Publications by authors named "Maria Van Dyck"

27 Publications

  • Page 1 of 1

Dietary Fibre Intake Is Associated with Serum Levels of Uraemic Toxins in Children with Chronic Kidney Disease.

Toxins (Basel) 2021 03 19;13(3). Epub 2021 Mar 19.

Nephrology Section, Department of Internal Medicine and Paediatrics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.

Imbalanced colonic microbial metabolism plays a pivotal role in generating protein-bound uraemic toxins (PBUTs), which accumulate with deteriorating kidney function and contribute to the uraemic burden of children with chronic kidney disease (CKD). Dietary choices impact the gut microbiome and metabolism. The aim of this study was to investigate the relation between dietary fibre and gut-derived PBUTs in paediatric CKD. Sixty-one (44 male) CKD children (9 ± 5 years) were prospectively followed for two years. Dietary fibre intake was evaluated by either 24-h recalls (73%) or 3-day food records (27%) at the same time of blood sampling for assessment of total and free serum levels of different PBUTs using liquid chromatography. We used linear mixed models to assess associations between fibre intake and PBUT levels. We found an inverse association between increase in fibre consumption (g/day) and serum concentrations of free indoxyl sulfate (-3.1% (-5.9%; -0.3%) ( = 0.035)), free p-cresyl sulfate (-2.5% (-4.7%; -0.3%) ( = 0.034)), total indole acetic acid (IAA) (-1.6% (-3.0%; -0.3%) ( = 0.020)), free IAA (-6.6% (-9.3%; -3.7%) ( < 0.001)), total serum p-cresyl glucuronide (pCG) (-3.0% (-5.6%; -0.5%) ( = 0.021)) and free pCG levels (-3.3% (-5.8%; -0.8%) ( = 0.010)). The observed associations between dietary fibre intake and the investigated PBUTs highlight potential benefits of fibre intake for the paediatric CKD population. The present observational findings should inform and guide adaptations of dietary prescriptions in children with CKD.
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http://dx.doi.org/10.3390/toxins13030225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003569PMC
March 2021

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

Pediatr Nephrol 2021 Jun 2;36(6):1589-1595. Epub 2021 Jan 2.

Nephrology Section, Department of Internal Medicine and Paediatrics, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

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.
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http://dx.doi.org/10.1007/s00467-020-04840-9DOI Listing
June 2021

De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.

Genet Med 2021 Apr 27;23(4):637-644. Epub 2020 Nov 27.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder.

Methods: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed.

Results: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing.

Conclusion: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
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http://dx.doi.org/10.1038/s41436-020-01031-7DOI Listing
April 2021

Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis.

J Am Soc Nephrol 2020 05 9;31(5):1092-1106. Epub 2020 Apr 9.

Division of Pediatric Nephrology, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium

Background: Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis.

Methods: We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1, IL-6, IL-18, and chitotriosidase enzyme activity.

Results: A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications.

Conclusions: Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.
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http://dx.doi.org/10.1681/ASN.2019080774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217422PMC
May 2020

Uremic Toxin Concentrations are Related to Residual Kidney Function in the Pediatric Hemodialysis Population.

Toxins (Basel) 2019 04 24;11(4). Epub 2019 Apr 24.

Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.

Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in a large pediatric HD cohort ( = 170) by comparing these with healthy and non-dialysis chronic kidney disease (CKD) stage 4-5 ( = 24) children. In parallel β2-microglobulin (β2M) and uric acid (UA) were evaluated. We then explored the impact of age and residual kidney function on uremic toxin levels and %PB using analysis of covariance and Spearman correlation coefficients (). We found higher levels of β2M, p-cresyl glucuronide (pCG), hippuric acid (HA), indole acetic acid (IAA), and indoxyl sulfate (IxS) in the HD compared to the CKD4-5 group. In the HD group, a positive correlation between age and pCG, HA, IxS, and pCS levels was shown. Residual urine volume was negatively correlated with levels of β2M, pCG, HA, IAA, IxS, and CMPF ( -0.2 to -0.5). In addition, we found overall lower %PB of PBUTs in HD versus the CKD4-5 group, and showed an age-dependent increase in %PB of IAA, IxS, and pCS. Furhtermore, residual kidney function was overall positively correlated with %PB of PBUTs. In conclusion, residual kidney function and age contribute to PBUT levels and %PB in the pediatric HD population.
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http://dx.doi.org/10.3390/toxins11040235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521157PMC
April 2019

