Enrolment of the first paediatric cohort into the Australian lupus registry and biobank: A single-centre experience.

INTRODUCTION: We aim to report on the feasibility of establishment of the first paediatric cohort as part of the longitudinal database of the Australian Lupus Registry and Biobank (ALRB) and to describe the enrolment data with a focus on clinical characteristics, serological data, treatment strategies and patient/parent-reported outcome measures. METHODS: All patients under the age of 18 years with a diagnosis of systemic lupus erythematosus (SLE) attending the paediatric rheumatology service of a single, tertiary hospital were identified. Patients were enrolled in the ALRB if they met ≥4/11 of the American College of Rheumatology (ACR) 1997 SLE classification criteria or the Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria. Enrolment data including demographics, clinical characteristics, serological profiles, disease activity and damage assessments were recorded. Peds-QL Rheumatology and General Modules were used to assess patient and parent-reported outcomes. RESULTS: Twenty-seven patients were eligible for inclusion, with 26 patients (96%) consenting for enrolment. Twenty-five patients (92%) consented for biobanking. Twenty patients (77%) were female. The median age at enrolment was 16 years (interquartile range (IQR) 13.7, 17.4). The median disease duration from diagnosis was 3.2 years (IQR 1.4, 5.3). Sixteen patients (62%) had synovitis, 16 (62%) had cutaneous involvement, 4 (15%) had serositis, 17 (65%) had haematological involvement and 7 (27%) had renal involvement at enrolment. Nineteen patients (73%) were prescribed at least two disease-modifying anti-rheumatic medications (DMARDs). Hydroxychloroquine (n = 22, 85%) and mycophenolate mofetil (n = 9, 35%) were the most commonly prescribed DMARDs. The median SLEDAI-2K score was 2 (IQR 2, 4). Six patients (23%) had active disease (SLEDAI-2K ≥6) at enrolment. Three patients (11.5%) had reported damage using the SLICC/ACR Damage Index. Twenty-three children (88%) and eighteen parents (69%) completed the Paediatric Quality of Life Inventory. Quality of life scores reported across domains of physical, emotional, social and school functioning at enrolment were comparable to previously studied paediatric cohorts with SLE and other chronic diseases. CONCLUSION: We have established our centre as the first paediatric participating site of the ALRB, providing contemporary data on the clinical characteristics, serological profile and health-related quality of life outcomes of Australian children with SLE. Paediatric involvement with this national registry will provide a unique perspective for future clinical and scientific research. Collection of Australian-specific paediatric longitudinal data will also enable a broader understanding of SLE within a multicultural Australian population.

Hospital admissions associated with dehydration in childhood kidney transplantation.

BACKGROUND: Paediatric kidney transplant recipients may be at a particular risk of dehydration due to poor kidney concentrating capacity and illness associated with poor fluid intake or losses. In this population, creatinine rise may be more likely with relatively mild dehydration, which may trigger hospital admission. This study describes hospital admissions in the first 12 months after transplantation with diagnosis of graft dysfunction associated with dehydration due to illness or poor fluid intake. We assess risk factors for these admissions. METHODS: Data was extracted from medical records of patients transplanted in two tertiary children hospitals. Following descriptive analysis, multiple failure regression analyses were used to identify factors associated with admission for acute kidney allograft dysfunction associated with dehydration. RESULTS: Of 92 children, 42% had at least 1 dehydration admission in the 12 months following transplantation. Almost half of the dehydration admissions were due to poor fluid intake, which accounted for 1/5 of all unplanned hospital admissions. Target fluid intake at first discharge of > 100 ml/kg/day was associated with dehydration admissions of all types (hazard ratio (HR) 2.04 (95% CI 1.13-3.68)). Teen age was associated with poor fluid intake dehydration admissions (HR 4.87 (95% CI 1.19-19.86)), which were more frequent in mid-summer. Use of enteric feeding tube, which correlated with age under 4, associated with contributing illness dehydration admissions (HR 2.18 (95% CI 1.08-4.41)). CONCLUSIONS: Dehydration admissions in the 12 months following childhood kidney transplantation are common. Highlighted admission risk factors should prompt further study into optimal fluid intake prescription and hydration advice given to children, teenagers, and their carers following kidney transplantation. Use of an enteric feeding tube may not protect patients from admission with dehydration associated with contributing illness. A highger resolution version of the Graphical abstract is available as Supplementary information.

Echocardiogram screening in pediatric dialysis and transplantation.

Transthoracic echocardiography is commonly used to identify structural and functional cardiac abnormalities that can be prevalent in childhood chronic kidney failure (KF). Left ventricular mass (LVM) increase is most frequently reported and may persist post-kidney transplant especially with hypertension and obesity. While systolic dysfunction is infrequently seen in childhood chronic KF, systolic strain identified by speckle tracking echocardiography has been frequently identified in dialysis and it can also persist post-transplant. Echocardiogram association with long-term outcomes has not been studied in childhood KF but there are many adult studies demonstrating associations between increased LVM, systolic dysfunction, strain, diastolic dysfunction, and cardiovascular events and mortality. There has been limited study of interventions to improve echocardiogram status. In childhood, improved blood pressure has been associated with better LVM, and conversion from hemodialysis to hemodiafiltration has been associated with better diastolic and systolic function. Whether long-term cardiac outcomes are also improved with these interventions is unclear. Echocardiography is a well-established technique, and regular use in childhood chronic KF seems justified. A case can be made to extend screening to include speckle tracking echocardiography and intradialytic studies in high-risk populations. Further longitudinal studies including these newer echocardiogram modalities, interventions, and long-term outcomes would help clarify recommendations for optimal use as a screening tool.

