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Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

The production of 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for glomerular filtration rate (GFR) measurement in Europe, was recently halted by the manufacturer. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance has so far mostly been restricted to assessment of separate renal function by scintigraphy, but scarcely used and validated for GFR measurement. We compared the performances of 51Cr-EDTA and 99mTc-DTPA for GFR and extracellular fluid measurement. In a multi-centre prospective study, 51Cr-EDTA and 99mTc-DTPA were simultaneously injected into 88 patients, and their urinary and plasma clearances, as well as their volumes of distribution, were measured during seven 30-min periods after a 90-min equilibrium time. Mean age was 52.2 ± 14.5 years, 59% were men. Urinary clearances of 51Cr-EDTA and 99mTc-DTPA were 64.1 ± 27.6 and 66.1 ± 28.0 mL/min, respectively, with a mean bias of 2.00 ± 2.25 mL/min, an accuracy within 10% of 95% [95% CI 91–99], and a coefficient of determination (R2) of 0.994. Plasma clearances of 51Cr-EDTA and 99mTc-DTPA were 66.1 ± 25.8 and 68.1 ± 26.6 mL/min, respectively, with a mean bias of 1.96 ± 3.32 mL/min, an accuracy within 10% of 91% [95% CI 85–97] and a R2 of 0.985. Distribution volumes were 17.3 ± 4.6 L for 51Cr-EDTA and 16.6 ± 4.6 L for 99mTc-DTPA (R2 0.930). The accuracy and precision of 99mTc-DTPA clearance, compared to 51Cr-EDTA clearance, was excellent for both urinary and plasma clearance methods, despite an approximate 2 mL/min overestimation, showing that the tracer is a reliable alternative to 51Cr-EDTA for GFR measurement.

Key points An UHPLC method to measure picomole amounts of magnesium has been developed. The method is sensitive, specific, accurate and reproducible. The method is suitable for quantifying magnesium transport across intact epithelia. Abstract Magnesium is involved in many biological processes. Extracellular magnesium homeostasis mainly depends on the renal handling of magnesium, the study of which requires measurement of low concentrations of magnesium in renal tubular fluid. We developed an ultra-high-performance liquid chromatography method to measure millimolar concentrations of magnesium in nanolitre samples. Within-assay and between-assay coefficients of variation were lower than 5% and 6.6%, respectively. Measurement of magnesium concentration was linear (r2 = 0.9998) over the range 0-4 mmol/l. Absolute bias ranged from -0.03 to 0.05 mmol/l. The lower limit of quantification was 0.2 mmol/l. Recovery was 97.5-100.3%. No significant interference with calcium, another divalent cation present in the same samples, was detected. The method was successfully applied to quantify transepithelial magnesium transport by medullary and cortical thick ascending limbs during ex vivo microperfusion experiments. In conclusion, ultra-high-performance liquid chromatography is suitable for measurement of picomole amounts of magnesium in renal tubular fluid. The method allows detailed studies of transepithelial magnesium transport across native epithelium.

Extracellular fluid calcium concentration must be maintained within a narrow range in order to sustain many biological functions, encompassing muscle contraction, blood coagulation, and bone and tooth mineralization. Blood calcium value is critically dependent on the ability of the renal tubule to reabsorb the adequate amount of filtered calcium. Tubular calcium reabsorption is carried out by various and complex mechanisms in 3 distinct segments: the proximal tubule, the cortical thick ascending limb of the loop of Henle, and the late distal convoluted/connecting tubule. In addition, calcium reabsorption is tightly controlled by many endocrine, paracrine, and autocrine factors, as well as by non-hormonal factors, in order to adapt the tubular handling of calcium to the metabolic requirements. The present review summarizes the current knowledge of the mechanisms and factors involved in calcium handling by the kidney and, ultimately, in extracellular calcium homeostasis. The review also highlights some of our gaps in understanding that need to be addressed in the future.

Annals of the New York Academy of Sciences 1516(1), 197-211 (2022). doi:10.1111/nyas.14865, In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations., Published by New York Acad. of Sciences, New York, NY

Phosphate homeostasis is a requirement for normal life. Phosphate is involved in the synthesis of membrane lipids, DNA, RNA, and energy-rich molecules (ATP and GTP), and the regulation of protein activity by phosphorylation/dephosphorylation. Moreover, phosphate is a component of apatite crystals, which provide stability to the bone, and is essential for normal growth. Phosphate balance in the body is the difference between net phosphate absorption through the intestine and phosphate excretion through the kidney. Numerous disorders, both genetic and acquired, may alter phosphate homeostasis. In affected individuals, it is crucial to identify the underlying mechanism(s) to provide adequate treatment; however, phosphate homeostasis assessment remains challenging. Besides the measurement of key hormones involved in the control of phosphate homeostasis (parathyroid hormone, vitamin D and metabolites, fibroblast growth factor 23), assessing the magnitude of phosphate reabsorption by the kidney is a crucial step. It makes it possible to distinguish between a primary disorder of renal phosphate reabsorption, associated with an intrinsic defect or endocrine disturbance, and a nutritional cause of phosphate deficiency. This strategy is described, and the potential consequences for therapeutic decisions are discussed.

