Update on vitamin D and evaluation of vitamin D status.

Knowledge about vitamin D has greatly improved during the last few years. Vitamin D cannot any more be considered as exclusively necessary to prevent ricket/osteomalacia. Its role in the prevention of some osteoporotic fractures in the elderly (in association with calcium nutrition) is now well demonstrated and many epidemiologic and laboratory data argue for a role in the prevention of several diseases or anomalies (cancer, auto-immune diseases, cardiovascular events, sarcopenia...). A few intervention studies confirming some of these effects also exist. Vitamin D status can easily be assessed by measuring serum 25 hydroxy vitamin D (25OHD) level. However, many experts have claimed that the population-based reference values for 25OHD are too low and that the cut-off value below which vitamin D insufficiency can be present is somewhere between 20 and 40ng/mL with a clear tendency to target values above 30ng/mL (75nmol/L). The main consequences are that vitamin D insufficiency is highly frequent whereas the currently recommended supplementation doses are not sufficient

A New Human NHERF1 Mutation Decreases Renal Phosphate Transporter NPT2a Expression by a PTH-Independent Mechanism

Background: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1) binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. Methods: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. Results: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A) located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. Conclusions: Our results indicate that the PDZ1 domain is critical for NHERF1- NPT2a interaction in humans and for th

Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease

International audienc

Age-adapted percentiles of measured glomerular filtration in healthy individuals:extrapolation to living kidney donors over 65 years

OBJECTIVES: Most data on glomerular filtration rate (GFR) originate from subjects <65 years old, complicating decision-making in elderly living kidney donors. In this retrospective multi-center study, we calculated percentiles of measured GFR (mGFR) in donors <65 years old and extrapolated these to donors ≥65 years old. METHODS: mGFR percentiles were calculated from a development cohort of French/Belgian living kidney donors <65 years (n=1,983), using quantiles modeled as cubic splines (two linear parts joining at 40 years). Percentiles were extrapolated and validated in an internal cohort of donors ≥65 years (n=147, France) and external cohort of donors and healthy subjects ≥65 years (n=329, Germany, Sweden, Norway, France, The Netherlands) by calculating percentages within the extrapolated 5th-95th percentile (P5-P95). RESULTS: Individuals in the development cohort had a higher mGFR (99.9 ± 16.4 vs. 86.4 ± 14 and 82.7 ± 15.5 mL/min/1.73 m(2)) compared to the individuals in the validation cohorts. In the internal validation cohort, none (0%) had mGFR below the extrapolated P5, 12 (8.2%) above P95 and 135 (91.8%) between P5-P95. In the external validation cohort, five subjects had mGFR below the extrapolated P5 (1.5%), 25 above P95 (7.6%) and 299 (90.9%) between P5-P95. CONCLUSIONS: We demonstrate that extrapolation of mGFR from younger donors is possible and might aid with decision-making in elderly donors

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

peer reviewed("[en] BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.","[en] ",""

Vitamine D et santé cardiovasculaire

Le déficit en vitamine D touche environ 50 % de la population mondiale. Au-delà de ces effets classiques sur le métabolisme minéral, la vitamine D possède de nombreux effets extra osseux parmi lesquels des effets sur le système cardiovasculaire qui sont essentiellement documentés par des études observationnelles, expérimentales et par de petites études d’intervention s’intéressant la plupart du temps à des paramètres intermédiaires du risque cardiovasculaire. Il est de ce fait temps de conduire de larges études interventionnelles randomisées contre placebo, ciblant les effets de la vitamine D native sur les événements et la mortalité cardiovasculaire

Caractérisation des conséquences fonctionnelles d'une nouvelle mutation du domaine PDZ1 de NHERF1 humain et études cliniques concernant la prise en charge des anomalies du métabolisme phosphocalcique après transplantation rénale

Mon travail de thèse a porté sur l étude de différentes anomalies du métabolisme phosphocalcique. L homéostasie du phosphate (P) est assurée par le rein grâce aux cellules tubulaires proximales qui réabsorbent le P par l intermédiaire du cotransporteur sodium-phosphate NPT2a. NHERF1, protéine comportant deux domaines PDZ, interagit avec i) NPT2a et favorise son expression membranaire, ii) le récepteur de la parathormone (PTH) et inhibe la production d AMPc en réponse à la PTH. Nous montrons que, par rapport à NHERF1 sauvage, la mutation E68A du domaine PDZ1 de NHERF1, mise en évidence chez une patiente présentant un diabète phosphaté, diminue l interaction entre NHERF1 et NPT2a, l adressage membranaire de NPT2a et le transport de phosphate. Contrairement aux mutations de NHERF1 précédemment décrites, situées dans PDZ2 ou entre PDZ1 et PDZ2, la mutation E68A n augmente pas la production d AMPc en réponse à la PTH et constitue donc un nouveau mécanisme de fuite rénale de phosphate chez l homme. L insuffisance en vitamine D concerne environ 85% des patients transplantés rénaux (PTR). Chez des PTR, nous montrons qu un traitement par fortes doses de vitamineD3 permet la correction de l insuffisance en vitamine D et diminue l hyperparathyroïdie secondaire, sans induire d effets indésirables. L hyperparathyroïdie autonomisée concerne environ 30% des PTR et peut être traitée par Cinacalcet (calcimimétique), proposé en alternative à la parathyroïdectomie. Nous montrons que le Cinacalcet induit une augmentation transitoire de la calciurie qui n altère pas la fonction rénale, et n entraîne pas de dépôts calciques rénaux après 9 mois de traitement.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Vitamin D in 2020: An Old Pro-Hormone with Potential Effects beyond Mineral Metabolism

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