Publications by authors named "Justine Bacchetta"

137 Publications

Sensenbrenner syndrome: a further challenge in evaluating sagittal synostosis and a need for a multidisciplinary approach.

Childs Nerv Syst 2021 Feb 19. Epub 2021 Feb 19.

Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France.

Background: Sensenbrenner syndrome, also known as cranioectodermal dysplasia (CED), is a genetically heterogeneous ciliopathy, characterized by dysmorphic features including dolichocephaly (with inconstant sagittal craniosynostosis), chronic kidney disease (CKD), hepatic fibrosis, retinitis pigmentosa, and brain abnormalities, with a partial clinical overlap with other ciliopathies.

Patients And Methods: A retrospective review of four children with Sensenbrenner syndrome treated at the Femme Mère Enfant University Hospital of Lyon from 2005 to 2020 was conducted.

Results: Variants in WDR35 or WDR19 were found in all children. Two of them underwent surgery for a scaphocephaly in the first months of life. All patients developed CKD leading to end-stage renal disease during the first/second decades.

Discussion: The diagnosis of scaphocephaly may precede the diagnosis of the underlying Sensenbrenner syndrome, thus highlighting the importance of a systematic multidisciplinary assessment and follow-up for craniosynostoses, in order to identify syndromic forms requiring specific management. In Sensenbrenner syndrome, patients' management should be coordinated by multidisciplinary teams of reference centers for rare diseases, with expertise in the management of craniofacial malformations as well as rare skeletal and renal disorders. Indeed, a prompt etiological diagnosis will result in an early diagnosis of multisystemic complications, notably renal involvement, thus improving global prognosis.
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http://dx.doi.org/10.1007/s00381-021-05075-1DOI Listing
February 2021

Review: Neonatal dialysis is technically feasible but ethical and global issues need to be addressed.

Acta Paediatr 2021 Mar 6;110(3):781-788. Epub 2020 Sep 6.

Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.

Aim: Our aim was to look at the technical, ethical and global issues related to neonatal dialysis.

Methods: We performed a PubMed research on manuscripts published from March 2010 to March 2020 and retrospectively reviewed all neonates who received dialysis in our French paediatric and neonatal intensive care units from April 2009 to March 2019.

Results: Dialysis is performed on neonates with pre-existing renal diseases, acute kidney injuries or inborn errors of metabolism. It is required in 0.5%-1% of neonates admitted to the neonatal intensive care units. Peritoneal dialysis and extracorporeal blood purification are both feasible, with more complications, but the results are close to those obtained in older infants, at least in children without multi-organ dysfunction. Novel haemodialysis machines are being evaluated. Ethical issues are a major concern. Multidisciplinary teams should consider associated comorbidities, risks of permanent end-stage renal disease and provide parents with full and neutral information. These should drive decisions about whether dialysis is in child's best interests.

Conclusion: Neonatal dialysis is technically feasible, but ethically challenging, and short-term and long-term data remain limited. Prospective studies and dialysis registries would improve global management and quality of life of these patients at risk of chronic kidney disease.
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http://dx.doi.org/10.1111/apa.15539DOI Listing
March 2021

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

Eur J Endocrinol 2021 Feb;184(2):347-355

Paediatric Unit, Limoges University Hospital, Limoges, France.

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.
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http://dx.doi.org/10.1530/EJE-20-1119DOI Listing
February 2021

Rare diseases of phosphate and calcium metabolism: Crossing glances between nephrology and endocrinology.

Ann Endocrinol (Paris) 2021 Feb 11;82(1):30-35. Epub 2020 Dec 11.

