Maria Van Dyck

Vitamin D metabolites in childhood nephrotic syndrome

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.

Cystinosis: a review

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.

Long-term therapy with enalapril in patients with nephrotic-range proteinuria

The effect of enalapril on urinary protein excretion and renal function was studied in six paediatric patients with various renal diseases causing nephroticrange proteinuria. In three younger children (aged 7–9 years) with steroid-resistant nephrotic syndrome, enalapril at a dose of 0.5 mg/kg per day given for 24 months yielded a temporary reduction of proteinuria in one child, a moderate and steady decrease in another and a complete disappearance of proteinuria in the third. Three adolescents, aged 17 years, took enalapril for 24 months at a dose of 20 mg/day. We observed no effect on proteinuria in one patient with Alport syndrome, a complete disappearance or urinary protein in one patient with membranoproliferative glomerulonephritis and a moderate decrease in the third patient who had idiopathic steroid-resistant nephrotic syndrome. Enalapril therapy resulted in an important reduction of proteinuria in two patients and a moderate decrease in three others. However this therapy was accompanied by a fall in glomerular filtration in all subjects, which was very marked in two patients. This fall in glomerular filtration may, however, simply reflect the natural course of the disease.

Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment

A girl, second child of healthy parents, was referred to the Renal Unit at the age of 9 months with haematuria (230 RBC/microl) and proteinuria (2.4 g/l). Serum creatinine was normal (0.25 mg/dl), albumin low (34 g/l) and cholesterol elevated (223 mg/dl). Physical examination showed bilateral webbing of the elbows, equinovarus of both feet and absent patellae. The clinical diagnosis of nail-patella syndrome was confirmed by demonstrating a splice mutation in the intron 5 (750 + 1 G>A) of the LMX1B gene. Treatment with enalapril for 2 years (0.1-1 mg/kg per day) did not bring about any change in urinary protein excretion. However, enalapril (1 mg/kg per day) associated with losartan (1 mg/kg per day) resulted in complete remission (proteinuria 140 mg/24 h) at the age of 7 years.

Children of non-Western origin with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health-related quality of life compared with Western children

BACKGROUND Many children with end-stage renal disease (ESRD) living in Western Europe are of non-Western European origin. They have unfavourable somatic outcomes compared with ESRD children of Western origin. In this study, we compared the Health-related Quality of Life (HRQoL) of both groups. METHODS All children (5-18 years) with ESRD included in the RICH-Q project (Renal Insufficiency therapy in Children-Quality assessment and improvement) or their parents were asked to complete the generic version of the Paediatric Quality-of-Life Inventory 4.0 (PedsQL). RICH-Q comprises the Netherlands, Belgium and a part of Germany. Children were considered to be of non-Western origin if they or at least one parent was born outside Western-European countries. Impaired HRQoL for children with ESRD of Western or non-Western origin was defined as a PedsQL score less than fifth percentile for healthy Dutch children of Western or non-Western origin, respectively. RESULTS Of the 259 eligible children, 230 agreed to participate. One hundred and seventy-four children responded (response rate 67%) and 55 (32%) were of non-Western origin. Overall, 31 (56%) of the ESRD children of non-Western origin, and 58 (49%) of Western origin had an impaired total HRQoL score. Total HRQoL scores of children with ESRD of Western origin and non-Western origin were comparable, but scores on emotional functioning and school functioning were lower in non-Western origin (P=0.004 and 0.01, respectively). The adjusted odds ratios (95% confidence interval) for ESRD children of non-Western origin to have impaired emotional functioning and school functioning, compared with Western origin, were 3.3(1.5-7.1) and 2.2(1.1-4.2), respectively. CONCLUSION Children with ESRD of non-Western origin in three Western countries were found to be at risk for impaired HRQoL on emotional and school functioning. These children warrant special attention.

Hardikar syndrome: Long term outcome of a rare genetic disorder†

Hardikar syndrome is a rare disorder of unknown etiology. Features of the syndrome are manifold with a predominance of liver and renal involvement. The syndrome is clearly distinct from other previously described syndromes such as Alagille syndrome, congenital hepatic fibrosis, Caroli disease, and Kabuki make‐up syndrome. To date, only four cases of Hardikar syndrome have been published worldwide. We report here on the long term outcome of these patients.

