Publications by authors named "Justine Bacchetta"

184 Publications

Cholecalciferol (vitamin D3) must not be considered as an endocrine disruptor

Geriatr Psychol Neuropsychiatr Vieil 2022 06;20(2):151-161

Membre du bureau et du Conseil scientifique de la Société française de gériatrie et gérontologie, Département de gériatrie et Centre mémoire ressources recherche, Centre de recherche sur l’autonomie et la longévité, Centre hospitalier universitaire, Angers, France ; UNIV ANGERS, UPRES EA 4638, Université d’Angers, Angers, France ; Gérontopôle Autonomie Longévité des Pays de la Loire, Nantes, France

A French ministerial decree planning to include cholecalciferol, i.e. vitamin D3 (VD3), in the endocrine disruptors (ED) list has generated a lot of concerns in French physicians and scientists. The aim of the present article was to discuss the scientific rationale that may support or not this decision, which seems to be due to the use of VD3 overdose as a rodenticide in some European countries. First, it is noticeable that cholecalciferol is not an “exogenous substance”, a term used in all the definitions of ED, as it is largely synthesized in the skin after UVB rays exposure. Second, we did not find any published article that may support the inclusion of VD3 in the ED list. The request “vitamin D AND endocrine disruptor” reported 33 references in the PubMed database on March, 10, 2022, most of them discussing disturbances of vitamin D metabolism by EDs. Third, a large amount of studies conclude that VD3 has or may have beneficial effects on many functions that are known to be altered by EDs. In addition, we warn that learning that VD3 could be legally considered as a PE may cause the general public to mistrust vitamin D supplementation, which is not desirable in terms of public health as it may increase the already too high prevalence of vitamin D deficient individuals. We consider the aberrant decision of including cholecalciferol in the ED list should be rapidly invalidated before being effective in France and possibly disseminated in the European Union.
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http://dx.doi.org/10.1684/pnv.2022.1031DOI Listing
June 2022

The appearance of oxalate crystals in a kidney biopsy is no proof of post-transplant oxalate nephropathy in primary hyperoxaluria type 1.

Kidney Int 2022 Aug;102(2):446

Centre de Référence des Maladies Rénales Rares Néphrogones, Hospices Civils de Lyon, Lyon, France; Université Claude-Bernard Lyon, Lyon, France.

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http://dx.doi.org/10.1016/j.kint.2022.04.043DOI Listing
August 2022

Improved Outcome of Infantile Oxalosis Over Time in Europe: Data From the OxalEurope Registry.

Kidney Int Rep 2022 Jul 20;7(7):1608-1618. Epub 2022 Apr 20.

Department of Pediatric Nephrology, Hospices Civils de Lyon and University de Lyon, Lyon, France.

Introduction: Infantile oxalosis is the most severe form of primary hyperoxaluria type 1 (PH1), with onset of end-stage kidney disease (ESKD) during infancy We aimed to analyze the outcome of these patients as our current understanding is limited owing to a paucity of reports.

Methods: A retrospective registry study was conducted using data from the OxalEurope registry. All PH1 patients with ESKD onset at age <1 year were analyzed.

Results: We identified 95 patients born between 1980 and 2018 with infantile oxalosis. Median (interquartile range [IQR]) age at ESKD was 0.4 (0.3-0.5) year. There were 4 patients diagnosed by family screening who developed ESKD despite early diagnosis. There were 11 patients who had biallelic missense mutations associated with vitamin B6 responsiveness. Of 89 patients, 27 (30%) died at a median age of 1.4 (0.6-2.0) years (5-year patient survival of 69%). Systemic oxalosis was described in 54 of 56 screened patients (96%). First transplantation was performed at a median age of 1.7 (1.3-2.9) years. In 42 cases, this procedure was a combined liver-kidney transplantation (LKTx), and in 23 cases, liver transplantations (LTx) was part of a sequential procedure. Survival rates of both strategies were similar. Patient survival was significantly higher in patients born after 2000. Intrafamilial phenotypic variability was present in 14 families of patients with infantile oxalosis.

Conclusion: Nearly all screened patients with infantile oxalosis developed systemic disease. Mortality is still high but has significantly improved over time and might further improve under new therapies. The intrafamilial phenotypic variability warrants further investigation.
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http://dx.doi.org/10.1016/j.ekir.2022.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263236PMC
July 2022

X-linked hypophosphatemia, obesity and arterial hypertension: data from the XLH21 study.

