PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2.

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.

Patient triage to specialist outpatient clinics-time to standardize terminology.

Objectives: The objectives of this study were to evaluate existing nomenclature used for outpatient referrals triage and propose a system, which meets the needs of McMaster Children's Hospital and can be modified for use in other hospitals. Methods: We reviewed triage practices in the Department of Pediatrics, McMaster Children Hospital, Hamilton, Ontario and conducted a literature search to assess terminology used for outpatient referrals triage at other institutions. Results: There is lack of unified terminology for triaging outpatient referrals. Existing systems are not widely accepted, lack uniformity, and often miss recording the true acuity of the referral. We developed a system that covers most outpatient triage scenarios, allocates either flexible or precise visit timelines to referrals and plans for logistics of the patient's visit. Triage categories are iMMediate (MM), Acute (A) (1 to 14 days), Semi-Acute (S) (1 to 3 months), Timetabled (T) (next available appointment slot), Evaluated (E) (used for either forwarding to another provider or requesting additional information), and Rejected (R) categories-McMASTER triage system. Several numbered subcategories are used in each category to define precise timelines, if needed. Visit logistics categories are the following: Hub (H) (place to see the patient), How to notify patient and referring provider (HP) and (HD), need to Start with tests prior to appointment (S), and need to Complete (C) other relevant local processes-HHSC logistics system. Both these systems may be adapted for local use in other institutions. Conclusion: This is the first publication that proposes terminology standardization in triaging outpatient referrals for specialist paediatric services.

Epidermal growth factor receptor deficiency: Expanding the phenotype beyond infancy.

Transmembrane tyrosine kinase receptors represent a fundamental mechanism for transducing extracellular signals into the activation of signaling cascades responsible for intercellular communication, embryogenesis and tissue integrity. The epidermal growth factor receptor (EGFR) is a canonical member of this family, regarded for its dysregulated function in various malignancies. Here, we describe a young female born prematurely with friable and immature skin who developed chronic diarrhea, recurrent gastrointestinal and respiratory infections, as well as an ichthyotic and inflammatory papulopustular rash accompanied by alopecia. Whole-exome sequencing revealed a constitutional homozygous variant in EGFR (NM_005228.3:c1283G>A; p.[G428D]), identified as a pathogenic loss-of-function variant in three patients with EGFR deficiency. These patients succumbed to early mortality; however, the proposita's condition has stabilized, despite only supportive interventions, with dermatological improvements and reduced frequency of infections at 8 years. This report provides a clinical phenotyping of the longest surviving individual with EGFR deficiency and substantiates our understanding of the natural history of this multisystemic dermatological disorder.

Anterior Ischemic Optic Neuropathy in a Child Receiving Chronic Hemodialysis.

Anterior ischemic optic neuropathy (AION) occurs due to hypoperfusion of the optic nerve and is a rare complication in patients receiving maintenance dialysis. To date, AION has only been reported in 22 children, all of whom were receiving peritoneal dialysis. We report the first case of AION in a 2-year 11-month-old child receiving chronic hemodialysis secondary to polycystic kidney disease from a phosphomannomutase 2 gene mutation. This case highlights the consideration for frequent blood pressure monitoring and ophthalmic screening in a certain cohort of children receiving chronic dialysis.

A cross-sectional study measuring vanadium and chromium levels in paediatric patients with CKD.

OBJECTIVES: Although many secondary effects of high levels of vanadium (V) and chromium (Cr) overlap with symptoms seen in paediatric patients with chronic kidney disease (CKD), their plasma V and Cr levels are understudied. DESIGN: Ancillary cross-sectional study to a prospective, longitudinal, randomised controlled trial. SETTING: Children's Hospital of Western Ontario, London Health Sciences Centre, London, Ontario, Canada. PARTICIPANTS: 36 children and adolescents 4-18 years of age with CKD. INTERVENTIONS: 1-6 trace element measurements per patient. Cystatin C (CysC) estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma V and Cr levels were measured using high-resolution sector field inductively coupled mass spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart programme. Water Cr and V data were obtained from the Ontario Water (Stream) Quality Monitoring Network. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes: plasma Cr and V. SECONDARY OUTCOMES: age, season, CysC, CysC eGFR, and Cr and V levels in environmental water. RESULTS: The median (IQR) eGFR was 51 mL/min/1.73 m2 (35, 75). The median V level was 0.12 µg/L (0.09, 0.18), which was significantly greater than the 97.5th percentile of the reference interval of 0.088 µg/L; 32 patients had at least one set of V levels above the published reference interval. The median Cr level was 0.43 µg/L (0.36, 0.54), which was also significantly greater than the established reference interval; 34 had at least one set of Cr levels above the published reference interval. V and Cr levels were moderately correlated. Only some patients had high environmental exposure. CONCLUSIONS: Our study suggests that paediatric patients with CKD have elevated plasma levels of V and Cr. This may be the result of both environmental exposure and a low eGFR. It may be necessary to monitor V and Cr levels in patients with an eGFR <30 mL/min/1.73 m2. TRIAL REGISTRATION NUMBER: NCT02126293; HC#172241.

