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The authors discuss barriers for clinical trials including the ethical approach to acquiring high level evidence for optimal decision making, lack of funding, paucity of partners, low interest from pharmaceutical industry, regulatory issues, under-recognition of children's rights and autonomy and attitudes of patients/caregivers and providers. Topics include differences between pediatric subspecialties, examples of some pediatric nephrology studies, and ethical considerations and harms.

Background: The diagnosis of hypertension and hypertension-induced target organ injury by the 2022 American Heart Association (AHA) ambulatory blood pressure threshold as compared with 2014 AHA and 2016 European Society of Hypertension (ESH) thresholds has not been evaluated. Methods: In a cross-sectional study (n = 291, aged 5–18 years, at a tertiary care outpatient clinic), we compared 2022 AHA with 2014 AHA and ESH thresholds (revised with 2018 adult ESH thresholds where applicable) to diagnose ambulatory hypertension (AH), and detect ambulatory arterial stiffness index (AASI) and left ventricular target organ injury (LVTOI). Results: The 2022 AHA threshold diagnosed significantly more AH (53%) than the 2014 AHA (42%, p < 0.01) and ESH (36%, p < 0.001) thresholds. The 2022 AHA threshold demonstrated only a moderate agreement with the 2014 AHA (kappa (k) = 0.77) and ESH (k = 0.66) thresholds to diagnose AH. Adjusted logistic regression analysis found that only the 2022 AHA threshold predicted elevated AASI significantly (odds ratio 2.40, 95% CI 1.09, 5.25, p = 0.02; AUC 0.61, p < 0.01). In those with elevated AASI, more participants had AH by the 2022 AHA threshold (72%) than the 2014 AHA (46%, p = 0.02) and ESH (48%, p = 0.03) thresholds. AH defined by the 2022 AHA threshold continued to maintain higher odds, larger AUC, and higher sensitivity to identify LVTOI than the 2014 AHA and ESH thresholds; however, the difference did not reach a statistically significant level. Conclusions: AH defined by the 2022 AHA threshold diagnoses more children with hypertension and identifies more children with hypertension-induced target organ injury than the 2014 AHA and ESH thresholds. [ABSTRACT FROM AUTHOR]

An editorial is presented on assessing kidney length in children and adolescents being overweight or obese. Topics include overweight and obese children which being a very interesting finding demonstrating the importance of external validation; and resulting in underestimation of kidney length and kidney volumes in overweight and obese patients overestimating it in thin patients.

Background: Sodium-23 magnetic resonance imaging (23Na MRI) allows non-invasive assessment of tissue sodium concentration ([Na+]). Age and chronic kidney disease (CKD) are associated with increased tissue [Na+] in adults, but limited information is available pertaining to children and adolescents. We hypothesized that pediatric CKD is associated with altered tissue [Na+] compared to healthy controls. Methods: This was a case–control exploratory study on healthy children and adults and pediatric CKD patients. Study participants underwent an investigational visit, blood/urine biochemistry, and leg 23Na MRI for tissue [Na+] quantification (whole leg, skin, soleus muscle). CKD was stratified by etiology and patients' tissue [Na+] was compared against healthy controls by computing individual Z-scores. An absolute Z-score > 1.96 was deemed to deviate significantly from the mean of healthy controls. Pearson correlation was used to compute the associations between tissue [Na+] and kidney function. Results: A total of 36 pediatric participants (17 healthy, 19 CKD) and 19 healthy adults completed the study. Healthy adults had significantly higher tissue [Na+] compared with pediatric groups; conversely, no significant differences were found between healthy children/adolescents and CKD patients. Four patients with glomerular disease and one kidney transplant recipient due to atypical hemolytic-uremic syndrome had elevated whole-leg [Na+] Z-scores. Reduced whole-leg [Na+] Z-scores were found in two patients with tubular disorders (Fanconi syndrome, proximal–distal renal tubular acidosis). All tissue [Na+] measures were significantly associated with proteinuria and hypoalbuminemia. Conclusions: Depending on etiology, pediatric CKD was associated with either increased (glomerular disease) or reduced (tubular disorders) tissue [Na+] compared with healthy controls. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

The article comments on a paper by Chloe Braun and colleagues on the estimation of glomerular filtration rate in pediatric and adult patients with acute kidney injury (AKI). Topics mentioned include the proposed formula for estimating baseline creatinine by age and sex, the link between serum creatinine and muscle mass, and the use of electronic health records with rule-based algorithms for immediate detection of AKI.