Enhanced Intrinsic Skin Aging in Nephropathic Cystinosis Assessed by High-Definition Optical Coherence Tomography.

J Invest Dermatol 2019 10 22;139(10):2242-2245.e5. Epub 2019 Apr 22.

Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Development & Regeneration, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.jid.2019.03.1153DOI Listing
October 2019

Growth Patterns After Kidney Transplantation in European Children Over the Past 25 Years: An ESPN/ERA-EDTA Registry Study.

Transplantation 2020 01;104(1):137-144

Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.

Background: Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry.

Methods: A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS.

Results: Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children <6 years were shortest at KT and showed the greatest increase in height, whereas there was no catch-up growth in children transplanted >12.

Conclusions: Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.
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http://dx.doi.org/10.1097/TP.0000000000002726DOI Listing
January 2020

Allogeneic HSCT transfers wild-type cystinosin to nonhematological epithelial cells in cystinosis: First human report.

Am J Transplant 2018 11 21;18(11):2823-2828. Epub 2018 Aug 21.

Department of Pediatric Nephrology & Development and Regeneration, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the defective transport of the amino acid cystine out of the lysosome due to a deficiency of cystinosin, the lysosomal cystine transporter. Patients have lysosomal cystine accumulation in various tissues, leading to cellular stress and damage, particularly in the kidney, cornea, and other extrarenal tissues. Cysteamine, a cystine-depleting agent, improves survival and delays the progression of disease, but it does not prevent the development of either renal failure or extrarenal complications. Furthermore, the drug has severe adverse effects that significantly reduce patient compliance. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently established as a therapeutic option for many inborn errors of metabolism, where the main pathologic driving factor is an enzyme deficiency. Recent studies in the cystinosis mouse-model suggested that HSCT could be a curative treatment alternative to cysteamine therapy. We treated a 16-year-old boy who had infantile cystinosis and side effects of cysteamine therapy with HSCT. We were able to demonstrate successful transfer of the wild-type cystinosin protein and CTNS mRNA to nonhematological epithelial cells in the recipient, as well as a decrease in the tissue cystine-crystal burden. This is the first report of allogeneic HSCT in a patient with cystinosis, the prototype of lysosomal membrane-transporter disorders.
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http://dx.doi.org/10.1111/ajt.15029DOI Listing
November 2018

Children on dialysis as well as renal transplanted children report severely impaired health-related quality of life.

Qual Life Res 2018 06 27;27(6):1445-1454. Epub 2018 Jan 27.

Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam, The Netherlands.

Objectives: To assess health-related quality of life (HRQoL) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant, and dialysis) in comparison with the healthy norm and other chronic health conditions, and to explore related patient factors.

Study Design: All prevalent end-stage renal disease (ESRD) patients aged 8-18 years who spent at least 6 months on their current treatment modality in the Netherlands, Belgium, and part of Germany were approached to complete the Pediatric Quality of Life Inventory 4.0 (PedsQL™) questionnaire. We determined the differences between groups on PedsQL™ mean scores, the proportion of children with an impaired HRQoL (≥ 1 SD lower than the healthy norm), the proportion of problems on individual items of the PedsQL™, and the effect of time on current treatment. Linear regression models were used to explore determinants of HRQoL.