Growth hormone therapy in chronic renal failure induces catch-up of head circumference

Abstract  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.

Evidence for Bone and Mineral Metabolism Alterations in Children with Autosomal Dominant Polycystic Kidney Disease.

Context: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Hypophosphatemia was demonstrated in adult patients with preserved renal function, together with high fibroblast growth factor 23 (FGF23) and low soluble Klotho levels. The latter explained the relative FGF23 hyporesponsiveness in this cohort. Objective: Evaluating phosphate and bone mineral metabolism in children with ADPKD compared with what is known in adult ADPKD patients. Design: Observational cross‐sectional study. Setting: Multicenter study via ambulatory care in tertiary centers. Participants: Ninety‐two children with ADPKD (52 males; mean ± standard deviation age, 10.2 ± 5.0 years) and 22 healthy controls (HCs, 10 males; mean ± standard deviation age, 10.3 ± 4.1 years). Main Outcome Measures: The predictor was early ADPKD stage. Bone mineral metabolism and renal phosphate handling were the main outcome measures. Performed measurements were serum phosphate, tubular maximum phosphorus reabsorption per glomerular filtration rate, FGF23, soluble Klotho, sclerostin, and bone alkaline phosphatase. Results: ADPKD children had significantly lower serum phosphate levels compared with HC. Low tubular maximum phosphorus reabsorption per glomerular filtration rate was observed in 24% of patients, although not significantly different from HC. Serum FGF23 and soluble Klotho levels were comparable between patients and HC. In addition, we showed decreased bone alkaline phosphatase levels in ADPKD children, suggesting suppressed bone formation. Conclusions: This report demonstrates hypophosphatemia and suppressed bone formation in a pediatric ADPKD cohort, with preserved renal function, compared with HC. Although FGF23 levels were not different from controls, they should be considered inappropriate, given the concomitant hypophosphatemia. Further studies are required to elucidate underlying pathophysiology and potential clinical consequences.

Cystinosis: a new perspective

Cystinosis is a rare, autosomal recessive inherited lysosomal storage disease. It is the most frequent and potentially treatable cause of the inherited renal Fanconi syndrome. If left untreated, renal function rapidly deteriorates towards end-stage renal disease by the end of the first decade of life. Due to its rarity and non-specific presentation, the entity is often not promptly recognized resulting in delayed diagnosis. Two major milestones in cystinosis management, cystine-depleting therapy with cysteamine and renal allograft transplantation, have had a considerable impact on the natural history and prognosis of cystinosis patients. However, due to its significant side effects and a strict 6-hourly dosing regimen, non-adherence to the immediate release of cysteamine bitartrate formulation (Cystagon®) is a major issue that might affect long-term outcome. Recently, a new twice-daily administered delayed-release enteric-coated formula of cysteamine bitartrate (ProcysbiTM) has been approved by the European Medical Agency for the treatment of cystinosis, and has been shown to be safe and effective. This delayed-release cysteamine has the potential to improve compliance and hence prognosis, through its better dosing regimen, positive impact on quality of life and possibly less side-effects, and is now tested in an ongoing long-term clinical trial. Longer survival of patients with cystinosis makes transition from pediatric to adult-oriented care another challenge in cystinosis management and requires an extended multidisciplinary approach.

Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation

AIMS Despite longstanding recognition of significant age‐dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long‐term follow‐up in children on tacrolimus. METHODS This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow‐up (AUC0–12hr) in recipients of a renal allograft (≤19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose‐corrected exposure was evaluated using mixed models. RESULTS A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0–12h corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3–8.7%) until ±14 years of age, followed by 13.4% increase (CI 8.7–18.3%). Moreover, exposure corrected for dose per m2 proved stable until 14 years (+0.8% annually; CI: −3.0 to +4.8%), followed by a steep increase ≥14 years (+11%; CI: 7.0–16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age. CONCLUSIONS Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: ±14 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition.