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Abstract Severe Neonatal Jaundice (SNJ) causes long-term neurocognitive impairment, cerebral palsy, auditory neuropathy, deafness, or death. We developed a mathematical model for allo-hemodialysis as a potential blood purification method for the treatment of SNJ in term or near-term infants. With allo-hemodialysis (allo-HD), the neonate’s blood flows through hollow fibers of a miniature 0.075 m2 hemodialyzer, while the blood of a healthy adult (“buddy”) flows counter-currently through the dialysate compartment. We simulated the kinetics of unconjugated bilirubin in allo-hemodialysis with neonate blood flow rates of 12.5 and 15 mL/min (for a 2.5 kg and 3.5 kg neonate, respectively), and 30 mL/min for the buddy. Bilirubin production rates in neonate and buddy were set to 6 and 3 mg/kg/day, respectively. Buddy bilirubin conjugation rate was calculated to obtain normal steady-state bilirubin levels. Albumin levels were set to 1.1, 2.1, 3.1 g/dL for the neonate and 3.3 g/dL for the buddy. Model simulations suggest that a 6-h allo-hemodialysis session could reduce neonatal bilirubin levels by > 35% and that this modality would be particularly effective with low neonatal serum albumin levels. Due to the high bilirubin conjugation capacity of an adult’s healthy liver and the larger distribution volume, the buddy’s bilirubin level increases only transiently during allo-hemodialysis. Our modelling suggests that a single allo-hemodialysis session may lower neonatal unconjugated bilirubin levels effectively. If corroborated in ex-vivo, animal, and clinical studies, this bilirubin reduction could lower the risks associated with SNJ, especially kernicterus, and possibly avoiding the morbidity associated with exchange transfusions.

Abstract Acute and chronic kidney disease continues to confer significant morbidity and mortality in the clinical setting. Despite high prevalence of these conditions, few validated biomarkers exist to predict kidney dysfunction. In this study, we utilized a novel kidney multiplex panel to measure 21 proteins in plasma and urine to characterize the spectrum of biomarker profiles in kidney disease. Blood and urine samples were obtained from age-/sex-matched healthy control subjects (HC), critically-ill COVID-19 patients with acute kidney injury (AKI), and patients with chronic or end-stage kidney disease (CKD/ESKD). Biomarkers were measured with a kidney multiplex panel, and results analyzed with conventional statistics and machine learning. Correlations were examined between biomarkers and patient clinical and laboratory variables. Median AKI subject age was 65.5 (IQR 58.5–73.0) and median CKD/ESKD age was 65.0 (IQR 50.0–71.5). Of the CKD/ESKD patients, 76.1% were on hemodialysis, 14.3% of patients had kidney transplant, and 9.5% had CKD without kidney replacement therapy. In plasma, 19 proteins were significantly different in titer between the HC versus AKI versus CKD/ESKD groups, while NAG and RBP4 were unchanged. TIMP-1 (PPV 1.0, NPV 1.0), best distinguished AKI from HC, and TFF3 (PPV 0.99, NPV 0.89) best distinguished CKD/ESKD from HC. In urine, 18 proteins were significantly different between groups except Calbindin, Osteopontin and TIMP-1. Osteoactivin (PPV 0.95, NPV 0.95) best distinguished AKI from HC, and β2-microglobulin (PPV 0.96, NPV 0.78) best distinguished CKD/ESKD from HC. A variety of correlations were noted between patient variables and either plasma or urine biomarkers. Using a novel kidney multiplex biomarker panel, together with conventional statistics and machine learning, we identified unique biomarker profiles in the plasma and urine of patients with AKI and CKD/ESKD. We demonstrated correlations between biomarker profiles and patient clinical variables. Our exploratory study provides biomarker data for future hypothesis driven research on kidney disease.

Abstract Background The COVID-19 pandemic has led to increased utilization of telemedicine services. Methods A retrospective analysis of all referral-based ambulatory telemedicine services in Ontario from November 2019 to June 2021 was collected from the Ontario Health Insurance Plan (OHIP) billing database. Only fee-for-service billings were included in the present analysis. Coincident COVID-19 cases were obtained from Public Health Ontario. Comparisons were made based on age bracket, sex, telemedicine and in-person care. Results Billings for telemedicine services in Ontario increased from $1.7 million CAD in November 2019 to $64 million CAD in April 2020 and the proportions reached a mean peak of 72% in April 2020 and declined to 46% in June 2021. A positive correlation was found between the use of telemedicine and COVID-19 cases (p = 0.05). The age group with the highest proportion of telemedicine use was the 10–20-year-olds, followed by the 20–50-year-olds (61 ± 9.0%, 55 ± 7.3%, p = 0.01). Both age groups remained above 50% telemedicine services at the end of the study period. There seemed to be higher utilization by females (females 54.2 ± 8.0%, males 47.9 ± 7.7%, ANCOVA p = 0.05) for all specialties, however, after adjusting for male to female ratio m:f of 0.952:1.0 according to the 2016 census, this was no longer significant. Conclusions The use of telemedicine services remained at a high level across groups, particularly the 10–50-year-olds. There were clear age preferences for using telemedicine. Studying these differences may provide insights into how the delivery of non-hospital-based medicine has changed during the COVID-19 pandemic.

