Mortality in Children Treated With Maintenance Peritoneal Dialysis: Findings From the International Pediatric Peritoneal Dialysis Network Registry.

RATIONALE & OBJECTIVE: Research on pediatric kidney replacement therapy (KRT) has primarily focused on Europe and North America. In this study, we describe the mortality risk of children treated with maintenance peritoneal dialysis (MPD) in different parts of the world and characterize the associated demographic and macroeconomic factors. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients younger than 19 years at inclusion into the International Pediatric Peritoneal Dialysis Network registry, who initiated MPD between 1996 and 2017. EXPOSURE: Region as primary exposure (Asia, Western Europe, Eastern Europe, Latin America, North America, and Oceania). Other demographic, clinical, and macroeconomic (4 income groups based on gross national income) factors also were studied. OUTCOME: All-cause MPD mortality. ANALYTICAL APPROACH: Patients were observed for 3 years, and the mortality rates in different regions and income groups were calculated. Cause-specific hazards models with random effects were fit to calculate the proportional change in variance for factors that could explain variation in mortality rates. RESULTS: A total of 2,956 patients with a median age of 7.8 years at the start of KRT were included. After 3 years, the overall probability of death was 5%, ranging from 2% in North America to 9% in Eastern Europe. Mortality rates were higher in low-income countries than in high-income countries. Income category explained 50.1% of the variance in mortality risk between regions. Other explanatory factors included peritoneal dialysis modality at start (22.5%) and body mass index (11.1%). LIMITATIONS: The interpretation of interregional survival differences as found in this study may be hampered by selection bias. CONCLUSIONS: This study shows that the overall 3-year patient survival on pediatric MPD is high, and that country income is associated with patient survival.

Protein energy wasting; what is it and what can we do to prevent it?

Some children with declining height and BMI SDS fail to respond to optimisation of nutritional intake. As well as poor growth, they have muscle wasting and relative preservation of body fat. This is termed protein energy wasting (PEW). The process results from an interaction of chronic inflammation alongside poor nutritional intake. This review discusses the causes and potential preventative therapies for PEW.

Assessment of nutritional status in children with kidney diseases-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

In children with kidney diseases, an assessment of the child's growth and nutritional status is important to guide the dietary prescription. No single metric can comprehensively describe the nutrition status; therefore, a series of indices and tools are required for evaluation. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. Herein, we present CPRs for nutritional assessment, including measurement of anthropometric and biochemical parameters and evaluation of dietary intake. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Audit and research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT.

Delivery of a nutritional prescription by enteral tube feeding in children with chronic kidney disease stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

The nutritional prescription (whether in the form of food or liquid formulas) may be taken orally when a child has the capacity for spontaneous intake by mouth, but may need to be administered partially or completely by nasogastric tube or gastrostomy device ("enteral tube feeding"). The relative use of each of these methods varies both within and between countries. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPRs) based on evidence where available, or on the expert opinion of the Taskforce members, using a Delphi process to seek consensus from the wider community of experts in the field. We present CPRs for delivery of the nutritional prescription via enteral tube feeding to children with chronic kidney disease stages 2-5 and on dialysis. We address the types of enteral feeding tubes, when they should be used, placement techniques, recommendations and contraindications for their use, and evidence for their effects on growth parameters. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgement. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.

Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Should we abandon GFR in the decision to initiate chronic dialysis?

The best time to start chronic dialysis during the course of CKD stage 5 is controversial. The first randomised control trial of dialysis initiation either in early or late CKD stage 5 in adults (IDEAL study), and 3 studies from the two largest paediatric registries, the U.S. Renal Data System (USRDS) and the European Society of Paediatric Nephrology (ESPN) Registry, have now provided us with evidence to guide us in this important decision-making process. The message 'no benefit from early start of dialysis' is the conclusion from all four studies. However, what are the limitations of these studies? Can GFR be assessed at CKD stages 4 and 5? What are the factors used to assess the benefit of early or late start? These issues are discussed in this review.

Catch-up growth in children with chronic kidney disease started on enteral feeding after 2 years of age.

