The efficacy and safety of a fixed-dose combination of apocynin and paeonol, APPA, in symptomatic knee OA: A double-blind, randomized, placebo-controlled, clinical trial.

OBJECTIVE: Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA). METHODS: A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2-3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period. APPA 800 mg or matching placebo was administered twice daily in a 1:1 ratio. Post-hoc analyses explored the response to APPA in sub-groups with more severe pain and structural severity. RESULTS: The two groups were comparable at baseline; 152 subjects were enrolled and 148 completed the trial. There was no statistically significant difference between groups with respect to the primary outcome, WOMAC pain (mean difference between groups was -0.89, 95% CI: -5.62, 3.84, p = 0.71), nor WOMAC function or WOMAC total. However, predefined subgroup analyses of subjects with symptoms compatible with nociplastic/neuropathic pain features showed a statistically significant effect of APPA compared to placebo. Adverse events (mainly gastrointestinal) were mild to moderate. CONCLUSION: Treatment with APPA 800 mg twice daily for 28 days in subjects with symptomatic knee OA was not associated with significant symptom improvement compared to placebo. The treatment was well-tolerated and safe. While the study was not powered for such analysis, pre-planned subgroup analyses showed a significant effect of APPA in subjects with nociplastic pain/severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted.

Hypertension and Cardiovascular Risk Among Children with Chronic Kidney Disease.

PURPOSE OF REVIEW: Cardiovascular disease is the most common cause of mortality across the lifespan of children with chronic kidney disease (CKD). Hypertension is a common and important contributor, but other factors such as obesity, dyslipidemia and mineral bone disease play a role. This narrative review focusses on studies published in the past five years that have investigated hypertension and cardiovascular risk among children with CKD. RECENT FINDINGS: Cohort studies such as Chronic Kidney Disease in Children (CKiD) and Cardiovascular Comorbidity in Children with CKD (4C) have continued to develop our understanding of blood pressure (BP) phenotypes, and of progressive changes in the structure and function of the heart and blood vessels occurring in children with CKD. Metabolic risk factors, such as dyslipidemia, may represent an under-recognized component of care. Trial data are less common than observational evidence, but support lifestyle interventions currently used, mainly the low sodium dietary approaches to stop hypertension (DASH) diet. The findings of the recently reported Hypertension Optimal Treatment in Children with Chronic Kidney Disease trial (HOT-KID) are described in relation to the use of office BP treatment targets. Cardiovascular health is critical to the long-term outcomes of children with CKD. Recognizing and treating hypertension remains a critical component to improving outcomes, along with measures to improve concurrent cardiovascular risk factors. Some cardiovascular changes may not be reversible with transplantation and further research is needed for children at all stages of CKD.

Baseline characteristics of participants in the NAVKIDS2 trial: a patient navigator program in children with chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing health services through care coordination. This trial aims to determine the effectiveness of a patient navigator program in children with CKD. METHODS: The NAVKIDS2 trial is a multi-center, waitlisted, randomized controlled trial of patient navigators in children with CKD conducted at five sites across Australia. Children (0-16 years) with CKD from low socioeconomic status rural or remote areas were randomized to an intervention group or a waitlisted control group (to receive intervention after 6 months). The study primary and secondary endpoints include the self-rated health (SRH) (primary), and utility-based quality of life, progression of kidney dysfunction of the child, SRH, and satisfaction with healthcare of the caregiver at 6 months post-randomization. RESULTS: The trial completed recruitment in October 2021 with expected completion of follow-up by October 2022. There were 162 patients enrolled with 80 and 82 patients randomized to the immediate intervention and waitlisted groups, respectively. Fifty-eight (36%) participants were from regional/remote areas, with a median (IQR) age of 9.5 (5.0, 13.0) years, 46% were of European Australian ethnicity, and 65% were male. A total of 109 children (67%) had CKD stages 1-5, 42 (26%) were transplant recipients, and 11 (7%) were receiving dialysis. CONCLUSION: The NAVKIDS2 trial is designed to evaluate the effectiveness of patient navigation in children with CKD from families experiencing socioeconomic disadvantage. A higher resolution version of the Graphical abstract is available as Supplementary information.

Childhood Systemic Lupus Erythematosus: Presentation, management and long-term outcomes in an Australian cohort.

OBJECTIVES: Systemic Lupus Erythematosus (SLE) is a serious autoimmune disease often resulting in major end-organ damage and increased mortality. Currently, no data exists focussing on the presentation, long-term management and progression of SLE in the Australian paediatric population. We conducted the first Australian longitudinal review of childhood SLE, focussing on response to treatment and outcomes. METHODS: Detailed clinical and laboratory data of 42 children diagnosed with SLE before 16 years from 1998 to 2018 resident in Western Australia was collected. Data was collected at diagnosis and key clinical review time points and compared using the Systemic Lupus Collaborating Clinics (SLICC) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria. End organ damage was assessed against Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Incidence rates of disease complications and end organ damage were determined. RESULTS: Of the 42 children, 88% were female with average age at diagnosis of 12.5 years. Indigenous Australians were over represented with an incidence rate 18-fold higher than non-Indigenous, although most children were Caucasian, reflecting the demographics of the Australian population. Median duration of follow-up was 4.25 years. On final review, 28.6% had developed cumulative organ damage as described by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (incidence rate: 0.08/PY (95% CI 0.04-0.14)), and one child died. Twenty-nine children had renal involvement (incidence rate: 0.38/PY (95% CI 0.26-0.56)). Of the 27 patients with biopsy proven lupus nephritis, 70% had Class III or IV disease. Average length of prednisolone use from diagnosis was 32.5 months. Hydroxychloroquine (n = 36) and mycophenolate mofetil (n =21) were the most widely used steroid sparing agents. 61.9% received rituximab and/or cyclophosphamide. CONCLUSION: This is the first longitudinal retrospective review of Australian children with SLE, with a markedly higher incidence in Indigenous children. Although improving, rates of end organ complications remain high, similar to international cohort outcomes. Longitudinal multi-centre research is crucial to elucidate risk factors for poor outcomes, and identifying those warranting early more aggressive therapy.

Urinary tract infections in children: building a causal model-based decision support tool for diagnosis with domain knowledge and prospective data.

BACKGROUND: Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. METHODS: We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with clinical domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. RESULTS: We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting Escherichia coli culture results, with a mean area under the receiver operating characteristic curve of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. CONCLUSION: Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation.

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38-2.95] compared to eGFR of 30-60 ml/min/1.73 m2; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62-0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

Impact of initial steroid response on transplant outcomes in children with steroid-resistant nephrotic syndrome.

BACKGROUND: Limited data suggest children with secondary steroid-resistant nephrotic syndrome (secondary SRNS) have increased risk of recurrence post transplantation. There are no data on the association between secondary steroid resistance and risk of transplant loss. METHODS: Children who received kidney transplantation between 2000 and 2019 for either primary or secondary SRNS in Australia and New Zealand were included. Children presenting with nephrotic syndrome before 12 months were excluded. Data were gathered from chart reviews and ANZDATA. Transplant survival was estimated using the Kaplan-Meier estimator with Cox modelling used to explore predictors of survival. RESULTS: There were seventy children, 38 (55%) male, median age at presentation 4 years (IQR 2-7) and 46 (66%) Caucasian. Median age at transplant was 11 years (IQR 7-15) and 39 (55%) received living donor transplant. Secondary SRNS occurred in 20/70 (29%). For those with secondary SRNS, 18/20 (90%) had recurrence post-transplant, compared to 18/50 (36%) with primary SRNS (p = 0.001). Every child with history of atopy (n = 11) or with hypoalbuminaemia at time of transplant (n = 13) experienced immediate recurrence. For children with secondary SRNS, 8/18 (44%) with post-transplant recurrence had no response to therapy. For children with primary SRNS, 4/18 (22%) with recurrence had no response to therapy (p = 0.3). Overall, 10-year transplant survival was 47% (95%CI 29-77%) for those with secondary SRNS, compared to 71 (95%CI 57-88%) for those with primary SRNS (p = 0.05). CONCLUSIONS: Secondary steroid resistance is strongly associated with SRNS recurrence. Atopy and hypoalbuminaemia at transplant may be novel risk factors for recurrence. Further research is needed to assess if secondary steroid resistance is associated with poorer transplant outcomes. "A higher resolution version of the Graphical abstract is available as Supplementary information".

