A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity.

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen α3α4α5 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation.

Assessment and management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation: clinical practice points from the Pediatric Renal Nutrition Taskforce.

Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.

Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Use of ClearGuard HD caps in pediatric hemodialysis patients.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of hospitalizations and mortality among patients receiving hemodialysis (HD) therapy, especially those with a central venous catheter (CVC) for dialysis access. The use of chlorhexidine impregnated catheter caps (ClearGuard) has been associated with a decrease in the rate of HD catheter-related BSIs (CA-BSIs) in adults; similar data have not been published for children. METHODS: We compared CA-BSI data from participating centers within the Standardizing Care to Improve Outcomes in Pediatric Endstage Kidney Disease (SCOPE) collaborative based on the center's use of ClearGuard caps for patients with HD catheter access. Centers were characterized as ClearGuard (CG) or non-ClearGuard (NCG) centers, with CA-BSI data pre- and post-CG implementation reviewed. All positive blood cultures in participating centers were reported to the SCOPE collaborative and adjudicated by an infectious disease physician. RESULTS: Data were available from 1786 SCOPE enrollment forms completed January 2016-January 2022. January 2020 served as the implementation date for analyzing CG versus NCG center data, with this being the time when the last CG center underwent implementation. Post January 2020, there was a greater decrease in the rate of HD CA-BSI in CG centers versus NCG centers, with a decrease from 1.18 to 0.23 and 0.41 episodes per 100 patient months for the CG and NCG centers, respectively (p = 0.002). CONCLUSIONS: Routine use of ClearGuard caps in pediatric dialysis centers was associated with a reduction of HD CA-BSI rates in pediatric HD patients.

Associations between anemia and FGF23 in the CKiD study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort. METHODS: Hemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects. RESULTS: In 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized ß (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized ß (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized ß (95% CI) 0.02 (-0.12, 0.15), p = 0.81). CONCLUSIONS: In this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.

Iodine-induced hypothyroidism (IIH) in paediatric patients receiving peritoneal dialysis: Is risk mitigation possible?

Children with kidney failure who receive maintenance peritoneal dialysis (PD) are at increased risk for thyroid dysfunction. A poorly appreciated cause of hypothyroidism related to PD is iodine overload from exposure to iodine-containing cleaning solutions, iodinated contrast agents or povidone-iodine-containing PD caps, particularly in infants and small children. An international survey was conducted to understand current practices regarding iodine exposure in PD patients, the frequency of iodine-induced hypothyroidism (IIH) in patients receiving PD, and to assess awareness of this issue among paediatric nephrologists. Eighty-nine paediatric nephrology centres responded to the survey. Hypothyroidism in PD patients was diagnosed in 64% (n = 57) of responding centres, although only 19 of these centres (33%) suspected or diagnosed IIH. Aetiologies of IIH included exposure to povidone-iodine-containing PD caps (53%), cleaning solutions with iodine (37%) and iodinated contrast (10%). While most centres (58%, n = 52) routinely evaluate thyroid function, only 34% (n = 30) specifically aim to limit iodine exposure. Of centres not routinely evaluating for or utilising methods to prevent iodine exposure and hypothyroidism, 81% reported being unaware of the risk of IIH in PD patients. Hypothyroidism is diagnosed in a substantial percentage of paediatric PD programmes internationally. Increased education on the risk of iodine exposure in children receiving PD may decrease the incidence of IIH as an aetiology of hypothyroidism.

Real-world evidence on the dosing and safety of C.E.R.A. in pediatric dialysis patients: findings from the International Pediatric Dialysis Network registries.

BACKGROUND: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD). METHODS: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021). RESULTS: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m2. Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years). CONCLUSIONS: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals.

Technical requirements and devices available for long-term hemodialysis in children-mind the gap!

Children requiring long-term kidney replacement therapy are a "rare disease" cohort. While the basic technical requirements for hemodialysis (HD) are similar in children and adults, key aspects of the child's cardiovascular anatomy and hemodynamic specifications must be considered. In this article, we describe the technical requirements for long-term HD therapy for children and the devices that are currently available around the world. We highlight the characteristics and major technical shortcomings of permanent central venous catheters, dialyzers, dialysis machines, and software available to clinicians who care for children. We show that currently available HD machines are not equipped with appropriately small circuits and sensitive control mechanisms to perform safe and effective HD in the youngest patients. Manufacturers limit their liability, and health regulatory agencies permit the use of devices, only in children according to the manufacturers' pre-specified weight limitations. Although registries show that 6-23% of children starting long-term HD weigh less than 15 kg, currently, there is only one long-term HD device that is cleared for use in children weighing 10 to 15 kg and none is available and labelled for use in children weighing less than 10 kg anywhere in the world. Thus, many children are being treated "off-label" and are subject to interventions delivered by medical devices that lack pediatric safety and efficacy data. Moreover, recent improvements in dialysis technology offered to adult patients are denied to most children. We, in turn, advocate for concerted action by pediatric nephrologists, industry, and health regulatory agencies to increase the development of dedicated HD machines and equipment for children.