Pediatr Nephrol 2022 Jun 27. Epub 2022 Jun 27.

Centre de Référence Des Maladies Rares du Calcium Et du Phosphate, Centre de Référence Des Maladies Rénales Rares, Filières Maladies Rares OSCAR, ORKID Et ERK-Net, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, 69500, France.

Background: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved.

Methods: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)).

Results: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab).

Conclusion: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-022-05636-9DOI Listing
June 2022

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet.

Int J Mol Sci 2022 Jun 8;23(12). Epub 2022 Jun 8.

Center for Pediatric and Adolescent Medicine, Division of Pediatric Nephrology, University of Heidelberg, 69120 Heidelberg, Germany.

Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gα/PKA and the Gα/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gα knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gα KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gα KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gα KO mice had similar bone morphology compared to WT, while CKD Gα-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gα-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gα-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gα/PKC KO further aggravates mineral bone disease.
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http://dx.doi.org/10.3390/ijms23126404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223847PMC
June 2022

Fluconazole in hypercalciuric patients with increased 1,25(OH)D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial.

Trials 2022 Jun 16;23(1):499. Epub 2022 Jun 16.

Centre de Référence des Maladies Rénales Rares, filières maladies rares ORKID and ERK-Net, Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Boulevard Pinel, 69677, Bron, Cedex, France.

Background: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)D levels.

Methods: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria.

Discussion: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients.

Trial Registration: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.
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http://dx.doi.org/10.1186/s13063-022-06302-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204961PMC
June 2022

Genetic assessment in primary hyperoxaluria: why it matters.

Pediatr Nephrol 2022 Jun 13. Epub 2022 Jun 13.

Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.

Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.
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http://dx.doi.org/10.1007/s00467-022-05613-2DOI Listing
June 2022

Rituximab as induction therapy in pediatric kidney transplantation: A single-center experience in four patients.

Pediatr Transplant 2022 Jun 2:e14329. Epub 2022 Jun 2.

Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, Hôpital Femme Mère Enfant, Rare Disease Networks ORKID and ERK-Net, Hospices Civils de Lyon, Bron, France.

Background: The anti-CD20 rituximab is often used in the treatment of children with steroid-resistant nephrotic syndrome or EBV-induced post-transplant lymphoproliferative disorder. This single-center series reports the use of rituximab as induction therapy in pediatric kidney transplantation.

Methods: Four children who received rituximab as induction therapy for kidney transplantation since 2016 were retrospectively analyzed. Clinical and laboratory data were extracted from medical records.

Results: The patients (2 boys and 2 girls) were aged from 6.1 to 11.9 years and were treated with rituximab on the day of the transplantation procedure; all the transplants came from deceased donors. In all patients, rituximab was used because of positive EBV viral loads before kidney transplantation. Viral loads remained undetectable for the first 6 months after the transplantation procedure and remained below the 4.5 log threshold thereafter. After a median follow-up of 2.3 years, none of the patients displayed rejection or de novo donor-specific antibodies; the glomerular filtration rate remained above 70 ml/min/1.73 m . No post-transplant lymphoproliferative disorder was observed.

Conclusion: The results suggest that rituximab can be used as induction therapy to prevent EBV replication and its complications in case of positive viral load prior to kidney transplantation.
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http://dx.doi.org/10.1111/petr.14329DOI Listing
June 2022

Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease.

Kidney Int 2022 May 27. Epub 2022 May 27.

Department of Marine Environmental Geochemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel, Germany.

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, Ca and Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light Ca is preferentially incorporated into bone, while heavier Ca is excreted. The ratio (Ca) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The Ca ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The Ca ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the Ca ratio and parathyroid hormone. The Ca ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the Ca ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2022.04.024DOI Listing
May 2022

Calcium homeostasis and hyperparathyroidism: Nephrologic and endocrinologic points of view.

Ann Endocrinol (Paris) 2022 Aug 19;83(4):237-243. Epub 2022 May 19.

Service de néphrologie et d'exploration fonctionnelle rénale, hôpital Édouard-Herriot, hospices civils de Lyon, Lyon, France; Université Lyon 1, Lyon, France; 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, Lyon, France.