BackgroundUrinary stone disease (USD) historically has affected older men, but studies suggest recent increases in women, leading to a near identical sex incidence ratio. USD incidence has doubled every 10 years, with disproportionate increases amongst children, adolescent, and young adult (AYA) women. USD stone composition in women is frequently apatite (calcium phosphate), which forms in a higher urine pH, low urinary citrate, and an abundance of urinary uric acid, while men produce more calcium oxalate stones. The reasons for this epidemiological trend are unknown.MethodsThis perspective presents the extent of USD with data from a Canadian Province and a North American institution, explanations for these findings and offers potential solutions to decrease this trend. We describe the economic impact of USD.FindingsThere was a significant increase of 46% in overall surgical interventions for USD in Ontario. The incidence rose from 47.0/100,000 in 2002 to 68.7/100,000 population in 2016. In a single United States institution, the overall USD annual unique patient count rose from 10,612 to 17,706 from 2015 to 2019, and the proportion of women with USD was much higher than expected. In the 10–17-year-old patients, 50.1% were girls; with 57.5% in the 18–34 age group and 53.6% in the 35–44 age group. The roles of obesity, diet, hormones, environmental factors, infections, and antibiotics, as well as the economic impact, are discussed.InterpretationWe confirm the significant increase in USD among women. We offer potential explanations for this sex disparity, including microbiological and pathophysiological aspects. We also outline innovative solutions – that may require steps beyond typical preventive and treatment recommendations.

Abstract Background Manganese (Mn) and Selenium (Se) deficiencies are noted in adult patients with chronic kidney disease (CKD). However, levels of these trace elements have not been well studied in the paediatric CKD population. We determined the Mn and Se levels in a single-institution cohort of paediatric patients with CKD. Methods Ancillary cross-sectional study to a prospective longitudinal randomized control trial on zinc supplementation, which included 42 children and adolescents aged 0 to 19 years with CKD stages I to IV not on dialysis, who had 1–6 trace element measurements. Cystatin C estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma Mn and Se levels were measured, and anthropomorphic data/blood parameters were collected from electronic health records. The trial was registered on clinicaltrials.gov, NCT02126293. Results There were 96 Mn and Se levels in 42 patients (age 12.5 ± 4.6 years). The median Mn concentration was 12.61 nmol/L [10.08, 16.42] with a trend towards lower values with lower eGFR (p = 0.0367 one-sided). Mn z-scores were significantly lower than the general paediatric reference population. The mean Se level was 1.661 ± 0.3399 µmol/L with a significant positive correlation with eGFR (p = 0.0159, r = 0.366). However, only 4 patients with low eGFR had abnormally low Se levels. Conclusions This single-institution study of children with CKD demonstrates a significant decrease in Se levels with decreasing eGFR, but no significant difference between mean Se z-scores of our cohort and the reference population. There was no significant relationship between Mn levels and eGFR however the mean Mn z-score was significantly lower than the theoretical mean. Trial registration: clinicaltrials.gov, NCT02126293, https://clinicaltrials.gov/ct2/show/NCT02126293 . Date: April 30, 2014.

Abstract Background The agreement between the commonly used ambulatory blood pressure (ABP) thresholds to diagnose ambulatory hypertension in children (patient’s 24-h mean ABP classified by 24-h 95th ABP percentile threshold, American Heart Association [AHA] threshold, or patient’s day and night mean ABP classified by day-night 95th ABP percentile thresholds) is not known. We evaluated the agreement among 24-h ABP threshold, AHA threshold, and day-night ABP thresholds to diagnose ambulatory hypertension, white coat hypertension (WCH) and masked hypertension (MH). Methods In a cross-sectional study design, we analyzed ABP recordings from 450 participants with suspected hypertension from a tertiary care outpatient hypertension clinic. The American Academy of Pediatrics thresholds were used to diagnose office hypertension. Results The 24-h ABP threshold and day-night ABP thresholds classified 19% ABP (95% confidence interval [CI], 0.15–0.23) differently into ambulatory normotension/hypertension (kappa [κ], 0.58; 95% CI, 0.51–0.66). Ambulatory hypertension diagnosed by 24-h ABP threshold in 27% participants (95% CI, 0.22–0.32) was significantly lower than that by day-night ABP thresholds in 44% participants (95% CI, 0.37–0.50; P