Centre de référence des maladies rares du calcium et du phosphore, centre de référence des maladies rénales rares, filières de santé maladies rares OSCAR, ORKID et ERKNet, service de néphrologie rhumatologie et dermatologie pédiatriques, hôpital femme mère enfant, Bron, France; INSERM 1033, prévention des maladies osseuses, Lyon, France; Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France. Electronic address:

Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it possible to better characterize them and to propose attractive therapeutic approaches based on the underlying pathophysiology. These diseases are often at the interface between nephrology and endocrinology. In this spirit of a multidisciplinary care, each specialty can bring its own critical point of view and its own specificities to improve patient care. The objective of this manuscript is to "read" with a nephrologist's point of view the main frameworks of diseases of phosphate/calcium metabolism, to illustrate the three crucial messages of nephro-protection sent to endocrinologists. First, calciuria must be interpreted both in absolute value (concentration hypercalciuria) and in ratio (flow hypercalciuria). Second, renal monitoring of therapies inducing hypercalciuria on kidneys with normal renal function (e.g. active vitamin D analogs or teriparatide) should be systematic. Last, hyperphosphatemia, often latent in hypoparathyroidism and pseudo-hypoparathyroidism, should be detected and at least benefit from dietary measures, in the context of Western diets rich in phosphate hidden in food additives.
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http://dx.doi.org/10.1016/j.ando.2020.12.005DOI Listing
February 2021

Big data and outcomes in paediatric haemodialysis: how can nephrologists use these new tools in daily practice?

Nephrol Dial Transplant 2021 Feb;36(3):387-391

Centre de Référence des Maladies Rénales Rares, Service de Néphrologie Rhumatologie Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Bron Cedex, France.

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http://dx.doi.org/10.1093/ndt/gfaa225DOI Listing
February 2021

Bone evaluation in paediatric chronic kidney disease: clinical practice points from the European Society for Paediatric Nephrology CKD-MBD and Dialysis working groups and CKD-MBD working group of the ERA-EDTA.

Nephrol Dial Transplant 2021 Feb;36(3):413-425

Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Mineral and bone disorder (MBD) is widely prevalent in children with chronic kidney disease (CKD) and is associated with significant morbidity. CKD may cause disturbances in bone remodelling/modelling, which are more pronounced in the growing skeleton, manifesting as short stature, bone pain and deformities, fractures, slipped epiphyses and ectopic calcifications. Although assessment of bone health is a key element in the clinical care of children with CKD, it remains a major challenge for physicians. On the one hand, bone biopsy with histomorphometry is the gold standard for assessing bone health, but it is expensive, invasive and requires expertise in the interpretation of bone histology. On the other hand, currently available non-invasive measures, including dual-energy X-ray absorptiometry and biomarkers of bone formation/resorption, are affected by growth and pubertal status and have limited sensitivity and specificity in predicting changes in bone turnover and mineralization. In the absence of high-quality evidence, there are wide variations in clinical practice in the diagnosis and management of CKD-MBD in childhood. We present clinical practice points (CPPs) on the assessment of bone disease in children with CKD Stages 2-5 and on dialysis based on the best available evidence and consensus of experts from the CKD-MBD and Dialysis working groups of the European Society for Paediatric Nephrology and the CKD-MBD working group of the European Renal Association-European Dialysis and Transplant Association. These CPPs should be carefully considered by treating physicians and adapted to individual patients' needs as appropriate. Further areas for research are suggested.
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http://dx.doi.org/10.1093/ndt/gfaa210DOI Listing
February 2021

Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD Stages 3-5.

Nephrol Dial Transplant 2021 Feb;36(3):442-451

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin-angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear.

Methods: In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol, the cardiac phenotype and local RAS activation were investigated compared with controls. A nested case-control study was performed within the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, including children with chronic kidney disease (CKD) Stages 3-5 [estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2] treated with and without active vitamin D. Echocardiograms, plasma FGF23 and soluble Klotho (sKlotho) were assessed at baseline and after 9 months.

Results: In rats with 5/6Nx, left ventricular (LV) hypertrophy, LV fibrosis and upregulated cardiac RAS were dose-dependently attenuated by calcitriol. Calcitriol further stimulated FGF23 synthesis in bone but not in the heart, and normalized suppressed renal Klotho expression. In the 4C study cohort, treatment over a mean period of 9 months with active vitamin D was associated with increased FGF23 and phosphate and decreased sKlotho and eGFR compared with vitamin D naïve controls, whereas LV mass index did not differ between groups.

