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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.

Background: Total kidney volume, measured by magnetic resonance imaging (MRI), is a validated disease progression marker in adults with autosomal dominant polycystic kidney disease (ADPKD). However, in childhood, MRI is burdensome, explaining the need for alternatives., Methods: Kidney volume (KV) was evaluated in 30 children with ADPKD, using three-dimensional ultrasound (3DUS), applying the ellipsoid method and manual contouring (KV 3DUS-ellipsoid, KV 3DUS-contour respectively); manual contouring on MRI (KV MRI ), and the ellipsoid method on two-dimensional ultrasound (2DUS, KV 2DUS ). Correlations and differences were evaluated using Pearson's r and Wilcoxon signed-rank tests, and variability using Bland-Altman plots., Results: All ultrasound volumetry methods showed significantly lower mean (± SD) KV (mL), compared with MRI-KV 2DUS : 159 (±101); K 3DUS-ellipsoid : 169 (±105); KV 3DUS-contour : 185 (±110); KV MRI : 206 (±130); all p < 0.001. All had a strong correlation with KV MRI : 2DUS: r = 0.96; 3DUS-ellipsoid: r = 0.89 and 3DUS-contour: r = 0.94. Both before and after correction factor application, Bland-Altman plots showed lower variability and absolute error for KV 3DUS-contour vs KV 2DUS and KV 3DUS-ellipsoid ., Conclusions: Compared with MRI, ultrasound volumetry was prone to underestimation. However, KV 3DUS-contour represents a valuable alternative for MRI in early ADPKD. Although more time-consuming, KV 3DUS-contour is recommended over KV 2DUS for estimation and follow-up of KV in ADPKD children, given its smaller error.

Background: Chronic kidney disease (CKD) in childhood is characterised by the accumulation of uraemic toxins resulting in a multisystem disorder that has a negative impact on quality of life. Childhood CKD is predominantly defined by a decrease in glomerular filtration rate, estimated (eGFR) by a single serum measurement of endogenous biomarkers, e.g. creatinine. The objective of this study was to evaluate how accurately eGFR predicts the concentration of uraemic toxins in a paediatric CKD cohort., Methods: In 65 children (10.8 [5.1; 14.7] years) with CKD (eGFR 44 [20; 64] mL/min/1.73 m 2 ), serum concentrations were determined of small solutes (uric acid [UA], urea, symmetric dimethylarginine [SDMA], asymmetric dimethylarginine [ADMA]), middle molecules (β2-microglobulin [β2M], complement factor D [CfD]) and protein-bound solutes (p-cresylglucuronide [pCG], hippuric acid, indole acetic acid, indoxyl sulphate [IxS], p-cresylsulfate [pCS] and 3-carboxy-4-methyl-5-propyl-furanpropionic acid [CMPF]). Spearman's correlation coefficients (r) were calculated to correlate uraemic toxin concentrations with three different eGFR equations, based on either serum creatinine or β2M., Results: Updated Schwartz eGFR was correlated reasonably well with concentrations of creatinine (r = -0.98), urea (r s  = -0.84), SDMA (r = -0.82) and middle molecules CfD and β2M (both r s  = -0.90). In contrast, poor correlation coefficients were found for CMPF (r s  = -0.32), UA (r s  = -0.45), ADMA (r s  = -0.47) and pCG (r s  = -0.48). The other toxins, all protein-bound, had r s between -0.75 and -0.57. Comparable correlations were found between the three evaluated eGFR equations and uraemic toxin concentrations., Conclusions: This study demonstrates that eGFR poorly predicts concentrations of protein-bound uraemic toxins, UA and ADMA in childhood CKD. Therefore, eGFR only partially reflects the complexity of the accumulation pattern of uraemic toxins in childhood CKD.

Background: Cystinosis is a rare, inherited autosomal recessive disease caused by the accumulation of free cystine in lysosomes. It is treated by the administration of cysteamine, which should be monitored by trough white blood cell (WBC) cystine measurements to ensure effective treatment., Case-Diagnosis/treatment: The index case had an older brother who had previously been diagnosed with cystinosis, allowing early diagnosis of the index case at the age of 5 months. Cysteamine therapy was started at the age of 3 years; however, monitoring of WBC cystine levels did not occur on a regular basis during most of his life. Growth retardation improved after correction of electrolyte disturbances, the initiation of cysteamine therapy and treatment with recombinant human growth hormone. Renal replacement therapy was started at the age of 11 years, and renal transplantation was performed at the age of 12 years. Extra-renal cystine accumulation caused multiple endocrinopathies (including adrenal insufficiency, hypothyroidism and primary hypogonadism), neurological symptoms, pancytopenia owing to splenomegaly and portal hypertension due to nodular regenerative hyperplasia, aggravated by splenic vein thrombosis and partial portal vein thrombosis. The patient died of diffuse intra-abdominal bleeding caused by severe portal hypertension., Conclusion: Cysteamine treatment should be started as early as possible, and dosage should be monitored and adapted based on trough WBC cystine levels., Relevant International Guideline: Emma F et al. (2014) Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29:iv87-iv94.