Objective: In previous studies, smaller renal volumes were reported in prematurely born infants, however, these renal volumes were not corrected for body surface area, the main determinant of renal size. Given the rapid growth of the renal cortex after premature birth, the authors hypothesized that corrected volumes would not differ from healthy controls. Methods: Ambispective cohort study with prospective follow-up of prematurely born babies in a large specialized center and retrospectively recruited healthy control group. Children were assessed for renal length and renal volumes at age 5 by three independent ultrasonographers. Detailed anthropometry, blood pressure and renal function were also obtained. Age independent z-scores were calculated for all parameters and compared using descriptive statistics. Results: Eighty-nine premature study participants (median 32 weeks gestational age) and 33 healthy controls (median 38 weeks gestational age) were studied. Study participants did not differ in age, sex, Afro-Colombian descent, height, blood pressure, serum creatinine, or new Schwartz eGFR. Premature study participants had a significantly lower weight (17.65 ± 2.93 kg) than controls (19.05 ± 2.81 kg, p = 0.0072) and lower body surface area. The right renal volumes were significantly smaller (39.4 vs 43.4 mL), but after correction for body surface area, the renal volume and renal length z-scores were identical for both kidneys (mean right kidney -0.707 vs -0.507; mean left kidney -0.498 vs -0.524, respectively). Conclusion: Renal volumes need to be corrected to body surface area. After correction for body surface area, 5-year-old healthy and prematurely born children have comparable renal volumes.

BackgroundPreterm birth is associated with decreased nephron endowment. Currently, there is no reliable non-invasive biomarker to identify or monitor decreased nephron number in at-risk patients. Urinary Kidney Injury Molecule-1 (KIM-1) is a biomarker of acute and chronic renal injury. We measured urinary KIM-1 among a wide array of other potential biomarkers.MethodsWe conducted an ambispective cohort study of 5-years-old children born prematurely and healthy controls identified from city schools. Detailed anthropometrics, renal ultrasound dimensions, and biochemical parameters were measured. Urinary KIM-1 was measured using Luminex® technology. Age independent z-scores were calculated and compared. Spearman correlations were used for estimating the association between measures and KIM-1.ResultsWe enrolled 129 children, 97 (75.2%) born pre-term and 32 (24.8%) healthy controls born at full-term. Pre-term patients had significantly lower weight and body surface area than controls. Pre-term patients and controls did not differ in current age, sex, race, height, blood pressure, urinary sodium, fractional sodium excretion, serum creatinine and estimated GFR. All spearman correlation between KIM-1 and gestational age, renal and serum measurements were weak without statistical significanceConclusionIn 5-year-old children born prematurely, KIM-1 was not correlated with gestational age. Further prospective studies need to confirm this finding.

Abstract The agreement between the traditionally‐used ambulatory blood pressure (ABP)‐load thresholds in children and recently‐recommended pediatric American Heart Association (AHA)/European Society of Hypertension (ESH) ABP thresholds for diagnosing ambulatory hypertension (AH), white coat hypertension (WCH), and masked hypertension (MH) has not been evaluated. In this cross‐sectional study on 450 outpatient participants, the authors evaluated the agreement between previously used ABP‐load 25%, 30%, 40%, 50% thresholds and the AHA/ESH thresholds for diagnosing AH, WCH, and MH. The American Academy of Pediatrics thresholds were used to diagnose office hypertension. The AHA threshold diagnosed ambulatory normotension/hypertension closest to ABP load 50% in 88% (95% CI 0.79, 0.96) participants (k 0.67, 95% CI 0.59, 0.75) and the ESH threshold diagnosed ambulatory normotension/hypertension closest to ABP load 40% in 86% (95% CI 0.77, 0.94) participants (k 0.66, 95% CI 0.59, 0.74). In contrast, the AHA/ESH thresholds had a relatively weaker agreement with ABP load 25%/30%. Therefore, the diagnosis of AH was closest between the AHA threshold and ABP load 50% (difference 3%, 95% CI ‐2.6%, 8.6%, p = .29) and between the ESH threshold and ABP load 40% (difference 4%, 95% CI ‐2.1%, 10.1%, p = .19) than between the AHA/ESH and ABP load 25%/30% thresholds. A similar agreement pattern persisted between the AHA/ESH and various ABP load thresholds for diagnosing WCH and MH. The AHA and ESH thresholds diagnosed AH, WCH, and MH closest to ABP load 40%/50% than ABP load 25%/30%. Future outcome‐based studies are needed to guide the optimal use of these ABP thresholds in clinical practice.

Abstract Background Telemedicine is increasingly utilized as an alternative to in person consultation. Current pandemic conditions are providing additional impetus to virtual care delivery. We compared both adolescent and caregiver (parent or guardian) attitudes towards telemedicine (here as tertiary center to remote health care location) as a crucial determinant of longer-term effectiveness. Methods This qualitative research study analyzed transcribed structured telephone interviews with both 11–18 year-old pediatric nephrology patients and their caregivers and performed a quantitative analysis of patient demographics, disease factors and distance to tertiary center vs. telemedicine center. Results The study was conducted in a medium-sized tertiary pediatric nephrology centre with a large catchment area of over 0.5 million square kilometers and 629,000 children and adolescents under 18 years of age. Eleven dyads of adolescents and caregivers were enrolled. Five adolescents were male. The mean age of the adolescents was 14.4 ± 2.5 years (range 11.2–18.0). The median distance to our tertiary center was 191 km (range 110–1378 km). Four adolescents lived more than 500 km from our tertiary center. The 11 adolescents had a total of 334 in person visits (mean 30 ± 25) and 86 telemedicine visits (mean 8 ± 7). A ratio of 2:1 telemedicine to in-person visits was favored; with caregivers more in favor of remote care than adolescents. Qualitative analysis found that experiences with telemedicine were distinguished by consultation-specific factors and contextual factors. Contextual factors (travel/cost savings) were valued for telemedicine by adolescents and caregivers. Consultation-specific factors, such as the ability to show the doctor physical symptoms, were more valued during in-person consultations, especially by adolescents. The overall visit type preference was related to the nature of the consultation. For regular check-ups, and for adolescents with less complex needs, participants felt that telemedicine offered a comparable experience to in-person visits. Adolescents with more complex conditions preferred in-person visits. Conclusions Indiscriminate transfer to chronic care predicated on mainly telemedicine approach is not compatible with user expressed attitudes (especially among adolescents). Accurately mapping models of care to these attitudes is an essential determinant of effective management and longer-term engagement with potentially life-long health challenges.

Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) (SLC34A3 gene, OMIM 241530) is an autosomal recessive disorder that results in a loss of function of the sodium-phosphate NPT2c channel at the proximal tubule. Phosphate supplementation rarely improves serum phosphate, hypercalciuria, nephrocalcinosis, 1,25(OH)2 vitamin D (1,25(OH)2D) levels or short stature. Methods: We describe 23Na MRI and the successful use of recombinant human growth hormone (rhGH) and Fluconazole to improve growth (possibly confounded by puberty) and hypercalciuria in a now 12-year-old male with HHRH (novel homozygous SLC34A3 mutation, c.835_846 + 10del.T). Results: The patient had chronic bone pain, hypophosphatemia (0.65 mmol/L[reference interval 1.1–1.9]), pathological fractures and medullary nephrocalcinosis/hypercalciuria (urinary calcium/creatinine ratio 1.66 mol/mmol[480 pmol/L[60–208]. Rickets Severity Score was 4. Treatment with 65 mg/kg/day of sodium phosphate and potassium citrate 10 mmol TID failed to correct the abnormalities.Adding rhGH at 0.35 mg/kg/week to the phosphate therapy, improved bone pain, height z-score from −2.09 to −1.42 over 6 months, without a sustained effect on TmP/GFR. Fluconazole was titrated to 100 mg once daily, resulting for the first time in a reduction of the 1,25(OH)2D to 462 and 426 pmol/L; serum phosphate 0.87 mmol/L, and calcium/creatinine ratio of 0.73.23Na MRI showed normal skin (z-score + 0.68) and triceps surae muscle (z-score + 1.5) Na+ levels; despite a defect in a sodium transporter, hence providing a rationale for a low sodium diet to improve hypercalciuria. Conclusions: The addition of rhGH, Fluconazole and salt restriction to phosphate/potassium supplementation improved the conventional therapy. Larger studies are needed to confirm our findings.

Abstract Background Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle’s loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy. Case presentation We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up. Conclusion Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered.

Introduction: The influence of using 24-hour ambulatory blood pressure (ABP) thresholds recommended by the American Heart Association (AHA) (24-hour mean ABP >95th percentile and ABP load >25%) or the European Society of Hypertension (ESH) (mean 24-hour ABP >95th percentile or >130/80 mm Hg if mean ABP 95th percentile exceeds 130/80 mm Hg) on the diagnosis of pediatric hypertension has been understudied. Methods: In a cross-sectional, retrospective study of 159 children from a tertiary care outpatient clinic, we classified office blood pressure (OBP) as normotension or hypertension based on the OBP thresholds recommended by the American Academy of Pediatrics (AAP) and the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents (herein referred to as the fourth report) by the National High Blood Pressure Educational Program Working Group on High Blood Pressure in Children and Adolescents separately. Thereafter, we evaluated the agreement between the ambulatory AHA and ESH thresholds for diagnosing normotension, white-coat hypertension (WCH), masked hypertension (MH), and hypertension based on the patient’s ABP and OBP hypertension pattern. Results: With office hypertension as per the AAP thresholds, the AHA and ESH thresholds classified 85% of subjects similarly into normotension, WCH, MH, and hypertension (κ = 0.78; 95% CI, 0.67–0.89). The agreement between the AHA and ESH thresholds did not change when OBP was reclassified by the fourth-report OBP thresholds (κ = 0.77; 95% CI, 0.65–0.88). With OBP classified by either AAP or fourth-report thresholds, the ESH thresholds diagnosed 6% to 7% more children as hypertensive, whereas the AHA threshold classified 11% more children as normotensive. Conclusion: The AHA and ESH thresholds have good agreement in classifying OBP. However, the ESH threshold classifies more OBP as hypertensive and the AHA threshold classifies more OBP as normotensive. Keywords: AAP blood pressure guidelines, 24-hour ABPM, AHA ambulatory thresholds, ambulatory thresholds, ESH ambulatory thresholds, fourth-report guidelines, pediatric hypertension