Conclusions: Active vitamin D ameliorates cardiac remodelling and normalizes renal Klotho expression in 5/6Nx rats but does not improve the cardiac phenotype in children with CKD Stages 3-5. This discrepancy may be due to further enhancement of circulating FGF23 and faster progression of CKD associated with reduced sKlotho and higher serum phosphate in vitamin D-treated patients.
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http://dx.doi.org/10.1093/ndt/gfaa227DOI Listing
February 2021

Long-term outcomes of peritoneal dialysis started in infants below 6 months of age: An experience from two tertiary centres.

Nephrol Ther 2020 Dec 8;16(7):424-430. Epub 2020 Nov 8.

Centre de référence des maladies rénales rares, hôpital femme-mère-enfant, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France. Electronic address:

Background: Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable.

Methods: We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centres. Results are presented as median (min;max).

Results: Seventeen patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients had associated comorbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) -1.3 (-5.7;1.6) and weight-SDS -1.4 (-3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was -1.0 (-4.3;0.7) weight-SDS -0.7 (-3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalisation stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n=6), transplantation (n=6), recovery of renal function (n=2) and death (n=1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling.

Conclusion: We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favourable growth outcome. Their quality of life will be impacted by recurrent hospitalisations and neurodevelopmental delay is frequent.
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http://dx.doi.org/10.1016/j.nephro.2020.08.002DOI Listing
December 2020

Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series.

Horm Res Paediatr 2020 29;93(5):304-312. Epub 2020 Oct 29.

Reference and Competence Centers for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR Network for Rare Diseases, Paris, France,

Aim: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France.

Methods: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019.

Results: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography.

Conclusion: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.
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http://dx.doi.org/10.1159/000511419DOI Listing
October 2020

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

Pediatr Nephrol 2021 Mar 9;36(3):581-589. Epub 2020 Sep 9.

Hospices Civils de Lyon, Service de Néphrologie Pédiatrique, et centre de référence maladies rénales et phosphocalciques rares- Néphrogones- Filière ORKiD -69500, Bron, France.

Introduction: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems.

Methods: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up.

Results: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine.

Conclusion: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04722-0DOI Listing
March 2021

Association between 25(OH) vitamin D and graft survival in renal transplanted children.

Pediatr Transplant 2020 11 26;24(7):e13809. Epub 2020 Aug 26.

Service de Néphrologie Pédiatrique, Centre de référence MARHEA, Hôpital Necker-Enfants malades, Paris, France.

Background: In children, vitamin D deficiency is common after renal transplantation. Besides promoting bone and muscle development, vitamin D has immunomodulatory effects, which could protect kidney allografts. The purpose of this study was to assess the association between vitamin D status and the occurrence of renal rejection.

Methods: We studied a retrospective cohort of 123 children, who were transplanted at a single institution between September 2008 and April 2019. Patients did not receive vitamin D supplementation systematically. In addition, factors influencing vitamin D status were analyzed using univariate and multivariate analyses.

Results: Median 25-hydroxy-vitamin D (25-OH-D) concentration was close to reference values at the time of transplantation (30 ng/mL (min-max 5-100)), but rapidly decreased within the first 3 months to 19 ng/mL (min-max 3-91) (P < .001). The overall acute rejection rate was 7%. The clinical rejection rate (5% vs 9%), subclinical rejection (12% vs 36%), and borderline changes (21% vs 28%) were not statistically different during the follow-up between the 3-month 25-OH-D < 20 ng/mL and 3-month 25-OH-D > 20 ng/mL groups. There was a correlation between the 25-OH-D levels and PTH concentration at 3 months (r = -.2491, P = .01), but no correlation between the 3-month 25-OH-D and the season of the year (F = 0.19, P = .90; F = 1.34, P = .27, respectively). Multivariate analyses revealed that age and mGFR at 3 months, were independent predictors of mGFR at 12 months.

Conclusion: Our data show that vitamin D deficiency can develop rapidly after transplantation; vitamin D levels at 3 months are not associated with lower mGFR or a higher rejection rate at 1 year in children as opposed to adult recipients.
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http://dx.doi.org/10.1111/petr.13809DOI Listing
November 2020

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

Am J Kidney Dis 2020 10 10;76(4):533-545. Epub 2020 Jul 10.

