episomal spread of resistance loci. Transfection of CTX-M-encoding plasmids failed. CONCLUSION: Our data suggest that the emergence of CTX-M-1-producing E. coli in western Austria may be attributed to multiple independent events.

Demand for evaluation of vaccination antibody titers in children considered for renal transplantation.

Vaccinations are recommended for achieving protection against vaccine-preventable infections in solid-organ transplant recipients. In order to evaluate the protection at the time of renal transplantation, the antibody titers against measles, mumps, rubella, varicella, hepatitis B, diphtheria, and tetanus were determined in 35 children one month prior to transplantation. Only 26% of patients on dialysis listed for transplantation showed protective antibodies against all tested pathogens. Particularly, low protection was found for hepatitis B. Children younger than four yr showed significantly lower protective antibody titers compared with older children for almost all vaccines. Children who completed vaccination in the last six months to six yr prior to renal transplantation showed higher rates of protective antibody titers against all pathogens compared with children who had vaccination more than six yr before transplantation. Preventive strategies in children with chronic renal failure include repeated measurements of serum antibodies and appropriate revaccination if titers decline. Our results underline the demand for continuous surveillance of specific antibody titers against vaccine-preventable diseases in the risk group of renal transplant recipients.

Mycophenolate mofetil (Cellcept) in pediatric renal transplantation.

Mycophenolate mofetil (MMF) was introduced in pediatric renal transplantation almost 10 years ago. In several pediatric studies, MMF has been associated with improved graft survival and improved renal function with standard immunosuppression of steroids and calcineurin inhibitors (CNI). Both drugs are associated with significant negative effects including influence on growth, blood pressure, glucose metabolism, and also cosmetic side effects. Reduction of CNI was possible with MMF without increased rejection, improving blood pressure and renal function. Information is accumulating that steroid-sparing protocols including CNI are also associated with clinical improvement. Recent reports are positive in the pediatric population using the combination of induction with interleukin-2-receptor antagonists and mTOR inhibitors to spare steroids and CNI. Therefore MMF remains a mainstay of immunosuppressive protocols in the pediatric renal transplantation.

[Surveillance of infectious foodborne diseases after enactment of the German Protection against Infection Act in 2001. Potentials and requirements]. / Surveillance Lebensmittel-übertragener Infektionserkrankungen durch das Infektionsschutzgesetz: Möglichkeiten und Anforderungen.

The epidemiology of infectious foodborne diseases has changed. Outbreaks more frequently occur geographically dispersed or protractedly over longer periods of time, and they often appear as a scatter of seemingly sporadic cases. This hampers and delays the identification of their epidemiological link. The surveillance of infectious foodborne diseases has to be refined accordingly to be able to detect these diffuse outbreaks. The German Protection against Infection Act, enacted in 2001, offers the potential of increased sensitivity due to timely electronic reporting of individual cases and detailed data accompanying each report. In addition to a timely and comprehensive reporting system, subtyping of pathogens has become an invaluable tool in identifying epidemiologically linked cases, i.e. outbreaks. Still, the sensitivity of foodborne disease surveillance still hinges on the willingness of physicians to order stool testing for enteric pathogens (and to report suspected outbreaks to local health departments). Without the active participation of physicians, the chance of detecting outbreaks and successfully investigating them is markedly reduced. Consequently, the general preventive strategy would be jeopardised, namely to understand the (often new) mechanisms by which contamination and disease transmission occur well enough to interrupt them.

Bilateral renal vein thrombosis in a twin newborn without known risk factors.

Neonatal renal vein thrombosis (RVT) is associated with neonatal stress, catheters and genetic prothrombotic risk factors. In an unusual case of bilateral RVT a twin newborn showed initial good adaptation at birth (weight 2,720 g). The placenta was monochorionic, diamnionic. The infant (gestational week 37) exhibited a severe macrohematuria within 24 hours after birth. Sonography of the kidneys showed a dense cortical parenchyma, loss of cortico-medullary differentiation and negative diastolic flow in both renal arteries and veins, while no thrombus in the main renal veins could be detected. No prothrombotic blood parameters and positive infection serology were detected. Because of acute renal failure peritoneal dialysis was necessary for 6 weeks. The patient was treated by heparinization for 5 days. Interestingly, it was kidney biopsy which confirmed the diagnosis of RVT in addition to the clinical presentation, whereas sonography was unspecific. Histology exhibited the picture of an ischemic contracted kidney with numerous siderophages. At present (age 19 months), the patient suffers from chronic renal failure (calculated glomerular filtration rate according to Schwartz 12 ml/min/1.73 m2). In conclusion, our case teaches that, despite the lack of a clinically obvious shock event, absence of known risk factors and indirect ultrasound findings, renal vein thrombosis should be considered in a macrohematuric newborn with renal failure. For clinical suspicion of RVT correct therapy was initiated, however, the diagnosis remained unclear until a renal biopsy was performed.