Pubertal luteinizing hormone levels in children with chronic kidney disease and association with change in glomerular filtration rate.

BACKGROUND: Children with chronic kidney disease (CKD) are at risk for abnormalities in pubertal development. We aimed to describe the timing of pubertal onset by luteinizing hormone (LH) levels and the association between hormonal onset of puberty with changes in GFR. METHODS: Data from the Chronic Kidney Disease in Children (CKiD) study were collected prospectively. GFR was estimated at annual visits and measured by iohexol clearance every other year. LH was measured from stored repository serum samples in a nested sample of 124 participants. Hormonal onset of puberty was defined as LH level greater than or equal to 0.3 IU/L. A mixed effects model with random intercepts and slopes was used to compare the slope of decline of GFR before and after hormonal onset of puberty. The model was adjusted for age, glomerular disease diagnosis, baseline proteinuria on the log scale, and BMI. RESULTS: Median age at hormonal onset of puberty was 9.9 years (IQR 8.1, 11.9) in girls and 10.2 years (IQR 9.2, 11.0) in boys. The mixed effects model showed faster decline in both estimated GFR and measured GFR in boys after hormonal onset of puberty (p < 0.001), and a similar but attenuated accelerated estimated GFR decline was observed for girls with no difference for measured GFR. CONCLUSIONS: LH levels in the post-pubertal range were observed prior to clinical manifestations of puberty in children with CKD. Hormonal onset of puberty was associated with faster decline in GFR, particularly among boys with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Plasma Metabolomics of Dietary Intake of Protein-Rich Foods and Kidney Disease Progression in Children.

OBJECTIVE: Evidence regarding the efficacy of a low-protein diet for patients with CKD is inconsistent and recommending a low-protein diet for pediatric patients is controversial. There is also a lack of objective biomarkers of dietary intake. The purpose of this study was to identify plasma metabolites associated with dietary intake of protein and to assess whether protein-related metabolites are associated with CKD progression. METHODS: Nontargeted metabolomics was conducted in plasma samples from 484 Chronic Kidney Disease in Children (CKiD) participants. Multivariable linear regression estimated the cross-sectional association between 949 known, nondrug metabolites and dietary intake of total protein, animal protein, plant protein, chicken, dairy, nuts and beans, red and processed meat, fish, and eggs, adjusting for demographic, clinical, and dietary covariates. Cox proportional hazards models assessed the prospective association between protein-related metabolites and CKD progression defined as the initiation of kidney replacement therapy or 50% eGFR reduction, adjusting for demographic and clinical covariates. RESULTS: One hundred and twenty-seven (26%) children experienced CKD progression during 5 years of follow-up. Sixty metabolites were significantly associated with dietary protein intake. Among the 60 metabolites, 10 metabolites were significantly associated with CKD progression (animal protein: n = 1, dairy: n = 7, red and processed meat: n = 2, nuts and beans: n = 1), including one amino acid, one cofactor and vitamin, 4 lipids, 2 nucleotides, one peptide, and one xenobiotic. 1-(1-enyl-palmitoyl)-2-oleoyl-glycerophosphoethanolamine (GPE, P-16:0/18:1) was positively associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 88% higher risk of CKD progression. 3-ureidopropionate was inversely associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 48% lower risk of CKD progression. CONCLUSIONS: Untargeted plasma metabolomic profiling revealed metabolites associated with dietary intake of protein and CKD progression in a pediatric population.

Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD.

BACKGROUND: Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD. METHODS: We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30-90 ml/min per 1.73 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR. RESULTS: There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide-and with intelligence: γ -glutamyl amino acids and aconitate. CONCLUSIONS: Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis.

Association Between Dialysis Facility Ownership and Mortality Risk in Children With Kidney Failure.

