Development of a Novel Prediction Tool for Response to First-Line Treatments of Monosymptomatic Nocturnal Enuresis-A Randomized, Controlled International Multicenter Study (DRYCHILD).

PURPOSE: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE. MATERIALS AND METHODS: A randomized, controlled, international multicenter study was conducted in 324 treatment-naïve children (6-14 years) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated. RESULTS: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (RR = 1.21 (1.02-1.45), P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (RR = 1.46 (1.14-1.87), P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (ROC 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improve response to first line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response.

Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Exploring lifelong overactive bladder: Transitions, evidence, and clinical implications; A modified Delphi process.

INTRODUCTION: Overactive bladder (OAB) is a prevalent urological condition characterized by urinary urgency, with or without urgency urinary incontinence, accompanied by increased daytime frequency and nocturia. However, the current definition of OAB lacks a specified time frame, hindering our understanding of the temporal aspects and transitions that occur within the OAB spectrum. METHODS: A modified Delphi study was conducted in three rounds, involving a panel of international experts in functional urology, urogynaecology, geriatrics, transitional medicine, and pediatric urology. The study took place between February 2023 and June 2023 and employed two sequential rounds of online surveys, followed by a final hybrid group discussion session in June 2023. RESULTS: The Delphi process resulted in a consensus definition of lifelong OAB as a persistent and continuous condition that may manifest differently from birth and evolve over time, with varying levels of clinical perception. The course of its progression is influenced by transition periods and modifying factors, mainly anatomical, hormonal, and psychosocial/stressors. Three main transition periods were identified: achievement of daytime continence, adulthood to elderly, and transition to frail elderly. The panel also considered the therapeutic and diagnostic implications of lifelong OAB, as well as future research prospects in terms of importance and feasibility. CONCLUSIONS: Future longitudinal research is needed to develop this concept and further identify transitions and temporal dynamics.

Transition in enuresis patients: Identifying the gaps and opportunities for the future.

BACKGROUND: Nocturnal enuresis is generally considered a children's condition, yet it may persist 1%-2% in adolescence and early adulthood. Refractory patients often demand follow-up by multidisciplinary teams, which is only restricted to some of the expert tertiary centers. However, there are no standardized transition programs/guidelines when follow-up must be passed from pediatric to adult healthcare providers. AIM, MATERIALS & METHODS: To investigate this issue, we conducted a literature search on enuresis transition, which resulted in no articles. We, therefore, proceeded in a rescue search strategy: we explored papers on transition programs of conditions that may be related and/or complicated by enuresis, nocturia, or other urinary symptoms (chronic diseases, CKD, bladder dysfunction, kidney transplant, neurogenic bladder). RESULTS: These programs emphasize the need for a multidisciplinary approach, a transition coordinator, and the importance of patient and parent participation, practices that could be adopted in enuresis. The lack of continuity in enuresis follow-up was highlighted when we investigated who was conducting research and publishing on enuresis and nocturia. Pediatric disciplines (50%) are mostly involved in children's studies, and urologists in the adult ones (37%). DISCUSSION: We propose a stepwise approach for the transition of children with enuresis from pediatric to adult care, depending on the clinical subtype: from refractory patients who demand more complex, multidisciplinary care and would benefit from a transition coordinator up to children/young adults cured of enuresis but who persist in having or present lower urinary tract symptoms (LUTS)/nocturia later on. In any case, the transition process should be initiated early at the age of 12-14 years, with adequate information to the patient and parents regarding relapses or LUTS/nocturia occurrence and of the future treating general practitioner on the enuresis characteristics and comorbidities of the patient.

Mental health and professional outcomes in parents of children with chronic kidney disease.