Deviations from the expected relationship between serum FGF23 and other markers in children with CKD: a cross-sectional study.

BACKGROUND: High levels of fibroblast growth factor-23 (FGF23) are associated with mortality. In chronic kidney disease (CKD), FGF23 levels rise as renal function declines. We analyzed the contribution of laboratory values to the variance of FGF23 levels in relationship to a curve of expected FGF23 levels for a given GFR. METHODS: Following approval by the research ethics boards, we measured FGF23, CysC eGFR, creatinine, urea, albumin, calcium, phosphate, vitamin D metabolites, PTH, alkaline phosphatase, CRP, and venous gases in 141 pediatric CKD patients (45, 37, 32, 13 and 14 CKD stages I, II, III, IV, and V, respectively). Data were expressed as median (25th, 75th percentile). RESULTS: FGF23 correlated significantly with CysC, CysC eGFR, PTH, 1.25 (OH)2 vitamin D, phosphate, and pH. The correlation of the latter three remained significant in the multivariate analysis. We calculated a formula for the expected FGF23 value for a given level of eGFR which reads Y = 1295 * e-0.07247*X + 38.35. Deviation by more than 20% from the curve also depended on phosphate, 1.25 (OH)2 vitamin D and pH. CONCLUSIONS: Our data emphasize the importance of phosphate and 1.25 (OH)2 vitamin D levels. The impact of acidosis on FGF23 warrants further studies.

High prevalence of elevated molybdenum levels in pediatric CKD patients. A cross-sectional and longitudinal study
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AIMS: Many of the secondary effects of high levels of molybdenum (Mo) overlap with symptoms commonly seen in pediatric patients with chronic kidney disease (CKD). We measured plasma Mo levels and examined the relationship between Mo levels and kidney function. MATERIALS AND METHODS: The study was carried out at the London Health Sciences Centre in London, Ontario, Canada with 36 children and adolescents 4 - 18 years of age with CKD. There were 1 - 6 trace element measurements (Mo and copper (Cu)) per patient. We studied the proportion of patients with abnormal trace element levels and the relationship between trace element levels and estimated glomerular filtration rate (eGFR), calculated using the Filler formula. Plasma Mo and Cu levels were measured using High Resolution Sector Field Inductively Coupled Mass Spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart program. RESULTS: Median eGFR was 51 mL/min/1.73m2 (35, 75). Median Mo level was 2.00 µg/L (1.40, 2.88). 20 patients had at least one set of Mo levels above the published reference interval in either unit, and the results of 46% of the tests were above the interval. There was a strong negative correlation between the Mo levels and the eGFR (Spearman's r = -0.627, p < 0.0001). CONCLUSIONS: Our study suggests that pediatric patients with CKD have elevated plasma levels of Mo, which may cause secondary effects commonly associated with CKD. The elevated Mo levels in our center's catchment area may cause an accumulation of this trace element in patients with impaired renal function.
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Process Mapping in a Pediatric Emergency Department to Minimize Missed Urinary Tract Infections.

Urinary tract infections (UTIs) are common in young children and are seen in emergency departments (EDs) frequently. Left untreated, UTIs can lead to more severe conditions. Our goal was to undertake a quality improvement (QI) initiative to help minimize the number of children with missed UTIs in a newly established tertiary care pediatric emergency department (PED). A retrospective chart review was undertaken to identify missed UTIs in children < 3 years old who presented to a children's hospital's ED with positive urine cultures. It was found that there was no treatment or follow-up in 12% of positive urine cultures, indicating a missed or possible missed UTI in a significant number of children. Key stakeholders were then gathered and process mapping (PM) was completed, where gaps and barriers were identified and interventions were subsequently implemented. A follow-up chart review was completed to assess the impact of PM in reducing the number of missed UTIs. Following PM and its implementation within the ED, there was no treatment or follow-up in only 1% of cases. Based on our results, the number of potentially missed UTIs in the ED decreased dramatically, indicating that PM can be a successful QI tool in an acute care pediatric setting.