Sydney School of Public Health, The University of Sydney, NSW, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia. Electronic address:

Rationale & Objective: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD.

Study Design: An online 2-round Delphi survey in English, French, and Hindi languages.

Settings & Participants: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale.

Analytical Approach: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically.

Results: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals.

Limitations: Most participants completed the survey in English.

Conclusions: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.
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http://dx.doi.org/10.1053/j.ajkd.2020.03.014DOI Listing
October 2020

Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD.

J Bone Miner Res 2020 11 6;35(11):2265-2274. Epub 2020 Aug 6.

INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.

Active vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4122DOI Listing
November 2020

The interest of oral calcium loads test in the diagnosis and management of pediatric nephrolithiasis with hypercalciuria: Experience from a tertiary pediatric centre.

J Pediatr Urol 2020 Aug 30;16(4):489.e1-489.e9. Epub 2020 May 30.

Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Centre de Référence des Maladies Rares Du Calcium et Du Phosphore, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France; INSERM 1033 Research Unit, Lyon, France. Electronic address:

Introduction: The use of calcium load has been forgotten in pediatrics until recently whereas it is of utmost importance to have a practical approach to guide management of hypercalciuric nephrolithiasis.

Objective: The purpose of this study was to evaluate the practical interest of oral calcium loads to improve the overall management of nephrolithiasis in children.

Methods: We retrospectively studied all pediatric patients having undergone an oral calcium load in our pediatric nephrology unit between September 2015 and April 2017.

Results: A total of 16 patients were included, at a median age of 12.0 (5.5-17.5) years. The indications of oral calcium load were: presence of an active urolithiasis without any obvious explanation after ruling out the "classical" biological abnormalities, or presence of hypercalciuria with stones composed of weddellite or carbapatite crystals. Among the 16 patients, 6 (38%) patients displayed absorptive hypercalciuria, 2 (12%) renal leak, 3 (19%) "unclassified" inadapted PTH, and 5 (31%) a normal calcium load test. The result of oral calcium load modified the clinical management in 14 (88%) patients, mainly based on the type of hypercalciuria. It allowed us to individualize nutritional advice: in patients with absorptive hypercalciuria, we proposed calcium intake within the lower normal range for age with dairy products not enriched with vitamin D, with the advice to avoid salt and calcium loads during evenings. Conversely, in patients with resorptive hypercalciuria, we proposed normal calcium intake for age. Showing the results of the calcium load is meaningful to patients and parents, and can be considered as an "educational" tool.

Discussion: To the best of our knowledge, this study is the first to evaluate the interest of calcium load in children with nephrolithiasis in an era of routine PTH and 1-25-D assessment. Here, we demonstrate the feasibility and safety of oral calcium load in children, its interest to understand the underlying mechanisms of hypercalciuria, and its major interest as an "educational tool" for patients to explain them the underlying mechanisms and thus guide the therapeutic management using an individualized dietary approach. This study did not include many patients, but to the best of our knowledge, this is the first study evaluating and validating the feasibility of a safe and non-expensive diagnosis tool in pediatric hypercalciuria.

Conclusion: Oral calcium load is helpful to guide therapeutic adaptation in pediatrics using an individualized dietary approach.
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http://dx.doi.org/10.1016/j.jpurol.2020.05.160DOI Listing
August 2020

Setting reasonable objectives for improving preemptive kidney transplantation rates in children.

Pediatr Nephrol 2020 12 25;35(12):2353-2360. Epub 2020 Jun 25.

Pediatric Nephrology Unit, Robert-Debré Hospital, APHP, Paris, France.

Background: This study aims to develop a method to estimate the potential of preemptive kidney transplantation (PKT) by identifying patients who were transplanted after a dialysis period (non-preemptive kidney transplantation (NPKT)) despite being medically suitable for PKT.