Background: Evidence-based guidelines for pediatric renal transplantation (Tx) are lacking. This may lead to unwanted treatment variations. We aimed to quantify the variation in treatment policies and its consequences in daily practice in 11 centers that provide renal Tx for children in three European countries., Methods: We surveyed Tx policies in all ten centers in the Netherlands and Belgium and one center in Germany. We compared Tx policies with the therapies actually provided and with recommendations from available published guidelines and existing literature. Information on treatment policies was obtained by a questionnaire; information on care actually provided was registered prospectively from 2007 to 2011. The clinical guidelines were identified by searches of MEDLINE and websites of pediatric nephrology organizations., Results: Between centers, we found discrepancies in policies on: the minimum accepted recipient weight (8-12 kg), the maximum living and deceased donor age (50-75 and 45-60 years, respectively). HLA-match policies varied between acceptation of all mismatches to at least 1A1B1DR match donor transplantations amounting to 49 % in the Netherlands versus 26 % in Belgium (p = 0.006)., Conclusions: Management policies for renal Tx in children vary considerably between centers and nations. This has a direct impact on the delivered care, and by extrapolation, on health outcome.

Background: Cystinosis is an autosomal recessive disorder characterized by intralysosomal cystine accumulation. Growth retardation is more pronounced in cystinosis than in other chronic kidney diseases and is mostly not corrected by cysteamine., Methods: Growth was evaluated in nine cystinosis patients, all treated with cysteamine, both after cysteamine and recombinant human growth hormone (rhGH) therapy initiation. Growth hormone (GH) secretion was studied by nocturnal GH measurements in four of nine patients and by glucagon test in four of nine patients., Results: RhGH was administered to seven of nine patients. At rhGH initiation, height was below -2 SDS in five of seven patients, final height was above -2 SDS in six of seven. In two patients not treated with rhGH, final height remained below -4 SDS despite cysteamine treatment being started at the age of 6.1 and 8.1 years, respectively. Nocturnal GH secretion was normal in all patients. Glucagon tests revealed GH deficiency in one patient; two of four patients had abnormal GH peak timing., Conclusions: We present the first reported case of GH deficiency in cystinosis. Although no overt GH deficiency was detected in other patients, abnormal GH peak timing can indicate a subclinical GH secretion problem. RhGH significantly improved growth in cystinosis patients and should be initiated early in life.

Because tacrolimus (Tac) has a narrow therapeutic index and highly inter- and intra-individual variable pharmacokinetic (PK) characteristics, monitoring of drug exposure is recommended, but limited data are available on the kinetics of Tac in paediatric renal transplant recipients, especially of limited sampling strategies. To investigate the correlation between Tac trough level (TL) and the 0-12 h area under the curve (AUC), and the value of abbreviated AUC monitoring, we evaluated 12 h PK profiles in 27 children at least 1 year after transplantation. There was a significant discrepancy between Tac TLs and 0-12 h AUC (r = 0.60). Every time point, different from C(0), gave a better prediction for the drug exposure, with C(4) and C(6) as best predictors (r = 0.93 and r = 0.92, respectively). The 0-12 h AUC was estimated with great precision by the use of a two- or three-point sampling strategy, and the latter is more time-point independent. In paediatric renal transplant recipients on Tac maintenance therapy, whose condition is stable, Tac TL is not a reliable tool for the estimation of drug exposure. Abbreviated monitoring, especially at three points in time, give reliable predictions of the complete 0-12 h AUC. We suggest a 0-12 h AUC of around 150 ng x h/ml for stable paediatric renal transplant recipients 1 year after transplantation and around 100 ng x h/ml in the following years. Target AUC values should be further established for paediatric transplant recipients according to the time after transplantation.

Five patients with severe hemolytic uremic syndrome (HUS) were followed for 10-18 years. Because of proteinuria, arterial hypertension, and reduced glomerular filtration rates, they received either captopril (n=2) or enalapril (n=3), or both (n=1) for 8-15 years. Blood pressure was normalized and proteinuria reduced in all; glomerular filtration improved in three patients and fell moderately in two. Four of the five patients have reached adult age with body weight and height, blood pressure, and serum creatinine levels within the normal range. At the last evaluation, median proteinuria was 220 mg/24 h (range 0-310) and glomerular filtration rate 56 ml/min per 1.73 m(2)(range 40-127). This long-term study indicates a renoprotective effect of angiotensin-converting enzyme inhibitors in patients with sequelae after HUS.