Introduction Les valeurs normales du debit de filtration glomerulaire (DFG) ne sont pas clairement etablies, notamment chez le sujet âge. Description L’objectif etait de decrire le declin physiologique du DFG selon l’âge et le sexe, chez le sujet sain, et d’evaluer les performances des equations d’estimation du DFG. Methodes Le DFG etait mesure par la clairance renale du 51Cr-EDTA chez 630 femmes et hommes en bonne sante, âges de 18–90 ans. Un modele GAMLSS a permis d’etablir les valeurs de reference du DFG. La relation entre DFG, âge et sexe a ete analysee a l’aide d’un modele lineaire par morceaux. Enfin, biais, precision et exactitude des equations CKD-EPI et FAS ont ete evaluees. Resultats Les participants (43 % d’hommes) avaient un DFG mesure (mDFG) moyen de 90,5 ± 15,9 mL/min/1,73 m2. Le 5e percentile restait superieur a 60 mL/min/1,73 m2 jusqu’a 80 ans chez les hommes, alors que ce seuil etait atteint par 5 % des femmes a 63 ans et par 25 % a 76 ans. Le mDFG diminuait physiologiquement avec l’âge a partir de 40 ans ( Fig. 1 ), plus rapidement chez la femme que chez l’homme, 0,83 ± 0,09 vs 0,67 ± 0,07 mL/min/1,73 m2 par an, p Globalement, le biais dans l’estimation du DFG etait significativement plus faible avec l’equation FAS qu’avec CKD-EPI, alors que la precision et l’exactitude ne differaient pas. Les performances des equations etaient similaires entre les deux sexes, mais CKD-EPI tendait a surestimer et FAS a sous-estimer le mDFG au-dessus de 65 ans. Conclusion Un declin physiologique plus rapide du DFG chez les femmes que chez les hommes pourrait expliquer le paradoxe associant une plus forte prevalence de la maladie renale chronique (MRC) a une plus faible incidence de la defaillance renale chez la femme. Les valeurs de reference sont a considerer pour le diagnostic de MRC et la prescription medicamenteuse, en particulier chez le sujet âge.

Introduction La maladie renale chronique (MRC) augmente le risque de fracture et la diminution de la densite minerale osseuse (DMO) en est un facteur predictif. Or, sa mesure n’est recommandee aux stades 3–5 de la MRC que si les resultats impactent les decisions therapeutiques. Une concentration elevee d’hormone parathyroidienne (PTH) est associee a des DMO basses et peut predire le risque fracturaire. On ignore si la PTH influence l’evolution longitudinale de la DMO chez ces patients. Description Nous avons analyse un sous-groupe de patients adultes participant a la cohorte prospective NephoTest, durant 4,3 ± 2,03 ans entre 2005 et 2013 pour lesquels les valeurs de DMO et de PTH etaient disponibles. Methodes Un modele lineaire mixte a evalue l’interaction entre PTH initiale et variation longitudinale de la DMO. Resultats Au total, 858 patients ont eu deux mesures de DMO (âge moyen 58,9 ± 15,2 ans, sex-ratio de 2/1). Deux pour cent etaient MRC stade 1, 18 % stade 2, 55 % stade 3, 20 % stade 4, 5 % stade 5. A l’inclusion, on retrouvait aux stades plus avances de MRC des concentrations plus elevees de PTH et des DMO plus basses (tous sites). Les DMO les plus basses etaient associees positivement aux concentrations les plus hautes de PTH, a un âge eleve, au sexe feminin et a un tabagisme actif. Apres 4,3 ans de suivi, avec un declin d’1,2 mL/min/an de debit de filtration glomerulaire (DFG), on n’a pas observe de lien entre la variation de DMO dans le temps ni avec le DFG ni avec la PTH initiale. Conclusion A l’inclusion dans l’etude, la PTH est inversement liee a la DMO. Le suivi de 4,3 ans ne retrouve pas de diminution significative de la DMO a tous les sites. La valeur initiale de PTH n’a pas d’impact sur l’infime variation de DMO chez les patients avec MRC aux stades 2–5.