BACKGROUND: This study evaluated parenting stress, anxiety, and depression symptoms and their associated factors in parents of children with chronic kidney disease (CKD). METHODS: This cross-sectional study compared parents of patients with CKD (0-18 years) with a matched control group of parents of healthy children. Both groups completed the Parenting Stress Index - Short Form, the Hospital Anxiety and Depression Scale, and a sociodemographic questionnaire. RESULTS: The study group consisted of 45 parents (median age 39; 32 mothers) of CKD patients (median age 8; 36% female). Nearly 75% of children had CKD stages 2, 3, or 4, and 44.5% had congenital anomaly of the kidney and urinary tract. Five children (11%) were on dialysis, and 4 (9%) had a functioning kidney graft. Compared with parents of healthy children, more stress and anxiety symptoms were reported. Since the CKD diagnosis, 47% of parents perceived a deterioration of their own health, and 40% reduced work on a structural basis. Higher levels of stress, anxiety, and depression symptoms were associated with a more negative perception of own health, and more child medical comorbidities and school absence. CONCLUSIONS: This study showed higher levels of parenting stress and anxiety symptoms in parents of children with CKD compared with parents of healthy children. This was associated with a less positive perception of their own health, especially if the child had more medical comorbidities or more absence from school. Psychosocial interventions to reduce the parental burden should be integrated in the standard care of pediatric nephrology departments.

First uninterrupted sleep period in children and adolescents with nocturnal enuresis: Added value in diagnosis and follow-up during therapy.

BACKGROUND: The first uninterrupted sleep period (FUSP, time up to the first episode of enuresis/nocturia after falling asleep) is a frequently investigated parameter in adults with nocturia, as it correlates with quality of life. However, it has not been included in pediatric enuresis studies. AIM: Investigate FUSP, circadian renal water and sodium handling, as well as sleep quality before and after desmopressin therapy in enuresis. MATERIALS AND METHODS: We conducted a post hoc analysis of a prospective study in 30 treatment-naïve children with enuresis who underwent a video-polysomnography and a 24-h urine concentration profile before and after 6 months of desmopressin therapy. We analyzed FUSP, periodic limb movements in sleep (PLMS), and arousal indexes and their correlations with the urinary parameters. RESULTS: Sixteen children with a mean age of 10.9 ± 3.1 years had full registrations and were included in this subanalysis. After therapy, FUSP was significantly longer (p < 0.001), and the PLMS index was lower (p = 0.023). Significant differences in the circadian rhythm of diuresis (night/day diuresis, p = 0.041), nocturnal urinary osmolality (p = 0.009), and creatinine (p = 0.001) were found, demonstrating the increase of urinary concentration overnight by desmopressin, as well as a significant antidiuretic effect (diuresis [p = 0.013] and diuresis rate (p = 0.008). There was no correlation between the difference of FUSP, PLMS index, and urinary parameters. Nevertheless, despite this study being underpowered, there are indications of a correlation between nocturnal diuresis and diuresis rate. RESULTS: Our results support the need for further research regarding FUSP in children with enuresis, in accordance with nocturia studies in adults, as this parameter could be valuable in the follow-up and evaluation of therapeutic strategies for enuresis.

The role of renal circadian biorhythms in lifelong LUTS.

INTRODUCTION: This article delves into the intricate relationship between kidney function, diuresis, and lower urinary tract symptoms (LUTS) throughout the transitions of the human lifespan. It explores circadian regulation of urine production, maturation of renal function from birth to adulthood, and effects of aging on kidney function and LUTS. The complex connections between these factors are highlighted, offering insights into potential interventions and personalized management strategies. METHODS: An international panel of seven experts engaged in online discussions, focusing on kidney function, diuresis, and LUTS throughout life. This manuscript summarizes expert insights, literature reviews, and findings presented during a webinar and subsequent discussions. RESULTS: Renal function undergoes significant maturation from birth to adulthood, with changes in glomerular filtration rate, diuresis, and tubular function. A circadian rhythm in urine production is established during childhood. Adolescents and young adults can experience persistent enuresis due to lifestyle factors, comorbidities, and complex physiological changes. In older adults, age-related alterations in kidney function disrupt the circadian rhythm of diuresis, contributing to nocturnal polyuria and LUTS. CONCLUSION: The interplay between kidney function, diuresis, and LUTS is crucial in understanding lifelong urinary health. Bridging the gap between pediatric and adult care is essential to address enuresis in adolescents and young adults effectively. For older adults, recognizing the impact of aging on renal function and fluid balance is vital in managing nocturia. This holistic approach provides a foundation for developing innovative interventions and personalized treatments to enhance quality of life for individuals with LUTS across all stages of life.

