Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.

SummaryBackground and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of ESRD in children, but the proportion of patients with individual CAKUT entities progressing to ESRD during adulthood and their long-term clinical outcomes are unknown. This study assessed the age at onset of renal replacement therapy (RRT) and patient and renal graft survival in patients with CAKUT across the entire age range.Design, setting, participants, & measurements Patients with CAKUT were compared with age-matched patients who were undergoing RRT for other renal disorders on the basis of data from the European Renal AssociationEuropean Dialysis and Transplant Association Registry. Competing risk and Cox regression analyses were conducted.Results Of 212,930 patients commencing RRT from 1990 to 2009, 4765 (2.2%) had renal diagnoses consistent with CAKUT. The proportion of incident RRT patients with CAKUT decreased from infancy to childhood and then increased until age 15-19 years, followed by a gradual decline throughout adulthood. Median age at RRT start was 31 years in the CAKUT cohort and 61 years in the non-CAKUT cohort (P,0.001). RRT was started earlier (median, 16 years) in patients with isolated renal dysplasia than in those with renal hypoplasia and associated urinary tract disorders (median, 29.5-39.5 years). Patients with CAKUT survived longer than age-and sex-matched non-CAKUT controls because of lower cardiovascular mortality (10-year survival rate, 76.4% versus 70.7%; P,0.001).Conclusions CAKUT leads to ESRD more often at adult than pediatric age. Treatment outcomes differ from those of acquired kidney diseases and vary within CAKUT subcategories.

Considerable variation exists in the current demographics of children treated with RRT across Europe.

Background CMV infections are common after solid organ transplantation (SOT). Valganciclovir (v-GCV) is increasingly used in children. The aim of the present study was to evaluate presently used dosing algorithms. Methods Data from 104 pediatric SOT recipients (kidney, liver and heart) aged 0.3–16.9 years and receiving v-GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a ganciclovir AUC 40-60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. Results Ganciclovir pharmacokinetics was well described by the non-parametric model. Clearance was dependent on GFR and Cockcroft-Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v-GCV dose is: weight [kg]*(0.07*GFR [mL/min]+k), where k=5 for GFR≤30 mL/min, k=10 for GFR>30 mL/min and weight>30 kg and k=15 for GFR>30 mL/min and weight≤30 kg, outperformed the other algorithms. Thirty-three percent of all patients achieve an exposure above and 21% within the therapeutic window. Conclusion We propose a simple algorithm for initial v-GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window.

Neisseria meningitidis causes meningitis, fulminant septicemia or mild meningococcemia attacking mainly children and young adults. Lipopolysaccharides (LPS) consist of a symmetrical hexa-acyl lipid A and a short oligosaccharide chain and are classified in 11 immunotypes. Lipid A is the primary toxic component of N. meningitidis. LPS levels in plasma and cerebrospinal fluid as determined by Limulus amebocyte lysate (LAL) assay are quantitatively closely associated with inflammatory mediators, clinical symptoms, and outcome. Patients with persistent septic shock, multiple organ failure, and severe coagulopathy reveal extraordinarily high levels of LPS in plasma. The cytokine production is compartmentalized to either the circulation or to the subarachnoid space. Mortality related to shock increases from 0% to > 80% with a 10-fold increase of plasma LPS from 10 to 100 endotoxin units/ml. Hemorrhagic skin lesions and thrombosis are caused by up-regulation of tissue factor which induces coagulation, and by inhibition of fibrinolysis by plasminogen activator inhibitor 1 (PAI-1). Effective antibiotic treatment results in a rapid decline of plasma LPS (half-life 1-3 h) and cytokines, and reduced generation of thrombin, and PAI-1. Early antibiotic treatment is mandatory. Three intervention trials to block lipid A have not significantly reduced the mortality of meningococcal septicemia.

Our objective was to assess the mental health and health-related quality of life (HRQOL) in children and their parents after renal transplantation (TX) compared to healthy controls and children with acute lymphoblastic leukemia (ALL) and to identify possible health status variables associated with impaired mental health and HRQOL. Thirty-eight TX children with a median age of 13 (range 3–19) years were investigated. Mental health was assessed by the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and the Strength and Difficulties Questionnaire (SDQ-20). Each mother’s own mental health and QOL were assessed by the General Health Questionnaire (GHQ-30) and the Quality of Life Scale (QOLS). Forty children with ALL [median age 11 (8.5–15.4) years] and 42 healthy children [median age 11 (8.9– 15) years] served as controls. Treadmill exercise results from 22 of the 38 patients were included in the analysis. TX children showed significantly higher levels of mental health problems and lower HRQOL at 2 to 16 years after transplantation compared to both control groups. Body mass index and maximal oxygen uptake (n = 22/38) were significant predictors of child mental health (SDQ) and child QOL (PedsQL), respectively. Based on these results, we suggest that rehabilitation after TX should include a focus on physical activity and QOL to reduce interconnected physical and psychological morbidity in kidney TX children.

Despite a widespread preconception that HD should be reserved for cases in which PD is not feasible, in Europe, we found 1 in 8 infants in need of maintenance dialysis to be initiated on HD therapy. Patient characteristics at dialysis therapy initiation, prospective survival, and time to transplantation were very similar for infants initiated on PD or HD therapy.

Chemokines are important in regulating leukocyte traffic during infection. We analyzed plasma chemokine levels of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha , interleukin (IL)-8, and RANTES in patients with meningococcal infection and correlated these to plasma lipopolysaccharide (LPS) levels, which are closely associated with clinical presentation. In patients with fulminant meningococcal septicemia, versus distinct meningitis or mild systemic meningococcal disease, MCP-1 (both P<.0001), MIP-1 alpha (both P<.0001), and IL-8 (P<.0001 and P=.011) were significantly higher and RANTES significantly lower (P=.007 and P=.021). MCP-1 (r=.88), MIP-1 alpha (r=.82), and IL-8 (r=.89) were positively correlated to plasma LPS levels, whereas RANTES was negatively correlated (r=-.49). In an ex vivo whole-blood model, heat-inactivated wild-type Neisseria meningitidis, purified meningococcal LPS, and (to a negligible extent) heat-inactivated LPS-deficient mutant N. meningitidis induced these chemokines. N. meningitidis LPS is the major cause of chemokine release in meningococcal disease.