Ten pediatric patients with Alport syndrome received enalapril for 5 years. There were nine boys. Eight patients have the X-linked form of the disease and two the autosomal recessive form. The median age at the start of treatment was 10.25 years. Only one patient was hypertensive. The starting dose of enalapril was 0.05 mg/kg; the target dose was 0.5 mg/kg per day. The median dose given effectively was 0.24, 0.37, 0.45, 0.43, and 0.49 mg/kg per day at years of study 1, 2, 3, 4, and 5, respectively. The median urinary protein/creatinine ratio was 1.58 g/g (range 0.49-4.60) before treatment. This decreased to 0.98, 1.09, 1.35, 1.11, and 1.38 g/g after 1, 2, 3, 4, and 5 years, respectively. The median creatinine clearance at baseline was 100 ml/min per 1.73 m2 (range 82-133) and after 5 years 92 ml/min per 1.73 m2 (range 22-115). Three patients did not reach the target dose of enalapril because of orthostatic hypotension. One of them was the only patient to develop chronic renal failure within 5 years. The present study indicates that enalapril reduces urinary protein excretion and preserves glomerular filtration in Alport patients as a group. However, there was individual variation, as in most studies of patients with proteinuric nephropathies given inhibitors of the angiotensin-converting enzyme.

Growth of head circumference was studied along with height, weight, and body mass index (BMI) in 21 prepubertal patients with chronic renal failure (CRF) before and during recombinant human growth hormone (rhGH) treatment. CRF was present from birth in 15 patients, in the 6 others it was acquired and existing for at least 1 year. Five patients were on chronic dialysis, and 16 children were on conservative treatment with a median glomerular filtration rate of 17 ml/min per 1.73 m2 at the start of rhGH therapy. rhGH was administered for 12 months in all patients, for 18 months in 19, and for 24 months in 12 patients. Mean height standard deviation score (SDS) increased significantly from -2.29 to -1.31 after 1 year and to -1.07 after 2 years. Mean BMI SDS was within the normal range throughout. Mean head circumference SDS improved significantly from -2.04 to -1.45 after 1 year and remained stable thereafter. Changes in head circumference differed between patients under 5 years and those over 5 years. In the former, the increase in head circumference SDS was already significant after 6 months of therapy, in the latter, significance was reached only after 1 year. It can be concluded that rhGH in CRF patients significantly improves head circumference SDS, albeit not to the same extent as height SDS.

Fifteen children with chronic renal failure from early infancy who did not require renal replacement therapy were followed for 3 years. Chronic renal failure was defined as a serum creatinine at or above 1 mg/dl for the entire 1st year of life. These patients were treated conservatively with diet and supplements of sodium bicarbonate and sodium chloride, calcium and vitamin D. Erythropoietin was given to 5 patients. Neither nasogastric nor gastrostomy tube feeding was used, and none of the patients received recombinant human growth hormone. We analyzed length, weight, and head circumference at 3, 12, 24, and 36 months of age. All three variables displayed a significant drop in the first 3 months, but remained stable for the whole observation period thereafter. At the age of 3 years, the patients' mean values of length, weight, and head circumference standard deviation score were -1.96, -1.37, and -1.07, respectively. Height velocity during the 1st, 2nd, and 3rd year was 22.2, 10.9, and 7.6 cm per year, respectively. The first two figures and the cumulative height velocity are significantly better than those from a large cohort of chronic renal failure patients collected by the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood; here the corresponding figures of height velocity were 12.3, 8.3, and 7.6 cm per year. Median serum calcium, phosphate, parathyroid hormone, and albumin levels remained within normal limits for the entire study period. Therapy-resistant hyperparathyroidism occurred in 1 patient and radiological signs of renal osteodystrophy in 4 patients. Kidney length, as measured by ultrasonography, showed almost no growth.

We measured serum levels of total and ionised calcium, phosphate, intact parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and the vitamin D binding protein (DBP) in 14 children with idiopathic nephrotic syndrome and 10 healthy, age-matched controls. In all nephrotics serum DBP levels were below the normal range. Serum 25(OH)D was below 7 ng/ml in 10 of 14 nephrotic children and in the low normal range in the remaining 4 patients. The average serum 1,25(OH)2D levels were lower in the nephrotic patients than in the controls. However, free 1,25(OH)2D levels were normal in the nephrotic patients. Both serum 25(OH)D and 1,25(OH)2D correlated positively with the concentration of DBP. There was a significant negative correlation between serum DBP levels and the urinary protein excretion and a significant positive correlation between the urinary excretions of DBP and albumin. From this study it can be concluded that the nephrotic child is capable of maintaining appropriate serum concentrations of free calcitriol despite important urinary losses of both substrate and bound calcitriol.