Circadian rhythm of water and solute excretion in nocturnal enuresis.

BACKGROUND: Nocturnal polyuria (NP) due to a suppressed vasopressin circadian rhythm is a well-documented pathogenetic mechanism in enuresis, mainly studied in monosymptomatic enuresis. A substantial percentage of patients do not respond to desmopressin. This suggests that NP may not only be related to vasopressin, but that other kidney components play a role. Solute handling and osmotic excretion have been investigated in the past, especially in refractory patients. Nevertheless, data in treatment-naïve populations with information on timing overnight are sparse. This study aims to investigate the diuresis and solute excretion in treatment-naïve patients with or without NP, with emphasis on circadian rhythms. METHODS: Retrospective analysis of 403 treatment-naïve children 5-18 years with severe enuresis (> 8 nights/2 weeks). Circadian rhythms were evaluated by a 24-h urine collection in 8 timed portions (4 day, 4 nighttime) at in-home settings. Urine volume, osmolality, and creatinine were measured. Patients were subdivided into three groups according to nocturnal diuresis (ND) and Expected Bladder Capacity (EBCage) ratio: (a) < 100%, (b) 100-129%, (c) > 130%. RESULTS: All groups maintained circadian rhythm for diuresis and diuresis rates. Patients with higher ND (100-129% and > 130% EBCage) had higher daytime volumes and less pronounced circadian rhythm. In the ND group > 130% EBCage, the ND rate was higher during the first night collection and osmotic excretion was significantly higher overnight. CONCLUSIONS: Overall 24-h fluid intake (reflected by 24-h diuresis) and nutritional intake (24-h osmotic excretion) might play a role in enuresis. Increased diuresis rate early in the night can be important in some patients, whereas the total night volume can be important in others. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Early corticosteroid withdrawal is associated with improved adult height in pediatric kidney transplant recipients.

BACKGROUND: Catch-up growth after pediatric kidney transplantation (kTx) is usually insufficient to reach normal adult height. We aimed to analyze the effect of pre-transplant recombinant human growth hormone (rhGH) and corticosteroid withdrawal on linear growth in the first year after kidney transplantation and identify factors associated with final height (FH). METHODS: Patients who underwent kTx between 1996 and 2018 at below 18 years old in five Belgian and Dutch centers were included. We analyzed the differences between height Z-scores at kTx and 1 year post-transplant (Δ height Z-score) in children with and without corticosteroids at 1 year (CS + /CS -) and with and without rhGH treatment before kTx (rhGH + /rhGH -). Univariable and multivariable linear regression analysis was applied to identify factors associated with height Z-score at 1 year post-kTx, Δ height Z-score, and FH Z-score. RESULTS: A total of 177 patients were included, with median age 9.3 years at kTx. Median height Z-scores pre-kTx and 1 year later in the CS - /rhGH - , CS + /rhGH - , CS - /rhGH + , and CS + /rhGH + groups were - 1.42/ - 0.80, - 0.90/ - 0.62, - 1.35/ - 1.20, and - 1.30/ - 1.60 (p = 0.001). CS use 1 year post-kTx was the only factor associated with Δ height (p = 0.003) on multivariable analysis. CS use at 1 year was the only variable associated with FH (p = 0.014) in children with pre-transplant height Z-score below - 1 (n = 52). CONCLUSIONS: Increase in height Z-score in the first year post-kTx was highest in the CS - /rhGH - group and lowest in the CS + /rhGH + group. The use of corticosteroids at 1 year post-kTx is associated with catch-up growth and in children with pre-transplant height Z-score below - 1 also with final height. A higher resolution version of the Graphical abstract is available as Supplementary information.