Parathyroid hormone (PTH) is a hypercalcemic hormone acting on kidneys, bone and intestine. PTH promotes calcium release from the bone, renal calcium reabsorption and phosphate excretion, and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D-3. Hyperparathyroidism consists in PTH elevation, which may be adapted (secondary hyperparathyroidism) or non-adapted to calcemia levels (primary hyperparathyroidism, familial hypercalcemia/hypocalciuria, tertiary hyperparathyroidism). Primary hyperparathyroidism (PHP) features hypercalcemia and elevated or inappropriate PTH elevation. PHP may be revealed by biological abnormalities such as hypercalcemia and can be accompanied by renal complications (hypercalciuria, nephrolithiasis, nephrocalcinosis) and/or osteoporosis. However, it can also be normocalcemic and calcium loading will be necessary to diagnosis it. The differential diagnosis of PHP is familial hypocalciuric hypercalcemia (FHH), a dominant autosomal disease implicating a calcium sensing receptor-inactivating mutation. It impairs parathyroid cell sensitivity to calcemia elevation and thus induces excessive PTH stimulation, leading to hypercalcemia. Secondary HP (SHP) consists in PTH elevation secondary to a stimulus that needs to be corrected. 25 OHvitD deficiency, kidney failure, renal hypercalciuria, malabsorption and some drugs can induce SHP. Tertiary HP (THP) consists in autonomous PTH secretion by the parathyroid glands after prolonged stimulation under SHP, of whatever cause. This parathyroid autonomy results from the polyclonal hyperplasia observed in SHP progressing toward monoclonal nodular proliferation, leading to nodular hyperplasia or parathyroid adenoma (or, exceptionally, carcinoma), with reduced expression of CaSR and vitamin D receptor. In patients under dialysis, the frontier between SHP and THP is a matter of debate. This review will focus on the pathophysiology of calcium, diagnosis, and management of hyperparathyroidism.
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http://dx.doi.org/10.1016/j.ando.2022.05.003DOI Listing
August 2022

Primary hyperoxaluria type 1: time for prime time?

Clin Kidney J 2022 May 17;15(Suppl 1):i1-i3. Epub 2022 May 17.

Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.

Oxalate crystals in the kidney were first described in 1925. Since then, many major milestones have been reached in the understanding of genetic primary hyperoxaluria(s). Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease due to a mutation in the gene, which encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), inducing excess oxalate production and further kidney stones, nephrocalcinosis and chronic kidney disease (CKD). Symptoms and age at diagnosis of PH1 vary dramatically, from the most severe infantile forms leading to end-stage kidney disease (ESKD) during the first months of life to the less severe adult forms with moderate CKD and recurrent kidney stones. In 2020, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved a therapy based on RNA interference (RNAi) that profoundly reduces endogenous oxalate synthesis and dramatically changes the treatment algorithm for patients with PH1. The aim of this supplement of includes contemporary reviews of the pathophysiology and genetics, (conventional) medical therapeutic management, urological therapeutic management and novel therapies (including not only RNAi, but also other therapeutic perspectives). The specific opinions of both adult and paediatric nephrologists will be compared and the ethical issues, as well as challenges faced by physicians and patients in developing countries, will also be discussed. Despite all the accomplishments, there are still looming questions that require further investigation and discovery.
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http://dx.doi.org/10.1093/ckj/sfab233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113466PMC
May 2022

Primary hyperoxaluria type 1: novel therapies at a glance.

Clin Kidney J 2022 May 17;15(Suppl 1):i17-i22. Epub 2022 May 17.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the gene that encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients' pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase/hydroxypyruvate reductase (), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase () and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential 'game changer' in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.
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http://dx.doi.org/10.1093/ckj/sfab245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113449PMC
May 2022

Nephrocalcinosis in very low birth weight infants: incidence, associated factors, and natural course.

Pediatr Nephrol 2022 Mar 28. Epub 2022 Mar 28.

Department of Neonatology, Hopital de la croix rousse, Hospices Civils de Lyon, 69004, Lyon, France.