Oral agents for acute severe hypertension in children with minimal or no symptoms.

Acute hypertension is common among children admitted to hospital, and large or rapid increases in blood pressure place children at risk of complications such as posterior reversible encephalopathy syndrome. Guidelines in the United States and Europe now include definitions guiding the identification of acute severe hypertension (otherwise known as hypertensive crisis) and its management. This review discusses these recommendations and the appropriate use of oral antihypertensive agents for children with minimal or no symptoms. We focus on the role of oral calcium channel blockers, including isradipine (a second-generation dihydropyridine), given recent changes to regulatory approvals in Australia. The differing pharmacokinetic and pharmacodynamic properties of agents are compared, with the aim of facilitating directed drug selection and dosing.

Paediatric deceased donor kidney transplant in Australia: A 30-year review-What have paediatric bonuses achieved and where to from here?

BACKGROUND: In this 30-year national review, we describe trends in DD transplantation for paediatric recipients, assess the impact of paediatric allocation bonuses and identify outstanding areas of need for this population. METHODS: A retrospective review of all DD kidney only transplants to paediatric recipients (<18 years old) in Australia between 1989 and 2018 was conducted using deidentified extracts from the ANZDATA. RESULTS: Of the 1011 kidney only transplants performed in paediatric recipients during the study period, 426 (42%) were from deceased donors. Paediatric candidates on the DD waiting list had consistently higher rates of transplantation and shorter time from dialysis initiation to transplantation compared with adult candidates (median 372 vs 832 days in 2018, for example). Donor characteristics remained more favourable for paediatric recipients, despite a decline in the overall quality of the donor pool. The mean number of HLA antigen mismatches for paediatric recipients of DD transplants increased each decade (2.86 [1989-1998], 3.85 [1999-2008], 4.01 [2009-2018]). Both patient and graft survival have improved for paediatric DD transplant recipients in the most recent era (5-year graft and patient survival 85% vs 65% and 99% vs 94%, respectively, for 2009-2018 vs 1999-2008). CONCLUSIONS: The current DD kidney allocation system in Australia provides rapid access to high-quality organs for paediatric recipients, and early graft loss has decreased significantly in recent years; however, additional targeted interventions to address HLA matching may improve long-term outcomes in this population.

Survival and transplant outcomes among young children requiring kidney replacement therapy.

BACKGROUND: Young children starting kidney replacement therapy (KRT) suffer high disease burden with unique impacts on growth and development, timing of transplantation and long-term survival. Contemporary long-term outcome data and how these relate to patient characteristics are necessary for shared decision-making with families, to identify modifiable risk factors and inform future research. METHODS: We examined outcomes of all children ≤ 5 years enrolled in the Australia and New Zealand Dialysis and Transplant Registry, commencing KRT 1980-2017. Primary outcomes were patient and graft survival. Final height attained was also examined. We used generalized additive modelling to investigate the relationship between age and graft loss over time post-transplant. RESULTS: In total, 388 children were included, of whom 322 (83%) received a kidney transplant. Cumulative 1-, 5- and 10-year patient survival probabilities were 93%, 86% and 83%, respectively. Death censored graft survival at 1, 5 and 10 years was 93%, 87% and 77%, respectively. Most children were at least 10 kg at transplantation (n = 302; 96%). A non-linear relationship between age at transplantation and graft loss was observed, dependent on time post-transplant, with increased risk of graft loss among youngest recipients both initially following transplantation and subsequently during adolescence. Graft and patient survival have improved in recent era. CONCLUSIONS: Young children commencing KRT have good long-term survival and graft outcomes. Early graft loss is no reason to postpone transplantation beyond 10 kg, and among even the youngest recipients, late graft loss risk in adolescence remains one of the greatest barriers to improving long-term outcomes.

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.

Baseline characteristics of patients with atypical haemolytic uraemic syndrome (aHUS): The Australian cohort in a global aHUS registry.