BACKGROUND: Enteral feeding by tube in chronic kidney disease (CKD) before 2 years of age improves growth. Whether it is effective after this age is unknown. We assessed whether height and weight SDS changed after tube feeding was started in children with CKD above 2 years of age. METHODS: Retrospective study of pre-transplant, pre-pubertal children (< 11 years) with CKD stages 2-5 started on nasogastric tube or gastrostomy feeds for the first time after age 2 years. Children were identified by searching dietetic records and the renal database. Children on growth hormone were excluded. Height, weight, and BMI were documented 1 year prior to and at the start of tube feeds, and after 1 and 2 years. Data collection ceased at transplantation. RESULTS: Fifty children (25 male) were included. The median (range) age at start of tube feeds was 5.6 (2.1-10.9) years. Sixteen children were dialysed (1 haemodialysis, 15 peritoneal dialysis); 34 predialysis patients had a median (range) eGFR of 22 (6-88) ml/min/1.73 m2. Overall height SDS (Ht SDS) improved from - 2.39 to - 2.27 at 1 year and - 2.18 after 2 years (p = 0.02). BMI SDS improved from - 0.72 to 0.23 after 1 year and was 0.09 after 2 years of enteral feeding (p < 0.0001). Height SDS improved more in children aged 2-6 years (- 2.13 to - 1.68, p = 0.03) and in children not on dialysis (- 2.33 to - 1.99, p = 0.002). CONCLUSIONS: Enteral tube feeding commenced after 2 years of age in prepubertal children with CKD improves height and weight SDS, with stability of BMI during the second year. Younger children and those not on dialysis had the greatest benefit.

Energy and protein requirements for children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2-5 and those on dialysis (CKD2-5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.

The dietary management of calcium and phosphate in children with CKD stages 2-5 and on dialysis-clinical practice recommendation from the Pediatric Renal Nutrition Taskforce.

In children with chronic kidney disease (CKD), optimal control of bone and mineral homeostasis is essential, not only for the prevention of debilitating skeletal complications and achieving adequate growth but also for preventing vascular calcification and cardiovascular disease. Complications of mineral bone disease (MBD) are common and contribute to the high morbidity and mortality seen in children with CKD. Although several studies describe the prevalence of abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels as well as associated clinical and radiological complications and their medical management, little is known about the dietary requirements and management of calcium (Ca) and phosphate (P) in children with CKD. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists, who develop clinical practice recommendations (CPRs) for the nutritional management of various aspects of renal disease management in children. We present CPRs for the dietary intake of Ca and P in children with CKD stages 2-5 and on dialysis (CKD2-5D), describing the common Ca- and P-containing foods, the assessment of dietary Ca and P intake, requirements for Ca and P in healthy children and necessary modifications for children with CKD2-5D, and dietary management of hypo- and hypercalcemia and hyperphosphatemia. The statements have been graded, and statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.

Assessment of dialysis adequacy: beyond urea kinetic measurements.

Adequacy of dialysis is a term that has been used for many years based on measurement of small solute clearance using urea and creatinine. This has been shown in some but not all studies in adults to correlate with survival. However, small solute clearance is just one minor part of the effectiveness of dialysis and in fact 'optimum' dialysis, rather than 'adequate' dialysis is what most paediatric nephrologists would want for their patients. Additional ways to assess the success of dialysis in children would include dialysis access complications and longevity, preservation of residual kidney function, body composition, biochemical and haematological control, nutrition and growth, discomfort during the dialysis process and psychosocial adjustment including hospitalisation and school attendance. These criteria need to be balanced against a dialysis programme that has the least possible adverse effects on quality of life.

Chronic kidney disease following twin-to-twin transfusion syndrome-long-term outcomes.