Clinical impact of genomic testing in patients with suspected monogenic kidney disease.

PURPOSE: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. METHODS: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. RESULTS: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). CONCLUSION: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

Metabolite diagnosis of primary hyperoxaluria type 3.

BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a recently described cause of childhood renal calculi. It results from mutations in the HOGA1 gene and most cases have been diagnosed after clinical ascertainment, exclusion of other genetic hyperoxalurias and mutation testing. Metabolite testing has not been widely applied but holds promise for the rapid screening and diagnosis of patients who are not specifically suspected to have PH3. CASE-DIAGNOSIS/TREATMENT: Two cases presented with renal calculi. Urine metabolite testing by tandem mass spectrometry was performed as part of the routine diagnostic work-up for this condition. Both had significantly increased levels of the PH3 urine marker 4-hydroxyglutamate and related metabolites. The diagnosis of PH3 was confirmed by the finding of bi-allelic damaging HOGA1 mutations. CONCLUSIONS: Urine screening by tandem mass spectrometry is a rapid, high-throughput test that can detect PH3 cases that may otherwise not be diagnosed.

The Use of Peritoneal Dialysis in Phenobarbitone Toxicity in a Critically Unwell Neonate.

BACKGROUND: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. OBJECTIVE: To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. METHODS: Assessment of PD drug clearance. RESULTS: A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. CONCLUSIONS: PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.

Australian deceased donor kidney allocation protocols: Transplant waiting and graft quality for children and adolescents.

DD kidney allocation protocols may influence timing of transplantation and graft quality for pediatric recipients. This study aimed to evaluate the effects of these protocols, including pediatric priority, on waiting time on dialysis, transplant type, donor age, and HLA matching according to state of transplant in Australia. De-identified information on patients <15 yr of age who commenced RRT in NSW, Qld, and Victoria from 2002 to 2011 was retrieved from the ANZDATA. Transplant type, donor age, and HLA mismatching were compared between states, with competing risk regression used to examine the time to transplant. There were significant differences in waiting time to DD transplantation between the three states. Children in NSW and Qld waited a median of 14 and 11 months vs. 21 months in Victoria. The ratio of LD to DD transplants was lower in NSW and Qld. Differences correlated with DD pediatric priority in NSW and Qld. DDs in NSW were older than in the other states. HLA matching did not differ. DD kidney allocation protocols with pediatric priority in Australian states were associated with shorter waiting times and increased DD proportion.

Copy-number variation associated with congenital anomalies of the kidney and urinary tract.

BACKGROUND: The most common cause of end-stage renal disease in children can be attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Despite this high incidence of disease, the genetic mutations responsible for the majority of CAKUT cases remain unknown. METHODS: To identify novel genomic regions associated with CAKUT, we screened 178 children presenting with the entire spectrum of structural anomalies associated with CAKUT for submicroscopic chromosomal imbalances (deletions or duplications) using single-nucleotide polymorphism (SNP) microarrays. RESULTS: Copy-number variation (CNV) was detected in 10.1 % (18/178) of the patients; in 6.2 % of the total cohort, novel duplications or deletions of unknown significance were identified, and the remaining 3.9 % harboured CNV of known pathogenicity. CNVs were inherited in 90 % (9/10) of the families tested. In this cohort, patients diagnosed with multicystic dysplastic kidney (30 %) and posterior urethral valves (24 %) had a higher incidence of CNV. CONCLUSIONS: The genes contained in the altered genomic regions represent novel candidates for CAKUT. This study has demonstrated that a significant proportion of patients with CAKUT harbour submicroscopic chromosomal imbalances, warranting screening in clinics for CNV.

Paediatric urological investigations--dose comparison between urology-related and CT irradiation.

BACKGROUND: Urological investigation in children frequently involves high radiation doses; however, the issue of radiation for these investigations receives little attention compared with CT. OBJECTIVE: To compare the radiation dose from paediatric urological investigations with CT, which is commonly regarded as the more major source of radiation exposure. MATERIALS AND METHODS: We conducted a retrospective audit in a tertiary paediatric centre of the number and radiation dose of CT scans, micturating cystourethrography exams and urological nuclear medicine scans from 2006 to 2011. This was compared with radiation doses in the literature and an audit of the frequency of these studies in Australia. RESULTS: The tertiary centre audit demonstrated that the ratio of the frequency of urological to CT examinations was 0.8:1 in children younger than 17 years. The ratio of the radiation dose of urological to CT examinations was 0.7:1. The ratio in children younger than 5 years was 1.9:1. In Australia the frequency of urological procedures compared with CT was 0.4:1 in children younger than 17 years and 3.1:1 in those younger than 5 years. The ratio of radiation-related publications was 1:9 favouring CT. CONCLUSION: The incidence and radiation dose of paediatric urological studies is comparable to those of CT. Nevertheless the radiation dose of urological procedures receives considerably less attention in the literature.

Cystinosis and lupus erythematosus: coincidence or causation.

A 14-year-old boy with known stable cystinosis, treated with cysteamine since infancy, presented with a deterioration of renal function with haematuria in conjunction with a nodular rash, arthralgia, leucopenia, hypocomplementaemia and raised antinuclear antibodies. He was diagnosed with spontaneous onset of systemic lupus erythematosus (SLE), and his renal biopsy was consistent with lupus nephritis. It is unusual for patients with one severe disease to develop another disease process completely unrelated to their original condition, but it can occur. However, other distinct variants of lupus have been described, including drug-induced lupus (DIL), which have features that over-lap with SLE. The potential differential diagnosis of the SLE as a form of DIL in association with cysteamine is discussed.