Background: Preterm kidney is exposed to various exogenous factors that may impact its function such as nephrotoxic drugs or nephrocalcinosis. We investigated prevalence and risk factors of nephrocalcinosis (NC) in recently born very low birth weight (VLBW) infants submitted to improved biological monitoring.

Methods: Retrospective, case-control study in very preterm infants (< 32 + 6 weeks, ≤ 1500 g) admitted to a tertiary care unit during a 6-year period. Each case (ultrasound-diagnosed NC) was matched with two controls (no NC). Data were collected at days 15 and 30 of life and 35 weeks corrected age, with follow-up at 18 months and 3 years.

Results: Of 525 eligible infants, overall prevalence of NC was 17.1% at 35 weeks corrected age. Prevalence was halved between 2012 (26.1%) and 2017 (11.8%). We included 265 infants, more than half being born before 28 weeks. Cases presented with more severe morbidity than controls, but reached statistical significance only in infants born < 28 weeks (88.2% vs. 68.3%, P = 0.01). Protein, energy, calcium, phosphorus, and vitamin D intakes were similar in the two groups and did not change significantly over the study period. Weight gain was similar in the two groups. Exposure to furosemide (OR [IC95%]: 1.26 [1.02; 1.57]) and postnatal growth (1.65 [1.04; 2.67]) were independent risk factors of NC. NC resolved 12-18 months after diagnosis in 61% of infants.

Conclusion: Prevalence of NC is significant but can be reduced. Furosemide should be cautiously prescribed in VLBW infants, and nutritional support must be well monitored to support postnatal growth and limit risk of nephrocalcinosis.

Trial Registration: ClinicalTrials.gov: NCT 04,860,583. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-021-05417-wDOI Listing
March 2022

Cardiac involvement in pediatric hemolytic uremic syndrome.

Pediatr Nephrol 2022 Mar 14. Epub 2022 Mar 14.

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

Background: Cardiac involvement is a known but rare complication of pediatric hemolytic uremic syndrome (HUS). We conducted a nationwide observational, retrospective case-control study describing factors associated with the occurrence of myocarditis among HUS patients.

Methods: Cases were defined as hospitalized children affected by any form of HUS with co-existent myocarditis in 8 French Pediatric Intensive Care Units (PICU) between January 2007 and December 2018. Control subjects were children, consecutively admitted with any form of HUS without coexistent myocarditis, at a single PICU in Lyon, France, during the same time period.

Results: A total of 20 cases of myocarditis were reported among 8 PICUs, with a mean age of 34.3 ± 31.9 months; 66 controls were identified. There were no differences between the two groups concerning the season and the typical, Shiga toxin-producing Escherichia coli (STEC-HUS), or atypical HUS (aHUS). Maximal leukocyte count was higher in the myocarditis group (29.1 ± 16.3G/L versus 21.0 ± 9.9G/L, p = 0.04). The median time between admission and first cardiac symptoms was of 3 days (range 0-19 days), and 4 patients displayed myocarditis at admission. The fatality rate in the myocarditis group was higher than in the control group (40.0% versus 1.5%, p < 0.001). Thirteen (65%) children from the myocarditis group received platelet transfusion compared to 19 (29%) in the control group (p = 0.03).

Conclusion: Our study confirms that myocarditis is potentially lethal and identifies higher leukocyte count and platelet transfusion as possible risk factors of myocarditis. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-022-05427-2DOI Listing
March 2022

Long-Term Transplantation Outcomes in Patients With Primary Hyperoxaluria Type 1 Included in the European Hyperoxaluria Consortium (OxalEurope) Registry.

Kidney Int Rep 2022 Feb 26;7(2):210-220. Epub 2021 Nov 26.

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

Introduction: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver-kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes.

Methods: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan-Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed.

Results: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver-KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01-0.75,  = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes ( = 0.025,  < 0.001) but not in patients with B6-responsive genotypes ( = 0.145,  = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes.

Conclusion: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes.
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http://dx.doi.org/10.1016/j.ekir.2021.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821040PMC
February 2022

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

Nephrol Dial Transplant 2022 Feb 7. Epub 2022 Feb 7.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.

Background: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies.

Methods: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Pediatric Nephrology (ESPN).