Methods: All children (< 18 years old) starting kidney replacement therapy (KRT) in France, between 2010 and 2016 and transplanted before December 31, 2017, were included. A propensity score (PS) of receiving PKT was estimated by multivariate logistic regression based on recipient medical characteristics. Healthcare use during the 24 months prior to KRT initiation was extracted from the French National Health Insurance database, and a pre-KRT follow-up of more than 18 months was considered sufficient to allow preemptive transplantation.

Results: Among 643 patients who started KRT, 149 (23.2%) were preemptively transplanted. Using PS stratification, among 391 NPKT patients, we identified 145 patients (37%) suitable for PKT, according to clinical characteristics. Mean age was 12.3 years, 67% were males, and 56% had urological abnormalities. Among those 145 patients, we identified 79 NPKT patients who started on dialysis despite early referral to a nephrologist (more than 18 months prior to KRT initiation).

Conclusions: This method estimates a potential of 228 (149 + 79) PKT (35%) among pediatric patients in France. A similar method could be used in adults or in other countries. Estimation of the rate of patients with CKD stage 5 medically suitable for PKT will be of interest for health policy makers when setting up objectives for improvement in preemptive kidney transplant access.
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http://dx.doi.org/10.1007/s00467-020-04653-wDOI Listing
December 2020

Eplet incompatibility in pediatric renal transplantation.

Pediatr Transplant 2020 09 10;24(6):e13721. Epub 2020 May 10.

Department of Pediatric Nephrology, Hopital Femme-Mere-Enfant, Lyon, France.

Eplet incompatibility appears to be a better predictor of the de novo appearance of DSA post-Tx than HLA antigen matching in adults. We evaluated the HLA Matchmaker® software (version 2.1) in our pediatric cohort to predict the appearance of DSA post-Tx. We included 70 pediatric patients (26 girls, 10 living donors, mean age 11.2 ± 3.9 years) after a first R-Tx (January 2010-August 2016), without prior immunization, having complete HLA typing (A, B, C, DRB1 and DQB1) and DSA follow-up for at least one year. The mean of HLA and eplet incompatibilities was 4.7 ± 1.3 and 15.5 ± 6.1, respectively, with a correlation coefficient r between these two variables of 0.34 (P < .001). The eplet load was 12.8 ± 5.0 in living donors vs 15.9 ± 6.2 in deceased donors (P = NS), 12.6 ± 6.1 in preemptive R-Tx (n = 14) vs 16.3 ± 5.9 for non-preemptive R-Tx (P = .04). Seven patients (10%) developed DSA during the 3.5 ± 1.2 years post-Tx. The eplet load was 13.7 ± 5.5 for those who developed DSA vs 15.7 ± 6.1 for the others (P = NS). In our single-center series of pediatric R-Tx with good HLA matching and lower eplet load than previously published series, eplet incompatibilities do not predict the development of DSA. The question of the HLA matching requirement and the daily interest of the HLA Matchmaker® software to help select the grafts remain open.
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http://dx.doi.org/10.1111/petr.13721DOI Listing
September 2020

The use of cinacalcet after pediatric renal transplantation: an international CERTAIN Registry analysis.

Pediatr Nephrol 2020 09 4;35(9):1707-1718. Epub 2020 May 4.

Reference Center for Rare Renal Disorders, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Department of Pediatric Nephrology, Rheumatology and Dermatology, Femme Mère Enfant Hospital, Bron Cedex, France.

Background: Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce.

Methods: In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile).

Results: At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m, plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported.

Conclusions: This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed.
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http://dx.doi.org/10.1007/s00467-020-04558-8DOI Listing
September 2020

Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis.

Pediatr Nephrol 2020 09 4;35(9):1679-1697. Epub 2020 May 4.

Department of Pediatric Nephrology, Rheumatology and Dermatology, Femme Mère Enfant Hospital, Bron, France.

Background: Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe.

Methods: This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies.

Results: The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies.

Conclusions: To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.
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http://dx.doi.org/10.1007/s00467-020-04516-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385021PMC
September 2020

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy.

Int J Mol Sci 2020 Apr 28;21(9). Epub 2020 Apr 28.