Importance: In adults, treatment at profit dialysis facilities has been associated with a higher risk of death. Objective: To determine whether profit status of dialysis facilities is associated with the risk of death in children with kidney failure treated with dialysis and whether any such association is mediated by differences in access to transplant. Design, Setting, and Participants: This retrospective cohort study reviewed US Renal Data System records of 15 359 children who began receiving dialysis for kidney failure between January 1, 2000, and December 31, 2019, in US dialysis facilities. The data analysis was performed between May 2, 2022, and June 15, 2023. Exposure: Time-updated profit status of dialysis facilities. Main Outcomes and Measures: Adjusted Fine-Gray models were used to determine the association of time-updated profit status of dialysis facilities with risk of death, treating kidney transplant as a competing risk. Cox proportional hazards regression models were also used to determine time-updated profit status with risk of death regardless of transplant status. Results: The final cohort included 8465 boys (55.3%) and 6832 girls (44.7%) (median [IQR] age, 12 [3-15] years). During a median follow-up of 1.4 (IQR, 0.6-2.7) years, with censoring at transplant, the incidence of death was higher at profit vs nonprofit facilities (7.03 vs 4.06 per 100 person-years, respectively). Children treated at profit facilities had a 2.07-fold (95% CI, 1.83-2.35) higher risk of death compared with children at nonprofit facilities in adjusted analyses accounting for the competing risk of transplant. When follow-up was extended regardless of transplant status, the risk of death remained higher for children treated in profit facilities (hazard ratio, 1.47; 95% CI, 1.35-1.61). Lower access to transplant in profit facilities mediated 67% of the association between facility profit status and risk of death (95% CI, 45%-100%). Conclusions and Relevance: Given the higher risk of death associated with profit dialysis facilities that is partially mediated by lower access to transplant, the study's findings indicate a need to identify root causes and targeted interventions that can improve mortality outcomes for children treated in these facilities.

Standardizing Blood Pressure Measurements in Pediatric Hemodialysis: a Collaborative Journey.

PURPOSE OF REVIEW: This manuscript details the development and execution of a quality improvement (QI) initiative aimed at standardizing blood pressure (BP) measurement practices in pediatric hemodialysis (HD) units across a national dialysis collaborative. RECENT FINDINGS: Although there are recommendations for the detection and treatment of hypertension in the pediatric population, currently there is no data or recommendations specific to the methodology of measuring blood pressure in a pediatric hemodialysis setting. In 2016, the Standardizing Care to Improve Outcomes in Pediatric End Stage Kidney Disease (SCOPE) Collaborative assembled a dedicated working group to thoroughly examine BP measurement practices across participating pediatric HD centers and, drawing from current research, to establish a standardized best practice for BP measurement in pediatric HD patients both in-center and at home. Employing QI methodology, the working group devised a standardized "BP Bundle" and implemented it throughout the SCOPE Collaborative. This work led to successful practice improvement by establishing a consistent approach to BP measurement in pediatric HD patients cared for in SCOPE centers. With a standard best practice now in place and over 85% compliance with the BP Bundle across the SCOPE Collaborative, researchers and healthcare professionals can more accurately study and ultimately enhance the cardiovascular health of pediatric HD patients.

Evidence of increased vascular stiffness and left ventricular hypertrophy in children with cystic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of mortality in chronic kidney disease (CKD). Children with early-onset CKD arguably experience the greatest lifetime CVD burden. We utilized data from the Chronic Kidney Disease in Children Cohort Study (CKiD) to evaluate two pediatric CKD cohorts: congenital anomalies of the kidney and urinary tract (CAKUT) and cystic kidney disease for CVD risks and outcomes. METHODS: CVD risk factors and outcomes including blood pressures, left ventricular hypertrophy (LVH), left ventricular mass index (LVMI), and ambulatory arterial stiffness index (AASI) scores were evaluated. RESULTS: Forty-one patients in the cystic kidney disease group were compared to 294 patients in the CAKUT group. Cystic kidney disease patients had higher cystatin-C levels, despite similar iGFR. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) indexes were higher in the CAKUT group, but a significantly higher proportion of cystic kidney disease patients was on anti-hypertensive medications. Cystic kidney disease patients had increased AASI scores and a higher incidence of LVH. CONCLUSIONS: This study provides a nuanced analysis of CVD risk factors and outcomes including AASI and LVH in two pediatric CKD cohorts. Cystic kidney disease patients had increased AASI scores, higher incidence of LVH, and higher rates of anti-hypertensive medication use which could imply a greater burden of CVD despite similar GFR. Our work suggests that additional mechanisms may contribute to vascular dysfunction in cystic kidney disease, and that these patients may need additional interventions to prevent the development of CVD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pediatric peritoneal dialysis training program and its relationship to peritonitis: a study of the International Pediatric Peritoneal Dialysis Network.