Results: 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I & II had the highest median PTH level (7.5 pmol/l) and 56% had hyperparathyroidism (PTH >7.0 pmol/l). Serum calcium was slightly lower in Bartter syndrome type I & II patients with hyperparathyroidism (2.42 vs. 2.49 mmol/l; p = 0.038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; p = 0.009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate - standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with TmP/GFR (rs 0.699; p < 0.001), suggesting renal phosphate wasting.

Conclusions: Hyperparathyroidism is frequent in patients with Bartter syndrome type I & II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.
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http://dx.doi.org/10.1093/ndt/gfac029DOI Listing
February 2022

The effect of lumasiran therapy for primary hyperoxaluria type 1 in small infants.

Pediatr Nephrol 2022 04 11;37(4):907-911. Epub 2022 Jan 11.

Service de Néphrologie Rhumatologie Et Dermatologie Pédiatriques, Centre de Référence Des Maladies Rénales Rares Néphrogones Filières Maladies Rares ORKID et ERK-Net, Hospices Civils de Lyon, Lyon, Bron, France.

Background: Lumasiran, a sub-cutaneous RNA-interference therapy, has been recently approved for primary hyperoxaluria type 1 (PH1), with doses and intervals according to body weight. Little is known as to its use in infants; the aim of this study was to describe treatment outcome in 3 infants who received lumasiran therapy before 2 years of age.

Case-diagnosis/treatment: Patient 1 was diagnosed antenatally and received lumasiran from day 9. According to the product information template (PIT), he received monthly lumasiran (3 times at 6 mg/kg, then 3 mg/kg), with hyperhydration and potassium citrate. Despite decreased plasma oxalate levels, persistent normal kidney function, and good tolerance, kidney ultrasound performed after 2 months found nephrocalcinosis, without normalization of urinary oxalate (UOx). The dose was increased back to 6 mg/kg, inducing a normalization in UOx. Nephrocalcinosis started to improve at month 10. Patient 2 was diagnosed at 2.5 months (acute kidney failure); nephrocalcinosis was present from diagnosis. She received monthly lumasiran (6 mg/kg), with progressive decrease in UOx and substantial improvement in kidney function but stable nephrocalcinosis after 9 injections. Patient 3 was diagnosed fortuitously (nephrocalcinosis) at 3.5 months and received lumasiran before genetic diagnosis, leading to decreased UOx and maintenance of normal kidney function. Nephrocalcinosis improved after 5 injections.

Conclusions: This report presents the youngest children treated with lumasiran worldwide. Lumasiran seems effective without side effects in infants but does not completely prevent the onset of nephrocalcinosis in the most severe forms. Higher doses than those proposed in the PIT might be required because of hepatic immaturity.
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http://dx.doi.org/10.1007/s00467-021-05393-1DOI Listing
April 2022

Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts.

Cells 2022 01 5;11(1). Epub 2022 Jan 5.

INSERM Research Unit 1033, Pathophysiology of Bone Disease, Faculté de Médecine Lyon Est, Université de Lyon, Rue Guillaume Paradin, 69008 Lyon, France.

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven.
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http://dx.doi.org/10.3390/cells11010170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749987PMC
January 2022

Renal Prognosis in Children With Tubulointerstitial Nephritis and Uveitis Syndrome.

Kidney Int Rep 2021 Dec 7;6(12):3045-3053. Epub 2021 Oct 7.

Service de Néphrologie pédiatrique, Centre Hospitalier Universitaire Montpellier, centre de référence maladies rénales rares du sud-ouest SORARE, Université de Montpellier-Filière ORKiD, Montpellier, France.

Introduction: Tubulointerstitial nephritis (TIN) and uveitis (TINU) syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults. However, data are scarce. We aimed to investigate the long-term renal prognosis in a French cohort of children with TINU syndrome.

Methods: We performed a national retrospective study including 23 French pediatric nephrology centers enrolling patients with TINU syndrome diagnosed between January 2000 and December 2018.

Results: A total of 46 patients were included (52% female, median age 13.8 years). At diagnosis of TIN, the median estimated glomerular filtration rate (eGFR) was 30.6 ml/min per 1.73 m (4.9-62.8). The median time between diagnosis of uveitis and TIN was 0.4 months (-4.1; +17.1). All patients had anterior uveitis, but 12 (29%) were asymptomatic. Nearly all patients (44 of 46) received steroid treatment, and 12 patients (26%) received a second-line therapy. At last follow-up (median 2.8 years), the median eGFR was 87.5 ml/min per 1.73 m (60.3-152.7) and <90 ml/min per 1.73 m in 20 patients.