Acute kidney disease predicts chronic kidney disease in pediatric non-kidney solid organ transplant patients. Impaired kidney function >90 days determines long-term kidney outcomes Keywords: acute kidney disease; acute kidney injury; children; transplantation EN acute kidney disease acute kidney injury children transplantation 1 3 3 08/16/22 20220901 NES 220901 Abbreviations AKD acute kidney disease AKI acute kidney injury CKD chronic kidney disease ESKD end-stage chronic kidney disease GFR glomerular filtration rate IDMS isotope-dilution mass spectrometry RAAS renin-angiotensin-aldosterone system INTRODUCTION Some organs of the human body have evolved to a degree that organoids, the functioning units of more complex organs, can only develop until a certain time in the development. Footnotes 1 Editorial for "Acute Kidney Disease Predicts Chronic Kidney Disease in Pediatric Non-Kidney Solid Organ Transplant Patients" by Mital Patel et al. [Extracted from the article]

The article comments on the study "Large Inter-Assay Difference of Serum Creatinine in the Pediatric Population: A Threat to Accurate Staging of Chronic Kidney Disease," by K. Lao and colleagues. Topics noted include the use of creatinine in estimating glomerular filtration rate, the factors that affect the levels of serum creatinine, the difference between the Abbott enzymatic method and the Abbott Jaffe method, and the need to standardize the calibration procedure in creatinine measurement.

Background: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis. Objective: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis. Results: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications. Conclusions: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis. [ABSTRACT FROM AUTHOR]

In a recent article in Pediatric Nephrology, EM Yang and colleagues (Pediatr Nephrol 2017: doi:) published a retrospective cross-sectional study involving a cohort of 442 children with an mean estimated glomerular filtration rate of >60 mL/min/1.73 m. The authors measured 24-h urine protein excretion (24-h UProt) alongside the morning spot urine protein to creatinine ratio (Prot/Cr) in this group of patients. While the Prot/Cr may be the only feasible way to routinely estimate the daily protein excretion of a young child, inter-individual variability in childrens' urinary creatinine excretion (UCr) may heavily influence the result. The authors sought to determine which equation was the most accurate in predicting UCr. Not only did they discover that the adult Cockcroft-Gault equation worked best, they also found that multiplying the Prot/Cr by the estimated UCr significantly improved the accuracy of the 24-h UProt estimate. In this editorial we discuss both the strengths and limitations of the study by EM Yang and colleagues. We also highlight the importance of adhering to internationally agreed upon reporting guidelines such as the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement. [ABSTRACT FROM AUTHOR]

Aim The 2006 World Health Organization ( WHO) growth charts have been widely adopted by Canadian dieticians for growth monitoring of Canadian children rather than the National Health and Nutrition Examination Survey ( NHANES III) reference data. It has been unclear as to which is the most appropriate. Methods We calculated height and weight z-scores of 3086 consecutive patients (1530 female, 49.6%) aged 0-5 years, attending outpatient clinics at a single tertiary care centre using reference data of the latest NHANES survey and the 2006 WHO growth charts. To address age dependency, data were stratified into age groups. Gender dependency was also investigated. Results Using NHANES III reference intervals, medians of both height z-score (+0.24) and weight z-score (+0.32) were significantly non-zero. The WHO growth charts yielded medians of height z-score (−0.15) and weight z-score (+0.36) respectively, also significantly non-zero. When comparing both reference populations for the entire cohort, Canadian children had significantly different height z-scores whereas weight z-scores did not differ. Age classification revealed a significant age dependency with NHANES III charts yielding higher weight z-scores for up to 8 months and lower z-scores from 8 to 26 months. No significant differences were observed for older than 26 months. Throughout, height z-scores were significantly higher with NHANES III charts across all age groups, with a degree of overestimation higher in younger boys than older ones. Conclusion Our results reveal substantial differences between both reference populations and thus interpretation needs to be done with caution, especially when labelling results as abnormal. [ABSTRACT FROM AUTHOR]