A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

[Sclerosing peritonitis without reduced ultrafiltration as complication of peritoneal dialysis]. / Sklerosierende Peritonitis als Komplikation bei Peritonealdialyse.

UNLABELLED: Peritoneal dialysis (PD) is the preferred method of renal replacement therapy in childhood and adolescence while waiting for a kidney transplant. As major complication, encapsulating peritoneal sclerosis (EPS), sometimes also referred to as "sclerosing peritonitis", may develop after prolonged periods of PD and lead to severe therapeutical problems. CASE REPORT: A 20-year-old patient with a history of three unsuccessful kidney transplants due to recurrence of his focal segmental glomerulosclerosis presented after 9 years of PD with acute abdominal pain and reduced bowel movements. Infectious peritonitis was excluded, ultrafiltration with 800-1 000 ml per day with low (1,36 %) glucose dialysate was not impaired. Plain abdominal X-ray, ultrasound and CT-scan illustrated characteristic peritoneal calcifications. Diagnosis of EPS was confirmed by peritoneal biopsy. The patients was switched to hemodialysis, enteral nutrition was continued, and the follow-up (now 16 months) was uncomplicated with the exception of a sterile ascites, which was twice relieved. Diagnostic and therapeutic options are discussed. CONCLUSION: In contrast to most reports, EPS may develop with unchanged ultrafiltration after prolonged periods of PD. We recommend regular functional and imaging studies in patients at risk.

Simultaneous voiding cystourethrography and voiding urosonography.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced voiding urosonography (VUS) and voiding cystourethrography (VCUG) during simultaneous performance of both examinations. MATERIAL AND METHODS: A total of 24 children, 16 girls and 8 boys, with a mean age of 3.5 years referred for reflux examination were recruited for the study. After transurethral bladder catheterization, radiographic contrast medium, followed directly by the US contrast medium, were administered. Fluoroscopic VCUG and VUS were carried out concurrently in the same patient. When 1 kidney was scanned by ultrasound, fluoroscopy was performed on the contralateral side. RESULTS: In 19 of the 47 kidney-ureter-units (KUU) vesicoureteral reflux (VUR) was detected. In 16 units the reflux was detected by both VCUG and VUS. In 3 KUUs the reflux was detected only at VCUG. All 3 cases were grade 1. Taking the VCUG as the reference standard, VUS had 84% sensitivity, 100% specificity, 100% and 90% positive and negative predictive values, respectively. CONCLUSION: A dependable comparison could be achieved by performing VCUG and VUS at the same time and under the same conditions. It reconfirmed that VUS is reliable in the exclusion or verification of reflux.

Function of von Willebrand factor in children with diarrhea-associated hemolytic-uremic syndrome (D+ HUS).