Pathophysiology, diagnosis and treatment of bone diseases, INSERM UMR 1033, 69008 Lyon, France.

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.
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http://dx.doi.org/10.3390/ijms21093109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246679PMC
April 2020

Discontinuation of RAAS Inhibition in Children with Advanced CKD.

Clin J Am Soc Nephrol 2020 05 6;15(5):625-632. Epub 2020 Apr 6.

Division of Pediatric Nephrology, University Hospital Heidelberg, Heidelberg, Germany.

Background And Objectives: Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study.

Design, Setting, Participants, & Measurements: In this study, 69 children with CKD (67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling.

Results: Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (-3.9 ml/min per 1.73 m per year; 95% confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m per year; 95% confidence interval, -2.4 to -0.6; =0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued.

Conclusions: Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD.
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http://dx.doi.org/10.2215/CJN.09750819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269205PMC
May 2020

Hyperphosphatemia and Chronic Kidney Disease: A Major Daily Concern Both in Adults and in Children.

Calcif Tissue Int 2021 Jan 29;108(1):116-127. Epub 2020 Jan 29.

Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Centre de Référence Des Maladies Rénales Rares, Centre de Référence Des Maladies Rares du Calcium et du Phosphore, Hôpital Femme Mère Enfant, Boulevard Pinel, 69677, Bron Cedex, France.

Hyperphosphatemia is common in chronic kidney disease (CKD). Often seen as the "silent killer" because of its dramatic effect on vascular calcifications, hyperphosphatemia explains, at least partly, the onset of the complex mineral and bone disorders associated with CKD (CKD-MBD), together with hypocalcemia and decreased 1-25(OH) vitamin D levels. The impact of CKD-MBD may be immediate with abnormalities of bone and mineral metabolism with secondary hyperparathyroidism and increased FGF23 levels, or delayed with poor growth, bone deformities, fractures, and vascular calcifications, leading to increased morbidity and mortality. The global management of CKD-MBD has been detailed in international guidelines for adults and children, however, with difficulties to obtain an agreement on the ideal PTH targets. The clinical management of hyperphosphatemia is a daily challenge for nephrologists and pediatric nephrologists, notably because of the phosphate overload in occidental diets that is mainly due to the phosphate "hidden" in food additives. The management begins with a dietary restriction of phosphate intake, and is followed by the use of calcium-based and non-calcium-based phosphate binders, and/or the intensification of dialysis. The objective of this review is to provide an overview of the pathophysiology of hyperphosphatemia in CKD, with a focus on its deleterious effects and a description of the clinical management of hyperphosphatemia in a more global setting of CKD-MBD.
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http://dx.doi.org/10.1007/s00223-020-00665-8DOI Listing
January 2021

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations.

J Bone Miner Res 2020 05 13;35(5):913-919. Epub 2020 Jan 13.

Normandie Université, UNICAEN, CHU de Caen Normandie, Department of Genetics, Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, EA7450 BioTARGen, Caen, France.

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding G α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The mother-specific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of G α in oocyte biology or embryogenesis, with implications for genetic counseling. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3948DOI Listing
May 2020

Intermittent cholecalciferol supplementation in children and teenagers followed in pediatric nephrology: data from a prospective single-center single-arm open trial.

Eur J Pediatr 2020 Apr 24;179(4):661-669. Epub 2019 Dec 24.

Centre de référence des maladies rénales rares Service de Néphrologie Rhumatologie Dermatologie Pédiatriques, Néphrogones, Filières ORKiD, Hôpital Femme Mère Enfant, Hospices Civils de Lyon,, 59 Boulevard Pinel, 69677, Bron Cedex, France.