Effects of acute exercise on markers of inflammation in pediatric chronic kidney disease: a pilot study.

BACKGROUND: Children and adolescents with chronic kidney disease (CKD) are chronically exposed to high levels of inflammation, placing them at an increased risk of secondary health complications. Regular exercise may represent an effective therapy to reduce inflammation. The aims of this pilot study were to determine the effects of acute exercise on inflammation and immune cell counts in CKD. METHODS: Nine children and adolescents (4 males) with CKD stages III-V performed a graded exercise test to determine peak oxygen uptake (VO2peak). Following a 10-min break, participants cycled for 20 min at 50 % of VO2peak. Blood samples were collected before and after the exercise period for the determination of complete blood counts, natural killer cells (NK(bright), NK(dim)) and circulating progenitor cell (CPC) counts, as well as interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) concentrations. RESULTS: Complete blood counts and NK(dim) cell and CPC counts were unchanged with exercise. Following exercise, NK(bright) cell counts increased (7.4 ± 4.3 vs. 12.2 ± 8.3 × 10(6) cells/L; p = 0.02), while trends were observed for an increase in IL-6 (2.1 ± 2.2 vs. 2.7 ± 2.6 pg/mL; p = 0.08), decrease in TNF-α (4.5 ± 1.2 vs. 4.2 ± 1.0 pg/mL; p = 0.08) and an increase in the IL-6:TNF-α ratio (0.6 ± 0.7 vs. 0.8 ± 0.8; p = 0.07). CONCLUSIONS: Our findings suggest that acute exercise may create an anti-inflammatory environment in children and adolescents with CKD stages III-V.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Strong anion determination in biological fluids by capillary electrophoresis for clinical diagnostics.

New methods for quantitative analysis of strong anions are required for diagnostic testing of human diseases. Current techniques suffer from poor selectivity and/or long analysis times that are not amenable for labile anions in high-saline or volume-restricted samples. We introduce a rapid assay (<5 min) based on capillary electrophoresis (CE) with indirect UV detection for simultaneous analysis of sulfate, sulfite, and chloride in human urine, plasma, and sweat specimens. Remarkable selectivity for strong anions is achieved by using an acidic background electrolyte under reversed polarity that results in electrokinetic rejection of matrix interferences at the capillary inlet. A dual co-ion probe system consisting of 5 mM naphthalene disulfonate (NDS) and 5 mM naphthalene trisulfonate (NTS) in 0.4 M formic acid, pH 2.0 is developed for detection of UV transparent anions (S/N ≈ 3, 60 µM with a 25 µm inner diameter fused-silica capillary) with good peak symmetry and baseline stability. Due to the chemical reactivity of sulfite, dilute formaldehyde is used as a reagent to form an acid-stable hydroxymethylsulfonate adduct. Method validation confirmed excellent linearity (R(2) > 0.999), good accuracy (mean bias ≈7%), and acceptable long-term reproducibility (CV < 10%) over 20 days. The assay allows for artifact-free determination of sulfate and sulfite with consistent results for chloride when compared to standard electrochemical methods (R(2) > 0.975). Preliminary data suggest that kidney-stone formers have lower urinary sulfate excretion relative to non-kidney-stone patient controls (p = 0.0261). CE offers a selective yet robust platform for routine analysis of strong anions that is needed for confirmatory testing of cystic fibrosis, sulfite oxidase deficiency, urolithiasis, and other disorders of sulfur metabolism and/or anion transport.

Cracking haematuria in adolescent with negative work up.

A 16-year-old girl was referred to our nephrology clinic with persistent visible haematuria (2 months), no urinary tract infection, proteinuria ranging from negligible to 1.5 g/l, normal kidney function and otherwise negative work up including immunology screen. After negative ultrasound scans of the kidneys and bladder, normal renal biopsy and normal cystoscopy, a CT angiogram was obtained. It showed no evidence of arteriovenous malformation but revealed compression of left renal vein (nutcracker syndrome).

The dangers of substance abuse in adolescents with chronic kidney disease: a review of the literature.