Results: 192 out of 278 patients (20% preemptive transplant, 58% non-preemptive transplant, 22% dialysis) filled in the PedsQL™ (response rate 69%). Independent of treatment modality, patients had significantly lower mean scores and consequently higher proportions of impaired HRQoL on almost all domains compared to the healthy norm and other chronic health conditions. Patients with a preemptive transplant only reported higher scores on physical health compared to the other treatment modalities. Having comorbidities was the most important determinant associated with lower HRQoL scores.

Conclusion: Dialysis and renal transplantation both have a severe impact on the HRQoL of children with ESRD. Physicians should be aware of this continuous burden. Furthermore, to develop tailored interventions for children with ESRD, qualitative studies are needed to gain more insight in the determinants of HRQoL in the different treatment modalities.
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http://dx.doi.org/10.1007/s11136-018-1789-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951873PMC
June 2018

3DUS as an alternative to MRI for measuring renal volume in children with autosomal dominant polycystic kidney disease.

Pediatr Nephrol 2018 05 6;33(5):827-835. Epub 2018 Jan 6.

Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

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 KV respectively); manual contouring on MRI (KV), and the ellipsoid method on two-dimensional ultrasound (2DUS, KV). 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: 159 (±101); K: 169 (±105); KV: 185 (±110); KV: 206 (±130); all p < 0.001. All had a strong correlation with KV: 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 vs KV and KV.

Conclusions: Compared with MRI, ultrasound volumetry was prone to underestimation. However, KV represents a valuable alternative for MRI in early ADPKD. Although more time-consuming, KV is recommended over KV for estimation and follow-up of KV in ADPKD children, given its smaller error.
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http://dx.doi.org/10.1007/s00467-017-3862-6DOI Listing
May 2018

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

J Clin Endocrinol Metab 2017 11;102(11):4210-4217

Department of Pediatric Nephrology, University Hospitals Leuven, Leuven 3000, Belgium.

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.
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http://dx.doi.org/10.1210/jc.2017-01157DOI Listing
November 2017

Accumulation of uraemic toxins is reflected only partially by estimated GFR in paediatric patients with chronic kidney disease.

Pediatr Nephrol 2018 02 22;33(2):315-323. Epub 2017 Sep 22.

Department of Nephrology, Ghent University Hospital, Ghent, Belgium.

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), 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 = -0.84), SDMA (r = -0.82) and middle molecules CfD and β2M (both r = -0.90). In contrast, poor correlation coefficients were found for CMPF (r = -0.32), UA (r = -0.45), ADMA (r = -0.47) and pCG (r = -0.48). The other toxins, all protein-bound, had r 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.
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http://dx.doi.org/10.1007/s00467-017-3802-5DOI Listing
February 2018

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

Br J Clin Pharmacol 2017 04 13;83(4):863-874. Epub 2016 Dec 13.

Dept. of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.

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 (AUC ) 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). AUC 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 m 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.
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http://dx.doi.org/10.1111/bcp.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346878PMC
April 2017

Rituximab in children with steroid-dependent nephrotic syndrome: experience of a tertiary center and review of the literature.

Acta Clin Belg 2017 Jun 13;72(3):147-155. Epub 2016 Jul 13.

a Department of Pediatric Nephrology , University Hospitals Leuven , Leuven , Belgium.

Objectives: Rituximab (RTX) is a new treatment option in children with difficult-to-treat steroid-dependent nephrotic syndrome (SDNS). We evaluated the experience of our tertiary center and reviewed the current literature.

Methods: This is a retrospective single-center study evaluating the efficacy and safety of RTX in children with difficult-to-treat SDNS. Age at diagnosis, type and duration of immunosuppression, age at administration, dose of RTX, possible adverse events, number of relapses, duration of remission, and B-cell count after administration of RTX were analyzed.

Results: Nine children with a median age at diagnosis of nephrotic syndrome of 4.75 (range 1.33-11.33) years and a median age at administration of RTX of 16.08 (range 3.33-19.25) years were included. Before administration of RTX they had a median number of relapses per year of 1.70 (range 0.82-4.80). At last follow-up (median 2.75 years, range 0.58-3.92), a reduction in the number of relapses per year to 0.26 (range 0-2.18) was noted, despite cessation or lowering the dose of immunosuppressive therapy. Four patients achieved complete remission after the first administration of RTX, four more patients after subsequent doses of RTX. No severe adverse events were noted.