BACKGROUND: The guidelines for training of patients and caregivers to perform home peritoneal dialysis (PD) uniformly include recommendations pertaining to the prevention of peritonitis. The objective of this study conducted by the International Pediatric Peritoneal Dialysis Network (IPPN) was to investigate the training practices for pediatric PD and to evaluate the impact of these practices on the peritonitis and exit-site infection (ESI) rate. METHODS: A questionnaire regarding details of the PD program and training practices was distributed to IPPN member centers, while peritonitis and ESI rates were either derived from the IPPN registry or obtained directly from the centers. Poisson univariate and multivariate regression was used to determine the training-related peritonitis and ESI risk factors. RESULTS: Sixty-two of 137 centers responded. Information on peritonitis and ESI rates were available from fifty centers. Training was conducted by a PD nurse in 93.5% of centers, most commonly (50%) as an in-hospital program. The median total training time was 24 hours, with a formal assessment conducted in 88.7% and skills demonstration in 71% of centers. Home visits were performed by 58% of centers. Shorter (< 20 hours) training duration and lower number of training tools (both p < 0.02) were associated with higher peritonitis rate, after adjustment for proportion of treated infants and income of country of residence. CONCLUSIONS: An association between training duration and the number of training tools represent potentially modifiable risk factors to reduce peritonitis rates within the pediatric PD population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Associations between collagen X biomarker and linear growth velocity in a pediatric chronic kidney disease cohort.

BACKGROUND: Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function. METHODS: We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. RESULTS: A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth. CONCLUSIONS: CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Lessons learned from regional training of paediatric nephrology fellows in Africa.

BACKGROUND: Access to care for children with kidney disease is limited in less well-resourced regions of the world and paediatric nephrology (PN) workforce development with good practical skills is critical. METHODS: Retrospective review of a PN training program and trainee feedback from 1999 to 2021, based at Red Cross War Memorial Children's Hospital (RCWMCH), University of Cape Town. RESULTS: A regionally appropriate 1-2-year training program enrolled 38 fellows with an initial 100% return rate to their country of origin. Program funding included fellowships from the International Pediatric Nephrology Association (IPNA), International Society of Nephrology (ISN), International Society of Peritoneal Dialysis (ISPD), and the African Paediatric Fellowship Program (APFP). Fellows were trained on both in- and out-patient management of infants and children with kidney disorders. "Hands-on skills" training included examination, diagnosis and management skills, practical insertion of peritoneal dialysis catheters for management of acute kidney injury and kidney biopsies. Of 16 trainees who completed > 1 year of training, 14 (88%) successfully completed subspecialty exams and 9 (56%) completed a master's degree with a research component. PN fellows reported that their training was appropriate and enabled them to make a difference in their respective communities. CONCLUSIONS: This training program has successfully equipped African physicians with the requisite knowledge and skills to provide PN services in resource-constrained areas for children with kidney disease. The provision of funding from multiple organizations committed to paediatric kidney disease has contributed to the success of the program, along with the fellows' commitment to build PN healthcare capacity in Africa. A higher resolution version of the Graphical abstract is available as Supplementary information.

Development of an adaptive clinical web-based prediction tool for kidney replacement therapy in children with chronic kidney disease.

Clinicians need improved prediction models to estimate time to kidney replacement therapy (KRT) for children with chronic kidney disease (CKD). Here, we aimed to develop and validate a prediction tool based on common clinical variables for time to KRT in children using statistical learning methods and design a corresponding online calculator for clinical use. Among 890 children with CKD in the Chronic Kidney Disease in Children (CKiD) study, 172 variables related to sociodemographics, kidney/cardiovascular health, and therapy use, including longitudinal changes over one year were evaluated as candidate predictors in a random survival forest for time to KRT. An elementary model was specified with diagnosis, estimated glomerular filtration rate and proteinuria as predictors and then random survival forest identified nine additional candidate predictors for further evaluation. Best subset selection using these nine additional candidate predictors yielded an enriched model additionally based on blood pressure, change in estimated glomerular filtration rate over one year, anemia, albumin, chloride and bicarbonate. Four additional partially enriched models were constructed for clinical situations with incomplete data. Models performed well in cross-validation, and the elementary model was then externally validated using data from a European pediatric CKD cohort. A corresponding user-friendly online tool was developed for clinicians. Thus, our clinical prediction tool for time to KRT in children was developed in a large, representative pediatric CKD cohort with an exhaustive evaluation of potential predictors and supervised statistical learning methods. While our models performed well internally and externally, further external validation of enriched models is needed.