Reports on von Willebrand factor (vWF) in hemolytic-uremic syndrome (HUS) are not unequivocal. Because of potential pathogenic implications, we examined the ability of vWF to bind to collagen in vitro, which reflects its function. Plasma vWF antigen (vWF:Ag) and collagen-binding activity (vWF:CBA) were measured by enzyme-linked immunosorbent assay in children with (1) diarrhea-associated (D+) HUS (n = 27), (2) chronic renal insufficiency (CRI) (n = 8), (3) gastroenteritis (GE) not associated with HUS (n = 15), (4) immune thrombocytopenia (ITP) (n = 40) and from controls (n = 35). Structural vWF was evaluated by multimer analysis. Children with D+ HUS had vWF:Ag of 2.53 and vWF:CBA of 1.98 U/mL. The corresponding values for patients with ITP were 1.35 and 1.82 U/mL, with CRI 1.55 and 1.55 U/mL, and with GE 1.68 and 2.10 U/mL; all values were higher than in controls (1.04 and 1.16 U/mL). The mean ratio of vWF:CBA to vWF:Ag ratio in controls was 1.13; only children with HUS had a dysfunctional vWF, as indicated by a low ratio of 0.78; the ratio was elevated in children with ITP (1.36) and GE (1.27) and was normal in those with CRI (1.06). No ultralarge molecular multimers of vWF were detected in any group, including HUS. The very high concentration of plasma vWF:Ag in HUS probably reflects endothelial cell damage or irritation. In contrast to all other groups, only children with HUS had a dysfunctional vWF, caused either by a primary (due to enterohemorrhagic Escherichia coli) or secondary (due to consumption of functionally active vWF) process. This abnormality was not obvious as structural anomaly by multimer analysis.

Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group.

BACKGROUND: Acute rejection episodes (ARE) of kidney transplants are considered as risk factor in the development of chronic rejection. In adult renal transplantation (RTx), ARE have been significantly reduced by mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) and steroids (Pred). Reports of pediatric RTx on a maintenance immunosuppression with MMF are restricted to patients (P) after antibody induction therapy. METHODS: The efficacy and safety of MMF combined with CyA and Pred in pediatric RTx without induction therapy were evaluated in an open-labeled multicenter study. RESULTS: From 10/1996 to 6/1999, 65 pediatric P (MMF group) were followed for at least 6 months, 58 of 65 for 12 months. These P were compared with 54 retrospectively analyzed pediatric P who were transplanted between 1990 and 1996 and had received CyA, Pred, and azathioprine for immunosuppression (historic AZA group). Within the first 6 months after RTx, 18 of 65 (MMF group) and 32 of 54 (historic AZA group) P showed clinical signs of acute rejection (P<0.01). Thereafter only one further P in the MMF group developed a first ARE. Graft loss due to rejection occurred in one MMF- and seven AZA-treated P (P<0.05). The creatinine-clearance 3 and 6 months after RTx was higher in the MMF group. Major adverse events (MMF group) included infections of the urinary and the upper respiratory tract, diarrhea, and leukopenia. Cytomegalovirus-infection occurred in 13 P and 2 P developed cytomegalovirus disease. One P developed PTLD 10 months after RTx and recovered after the reduction of immunosuppression. CONCLUSIONS: The combination of MMF, CyA, and Pred reduced ARE in pediatric RTx without incurring major side effects.

Renal function in long-term survivors of stem cell transplantation in childhood. A prospective trial.

The aim of this prospective study was to assess glomerular and tubular renal function before, and 1 and 2 years after hematological stem cell therapy (HSCT) in children and adolescents. 137 consecutive patients undergoing HSCT, for malignant diseases, were included in a prospective trial. Forty-four patients were followed for up to 1 year after HSCT and 36 for up to 2 years, without relapse. Ninety healthy school children were used as a control group. The following parameters were investigated: inulin clearance (GFR), urinary excretion of albumin, alpha1-microglobulin (alpha1-MG), calcium, beta-N-acetylglucosaminidase (beta-NAG) and Tamm-Horsfall protein (THP), tubular phosphate reabsorption (TP/Cl(cr)) and percent reabsorption of amino acids (TAA). Significantly lower GFR was found 1 and 2 years after HSCT but within the normal range in the period before HSCT. There was no correlation between GFR within the first month after HSCT and long-term outcome of GFR. Tubular dysfunction was found in 14-45% of patients 1 and 2 years after HSCT depending on the parameter investigated. Pathological values 1 and 2 years after HSCT were found for alpha1-MG excretion in 40% and 39%, respectively, for TP/Cl(cr) in 44% and 45%, for beta-NAG in 26% and 19%. Median TP/Cl(cr) was significantly lower 2 years after HSCT than before. TAA was mildly impaired in 7/14 patients before, in 5/29 one and in 9/29 2 years after HSCT, but median TAA was within normal range at all times. The median excretion of albumin, THP and calcium was within the normal range at all investigations. No influence of ifosfamide pre-treatment on the severity of tubulopathy was found. The investigation of tubular renal function should be part of a long-term follow-up in children after HSCT.