Vitamin D deficiency is frequent in pediatric nephrology. The 2017 European guidelines recommend keeping 25OH vitamin D (25-D) levels within the 75-120 nmol/L range, ideally with daily supplementation. Intermittent supplementation with D3 has also been proposed. We aimed to assess the influence of our local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months. VITATOL is a prospective single-center study performed in our tertiary unit in children and teenagers followed for chronic kidney disease (CKD), kidney transplantation, or stable chronic nephrotic syndrome with 25-D levels below 75 nmol/L. Intermittent oral cholecalciferol (100,000 IU) was administered depending on baseline vitamin D levels and body weight. The primary outcome was the change in 25-D levels between baseline and 2 months. Secondary outcomes were the evolution of the main mineral biomarkers. Thirty-seven patients were included. Two months after beginning supplementation, corresponding to a median(min-max) of 46 (14-79) days after the last dose of vitamin D, 25-D levels increased from 50 to 76 nmol/L (p < 0.001), 18 patients having 25-D levels within the target range and 2 above. All patients displayed 25-D levels above 50 nmol/L. There were no significant changes in phosphate, PTH, alkaline phosphatase, and FGF23 levels before and after supplementation. Calcium levels increased from 2.39 to 2.44 mmol/L (p = 0.017), but no differences in calciuria and urinary calcium/creatinine ratio were observed.Conclusion: This vitamin D supplementation protocol using intermittent moderate doses of cholecalciferol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria. What is Known: • Vitamin D deficiency is frequent in pediatric nephrology. • The 2017 European guidelines recommend keeping 25OH vitamin D levels within the 75-120 nmol/L range ideally with daily supplementation, but intermittent supplementation with D3 has also been proposed. What is New: • We assessed the influence of a local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months in children and teenagers followed in pediatric nephrology. • The intermittent cholecalciferol supplementation protocol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria.
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http://dx.doi.org/10.1007/s00431-019-03553-yDOI Listing
April 2020

Treatment of hyperphosphatemia: the dangers of high PTH levels.

Pediatr Nephrol 2020 03 6;35(3):493-500. Epub 2019 Nov 6.

Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, Hôpital Femme Mère Enfant, Boulevard Pinel, 69677, Bron Cedex, France.

The control of secondary hyperparathyroidism (SHPT) in pediatric chronic kidney disease is of utmost importance. Even though parathyroid hormone (PTH) is an important biomarker of mineral and bone disorders associated to CKD (CKD-MBD), calcium, phosphate, alkaline phosphatase, and vitamin D are also crucial and should be assessed together. In pediatric dialysis, high PTH levels have been associated with impaired longitudinal growth, bone disease, cardiovascular comorbidities, left ventricular hypertrophy, anemia, and even mortality (when PTH levels were above 500 pg/mL, i.e., 8.3-fold the upper normal limit (UNL)). As such, high PTH levels are for sure deleterious, but too low PTH levels have also been shown to impair growth and to promote vascular calcifications because of the underlying adynamic bone. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in pediatric CKD, focusing on the pros. High bone turnover lesions can occur at lower PTH levels than "current" guidelines would suggest; thus, PTH alone is not a good predictor of the underlying osteodystrophy. PTH results can vary locally depending on the assay. Existing guidelines for PTH targets are conflicting and based on a very little evidence. However, the 120-180 pg/mL (2- to 3-fold the UNL) range is common to most of the guidelines; it seems to be a reasonable target in children undergoing dialysis, even though it does not correspond to "normal" PTH levels. As always, the philosophy of PTH levels in pediatric dialysis may be balanced, i.e., "not too low, not too high, and keep phosphate under control."
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http://dx.doi.org/10.1007/s00467-019-04400-wDOI Listing
March 2020

Cinacalcet use in paediatric dialysis: a position statement from the European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders Working Group of the ERA-EDTA.

Nephrol Dial Transplant 2020 01;35(1):47-64

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Children's Hospital, Hannover, Germany.

Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested.
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http://dx.doi.org/10.1093/ndt/gfz159DOI Listing
January 2020

Defects in tA tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.

Nat Commun 2019 09 3;10(1):3967. Epub 2019 Sep 3.

Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.

N-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (tA) is a universal modification essential for translational accuracy and efficiency. The tA pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
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http://dx.doi.org/10.1038/s41467-019-11951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722078PMC
September 2019

Determinants of Statural Growth in European Children With Chronic Kidney Disease: Findings From the Cardiovascular Comorbidity in Children With Chronic Kidney Disease (4C) Study.