Illness-related parental stress and quality of life in children with kidney diseases.

BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations.

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.

Validity and reliability of the Dutch version of the PedsQL™ 3.0 End Stage Renal Disease Module in children with chronic kidney disease in Belgium.

BACKGROUND: Children with chronic kidney disease (CKD) have a low quality of life (QoL). The PedsQL™ 4.0 Generic Core Scales are widely used to assess general QoL in children. The aim of this cross-sectional study was to translate the original version of the CKD-specific PedsQL™ 3.0 End Stage Renal Disease Module into a Dutch version and to evaluate its validity and reliability. METHODS: The forward-backward translation method based on the guidelines from the original developer was used to produce the Dutch version of the PedsQL™ 3.0 ESRD Module. Fifty-eight CKD patients (aged 8-18 years) and their parents (n = 31) filled in both generic and disease-specific modules. The non-clinical control group consisted of the same number of healthy children (matched for gender and age) and their parents. RESULTS: Cronbach's alpha coefficients (α's) for the PedsQL™ 3.0 ESRD Module demonstrated excellent reliability for the Total Scale scores. For all 7 subscales, α's were greater than 0.60, except for Perceived Physical Appearance. Overall, intercorrelations with the PedsQL™ 4.0 Generic Core Scales were in the medium to large range, supporting construct validity. Parent proxy reports showed lower generic QoL for all domains in CKD patients compared to healthy children. Child self-reports only demonstrated lower QoL on the domain School Functioning in children with CKD compared to healthy children. CONCLUSIONS: This study shows good validity and reliability for the Dutch version of the PedsQL™ 3.0 ESRD Module. However, testing with a larger study group is recommended in order to make final conclusions about the psychometric qualities of this measure. A higher resolution version of the Graphical abstract is available as Supplementary information.

Potassium and fiber: a controversial couple in the nutritional management of children with chronic kidney disease.

BACKGROUND: Fruit and vegetable intake is commonly discouraged in children with chronic kidney disease (CKD) to avoid hyperkalemia. However, direct evidence in support of this widespread practice is lacking. Furthermore, the resultant restricted fiber exposure may deprive CKD patients from potential health benefits associated with the latter. Therefore, we investigated associations between dietary potassium intake, fiber intake, and serum potassium levels in pediatric CKD. METHODS: This study is a longitudinal analysis of a 2-year, prospective, multi-institutional study, following children with CKD at 3-month intervals. At each visit, dietary potassium and fiber intake were assessed, using 24-h recalls and 3-day food records. On the same occasion, serum potassium concentrations were determined. Associations between dietary potassium intake, dietary fiber intake, and serum potassium concentrations were determined using linear mixed models. RESULTS: Fifty-two CKD patients (7 transplant recipients, none on dialysis) aged 9 [4;14] years with an estimated glomerular filtration rate (eGFR) of 49 [25;68] mL/min/1.73 m2 were included. For every g/day decrease in dietary potassium intake, the estimated mean daily fiber intake was 5.1 g lower (95% confidence interval (CI), 4.3-5.9 g/day; p < 0.001). Neither dietary potassium intake (p = 0.40) nor dietary fiber intake (p = 0.43) was associated with circulating potassium in a model adjusted for time point, eGFR, treatment with a renin-angiotensin-aldosterone system blocker, serum bicarbonate concentration, and body surface area. CONCLUSIONS: Dietary potassium and fiber intake are closely related but were not associated with circulating potassium levels in pediatric CKD. A higher-resolution version of the graphical abstract is available as Supplementary information.

Mental Health Outcomes Among Parents of Children With a Chronic Disease During the COVID-19 Pandemic: The Role of Parental Burn-Out.