Conclusion: In our study, nearly half of the patients had renal sequelae at last follow-up. Given the possible progression to chronic kidney disease, long-term monitoring of children with TINU syndrome is mandatory. Approximately a quarter of the children had asymptomatic uveitis suggesting all children presenting with TIN should undergo systematic ophthalmologic screening even in the absence of ocular signs.
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http://dx.doi.org/10.1016/j.ekir.2021.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640547PMC
December 2021

An Expert Perspective on Phosphate Dysregulation With a Focus on Chronic Hypophosphatemia.

J Bone Miner Res 2022 01 23;37(1):12-20. Epub 2021 Dec 23.

University of Zurich, Zurich.

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306528PMC
January 2022

TmP/GFR reference values from childhood to adulthood in the era of IDMS-standardized creatinine values.

Nephrol Dial Transplant 2021 Nov 27. Epub 2021 Nov 27.

Centre de Référence des Maladies Rénales Rares, filière maladies rares ORKID and ERKNet, Hospices Civils de Lyon, Bron, France.

Background: The assessment of phosphate homeostasis in clinical practice relies on circulating phosphate levels but also on phosphate tubular reabsorption, ideally assessed using the Tubular maximum Phosphate Reabsorption per Glomerular Filtration Rate (TmP/GFR). TmP/GFR reference values were established before the onset of IDMS-standardized creatinine assays, and thus need to be updated. Our objective is to provide reference values for TmP/GFR from childhood to adulthood, using the gold-standard of GFR assessment and IDMS-standardized creatinine values.

Methods: We retrospectively analyzed all the inulin and iohexol clearances (mGFR) performed in children and in adults screened for a living-donation in our unit since the beginning of IDMS-creatinine assays. TmP/GFR was calculated on a fasting sample, using the conventional formula without correction for TRP in subjects below 19 years of age.

Results: A total of 2051 subjects (1711 children, 340 adults), aged from 1.9 to 73.4 years with normal GFR, normal phosphate and normal calcium levels, was included for TmP/GFR analysis. As expected, there was a progressive decrease along puberty in both genders of plasma phosphate and TmP/GFR, the decrease occurring earlier in girls. After the age of 19, there was a stabilization of plasma phosphate and TmP/GFR levels until the age of 55, phosphate levels and TmP/GFR being slightly lower in men than in women.

Conclusion: We present the largest cohort describing TmP/GFR reference values in the era of IDMS-standardized creatinine assays. We believe that these data will help physicians to better diagnose and manage patients with abnormal phosphate metabolism in daily clinical routine.
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http://dx.doi.org/10.1093/ndt/gfab331DOI Listing
November 2021

Intermittent Bi-Daily Sub-cutaneous Teriparatide Administration in Children With Hypoparathyroidism: A Single-Center Experience.

Front Pediatr 2021 8;9:764040. Epub 2021 Nov 8.

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.

The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy. We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th-75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed. At a median age of 10.7 (8.1-12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95-118) mL/min/1.73 m, calcium levels of 1.87 (1.81-1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5-4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7-1.5) μg/kg/day (20 μg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90-122) mL/min/1.73 m, 2.36 (2.23-2.48) mmol/L, 0.5 (-0.1 to 1.5), and 68 (63-74) nmol/L, respectively, with a significant decrease in phosphate levels ( = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared. Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children.
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http://dx.doi.org/10.3389/fped.2021.764040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606674PMC
November 2021

Peripheral Blood Mononuclear Cells (PBMCs) to Dissect the Underlying Mechanisms of Bone Disease in Chronic Kidney Disease and Rare Renal Diseases.

Curr Osteoporos Rep 2021 12 13;19(6):553-562. Epub 2021 Nov 13.

INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard Lyon1, Lyon, France.

Purpose Of Review: To describe the methods that can be used to obtain functional and mature osteoclasts from peripheral blood mononuclear cells (PBMCs) and report the data obtained with this model in two peculiar diseases, namely pediatric chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and nephropathic cystinosis. To discuss future research possibilities in the field.