Front Pediatr 2019 5;7:278. Epub 2019 Jul 5.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Failure of statural growth is one of the major long-term sequelae of chronic kidney disease (CKD) in children. In recent years effective therapeutic strategies have become available that lead to evidence based practice recommendations. To assess the current growth performance of European children and adolescents with CKD, we analyzed a cohort of 594 patients from 12 European countries who were followed prospectively for up to 6 years in the 4C Study. While all patients were on conservative treatment with a mean estimated glomerular filtration rate of 28 ml/min/1.73 m at study entry, 130 children commenced dialysis during the observation period. At time of enrolment the mean height standard deviation score (SDS) was -1.57; 36% of patients had a height below the third percentile. The prevalence of growth failure varied between countries from 7 to 44% Whereas patients on conservative treatment showed stable growth, height SDS gradually declined on those on dialysis. Parental height, pubertal status and treatment with recombinant growth hormone (GH) were positively, and the diagnosis of syndromic disease and CKD stage were negatively associated with height SDS during the observation period. Unexpectedly, higher body mass index (BMI) SDS was associated with lower height SDS both at enrolment and during follow up. Renal anemia, metabolic acidosis, and hyperparathyroidism were mostly mild and not predictive of growth rates by multivariable analysis. GH therapy was applied in only 15% of growth retarded patients with large variation between countries. When adjusting for all significant covariates listed above, the country of residence remained a highly significant predictor of overall growth performance. In conclusion, growth failure remains common in European children with CKD, despite improved general management of CKD complications. The widespread underutilization of GH, an approved efficacious therapy for CKD-associated growth failure, deserves further exploration.
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http://dx.doi.org/10.3389/fped.2019.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625460PMC
July 2019

Assessment of mineral and bone biomarkers highlights a high frequency of hypercalciuria in asymptomatic healthy teenagers.

Acta Paediatr 2019 12 15;108(12):2253-2260. Epub 2019 Jul 15.

Laboratoire de Biochimie et Biologie Moléculaire, Groupe Hospitalier Sud, Hospices Civils de Lyon, Lyon, France.

Aim: Assessment of mineral metabolism is complex in paediatrics.

Methods: We assessed the evolution of the main mineral and bone biomarkers (total/bone alkaline phosphatase ALP/BAP, β-crosslaps, osteocalcin, sclerostin, C-terminal and intact FGF23) in 100 healthy teenagers (10-18 years, 50 boys).

Results: At a mean age of 13.7 ± 2.2 years, phosphatemia, tubular phosphate reabsorption, ALP and BAP significantly decreased along puberty in both genders, whilst parathyroid hormone (PTH), 25-vitamin D (25D), FGF23, plasma calcium and urinary calcium were not modified. In girls, osteocalcin, β-crosslaps and sclerostin significantly decreased at the end of puberty. Calciuria above the crystallisation threshold (>3.8 mmol/L) and urinary calcium/creatinine ratio >0.7 mmol/mmol were found in 39% and 6% of subjects, respectively. Multivariable analyses showed that renal function and PTH were significant predictors of calciuria and urinary calcium/creatinine, whilst 25D remained a predictor only of urinary calcium/creatinine ratio.

Conclusion: Using the most recent assays, this study provides data for mineral/bone biomarkers across puberty and highlights the risk of hyper-calciuria in apparent asymptomatic healthy teenagers, not related to calcium intake but rather to 25D. Future studies are required to dissect the underlying mechanisms increasing calciuria and prevent nephrolithiasis as early as during childhood.
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http://dx.doi.org/10.1111/apa.14907DOI Listing
December 2019

Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease.

Nat Rev Nephrol 2019 09 13;15(9):577-589. Epub 2019 Jun 13.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD-Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3-5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045-0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making.
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http://dx.doi.org/10.1038/s41581-019-0161-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136166PMC
September 2019

Management of bone disease in cystinosis: Statement from an international conference.

J Inherit Metab Dis 2019 09 5;42(5):1019-1029. Epub 2019 Aug 5.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.
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http://dx.doi.org/10.1002/jimd.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379238PMC
September 2019