OBJECTIVE: The COVID-19 pandemic and associated quarantine measures highly impacted parental psychological well-being. Parents of children with chronic diseases might be specifically vulnerable as they already face multiple challenges to provide adequate care for their child. The research questions of the current study were twofold: (a) to examine whether parents of children with a chronic disease experienced more anxiety and depression compared to parents of healthy children and (b) to examine a series of risk factors for worsened well-being (i.e., depression, anxiety, and sleep problems), such as sociodemographic variables, COVID-19-specific variables (i.e., financial worries, living space, and perceived quality of health care), and parental psychological experiences (i.e., parental burn-out and less positive parenting experiences). METHODS: Parents of children with a chronic disease (i.e., the clinical sample; N = 599 and 507 for Research Questions 1 and 2, respectively) and parents of healthy children (i.e., the reference sample: N = 417) filled out an online survey. RESULTS: Findings demonstrated that the parents in the clinical sample reported higher levels of anxiety than parents in the reference sample. Analyses within the clinical sample indicated that COVID-19-specific stressors and parental psychological experiences were associated with higher levels of anxiety, depression, and sleep problems. Mediation analyses furthermore indicated that the association of COVID-19-specific stressors with all outcome measures was mediated by parental burn-out. CONCLUSIONS: Parents of children with a chronic disease constitute a vulnerable group for worse well-being during the current pandemic. Findings suggest interventions directly targeting parental burn-out are warranted.

Body mass index is associated with hyperparathyroidism in pediatric kidney transplant recipients.

BACKGROUND: Hyperparathyroidism persists in up to 50% of pediatric kidney transplant recipients. The aims of this study were to describe the evolution of parathyroid hormone (PTH) in the first year after transplantation and to identify factors associated with hyperparathyroidism. METHODS: This retrospective study included children who underwent kidney transplantation at the University Hospitals of Ghent, Leuven, Rotterdam, or Amsterdam. Data from 149 patients were collected before and up to 12 months after transplantation. Severe hyperparathyroidism was defined as PTH 2-fold above the reference value. Factors associated with hyperparathyroidism and severe hyperparathyroidism were identified using multivariate logistic regression analysis. RESULTS: Before transplantation, 97 out of 137 patients (71%) had hyperparathyroidism. The probability of hyperparathyroidism and severe hyperparathyroidism declined from 0.49 and 0.17 to 0.29 and 0.09 at 3 and 12 months after transplantation, respectively. BMI SDS (ß: 0.509; p = 0.011; 95% CI: 1.122-2.468), eGFR (ß: - 0.227; p = 0.030; 95% CI: 0.649-0.978), and pre-transplant hyperparathyroidism (ß: 1.149; p = 0.039; 95% CI: 1.062-9.369) were associated with hyperparathyroidism 12 months after transplantation. Pre-transplant hyperparathyroidism (ß: 2.115; p = 0.044; 95% CI: 1.055-65.084), defined as intact parathormone (iPTH) levels > 65 ng/l (6.9 pmol/l) or 1-84 PTH > 58 ng/l (6.2 pmol/l), was associated with severe hyperparathyroidism at 3 months. Only eGFR (ß: - 0.488; p = 0.010; 95% CI: 0.425-0.888) was inversely associated with severe hyperparathyroidism at 9 months after transplantation. CONCLUSIONS: Allograft function remains the main determinant of severe hyperparathyroidism after transplantation. Our findings emphasize the importance of BMI and pre-transplant PTH control.

Dietary fibre intake is low in paediatric chronic kidney disease patients but its impact on levels of gut-derived uraemic toxins remains uncertain.