AIMS: To describe the baseline characteristics and treatment of Australian patients diagnosed with atypical haemolytic uraemic syndrome (aHUS) reported to the Global aHUS Registry. METHODS: Descriptive analysis of the Australian cohort with aHUS (n = 106) was undertaken for demographics, disease characteristics and prior treatment with eculizumab; comparing with the global cohort (n = 1688) for certain pre-specified disease characteristics. RESULTS: In Australia, almost two-thirds of patients diagnosed with aHUS were female and over 80% of patients were Caucasians, with similar proportions reported in the global cohort. Less than 6% of patients in the Australia and global cohorts were reported to have a history of autoimmune disease (4% vs 2%, respectively; P = .21) or cancer (5% vs 5%, respectively; P = .93), conditions that have been associated with secondary HUS. In the Australian cohort, 26% had received a kidney transplant and 68% of patients had received eculizumab. Kidneys were the most common organ involvement, followed by gastrointestinal tract (26%) and cardiovascular system (19%), with 35% of patients reported to have had at least two organs involved within 6 months prior to baseline visit or entry into the registry. Complement factor H was the most common pathogenic complement gene variant in the Australian patients. CONCLUSION: Data from the aHUS registry confirms and defines region-specific disease characteristics among a selected group of Australian children and adults with aHUS reported to the registry. Ongoing and more inclusive data will provide further information about temporal trends and treatment outcomes, representing a unique opportunity for clinicians and researchers to further develop knowledge surrounding this rare disease.

Allograft outcome following repeat transplantation of patients with non-adherence-related first kidney allograft failure: a population cohort study.

Nonadherence is an important risk factor for premature allograft failure after kidney transplantation, but outcomes after re-transplantation remain uncertain. Using data from the Australian and New Zealand Dialysis and Transplant registry, the associations between causes of first allograft failure and acute rejection-related and non-adherence-related allograft failure following re-transplantation were examined using competing risk analyses, treating the respective alternative causes of allograft failure and death with functioning graft as competing events. Fifty-nine of 2450 patients (2%) lost their first allografts from nonadherence. Patients who lost their first kidney allograft from nonadherence were younger at the time of first kidney allograft failure but waited longer for a second allograft (>5 years: 54% vs. 20%, P < 0.001) compared with other causes. Compared with patients who lost their first allograft from causes other than nonadherence, the adjusted subdistribution hazard ratio (HR and 95% CI) for acute rejection-related second allograft failure was 0.58 (0.08, 4.07; P = 0.582) for patients with allograft failure attributed to nonadherence and was 6.30 (1.34, 29.67; P = 0.020) for non-adherence-related second allograft failure. In this cohort of transplant recipients who have received second allografts, first allograft failure secondary to nonadherence was associated with a marginally greater risk of allograft failure attributed to nonadherence in subsequent transplantation.

A guide to missing data for the pediatric nephrologist.

Missing data is an important and common source of bias in clinical research. Readers should be alert to and consider the impact of missing data when reading studies. Beyond preventing missing data in the first place, through good study design and conduct, there are different strategies available to handle data containing missing observations. Complete case analysis is often biased unless data are missing completely at random. Better methods of handling missing data include multiple imputation and models using likelihood-based estimation. With advancing computing power and modern statistical software, these methods are within the reach of clinician-researchers under guidance of a biostatistician. As clinicians reading papers, we need to continue to update our understanding of statistical methods, so that we understand the limitations of these techniques and can critically interpret literature.

The population-based prevalence of hypertension and correlates of blood pressure among Australian children.

OBJECTIVE: Hypertension is increasingly recognized as a disease spanning the entire life course. Continued efforts to refine the diagnosis and management of hypertension in children are highlighted by the recent American Academy of Pediatrics (AAP) guidelines, which include lower threshold values than the previous reference standard (Fourth Report). We aimed to determine the population-based prevalence of children exceeding thresholds for hypertension using these two guidelines. We also sought to identify the correlates of blood pressure (BP) among Australian children. METHODS: Cross-sectional data from the Growing Up in Australia: Longitudinal Survey of Australian Children were analyzed. Blood pressure was measured in 7139 Australian children aged 10-12 years and sampled using population-based methodology. The association between BP and explanatory variables linked to BP in other populations was examined using multiple linear regression with fractional polynomial terms for continuous, non-linear relationships. RESULTS: The threshold for hypertension was exceeded in 3.1% and 5.4%, and prehypertension in 3.0% and 3.7% of children, using the Fourth Report and AAP guidelines respectively. Children at the threshold for obesity had a 9.1 mmHg higher adjusted BP than those on the 50th centile for body mass index (BMI) (95% CI 8.4 to 9.9). BMI had a non-linear relationship with BP, and the magnitude of association between BMI and BP increased with BMI. Socioeconomic status, hypertension during pregnancy, birth weight, and sports participation were also independently associated with BP. CONCLUSIONS: Using the AAP guidelines is likely to substantially increase the population prevalence of hypertension. The association between BMI and BP was strongest and non-linear for obese children, who should be the focus of interventional trials.