Recent Findings: Bone tissue undergoes continuous remodeling throughout life to maintain bone architecture; it involves two processes: bone formation and bone resorption with the coordinated activity of osteoblasts, osteoclasts, and osteocytes. Animal models fail to fully explain human bone pathophysiology during chronic kidney disease, mainly due to interspecies differences. The development of in vitro models has permitted to mimic human bone-related diseases as an alternative to in vivo models. Since 1997, osteoclasts have been generated in cell cultures, notably when culturing PBMCs with specific growth factors and cytokines (i.e., M-CSF and RANK-L), without the need for osteoblasts or stromal cells. These models may improve the global understanding of bone pathophysiology. They can be been used not only to evaluate the direct effects of cytokines, hormones, cells, or drugs on bone remodeling during CKD-MBD, but also in peculiar genetic renal diseases inducing specific bone impairment.
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http://dx.doi.org/10.1007/s11914-021-00707-6DOI Listing
December 2021

Teenagers and young adults with a past of allogenic hematopoietic stem cell transplantation are at significant risk of chronic kidney disease.

Pediatr Nephrol 2022 06 4;37(6):1365-1375. Epub 2021 Nov 4.

Institut d'Hématologie et d'Oncologie Pédiatrique, Hospices Civils de Lyon, Université Lyon 1, 1 place Professeur Joseph Renault, 69008, Lyon, France.

Background: Allogenic hematopoietic stem cell transplantation (aHSCT) remains the treatment of choice for some malignant hemopathies in children, albeit with the risk of long-term consequences, including chronic kidney disease (CKD).

Methods: In our single tertiary referral center, we retrospectively assessed the long-term renal outcome in a cohort of children and adolescents who had undergone aHSCT for malignant hemopathies between 2003 and 2017. We distinguished glomerular and tubular dysfunctions and assessed the accuracy of the most common formula(s) to estimate glomerular filtration rate (GFR) during standard clinical follow-up.

Results: Among the 166 patients who had received aHSCT, 61 underwent kidney functional assessment 1 to 10 years post-transplantation. Twenty-seven patients (44.3%) had a CKD with glomerular impairment, including 20 patients with a GFR < 90 mL/min/1.73 m, and among these, 5 patients < 60 mL/min/1.73 m. Patients with tubular signs had a significantly higher baseline GFR: 112 mL/min/1.73 m [100; 120] versus 102 [99.0; 112.5] for patients without kidney involvement, and 76 [61; 86] for patients with CKD (p < 0.01). Schwartz, CKiDU25, and EKFC formulas significantly overestimated mGFR, with a P30% ≤ 30%, which could lead to overlooking CKD diagnosis in this population. No patient reached kidney failure.

Conclusions: In conclusion, our study shows that CKD represents an important long-term sequela for children and adolescents who undergo aHSCT for malignant hemopathies, either with glomerular dysfunction or with the more insidious tubular dysfunction which could potentially impact growth. These patients could benefit from specialized long-term nephrology follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-021-05319-xDOI Listing
June 2022

Overlapping Phenotypes Associated With , , and Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D.

Front Endocrinol (Lausanne) 2021 13;12:736240. Epub 2021 Oct 13.

Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France.

Mutations in (vitamin D 24-hydroxylase) and (renal phosphate transporter NPT2a) cause autosomal recessive Infantile Hypercalcemia type 1 and 2, illustrating links between vitamin D and phosphate metabolism. Patients may present with hypercalciuria and alternate between chronic phases with normal serum calcium but inappropriately high 1,25-(OH)D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in and have been associated with phosphate wasting without hypercalcemia. The aims of this study were to evaluate the frequency of mutations in these genes in patients with a medical history suggestive of mutation to search for a specific pattern. Using next generation sequencing, we screened for mutations in 185 patients with PTH levels < 20 pg/mL, hypercalcemia and/or hypercalciuria, and relatives. Twenty-eight (15%) patients harbored biallelic mutations in (25) and (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in and a normal phosphatemia was reported in 2 patients with biallelic mutations in . Rare variations in and were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying or variation may present with biochemical changes in mineral metabolism. Two patients' genotype may suggest digenism (heterozygous variations in different genes). No variation was found in As no specific pattern can be found, patients with medical history suggestive of mutation should benefit from and analysis.
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http://dx.doi.org/10.3389/fendo.2021.736240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548709PMC
February 2022

Orthopedic and neurosurgical care of X-linked hypophosphatemia.

