Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up. SectionsUnanswered questions and research agenda Conclusions

Acute kidney injury (AKI) is a common and serious complication in patients in the Pediatric Intensive Care Unit (PICU). We conducted this study to estimate the incidence and the mortality rate of AKI in critically ill children as well as to describe some other related factors. A retrospective study was conducted at PICU of Queen Rania Abdulla Children Hospital, Amman, Jordan for the period extending from May 2011 to June 2013. The medical records of all patients admitted during this period, and their demographic data were reviewed. Patients with AKI were identified, and management and outcomes were reviewed and analyzed. AKI was evaluated according to modified RIFLE criteria. Of the 372 patients admitted to PICU, 64 (17.2%) patients developed AKI. Of these 64 patients who had AKI, 28 (43.7%) patients reached RIFLE max of risk, 21 (32.8%) patients reached injury, and 15 (23.4%) reached failure. Mean Pediatric Risk of Mortality II score at admission was significantly higher in patients with AKI than those without P <0.001. The age ranged between one month and 14 years with the median age as 5.4 year. Thirty-five (54.7%) were males. Sepsis was the most common cause of AKI. The mortality rate in critically ill children without AKI was 58.7%, whereas increased in children with AKI to 73.4%. The mortality rate in patients who received renal replacement therapy was 71.4% and was higher (81.5%) in patients who received mechanical ventilation (95%, [confidence interval (CI)] 79.3-83.4%) and was significantly higher in patients with multi-organ system dysfunction 90.3% (95%, [CI] 88.7-92.5%). The incidence of AKI in critically ill children is high and increased their mortality rate and higher mortality seen in the younger age group, especially those below one year. High mortality rate was associated with multi-organ system dysfunction and the need for mechanical ventilation.

Background Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney‐transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non‐invasive alternative compared with plasma. Methods A population physiologically based pharmacokinetic (Pop‐PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney‐transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC‐MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. Results The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop‐PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop‐PBPK predicted and observed) and MPA (Pop‐PBPK predicted). Conclusion Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney‐transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop‐PBPK model.

Aims: The aim of this study was, to use a multiple methods approach, including, for the first time, dried blood spot (DBS) sampling with population pharmacokinetic interpretation, to assess adherence to mycophenolate in children with kidney transplant. A second aim was to identify patient/parental factors that influenced adherence and to link adherence behaviour to clinical outcomes.Methods: A convenience sample of 33 children with kidney transplant (age ≤ 18 years) who had been prescribed mycophenolate for at least 3 months were recruited from participating outpatient clinics in the UK and Jordan. Medication adherence was determined via self-report questionnaires, medication refill data from dispensing records, and via mycophenolic acid concentrations in plasma and DBS samples obtained from children during a clinic visit.Results: Through triangulation of results from the different methodological approaches a total of 12 children (36.4%) were deemed to be nonadherent with their prescribed mycophenolate treatment. Logistic regression analysis indicated that nonadherence was significantly associated with the presence of mycophenolate side effects. Poor adherence was positively linked to measures of poor clinical outcomes (hospitalisation and the need for kidney biopsy).Conclusions: Despite the imperative regarding medication adherence to help prevent organ rejection, a significant proportion of children are not fully adherent with their therapy. Side-effects appear to be an important factor leading to nonadherence.Measurement of mycophenolate in DBS samples, coupled with the use of population pharmacokinetics modelling, was a convenient direct approach to assessing adherence in children with kidney transplant and has the potential to be introduced into routine practice. KEYWORDS adherence, dried blood spot, kidney transplant, mycophenolic acid The clinical responsibility for patients throughout the study lay with their hospital doctors and their individual general practitioners. Dr Reham Almardini acted as local PI in Queen Rania Hospital for Children, Amman while Dr Karl McKeever acted as local PI in the Royal Belfast Hospital for Sick Children.

Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.