Antonia H. Bouts

Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy

Sirs, n nSpurred by the reported spectacular results of eculizumab treatment in atypical hemolytic uremic syndrome (aHUS) due to aberrations in the complement system, an increasing number of children will receive this treatment in future. The main adverse effect of this therapy is an increased susceptibility to meningococcal infection due to inhibition of the complement system’s membrane-attack complex. In patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab, the reported occurrence of meningococcal infection is between 0% and 1.5% [1–3]. These data, concerning adult patients, cannot be extrapolated to children because the age-specific incidence of meningococcal disease is much higher in children. n nAccording to the medication guide of the U.S. Food and Drug Administration, a tetravalent unconjugated polysaccharide vaccine (serogroups A, C, Y, W135) has to be provided at least 2 weeks before the first dose of eculizumab. In our opinion, this approach is not sufficient for prevention in many countries, because none of the available vaccines contains a serogroup B antigen [4]. The serogroup distribution among meningococcal infections in The Netherlands is presented in Fig.xa01. Since June 2002, a conjugated vaccine against serogroup C has been included in the national immunization program. In 2009, 84% of isolates belonged to serogroup B, 7% to serogroup C, and the remaining to other serogroups, such as X, Y, and W135 [5]. Thus, the advised vaccination only offers limited protection. The peak incidence of serogroup B meningococcal disease is in children younger than 5xa0years and between the age of 15 to 19xa0years. Based on the risk of meningococcal infection in children treated with eculizumab and the high prevalence of serogroup B disease that cannot yet be prevented by vaccination, penicillin prophylaxis should not only be considered [6] but strongly advised to patients. Beside this, vaccination with a conjugated vaccine might give better protection than the unconjugated polysaccharide vaccine [7]. Serogroup B prevalence is highest not only in The Netherlands but in the rest of Europe and other parts of the world [8]. The best strategy depends on the distribution of meningococcal serogroups and the availability of vaccines in different countries [9]. n n n nFig.xa01 n nDistribution of meningococcal serogroups 1959–2009 (adapted from Netherlands Reference Laboratory for Bacterial Meningitis, used with permission)

Renal Dysfunction and Elevated Blood Pressure in Long-Term Childhood Cancer Survivors

BACKGROUND AND OBJECTIVESnLittle is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnEstimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors ≥5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes.nnnRESULTSnAt a median age of 19.3 years (interquartile range, 15.6-24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8-17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR <90 ml/min per 1.73 m(2). Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4-21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63-9.19), as did male sex, higher body mass index, and longer time since cancer treatment.nnnCONCLUSIONnAlmost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage.

Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome

Patients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein (CD46) are known to have a better prognosis than those with mutations in factor H (CFH) or factor I (CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4xa0years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutation.

Intra-patient variability in tacrolimus trough concentrations and renal function decline in pediatric renal transplant recipients.

Prytula AA, Bouts AH, Mathot RAA, van Gelder T, Croes LK, Hop W, Cransberg K. Intra‐patient variability in tacrolimus trough concentrations and renal function decline in pediatric renal transplant recipients.

High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques. Methods and results We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlexHS (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24–31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4s mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients. Conclusions Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlexHS provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUNDnThe low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children.nnnMETHODSnWe surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010.nnnRESULTSnData on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available.nnnCONCLUSIONSnHealth care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Cytomegalovirus prophylaxis in pediatric kidney transplantation: The Dutch experience