The management of steroid-dependent nephrotic syndrome, especially in patients who have failed to respond to cytotoxic drugs, such as cyclophosphamide, remains challenging. Rituximab represents a new (off-label) therapeutic option. In a significant portion of patients, it has a short serum half-life following the recovery of CD20-positive cells. The addition of mycophenolate mofetil (MMF) as a maintenance therapy is also an attractive option, but one which requires testing in a prospective randomized clinical trial with therapeutic drug monitoring and mechanistic ancillary studies. [ABSTRACT FROM AUTHOR]

The objective of this case series was to review the safety and efficacy of aliskiren in combination with losartan in pediatric chronic kidney disease (CKD) patients. This was a retrospective study in which the medical files of all patients who had received aliskiren were reviewed. Four patients were identified between 5 and 18 years of age who had received aliskiren and losartan for the reduction of refractory proteinuria. While proteinuria was reduced in all four of these patients by 45, 96, 53, and 64%, respectively, three patients experienced side effects requiring changes in the aliskiren dose. A significant side effect occurred in the patient with CKD stage 3 who suffered accelerated loss of kidney function leading to dialysis after only a short course of therapy. The data from this preliminary trial strongly suggest that clinicians should exercise caution when prescribing aliskiren in combination with losartan until appropriate pediatric trials establish dosing, efficacy, and safety. [ABSTRACT FROM AUTHOR]

Potential age-dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver–kidney, two liver, mean age 8.0 ± 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady-state with 10 samples drawn over 12 h post-intake to calculate the AUC0–12 h. Concentrations of sirolimus and metabolite were quantified using a validated LC-MS/MS assay and metabolite structures were identified directly in blood extracts using LC-MS/iontrap. Average sirolimus AUC0–12 h was 64.9 ± 29.7 ng h/mL. Median (range) AUC0–12 h for each metabolite (ng h/mL) was: 12-hydroxy-sirolimus 7.6 (0.2–18.8), 46-hydroxy sirolimus 3.1 (0.0–12.4), 24-hydroxy sirolimus 4.3 (0.0–12.6), piperidine-hydroxy sirolimus 3.5 (0.0–8.3), 39- O-desmethyl sirolimus 3.6 (0.0–11.3), 16- O-desmethyl sirolimus 5.0 (0.1–9.9), and di-hydroxy sirolimus 4.3 (0.0–32.5). The metabolites reached a median total AUC0–12 h of 60% of that of sirolimus. The range was 2.6–136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39- O-desmethyl sirolimus accounted for only 8.4% of the AUC0–12 h. This is clinically relevant as 39- O-desmethyl sirolimus shows 86–127% cross-reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically. [ABSTRACT FROM AUTHOR]

Few studies report Ganciclovir or Valganciclovir levels in children. Single-center, retrospective study of all available Ganciclovir levels in transplanted children. Ganciclovir monitoring was performed as previously described [G. Filler (1998); Pediatric Nephrology, 12, 6]. For the normalization of dosing to GFR and target trough levels, we assumed first-order kinetics. We analyzed 57 Ganciclovir levels in 20 children (mean age 8.6 ± 5.5 yr) treated with intravenous or oral Ganciclovir or oral Valganciclovir. Ganciclovir levels were drawn after IV therapy (n = 9), during oral Ganciclovir (n = 5), or during oral Valganciclovir (n = 15). Oral bioavailability of Valganciclovir was 42.0 ± 21.8%. The dose-normalized intrapatient Valganciclovir variability was 83%. Mean GFR was 92 ± 22 mL/min/1.73 m2. Mean Ganciclovir concentration at last available measurement was 0.60 ± 0.09 mg/L. While target trough Ganciclovir levels have not been established, possibly subtherapeutic Ganciclovir levels <0.5 mg/L on recommended IV doses were found in eight patients. This subset of patients was significantly younger (4.5 ± 3.1 vs. 11.4 ± 5.0 yr). Levels <0.5 mg/L were found in 24/57 instances and 10 patients subsequently had their dose increased. The last Valganciclovir dose adjusted to a GFR of 100 mL/min/1.73 m2 was 842 ± 323 mg/m2/day. A high proportion of patients had low Ganciclovir levels both on intravenous and oral therapy. The oral bioavailability of Valganciclovir was 42%. Our data suggest substantial inter- and intrapatient variability of Ganciclovir levels after pediatric renal transplantation and may support the need for pharmacokinetic monitoring of Ganciclovir and Valganciclovir therapy for the prevention and treatment of CMV disease after pediatric transplantation. It is currently unclear what target trough level would be most suitable. [ABSTRACT FROM AUTHOR]