The incidence of nephrolithiasis is increasing worldwide. Understanding how gut microbiome influences oxalate homeostasis has the potential to offer new strategies to prevent nephrolithiasis. The literature was reviewed to gather the evidence on the association between gut microbiome, hyperoxaluria and nephrolithiasis, and to identify the therapeutic interventions focused on the gut microbiome that could decrease hyperoxaluria and prevent nephrolithiasis. Gut microbiome is constituted by a plethora of microbiota including Oxalobacter formigenes (Oxf) and lactobacilli. Oxf can degrade dietary oxalate and induce enteral oxalate secretion. Animal studies suggested an association between oral Oxf supplementation and a decrease in hyperoxaluria. However, human studies have showed inconsistent results. Oral supplementation of lactobacilli did not show benefit in decreasing the hyperoxaluria. Antibiotic exposure, by affecting the gut microbiome, has been associated with an increase in nephrolithiasis. In vivo studies suggest fecal transplantation as a potential treatment option for reducing nephrolithiasis, but needs further evaluation in clinical studies. The current evidence suggests an association between gut microbiome and nephrolithiasis. However, the strategies focused on modulating gut microbiome for decreasing hyperoxaluria and preventing nephrolithiasis need further research. Judicious use of antibiotics in those predisposed to nephrolithiasis offers a preventative strategy for decreasing nephrolithiasis.

Management of acute liver failure (ALF) and acute on chronic liver failure (ACLF) in the pediatric population can be challenging. Kidney manifestations of liver failure, such as hepatorenal syndrome (HRS) and acute kidney injury (AKI), are increasingly prevalent and may portend a poor prognosis. The overall incidence of AKI in children with ALF has not been well-established, partially due to the difficulty of precisely estimating kidney function in these patients. The true incidence of AKI in pediatric patients may still be underestimated due to decreased creatinine production in patients with advanced liver dysfunction and those with critical conditions including shock and cardiovascular compromise with poor kidney perfusion. Current treatment for kidney dysfunction secondary to liver failure include conservative management, intravenous fluids, and kidney replacement therapy (KRT). Despite the paucity of evidence-based recommendations concerning the application of KRT in children with kidney dysfunction in the setting of ALF, expert clinical opinions have been evaluated regarding the optimal modalities and timing of KRT, dialysis/replacement solutions, blood and dialysate flow rates and dialysis dose, and anticoagulation methods.

Abstract Background To assess reasons for continuing practice variation in the management of childhood nephrotic syndrome despite expert reviews and guidelines, we are conducting a longitudinal cohort study in children with glucocorticoid sensitive nephrotic syndrome. Objectives of this mid-study report are to describe patient and physician recruitment characteristics, glucocorticoid prescriptions, use of second line agents, biopsy practices, and adherence to study protocol. Methods Children with new onset nephrotic syndrome and providers are being recruited from all 12 pediatric nephrology centres across Canada with > 2½ years follow-up. Data collection points of observation are over a minimum 36 months. Details of prescribed glucocorticoids and of all second line agents used during treatment are being collected. All relapses are being recorded with time to urinary remission of proteinuria. Results To date, 243 patients (57.1% male) from 12 centres were included. Median number of patients per centre was 29 (range 2–45), and median age of cohort was 7.3 (IQR 4.2) at enrollment. Forty-eight physicians were recruited, median 5 (range 2–8) per site. Median number of relapses per patient year of follow-up was 2.1 (IQR 4). Cumulative dose variability of glucocorticoids prescribed per episode of proteinuria and length of treatment was observed between participating centres. Conclusion The Canadian pediatric nephrology community established a longitudinal childhood nephrotic syndrome cohort study that confirms ongoing practice variability. The study will help to evaluate its impact on patient outcomes, and facilitate clinical trial implementation in nephrotic syndrome.

Renal infarction is a rare finding in children. Associations between SARS-CoV-2 infections and thromboembolic events including renal infarcts have been described in adults. Although a similar association in children has not yet been described with this pandemic, the pediatric literature is still evolving with the recognition of new manifestations including the post-infectious Multisystem Inflammatory Syndrome in Children (MIS-C). We report the rare event of multiple renal infarcts in a 6-year-old boy manifesting several features of MIS-C 9 weeks following a self-limiting febrile illness characteristic of COVID-19. An underlying Factor V Leiden mutation was identified in this child but felt to be insufficient on its own to explain his clinical presentation. As SARS-CoV-2 testing was delayed, the failure to identify viral RNA or antibodies may not exclude the virus' potential role in precipitating the infarct in this host. Given that renal infarcts have been described in adult patients with COVID-19, reporting this perplexing case where SARS-CoV-2 may have played a role, may help identify this potential complication.