Many children receiving a kidney transplant are seronegative for CMV and therefore, highly susceptible to a primary CMV infection. This study aims at evaluating incidence, time of occurrence, and severity of CMV infection in the first year post‐transplantation in relation to different types of CMV prophylaxis. Transplantations in three centers in the Netherlands between 1999 and 2010 were included. Retrospective, observational, multicenter study. Clinical data and PCR measurements of CMV were collected. Prophylaxis in high‐risk patients (CMV serostatus D+R−) consisted of (val)ganciclovir during three months, or acyclovir plus CMV immunoglobulin at a former stage. Intermediate‐risk patients (R+) received (val)acyclovir, or acyclovir plus CMV immunoglobulin at a former stage. Low‐risk patients (D−R−) did not receive prophylaxis. Infection was defined as CMV PCR above 50 geq/mL plasma or whole blood, a clinically relevant infection above 1000 geq/mL. One hundred and fifty‐nine transplantations were included. CMV infection was documented for 41% of high‐risk, 24% of intermediate‐risk, and 13% of low‐risk patients, in the latter two groups typically during the first three months. The infection rate was highest in the high‐risk group after cessation of valganciclovir prophylaxis. Valganciclovir provided better protection than did acyclovir + CMV immunoglobulin. Adding an IL2‐receptor blocker to the immunosuppressive regimen did not affect the infection rate. Acute graft rejection was not related with CMV infection. Valganciclovir prophylaxis effectively prevents CMV infection in high‐risk pediatric kidney recipients, but only during prophylaxis. Valacyclovir prophylaxis in intermediate‐risk patients is less effective.

Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children

BACKGROUNDnIn the Netherlands and Belgium, an increasing number of children who have end-stage renal disease (ESRD) are of non-Western origin. We analysed renal transplantation practices and outcome for immigrant ESRD children as compared to native children in both countries.nnnMETHODSnAll Dutch and Belgian children aged <19 years who received their first renal transplantation between 1 September 2007 and 1 January 2011 were included. Therapy characteristics and outcomes were registered prospectively on a 3-monthly basis. Immigrants were defined as children of whom one or both parents had been born outside Western European countries. Multivariable Cox regression analysis was used to quantify the hazard ratio for acute rejection.nnnRESULTSnOne hundred and nineteen first renal transplant recipients were included, of which 41 (34%) were immigrants. Median [range] follow-up time of transplantation was 18 [2-28] months. Compared to native children, immigrants had pre-emptive transplantations (15 versus 32%, P = 0.040) and transplantations with a kidney from a living donor less often (24 versus 59%, P < 0.001). Survival analysis in 96 children with at least 3 months of follow-up showed an increased risk for acute rejection in immigrants adjusted for donor source, duration of dialysis and number of HLA mismatches on the DR locus [hazard ratio (95% confidence interval) 2.5 (1.1-5.9)].nnnCONCLUSIONSnImmigrant children receive fewer pre-emptive and living donor transplantations compared to native children. After transplantation, immigrant children are at higher risk for acute rejection irrespective of the mode of transplantation.

Prevention of large-vessel stenoses in atypical hemolytic uremic syndrome associated with complement dysregulation