Although there exist no specific data on the prevalence of substance abuse among children and adolescents with chronic kidney diseases (CKD), the magnitude of this problem should not be underestimated, as almost half of twelfth-graders in the U.S. admit to a history of using illegal drugs at least once when asked (National Institute on Drug Abuse, 2011). According to the 2010 Canadian Alcohol and Drug Use Monitoring Survey (Health Canada, n.d.), the prevalence of drug abuse among Canadian youths and young adults aged 15 to 24 remains higher than in adults older than 25 years of age, and the rates of drug use (excluding cannabis) in the past years were 7.9% and 0.8%, respectively, illustrating an almost 10 times higher rate in the younger age group (Health Canada, n.d.). Drug abuse can lead to numerous medical problems, including renal injury, and it is clearly a major public health concern, especially in patients with subnormal kidney function (Vupputuri et al., 2004). As most of the children and adolescents that suffer from CKD have long-term and trustful relationships with the nephrology team, we have the obligation and are in an excellent position to address this particular health issue (Finkelstein & Finkelstein, 2000; Kimmel, 2002; Kimmel, Cohen, & Peterson, 2008). This review summarizes the available data on the nephrotoxic effects of various commonly abused drugs with special emphasis on the additional damage that occurs in patients with pre-existing CKD. These data were obtained from a thorough search of the available primary literature, specifically using the PubMed database. The purpose is to provide health professionals with a resource to properly educate their CKD patients on the dangers of these drugs.

Measurement of saliva tacrolimus levels in pediatric renal transplant recipients.

The aim of this study was to investigate whether a strong and clinically applicable correlation exists between saliva and whole-blood tacrolimus levels measured by high-performance liquid chromatography-tandem mass spectrometry. A high degree of correlation would potentially allow pain-free saliva sample collection to replace blood sampling for the measurement of tacrolimus levels. Enrolled in the study were 37 children (24 boys) aged 8-18 years [median (IQR) 16.2 (12.9-17.5) years] attending the renal transplant clinic at the Royal Manchester Children's Hospital and 77 paired blood saliva samples were collected. The mean (SD) saliva tacrolimus level was 0.14 (0.16), range 0-0.7 µg/l. In ten cases, tacrolimus was not detected in the saliva despite being present in blood. The ratio of blood-to-saliva tacrolimus levels varied from 2.6 to 550. The Pearson product-moment correlation suggested a weak linear relationship between tacrolimus levels in blood and saliva with a coefficient 0.36. Individual patients did not demonstrate consistent tacrolimus blood/saliva ratios with a mean correlation of 0.08. Additional experiments excluded saliva contamination with blood and sample collection and storage conditions as causes of poor correlation. The measurement of saliva tacrolimus levels in place of or as an adjunct to blood sampling therefore cannot be recommended.

Dual left anterior descending artery distribution.

Dual left anterior descending (LAD) coronary artery with distribution of the vessels from the left main coronary artery and the right aortic sinus of Valsalva is a rare coronary anomaly. Here, we report such a rare anomaly in a young female with anterior wall myocardial infarction and stenting of the 'short' LAD coronary artery, which was subsequently confirmed in the operating room and by multi-slice cardiac computerized tomography after surgery.

Clinical features in 17 paediatric patients with Wegener granulomatosis.

The aim of this report was to describe childhood patients with Wegener granulomatosis (WG) from one centre, to analyse the variety of clinical manifestations seen and compare the data with other published paediatric and adult series. The records of 17 patients with WG who were under the care of Great Ormond Street Hospital for Children (GOSH) from 1981 to 1998 were reviewed. We analysed presenting features before admittance to GOSH and the clinical signs observed whilst the children were under the care of the hospital. Of 17 patients, 13 were females and there was a male/female ratio of 1:3.25. Among the patients there were 2 sisters. The age of the patients at disease onset varied from 2 weeks to 14 years. The median/mean age was 6/6.3 years. American College of Rheumatology criteria for diagnosing WG were fulfilled in 11 of 17 patients. The frequency of different system involvement was: respiratory 87%, kidneys 53%, sinuses 35%, joints 53%, eyes 53%, nervous system 12%, skin 53%. cANCA was positive in 10 patients (59%), but pANCA was negative in all measured sera. Kidneys were involved in 2 of 8 patients (25%) with the disease onset from 0 to 5 years and in 7 of 9 patients (78%) with the disease onset from 6 to 14 years ( P<0.05). cANCA was positive in 7 of 9 patients with kidney disease (78%) and in 2 of 8 patients (25%) without kidney involvement ( P<0.05). Colchicine as a supplement to prednisolone and cytotoxic/immunosuppressant drugs was used effectively in 5 patients.