BACKGROUND: Amongst other sequelae, acute kidney injury (AKI) is a well-recognised post-natal complication of twin-to-twin transfusion syndrome (TTTS). Despite this, there has been a lack of data reporting long-term renal outcomes. Our aim was to report the long-term renal outcomes of infants born with TTTS. METHODS: We performed a retrospective case note review of all infants referred to our centre between 1998 and 2018 with a primary diagnosis of TTTS. Subjects with confirmed TTTS were divided into a chronic kidney disease (CKD) group and a non-CKD group for comparison. RESULTS: Twenty-six infants with TTTS were included for analysis. Eight (31%) subjects developed CKD. Within the CKD group, 50% went on to require long-term renal replacement therapy (RRT) of whom all underwent renal transplantation. For subjects who had neonatal AKI, cumulative survival rate before RRT at 5 and 10 years was 79% and 70%, respectively. Subjects with CKD had a significantly higher incidence of AKI in the neonatal period and were more likely to be the donor twin. Gestational age at birth, gender, antenatal interventions and comorbidities did not affect long-term renal outcome between the two groups. CONCLUSION: This is the first long-term follow-up study demonstrating that CKD progressing to the need for RRT can develop after TTTS. Donor-twin status and neonatal AKI associated with adverse long-term outcomes warranting long-term surveillance in this group.

Assessing the hydration status of children with chronic kidney disease and on dialysis: a comparison of techniques.

Background: Fluid balance is pivotal in the management of children with chronic kidney disease (CKD) and on dialysis. Although many techniques are available to assess fluid status, there are only a few studies for children, of which none have been comparable against cardiovascular outcome measures. Methods: We performed a longitudinal study in 30 children with CKD5-5D and 13 age-matched healthy controls (71 measurements) to determine a correlation between optimal weight by bioimpedance spectroscopy (Wt-BIS) and clinical assessment (Wt-CA). The accuracy of Wt-BIS [relative overhydration (Rel-OH)] was compared against indicators of fluid status and cardiovascular measures. Results: There was poor agreement between Wt-CA and Wt-BIS in children on dialysis (P = 0.01), but not in CKD5 or control subjects. We developed a modified chart to plot Rel-OH against systolic blood pressure (SBP) z-score for the appropriate representation of volume status and blood pressure (BP) in children. In total, 25% of measurements showed SBP >90th percentile but not with concurrent overhydration. Rel-OH correlated with peripheral pulse pressure (P = 0.03; R = 0.3), higher N-terminal pro-brain natriuretic peptide (P = 0.02; R = 0.33) and left ventricular end-diastolic diameter (P = 0.05; R = 0.38). Central aortic mean and pulse pressure significantly associated with the left ventricular end-diastolic diameter (P = 0.03; R = 0.47 and P = 0.01; R = 0.50, respectively), but not with Rel-OH. SBP was positively associated with pulse wave velocity z-score (P = 0.04). In total, 40% of children on haemodialysis and 30% on peritoneal dialysis had increased left ventricular mass index. Conclusions: BIS provides an objective method for the assessment of hydration status in children on dialysis. We noted a marked discrepancy between BP and hydration status in children on dialysis that warrants further investigation.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS.

Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.

Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

Growth hormone therapy in children with CKD after more than two decades of practice.

This review focuses on the evidence for the efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with all stages of chronic kidney disease (CKD) and at all ages. It describes the improving height prognosis for our patients both with and without rhGH; explains the underlying hormonal abnormalities that provide the rationale for rhGH use in CKD and the endocrine changes that accompany treatment; and views on who warrants treatment, with what dose, and how long for.

The demise of calcium-based phosphate binders-is this appropriate for children?

In children with chronic kidney disease (CKD) optimal control of mineral and bone disorder (MBD) is essential not only for the prevention of debilitating skeletal complications and for achieving adequate growth, but also for preserving long-term cardiovascular health. The growing skeleton is particularly vulnerable to the effects of CKD, and bone pain, fractures and deformities are common in children on dialysis. Defective bone mineralisation has been linked with ectopic calcification, which in turn leads to significant morbidity and mortality. Despite national and international guidelines for the management of CKD-MBD, the management of mineral dysregulation in CKD can be extremely challenging, and a significant proportion of patients have calcium, phosphate or parathyroid hormone levels outside the normal ranges. Clinical and experimental studies have shown that, in the setting of CKD, low serum calcium levels are associated with poor bone mineralisation, whereas high serum calcium levels can lead to arterial calcification, even in children. The role of calcium in CKD-MBD is the focus of this review.