Conclusion: RTX was an effective and safe therapeutic option in our cohort of children with difficult-to-treat SDNS, resulting in a significant reduction of yearly relapses in the absence of severe adverse events and facilitating the reduction of other immunosuppressive medication.
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http://dx.doi.org/10.1080/17843286.2016.1208955DOI Listing
June 2017

Cystinosis: a review.

Orphanet J Rare Dis 2016 Apr 22;11:47. Epub 2016 Apr 22.

Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & KU Leuven, UZ Herestraat 49-3000, Leuven, Belgium.

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.
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http://dx.doi.org/10.1186/s13023-016-0426-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841061PMC
April 2016

Management dilemmas in pediatric nephrology: Cystinosis.

Pediatr Nephrol 2015 Aug 9;30(8):1349-60. Epub 2015 May 9.

Department of Pediatric Nephrology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium,

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.
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http://dx.doi.org/10.1007/s00467-015-3117-3DOI Listing
August 2015

Cystinosis: a new perspective.

Acta Clin Belg 2016 Jun;71(3):131-7

a Department of Pediatrics, Pediatric Nephrology , University Hospitals Leuven , Belgium.

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 (Procysbi(TM)) 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.
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http://dx.doi.org/10.1179/2295333714Y.0000000113DOI Listing
June 2016

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.

Nephrol Dial Transplant 2014 Feb 13;29(2):448-57. Epub 2013 Nov 13.

Department of Paediatric Nephrology, Emma Children's Hospital Academic Medical Centre, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1093/ndt/gft436DOI Listing
February 2014

Diastolic dysfunction measured by tissue Doppler imaging in children with end-stage renal disease: a report of the RICH-Q study.

Cardiol Young 2014 Apr 5;24(2):236-44. Epub 2013 Mar 5.

1 Department of Paediatric Nephrology, Emma Children's Hospital AMC Amsterdam, The Netherlands.

Introduction: Early detection of cardiovascular disease in children with end-stage renal disease is essential in order to prevent cardiovascular morbidity and mortality in early adulthood. Tissue Doppler imaging has shown to be a promising method to detect and quantify subtle abnormalities in diastolic function. We therefore compared assessment of diastolic function by conventional echocardiography and tissue Doppler imaging.

Methods: We performed conventional echocardiography and tissue Doppler imaging in 38 children with end-stage renal disease and 76 healthy controls. We compared outcomes on parameters related to diastolic function (E/a ratio for conventional echocardiography and E/E' ratio for tissue Doppler imaging) for both groups using multiple linear regression analysis. Diastolic dysfunction was defined as E/a ratio <1 or E/E' ratio > 95th percentile for age. To assess the intra-observer reproducibility, the coefficient of variation was calculated.

Results: Children with end-stage renal disease had on average a lower E/a ratio (p = 0.004) and a higher mitral and septal E/E' ratio (both p < 0.001) compared with controls. In all, two children with end-stage renal disease (5%) had diastolic dysfunction according to the E/a ratio, 11 according to the mitral E/E' ratio (29%), and 16 according to the septal E/E' ratio (42%) compared with none of the controls (p = 0.109, p < 0.001, and p < 0.001, respectively). The coefficients of variation of the mitral (7%) and septal E/E' ratio (4%) were smaller than the coefficient of variation of the E/a ratio (11%).

Conclusions: Tissue Doppler imaging is a more sensitive and reliable method to detect diastolic dysfunction than conventional E/a ratio in children with end-stage renal disease.
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http://dx.doi.org/10.1017/S1047951113000188DOI Listing
April 2014

Policy variation in donor and recipient status in 11 pediatric renal transplantation centers.

Pediatr Nephrol 2013 Jun 16;28(6):951-7. Epub 2013 Jan 16.