Background: Patients with cystic fibrosis (CF) have frequent infectious complications requiring nephrotoxic medications, necessitating monitoring of renal function. Although adult studies have suggested that cystatin C (CysC)-based estimated glomerular filtration rate (eGFR) may be preferable due to reduced muscle mass of patients with CF, pediatric patients remain understudied. Objective: Our objective was to determine which eGFR formula is best for estimating glomerular filtration rate (GFR) in pediatric patients with CF. Methods: A total of 17 patients with CF treated with nephrotoxic antibiotics were recruited from the Children’s Hospital at London Health Sciences Centre, London, Ontario, Canada. 99 Tc DTPA GFR (measured GFR [mGFR]) was measured with 4-point measurements starting at 120 minutes using a 2-compartmental model with Brøchner-Mortensen correction, with simultaneous measurement of creatinine, urea, and CysC. The eGFR was calculated using 16 known equations based on creatinine, urea, CysC, or combinations of these. Primary outcome measures were correlation with mGFR, and agreement within 10% for various eGFR equations. Results: Mean mGFR was 136 ± 21 mL/min/1.73 m 2 . Mean creatinine, CysC, and urea were 38 ± 10 μmol/L, 0.72 ± 0.08 mg/L, and 3.9 ± 1.4 mmol/L, respectively. The 2014 Grubb CysC eGFR had the best correlation coefficient ( r = 0.75, P = .0004); however, only 35% were within 10%. The new Schwartz formula with creatinine and urea had the best agreement within 10%, but a relatively low correlation coefficient ( r = 0.63, P = .0065, 64% within 10%). Conclusions: Our study suggests that none of the eGFR formulae work well in this small cohort of pediatric patients with CF with preserved body composition, possibly due to inflammation causing false elevations of CysC. Based on the small numbers, we cannot conclude which eGFR formula is best.

Abstract Background The hepatic circulation is involved in adaptive systemic responses to circulatory stress. However, it is vulnerable to both chronic hypervolemia and cardiac dysfunction. The influence of hemodialysis (HD) and ultrafiltration (UF) upon liver water content has been understudied. We conducted a detailed pilot study to characterize the effects of HD upon liver water content and stiffness, referenced to peripheral fluid mobilization and total body water. Methods We studied 14 established HD patients without liver disease. Magnetic resonance imaging (MRI) together with ultrasound-based elastography and bioimpedance assessment were employed to measure hepatic water content and stiffness, body composition, and water content in the calf pre- and post-HD. Results Mean UF volume was 8.13 ± 4.4 mL/kg/hr. Fluid removal was accompanied with effective mobilization of peripheral water (measured with MRI within the thigh) from 0.85 ± 0.21 g/mL to 0.83 ± 0.18 g/mL, and reduction in total body water (38.9 ± 9.4 L to 37.4 ± 8.6 L). However, directly-measured liver water content did not decrease (0.57 ± 0.1 mL/g to 0.79 ± 0.3 m L/g). Liver water content and IVC diameter were inversely proportional (r = − 0.57, p = 0.03), a relationship which persisted after dialysis. Conclusions In contrast to the reduced total body water content, liver water content did not decrease post-HD, consistent with a diversion of blood to the hepatic circulation, in those with signs of greater circulatory stress. This novel observation suggests that there is a unique hepatic response to HD with UF and that the liver may play a more important role in intradialytic hypotension and fluid shifts than currently appreciated.

Abstract Background While there is a great deal of research updating methods for estimating renal function, many of these methods are being developed in either adults with CKD or younger children. Currently, there is limited understanding of the agreement between the modified new bedside Schwartz estimated glomerular filtration rate (eGFR) formula and the adult CKD-EPI formula in adolescents and young adults (AYAs) with chronic kidney disease (CKD) measured longitudinally. Methods Longitudinal cohort study of 242 patients (10–30 years) with CKD, followed retrospectively in a single tertiary centre as they transitioned from the paediatric- to adult-focused settings. The study population came from a longitudinal cohort of AYAs undergoing healthcare transition at the STARx Program at the University of North Carolina, in the South-Eastern USA, from 2006 to 2015. We calculated and compared the eGFR using the new bedside Schwartz formula and the CKD-EPI eGFR. Measurements were repeated for each age in years. Agreement was tested using Bland & Altman analysis. Subgroup analysis was performed using the following age groups 10–15, 15–20, 20–25 and 25–30 years, glomerular and non-glomerular causes of CKD and height z-score. Results Using repeated measures, concordance between the new Schwartz and CKD-EPI eGFR was low at 0.74 (95% C.I. 0.67, 0.79) at the lowest age range of 10–15, 0.78 (95% C.I. 0.71, 0.84) at age 15–20, 0.80 (0.70, 0.87) at ages 20–25, and 0.82 (95% C.I. 0.70, 0.90) at age 25–30. Discordance was worse in males and largest in the 10–15 year-old age group, and in patients with stunted growth. Conclusions The Schwartz and CKD-EPI equations exhibit poor agreement in patients before and during the transition period with CKD-EPI consistently yielding higher eGFRs, especially in males. Further studies are required to determine the appropriate age for switching to the CKD-EPI equation after age 18.