BACKGROUND: Chronic kidney disease (CKD) in children is a pro-inflammatory condition leading to a high morbidity and mortality. Accumulation of organic metabolic waste products, coined as uraemic toxins, parallels kidney function decline. Several of these uraemic toxins are protein-bound (PBUT) and gut-derived. Gut dysbiosis is a hallmark of CKD, resulting in a state of increased proteolytic fermentation that might be counteracted by dietary fibre. Data on fibre intake in children with CKD are lacking. We aimed to assess dietary fibre intake in a paediatric CKD cohort and define its relationship with PBUT concentrations. METHODS: In this multi-centre, cross-sectional observational study, 61 non-dialysis CKD patients (9 ± 5 years) were included. Dietary fibre intake was assessed through the use of 24-h recalls or 3-day food records and coupled to total and free levels of 4 PBUTs (indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG) and indole acetic acid (IAA). RESULTS: In general, fibre intake was low, especially in advanced CKD: 10 ± 6 g/day/BSA in CKD 4-5 versus 14 ± 7 in CKD 1-3 (p = 0.017). Lower concentrations of both total (p = 0.036) and free (p = 0.036) pCG were observed in the group with highest fibre intake, independent of kidney function. CONCLUSIONS: Fibre intake in paediatric CKD is low and is even worse in advanced CKD stages. Current dietary fibre recommendations for healthy children are not being achieved. Dietary management of CKD is complex in which too restrictive diets carry the risk of nutritional deficiencies. The relation of fibre intake with PBUTs remains unclear and needs further investigation. Graphical abstract.

Haemodiafiltration does not lower protein-bound uraemic toxin levels compared with haemodialysis in a paediatric population.

BACKGROUND: Haemodiafiltration (HDF) is accepted to effectively lower plasma levels of middle molecules in the long term, while data are conflicting with respect to the additive effect of convection on lowering protein-bound uraemic toxins (PBUTs). Here we compared pre-dialysis ß2-microglobulin (ß2M) and PBUT levels and the percentage of protein binding (%PB) in children on post-dilution HDF versus conventional high- (hf) or low-flux (lf) haemodialysis (HD) over 12 months of treatment. METHODS: In a prospective multicentre, non-randomized parallel-arm intervention study, pre-dialysis levels of six PBUTs and ß2M were measured in children (5-20 years) on post-HDF (n = 37), hf-HD (n = 42) and lf-HD (n = 18) at baseline and after 12 months. Analysis of variance was used to compare levels and %PB in post-HDF versus conventional hf-HD and lf-HD cross-sectionally at 12 months and longitudinal from baseline to 12 months. RESULTS: For none of the PBUTs, no difference was found in either total and free plasma levels or %PB between post-HDF versus the hf-HD and lf-HD groups. Children treated with post-HDF had lower pre-dialysis ß2M levels [median 23.2 (21.5; 26.6) mg/dL] after 12 months versus children on hf-HD [P<0.01; 35.2 (29.3; 41.2) mg/dL] and children on lf-HD [P<0.001; 47.2 (34.3; 53.0) mg/dL]. While ß2M levels remained steady in the hf-HD and lf-HD group, a decrease in ß2M was demonstrated for children on post-HDF (P<0.01). CONCLUSIONS: While post-HDF successfully decreased ß2M, no additive effect on PBUT over 12 months of treatment was found. PBUT removal is complex and hampered by several factors. In children, these factors might be different from adults and should be explored in future research.

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes.

BACKGROUND: This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. METHODS: This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. RESULTS: We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. CONCLUSIONS: Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.

Drug-metabolizing enzymes CYP3A as a link between tacrolimus and vitamin D in renal transplant recipients: is it relevant in clinical practice?

CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D. In this review, we summarize the clinical aspects of CYP3A-mediated metabolism of tacrolimus and vitamin D with emphasis on the influence of single-nucleotide polymorphisms on tacrolimus disposition. We describe the utility of 4ß hydroxycholesterol as a marker of CYP3A activity. Then, we discuss the possible interaction between calcineurin inhibitors and vitamin D in solid organ transplant recipients. Also, we review other mechanisms which may contribute to side effects of calcineurin inhibitors on bone. Lastly, suggestions for future research and clinical perspectives are discussed.