A narrative review of proteinuria and albuminuria as clinical biomarkers in children.

Proteinuria is an important biomarker commonly used to detect and manage kidney disease in children. There are now a variety of methods available to measure urinary protein loss, and physicians are faced with several contrasting strategies: 24-h or timed collection versus spot samples (first-morning or random), measurement of total urinary protein versus selective measurement of urinary albumin, unadjusted urine protein concentration versus protein-to-creatinine ratio and the use of dipstick versus laboratory-based methods. In this review, we will discuss the advantages and disadvantages of these different approaches. We will then summarise the evidence base for proteinuria as a clinical biomarker in different settings, including discussion of the current and potential role of measuring low-level albuminuria. Finally, we will highlight gaps in the literature and opportunities for further research into proteinuria among children.

Epitope matching in kidney transplantation: recent advances and current limitations.

PURPOSE OF REVIEW: Evolution of human leukocyte antigen (HLA) molecular typing techniques has progressively enabled more accurate determination of the three-dimensional building blocks that form the antibody accessibility and binding sites of each HLA allele. These immunogenic HLA regions known as epitopes are composed of polymorphic sequences of amino acid residues termed eplets. This review provides a critical appraisal of the current understanding of epitope compatibility in kidney transplantation. RECENT FINDINGS: There is a tendency to suggest that epitope matching is likely to be superior to broad antigen HLA matching such that the allocation of donor kidneys to patients with a more favorable epitope compatibility profile may lead to better allograft outcomes. A growing body of work has highlighted the association between a greater number of eplet mismatches and adverse allograft outcomes, and approaches using eplet matching have been successfully implemented in organ allocation programs. However, our understanding of epitope compatibility remains in its infancy, requiring further and more in-depth evaluation. Critically, it remains unclear how best to translate findings derived at the population level to the care of individual patients. Questions that need to be answered include a lack of consensus in the definition and interpretation of epitope compatibility, are class I and II compatibility of similar clinical importance, how best to define predetermined mismatch thresholds for utilization in organ allocation, and whether other properties such as differences in electrostatic potential between donor and recipient HLA alleles are also important in determining immunological compatibility. SUMMARY: Epitope matching likely represents a valid progression in understanding donor-recipient HLA compatibility. However, more clinical data and a better understanding about differences in methods to determine epitope compatibility are required before the approach can be widely applied in clinical practice.

The prevalence and predictors of hypertension in a National Survey of Australian Children.

PURPOSE: To determine the prevalence of hypertension and predictors of blood pressure (BP) in a population based survey of Australian children. SUBJECTS AND METHODS: We analysed cross-sectional data for 2071 children, aged 5-17 years, from the Australian Health Survey 2011-13. Hypertension and high-normal BP were defined by a systolic or diastolic BP greater than the 95th and 90th centiles respectively, using the National High Blood Pressure Education Program fourth report reference data. We also examined the association of several predictor variables (age, sex, remoteness, socioeconomic status, body mass index) with BP as a continuous variable. RESULTS: A total of 5.8% (95%CI 4.4-7.2) of children had hypertension, and a further 6.8% (95%CI 5.4-8.3) had high-normal BP. The strongest predictor of BP was body mass index. After adjustment, children in the overweight and obese categories had a BP that was on average 4 (95%CI 2-6) and 8 mmHg (95%CI 6-11) higher than those of normal weight. Socio-economic status was a statistically significant predictor of BP, but the effect size was more modest (2 mmHg [95%CI 0-4] between the highest and lowest tertile). CONCLUSIONS: Hypertension or high-normal BP is present in 12.6% of Australian children. Body mass index is the most important predictor of BP, followed by low socioeconomic status. These at-risk children may be suitable for screening and intervention studies.