Abstract Background Pediatrician and pediatric subspecialist density varies substantially among the various Canadian provinces, as well as among various states in the US. It is unknown whether this variability impacts health outcomes. To study this knowledge gap, we evaluated pediatric asthma admission rates within the 2 Canadian provinces of Manitoba and Saskatchewan, which have similarly sized pediatric populations and substantially different physician densities. Methods This was a retrospective cross-sectional cohort study. Health regions defined by the provincial governments, have, in turn, been classified into “peer groups” by Statistics Canada, on the basis of common socio-economic characteristics and socio-demographic determinants of health. To study the relationship between the distribution of the pediatric workforce and health outcomes in Canadian children, asthma admission rates within comparable peer group regions in both provinces were examined by combining multiple national and provincial health databases. We generated physician density maps for general practitioners, and general pediatricians practicing in Manitoba and Saskatchewan in 2011. Results At the provincial level, Manitoba had 48.6 pediatricians/100,000 child population, compared to 23.5/100,000 in Saskatchewan. There were 3.1 pediatric asthma specialists/100,000 child population in Manitoba and 1.4/100,000 in Saskatchewan. Among peer-group A, the differences were even more striking. A significantly higher number of patients were admitted in Saskatchewan (590.3/100,000 children) compared to Manitoba (309.3/100,000, p

Abstract 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.

BackgroundNeonatal asphyxia caused kidney injury and severe hypertension in a newborn. An unusually dilatated ascending aorta developed. Dialysis and pharmacological treatment led to partial recovery of the ascending aortic diameters. It was hypothesized that the aortic dilatation may be associated with aortic stiffening, peripheral resistance, and cardiovascular changes. Mathematical modeling was used to better understand the potential causes of the hypertension, and to confirm our clinical treatment within the confines of the model’s capabilities.MethodsThe patient’s systolic arterial blood pressure showed hypertension. Echocardiographic exams showed ascending aorta dilatation during hypertension, which partially normalized upon antihypertensive treatment. To explore the underlying mechanisms of the aortic dilatation and hypertension, an existing lumped parameter hemodynamics model was deployed. Hypertension was simulated using realistic literature informed parameter values. It was also simulated using large parameter perturbations to demonstrate effects. Simulations were designed to permit examination of causal mechanisms. The hypertension inducing effects of aortic stiffnesses, vascular resistances, and cardiac hypertrophy on blood flow and pressure were simulated. Sensitivity analysis was used to stratify causes.ResultsIn agreement with our clinical diagnosis, the model showed that an increase of aortic stiffness followed by augmentation of peripheral resistance are the prime causes of realistic hypertension. Increased left ventricular elastance may also cause hypertension. Ascending aortic pressure and flow increased in the simultaneous presence of left ventricle hypertrophy and augmented small vessel resistance, which indicate a plausible condition for ascending aorta dilatation. In case of realistic hypertension, sensitivity analysis showed that the treatment of both the large vessel stiffness and small vessel resistance are more important in comparison to cardiac hypertrophy.Conclusion and DiscussionLarge vessel stiffness was found to be the prime factor in arterial hypertension, which confirmed the clinical treatment. Treatment of cardiac hypertrophy appears to provide significant benefit but may be secondary to treatment of large vessel stiffness. The quantitative grading of pathophysiological mechanisms provided by the modeling may contribute to treatment recommendations. The model was limited due to a lack of data suitable to permit model identification.

Postural Orthostatic Tachycardia Syndrome (POTS) is a debilitating disease with a commonly non-uniform and unspecific presentation that makes diagnosis difficult. A twelve-year-old girl, recently diagnosed with Addison’s Disease, was referred to paediatric nephrology for Fludrocortisone-induced nocturnal hypertension. She had fallen off the growth curve for both height and weight from the 50th percentile at birth to below the 5th percentile at presentation. The severity and multitude of her symptoms, including muscle weakness, poor body control, dizziness, light headedness, persistent fatigue, excessive sweating, tachycardia, chronic constipation and recurrent infection hinted at the unusual nature of this case of Addison’s. At the time of referral, she had been seen by more than a dozen specialists and subspecialists as well as undergone a number of tests including neurophysiological testing without sufficient explanation. With the help of tilt-table testing, we established the diagnosis of POTS. There is a lack of tested treatment options for POTS, and we established dosing of pyridostigmine in children, based on the emerging literature in adults. While pyridostigmine therapy substantially improved her quality of life, it took another 6 years and referral outside the country, before a final unifying diagnosis was made. Eventually, the patient was diagnosed with Ehlers Danlos Syndrome with associated autonomic dysfunction, including POTS, as well as primary adrenal insufficiency. The parents and the patient experienced considerable stress due to the lack of willingness of many physicians that the family encountered to search for a diagnosis and a treatment.

Background: Continuous renal replacement therapy (CRRT) is an excellent method used to remove fluid and solutes. It may also reduce the systemic inflammatory response for patients on extracorporeal membrane oxygenation (ECMO) support. The objective of this report is to describe a case where CRRT in combination with ECMO was insufficient to control hyperkalemia. Methods: We report the case of an adolescent patient with refractory symptomatic hyperkalemia due to substantial rhabdomyolysis in which CRRT insufficiently cleared the patient’s excess potassium. Results: Intermittent hemodialysis (IHD) was added and proved successful. The patient was weaned off ECMO, CRRT, and IHD, and his cardiac and renal function eventually normalized. Conclusions: Two important lessons can be learned from this case report: (1) If CRRT is insufficient in achieving a desirable potassium balance, additional IHD should be considered and (2) separate IHD access should be considered to improve efficacy.

In the original publication of this article [1], the institutional author’s name needs to be revised from The Paediatric Chairs of Canada Mark Bernstein to The Paediatric Chairs of Canada.