The Cockcroft-Gault formula should not be used in children.Background.Although designed for adults, the Cockcroft-Gault formula was recently proposed for use in children≥13 years of age.Methods.We compared the feasibility of the Cockcroft-Gault formula against the standard pediatric Schwartz formula and a novel cystatin C–based formula. Our patient cohort included 262 children aged 1 to 18 years with various renal pathologies, who underwent a 99-technetium diethylenetriaminepentaacetate (99Tc DTPA) glomerular filtration rate (GFR) renal scan. Calculations were performed in Système International (SI) units using published constants and recalculated constants from our patient population. Agreement was assessed using Bland and Altman analysis.Results.Published and recalculated constants for the Cockcroft-Gault formula were 1.23 and 0.96, respectively, for boys, and 1.05 and 0.90, respectively, for girls. The published and recalculated constants for the Schwartz formula were 48 and 49.9, respectively, for boys≥13 years old, and 38 and 46.2, respectively, for all girls and for boys<13 years old. Using published constants, there was agreement between GFR and Cockcroft-Gault formula in boys≥13 years old (average bias 5.0± 23.5%) while there was an average error of−19.0%± 36.4% for all ages. Similarly, the average bias with Schwartz for boys≥13 years old was−6.8± 24.0% and for all patients was−12.8± 24.2%. Using recalculated constants, the average bias with Cockcroft-Gault in boys≥13 years old was−19.8± 23.5% and for all patients was−38.5± 35.2%. Similarly, the average bias with Schwartz for boys≤13 years old was−1.1± 24.3% and for all patients was 3.0± 24.0%. The novel cystatin C–based GFR calculations showed an average error of−4.9± 20.3% in the adolescent boys and 2.4± 20.4% for all ages.Conclusion.Cockcroft-Gault formula showed the worst agreement with GFR, regardless of using published or recalculated constants. The cystatin C–based approach resulted in the least error, and should be used for estimation of GFR. [ABSTRACT FROM AUTHOR]

It is common practice to estimate glomerular filtration rate (GFR) from the Schwartz formula (a height creatinine/ratio), although it has its limitations. Cystatin C was found to be a superior marker of GFR. No formula has been validated to estimate GFR from cystatin C in children. Children (aged 1.0–18 years, n=536) with various renal pathologies undergoing nuclear medicine GFR clearance studies ([sup 99m]Tc-DTPA single-injection technique) were tested. Cystatin C was measured with a nephelometric assay. The Schwartz GFR was calculated using enzymatically determined serum creatinine in micromoles per liter using the constant 48 for adolescent males and 38 otherwise. Using multiple stepwise regression analysis on log/log-transformed data, we derived the following relationship between the cystatin C concentration and GFR: . Using the Bland and Altman analysis to test agreement between the Schwartz formula and gold standard GFR showed considerable bias, with a mean difference of +10.8% and a trend towards overestimation of the GFR by the Schwartz formula with lower GFRs. In contrast, the Bland and Altman analysis applied on the GFR estimate derived from cystatin C showed the mean difference to be negligible at +0.3% and no trend towards overestimation of the GFR with lower GFRs. In the regression analysis of the estimate and the GFR, the Schwartz estimate showed significant deviation from linearity, whereas the cystatin C estimate did not. In conclusion, the data suggest that this novel cystatin C-based GFR estimate shows significantly less bias and serves as a better estimate for GFR in children. [ABSTRACT FROM AUTHOR]

Abstract: Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1-yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long-term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long-term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125 I-iothalamate clearance and serum cystatin C (cys-C). Of all the serum markers, cys-C is the most reliable and the most promising. However, cys-C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125 I-iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125 I-iothalamate remain costly and time consuming. [ABSTRACT FROM AUTHOR]

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/V but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/V. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters. [ABSTRACT FROM AUTHOR]

The article presents the author's views regarding an approach to cardio-renal dysfunction in children diagnosed with congenital heart disease. Identification on the pathophysiological interplay between kidney and heart as cardiorenal syndrome (CRS), is highlighted. Also cited is the significant early CRS recognition to guide therapy and improve results of affected patients.

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. [ABSTRACT FROM AUTHOR]