Sirs, n nThe oldest of three sisters, two of whom are monozygous twins, presenting all with atypical hemolytic uremic syndrome (aHUS) associated with a CFH mutation, was referred at the age of 3xa0years to the Emma Children’s Hospital/Academic Medical Centre of Amsterdam (Fig.xa01) [1, 2]. She never recovered renal function and commenced peritoneal dialysis. Bilateral nephrectomy was performed 1 year later because of hypertension. She lost two transplants by recurrence, one immediately posttransplantation and the other one 2xa0months posttransplant despite preventive plasma exchanges (PEs) contemporary to frequency reduction of PE. From the age of 15xa0years, she began to experience transient sensory and motor symptoms on both sides of her body associated with low blood pressure (BP) during hemodialysis. Magnetic resonance angiogram (MRA) showed severe stenoses of both middle and both anterior cerebral arteries (Fig.xa02a) (partial report in [3]). She did not present any additional risk factors for developing arteriosclerosis (such as long-duration hypertension, diabetes, uncontrolled hyperparathyroidism). No arterial calcification and no left ventricular hypertrophy were shown. n n n nFig.xa01 n nClinical course in patient and her twin sisters n n n n n nFig.xa02 n nThree-Tesla magnetic resonance images (MRIs) of patient 2 (a, b) and her sister (c). Coronal 3D time-of flight (TOF) MRA maximum intensity projection (MIP) (a) image of patient at the age of 15 years demonstrates (near) occlusion of the M1 segment of ... n n n nAt the age of 17xa0years, the patient was transplanted for the third time under pre- and postoperative prophylactic PEs [1, 2]. Postoperatively, she developed infarcts in the right frontal and frontoparietal regions (Fig.xa02b). She recovered almost completely. Ten months after transplantation, the child developed bronchospasm and hypotension during PE. For this reason, she was switched to eculizumab [2]. Under this treatment, she presented no HUS recurrence, and renal function remained stable (plasma creatinine 120xa0μmol/L) 16xa0months after PE discontinuation. The first of her twin sisters (twin 1) developed aHUS at the age of 5.3xa0years. She required chronic dialysis despite initial daily PE for 10xa0days and three intermittent courses of fresh frozen plasma (FFP) infusions. Two years later, she received a cadaver renal transplant under PE prophylaxis. At 7.5xa0years follow-up, the graft function is satisfactory (serum creatinine 137xa0μmol). The second twin (twin 2) presented aHUS at the age of 5.8xa0years (Fig.xa01) [1]. She was treated immediately with daily PE and, following remission, with one PE every 2xa0weeks to this time. At 9.5xa0years after HUS onset, native renal function (serum creatinine 49xa0μmol/L) was normal. MRA showed normal cerebral vasculature in both twins at age 14 years (Fig.xa02c). Contrary to their older sister with cerebral artery stenoses who was treated by prophylactic PE for 2xa0months only, the twin sisters received prophylactic PE without interruption for, respectively, 7.5 (twin 1) and 9xa0(twin 2) years. n nAlthough brain ischemia sometimes resulting in cerebral infarct is observed in aHUS, stenosis of large vessels has been reported in aHUS only once—in a child presenting with a Lys350Asp gain of function CFB mutation [4]. Of note, this patient, as ours, was dialyzed for long periods from the age of 4xa0months. At the age of 10xa0years, she started having episodes of bilateral hemiparesis during hemodialysis in relation with multiple stenoses of cerebral arteries. Stenoses of large arteries have never been reported as a complication of renal replacement therapy (RRT) in children [5]. Chronic continuous complement dysregulation might contribute to vascular lesions. Indeed complement activation occurs both in human and experimental atherosclerosis, and the deposition of C5b-9 correlates with disease state [6]. n nOur patient and the patient reported recently by Loirat et al. [4] suggest that aHUS with complement dysregulation, a disease of microvascularization, may also involve large arteries, especially when patients have to face long periods of dialysis when plasma therapy is not used. The latter reports also raise the question of preventing vascular lesions by avoiding complement system disorders. This emphasizes the importance of including patients at an early stage in specific programs of kidney transplantation using preventive plasma therapy or combined liver transplantation. Inhibition of the complement system by anti-C5 antibody that is actually under investigation might be valuable for this purpose in the future [2].

The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients

BackgroundThe aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1xa0year after renal transplantation and simulate individualised dosage regimens.Patients and methodsWe included 54 children with median age of 11.1xa0years (range 3.8–18.4xa0years) with 120 pharmacokinetic profiles performed over 2 to 4xa0h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM®). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C→T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated.ResultsA two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (Pxa0<xa00.05) and γ-glutamyl transpeptidase (γGT) (Pxa0<xa00.001) and was increased by 45xa0% in carriers of the CYP3A5*1 allele (Pxa0<xa00.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2xa0mg/kg generates a pre-dose concentration (C0) ranging from 5 to 10xa0µg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration–time curve (AUC) corresponding with a tacrolimus C0 of 4–8xa0µg/L was 97xa0h·µg/L (interquartile range 80–120).ConclusionsIn patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.