Departments of Pediatric Nephrology, Emma Children's Hospital Academic Medical Center, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1007/s00467-012-2396-1DOI Listing
June 2013

Detailed studies of growth hormone secretion in cystinosis patients.

Pediatr Nephrol 2012 Nov 5;27(11):2123-2127. Epub 2012 Jun 5.

Department of Pediatric Nephrology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

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.
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http://dx.doi.org/10.1007/s00467-012-2213-xDOI Listing
November 2012

Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients.

Pediatr Nephrol 2010 Feb 3;25(2):335-42. Epub 2009 Nov 3.

Department of Paediatric Medicine, University Hospital Leuven, Herestraat 49, Louvain, 3000 Vlaams-Brabant, Belgium.

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.
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http://dx.doi.org/10.1007/s00467-009-1331-6DOI Listing
February 2010

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

Nephrol Dial Transplant 2009 Apr 15;24(4):1335-8. Epub 2009 Jan 15.

Renal Unit, Department of Pediatrics, University Hospital Gasthuisberg, 3000 Leuven, Belgium.

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.
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http://dx.doi.org/10.1093/ndt/gfn725DOI Listing
April 2009

Hardikar syndrome: long term outcome of a rare genetic disorder.

Am J Med Genet A 2008 Oct;146A(19):2468-72

Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Victoria, Australia.

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.
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http://dx.doi.org/10.1002/ajmg.a.32226DOI Listing
October 2008

Renal outcome of children with one functioning kidney from birth. A study of 99 patients and a review of the literature.

Eur J Pediatr 2008 Aug 17;167(8):885-90. Epub 2007 Oct 17.

Pediatric Nephrology, University Hospital Leuven, Herestraat 49, 3000, Leuven, Belgium.

In patients with a single functioning kidney, renal function was assessed at regular intervals over a period of 10 years. Serum creatinine, glomerular filtration rate (GFR), blood pressure, and urinary protein-creatinine ratio were assessed at the age of 2, 5 and 10 years. Between January 1980 and December 2005, 99 such patients were diagnosed in the first year of life. They were divided into three groups: A, patients with multicystic kidney disease and a normal contralateral kidney (n = 36); B, patients with a normal solitary kidney without uropathy (n = 20); and C, patients with obstructive uropathy and one nonfunctioning kidney (n = 43). Serum creatinine levels increased significantly with increasing age in every group. In group C, serum creatinine was significantly elevated compared with group A in all age categories (p = 0.043, p = 0.019, p = 0.001 respectively). Median figures of GFR remained within normal limits over the 10-year period. GFR was significantly lower in group C compared with group A (p = 0.001, p = 0.009, p = 0.019 respectively) and B in all age categories (p = 0.013, p = 0.002, p = 0.016 respectively). There were no changes in blood pressure over time and no differences among the three groups were observed. At the age of 10 years, the patients in group C had a significantly higher median urinary protein-creatinine ratio (p = 0.022) than those in groups A and B. There was also an increasing level of proteinuria with increasing age in group C (p = 0.002). In conclusion, renal function was stable over time in all patients, but children with obstructive uropathy have a lower median GFR and higher serum creatinine level for the whole study period. Hypertension was exceptionally observed in group C, with obstructive uropathy, as was an elevated urinary protein-creatinine ratio.
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http://dx.doi.org/10.1007/s00431-007-0612-yDOI Listing
August 2008

Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome.

Pediatr Nephrol 2004 Jun 3;19(6):688-90. Epub 2004 Apr 3.

Renal Unit, Department of Pediatrics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

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.
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http://dx.doi.org/10.1007/s00467-004-1451-yDOI Listing
June 2004

Enalapril in children with Alport syndrome.

Pediatr Nephrol 2004 Mar 24;19(3):271-5. Epub 2004 Jan 24.

Renal Unit, Department of Pediatrics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

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.
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http://dx.doi.org/10.1007/s00467-003-1366-zDOI Listing
March 2004