Pediatric urolithiasis has increased globally in the last few decades. There has been a change in the pattern of stone composition with an increase in the frequency of kidney stones and a decrease in bladder stones. The role of familial predisposition and environmental factors in pediatric urolithiasis is now better understood. Metabolic factors are more common in pediatric urolithiasis than in adult stone disease. This review updates on the epidemiology of pediatric urolithiasis with a focus on the changing trends in the stone disease, current spectrum of stone disease encountered in clinical practice, individual predisposition and the role of environmental factors in stone formation.

Background: Severe hypercalcaemia is a rare but clinically significant condition in infancy and childhood. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcaemia resulting from a malignancy is rare and only a handful of case reports have outlined its incidence alongside a benign condition. Objectives: To describe the diagnostic workup and management of an infant with hypercalcaemia, renal dysplasia, and elevated PTHrP levels. Design: Case report. Setting: The Victoria Hospital campus of the London Health Sciences Centre in London, Ontario, Canada. Patients: A child with congenital anomalies of the kidneys and urinary tract (CAKUT), stage 2 chronic kidney disease (CKD), and renal dysplasia who presented with severe hypercalcaemia. Measurements: Weight, renal ultrasound, creatinine, cystatin C, eGFR, calcium, urea, bicarbonate, serum sodium, fractional sodium excretion, urine calcium to creatinine ratio, PTH, TSH, Free T4, AM cortisol, HMA, VMA, 25-vitamin D, 1,25 dihydroxy-vitamin D, calcitriol, vitamin A, ACE levels, skull and chest x-rays, alkaline phosphatase, CBC, tumour lysis profile, catecholamine breakdown, whole-body MRI, PTHrP. Methods: Full diagnostic workup and patient management. Patient treated with intravenous hydration, furosemide, calcitonin and CalciLo. Results: PTHrP was elevated and no evidence of a malignancy was found. Treatment consisting of a low-calcium CalciLo diet (in place of breast milk) adequately controlled the patient's hypercalcaemia. Hypercalcaemia associated with CAKUT in infancy is not all that uncommon and was reported in 15/99 infants in another study, most of whom had a suppressed PTH similar to that of our patient. PTHrP was not measured in these cases and may have also been elevated. Limitations: The study is limited in that it is a description of a single patient case. Future measurement of PTHrP in similar patients is necessary to confirm our results. Conclusions: The possibility of elevated PTHrP levels must be considered in patients with known renal dysplasia who are differentially diagnosed with hypercalcaemia.

Background: Nephrotic syndrome is a commonly acquired kidney disease in children that causes significant morbidity due to recurrent episodes of heavy proteinuria. The management of childhood nephrotic syndrome is known to be highly variable among physicians and care centres. Objectives: The primary objective of the study is to determine centre-, physician-, and patient-level characteristics associated with steroid exposure and length of steroid treatment. We will also determine the association of dose and duration of steroid treatment and time to first relapse as a secondary aim. An embedded qualitative study utilizing focus groups with health care providers will enrich the quantitative results by providing an understanding of the attitudes, beliefs and local contextual factors driving variation in care. Design: Mixed-methods study; prospective observational cohort (quantitative component), with additional semi-structured focus groups of healthcare professionals (qualitative component). Setting: National study, comprised of all 13 Canadian pediatric nephrology clinics. Patients: 400 patients under 18 years of age to be recruited over 2.5 years. Measurements: Steroid doses for all episodes (first presentation, first and subsequent relapses) tracked over course of the study. Physician and centre-level characteristics catalogued, with reasons for treatment preferences documented during focus groups. Methods: All patients tracked prospectively over the course of the study, with data comprising a prospective registry. One focus group at each site to enrich understanding of variation in care. Limitations: Contamination of treatment protocols between physicians may occur as a result of concurrent focus groups. Conclusions: Quantitative and qualitative results will be integrated at end of study and will collectively inform strategies for the development and implementation of standardized evidence-based protocols across centres.

Background. Serum concentration of NT-proBNP correlates well with the severity of cardiac disease in adults. Few studies have been performed on the applicability of NT-proBNP for monitoring children with congenital heart disease. Objective. To assess the potential of NT-proBNP for monitoring the success of interventions in children with stenotic cardiac lesions. Methods. NT-proBNP was measured in 42 children aged 1 day to 17 years (y) before and 6 to 12 weeks after surgical or interventional correction of obstructive lesions of the heart. Comparison is made with the clinical status and echocardiographic data of the child. Results. NT-proBNP levels (median 280, range 10–263,000 pg/mL) were above the reference value in all but 6 patients (pts) prior to the intervention. Higher levels were found in more compromised patients. The 35 children with clinical improvement after the procedure showed a decline of their NT-proBNP level in all but 4 patients, whose levels remained unchanged. Five patients with unchanged gradients despite a therapeutic intervention also demonstrated unchanged NT-proBNP levels after the intervention. Thus, the success rate of the procedure correlated well to clinical and echocardiographic findings. Conclusion. NT-proBNP can be used to assess the efficiency of an intervention.