Arch Pediatr 2021 Oct 6;28(7):599-605. Epub 2021 Oct 6.

AP-HP, Endocrinology and Diabetology for Children, Bicêtre Paris Sud Hospital, Le Kremlin-Bicêtre, France; AP-HP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, filière OSCAR, Paris, France; AP-HP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France. Electronic address:

X-linked hypophosphatemia (XLH) is due to mutations in the PHEX gene leading to unregulated production of FGF23 and uncontrollable hypophosphatemia. XLH is characterized in children by rickets, short stature, waddling gait, and leg bowing of variable morphology and severity. Phosphate supplements and oral vitamin D analogs partially or, in some cases, fully restore the limb straightness. XLH patients may also be affected by premature, complete, or partial ossification of sutures between cranial bone, which could eventually result in cranial dysmorphia, decreased intracranial volume, and secondary abnormally high intracranial pressure with a cerebral compression. Our goal is to address the criteria and the management of the skeletal complications associated with XLH, mainly orthopedic and neurosurgical care, and reflect on decision-making and follow-up complexities.
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http://dx.doi.org/10.1016/j.arcped.2021.09.003DOI Listing
October 2021

A third of premature neonates displayed inadequate 25-hydroxyvitamin D levels before being discharged from a French neonatal intensive care unit.

Acta Paediatr 2022 Jan 2;111(1):104-106. Epub 2021 Oct 2.

Hospices Civils de Lyon, Departement of Neonatal Intensive Care Hôpital Femme Mère Enfant, Bron, France.

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http://dx.doi.org/10.1111/apa.16126DOI Listing
January 2022

Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation.

Cells 2021 09 21;10(9). Epub 2021 Sep 21.

Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, Filières de Santé Maladies Rares OSCAR, ORKID et ERK-Net, Hôpital Femme Mère Enfant, 69500 Bron, France.

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2-61) years, and a eGFR of 64 (23-149) mL/min/1.73 m. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.
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http://dx.doi.org/10.3390/cells10092498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467406PMC
September 2021

Hemodiafiltration Is Associated With Reduced Inflammation and Increased Bone Formation Compared With Conventional Hemodialysis in Children: The HDF, Hearts and Heights (3H) Study.

Kidney Int Rep 2021 Sep 6;6(9):2358-2370. Epub 2021 Jul 6.

Pediatric Nephrology Unit, Istanbul University, Faculty of Medicine, Istanbul, Turkey.

Background: Patients on dialysis have a high burden of bone-related comorbidities, including fractures. We report a analysis of the prospective cohort study HDF, Hearts and Heights (3H) to determine the prevalence and risk factors for chronic kidney disease-related bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD).

Methods: The baseline cross-sectional analysis included 144 children, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Circulating biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23, and klotho were measured.

Results: Inflammatory markers interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein were lower in HDF than in HD cohorts at baseline and at 12 months ( < .001). Concentrations of bone formation (bone-specific alkaline phosphatase) and resorption (tartrate-resistant acid phosphatase 5b) markers were comparable between cohorts at baseline, but after 12-months the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio increased in HDF ( = .004) and was unchanged in HD ( = .44). On adjusted analysis, the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio was 2.66-fold lower (95% confidence interval, -3.91 to -1.41;  < .0001) in HD compared with HDF. Fibroblast growth factor-23 was comparable between groups at baseline ( = .52) but increased in HD ( < .0001) and remained unchanged in HDF ( = .34) at 12 months. Klotho levels were similar between groups and unchanged during follow-up. The fibroblast growth factor-23/klotho ratio was 3.86-fold higher (95% confidence interval, 2.15-6.93;  < .0001) after 12 months of HD compared with HDF.

Conclusion: Children on HDF have an attenuated inflammatory profile, increased bone formation, and lower fibroblast growth factor-23/klotho ratios compared with those on HD. Long-term studies are required to determine the effects of an improved bone biomarker profile on fracture risk and cardiovascular health.
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http://dx.doi.org/10.1016/j.ekir.2021.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418977PMC
September 2021
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