Introduction Les tubulopathies hereditaires sont des nephropathies rares et peu de donnees existent concernant leur prevalence et pronostic renal a long terme. Description Cette etude vise a evaluer la prevalence de l’insuffisance renale chronique (IRC) au moment de la confirmation du diagnostic genetique chez des patients adultes, ainsi qu’a decrire les caracteristiques cliniques et genetiques de cette population. Elle s’interesse aux tubulopathies susceptibles d’impacter la fonction renale. Methodes Une analyse retrospective des donnees cliniques et biologiques de patients adultes adresses entre 2001 et 2019 pour etude genetique des tubulopathies a ete realisee. La creatinine au moment de la demande a ete utilisee pour estimer le debit de filtration glomerulaire (DFG) a partir de la formule MDRD. La presence d’une IRC etait definie par un DFG Resultats Au total, 2145 patients presentant un tableau evocateur d’une des tubulopathies selectionnees ont beneficie d’un test genetique. Une tubulopathie hereditaire a ete confirmee chez 1023 patients (47,7 %). La fonction renale a pu etre estimee dans 86,6 % des cas. Parmi les 116 patients avec tubulopathie hereditaire confirmee et IRC, le test genetique etait realise en moyenne a 43 ans. Une nephrocalcinose etait presente chez 61,1 % des patients. Les pathologies les plus representees etaient le syndrome de Dent (31 %) et l’acidose tubulaire distale (19,8 %). Le pronostic renal etait particulierement impacte chez les patients atteints d’hypomagnesemie familiale avec hypercalcemie et nephrocalcinose et de syndrome de Dent ( Fig. 1 ). Conclusion Dans cette cohorte, 13 % des adultes atteints de tubulopathie hereditaire presentaient une IRC au moment du diagnostic genetique, ce chiffre variant considerablement en fonction des pathologies. Un diagnostic plus precoce de tubulopathie hereditaire devant un tableau compatible ou une IRC d’etiologie inconnue est indispensable pour ameliorer la prise en charge des patients et de leurs familles.

Introduction Les recommandations internationales pour le diagnostic de SIAD n’ont pas retenu le test de charge hydrique par manque de donnees publiees. Notre objectif est d’evaluer l’interet de realiser un test de charge hydrique chez les patients avec un antecedent d’hyponatremie. Description Nous analysons retrospectivement les donnees de patients adresses en service specialise (Physiologie, HEGP, Paris). Ils ont recu une charge hydrique orale de 20 mL/kg en 30 minutes. Le diagnostic de SIAD est retenu si la natremie (PNa) est Methodes Nous comparons les donnees de patients ayant un SIAD avec PNa Resultats Parmi les 174 patients analyses, 21 (12 %) sont consideres comme normaux, 80 (46 %) ont un SIAD et 72 (42 %) une hyponatremie liee a une autre cause. Parmi les patients avec SIAD, 41 % sont ‘normonatremiques’ (PNa ≥ 135 mM) a jeun (apres 12 heures de restriction hydrique) : leurs donnees demographiques ne different pas des patients hyponatremiques a jeun. Leur PNa diminue en cours de test mais reste superieure a celle des patients hyponatremiques a jeun (132 ± 2 vs 127 ± 3 mM, p Conclusion Realisee en conditions calibrees (a jeun), la biologie ne permet pas le diagnostic de SIAD dans 41 a 63 % des cas. Le test de charge hydrique permet d’identifier un groupe de patients avec une anomalie d’excretion de l’eau, possiblement une forme plus moderee de SIAD.

Nephrolithiasis is a very common (prevalence around 10 to 12% in France) and recurrent disorder. Nephrolithiasis is associated to chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, mainly if it is associated to nephrocalcinosis or to a monogenic disorder (1.6% of nephrolithiasis in adults, among them 1% of cystinuria). To understand the underlying pathophysiological processes, stone analysis (morphology and using infrared spectrophotometry) as well as minimal biological assessment including urine crystal research are required. The calcic nephrolithiasis is the more frequent subtype (>80%). Its medical treatment relies on simple dietary rules: non-alkaline hyperdiuresis>2 liters/day, calcium intake normalization (1 gram per day divided between the three principal meals), normalization of sodium (6 to 7 grams per day) and protein intake (1g/kg of theoretical body weight/day), and eviction of foods rich in oxalate. In case of persistent hypercalciuria (>0.1mmol/kg of theoretical body weight/day on free diet), a thiazide diuretic can be started while being aware to correct iatrogenic decrease in plasma potassium and urine citrate excretion. Measurement of bone mineral density must systematically be performed in patients with high 24 h-urinary calcium excretion. The medical treatment of uric acid nephrolithiasis relies on alkaline hyperdiuresis (goal of urine pH: 6.2 to 6.8). The use of allopurinol is justified only if urine uric acid is over 4mmol/day. Thanks to a well-managed preventive medical treatment, one can expect to stop the activity of nephrolithiasis in more than 80% of cases, making it one of the most accessible renal pathologies to preventive medical treatment.

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively.This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT.This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults.There were no interventions.Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured.In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped.In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.

Introduction Les mutations des CLDN 16 et 19 causent le syndrome FHHNC associant perte renale de Ca et de Mg, hypomagnesemie, nephrocalcinose et insuffisance renale. Ces Cldn sont exprimees a la jonction serree (JS) dans la branche large ascendante de l’anse de Henle (BLAAH), jouant un role dans la reabsorption paracellulaire de Ca et de Mg. Les souris Cldn16 knock-out n’ont ni nephrocalcinose ni insuffisance renale et les souris Cldn16 knock-down ont une perte renale de NaCl et un hyperaldosteronisme, qui n’existent pas chez l’humain. Description Un modele knock-in avec le variant humain le plus frequent de CLDN16 (p.L151F) pourrait permettre de mieux decrire ce syndrome. Methode Les souris Cldn16L151F/L151F ont ete generees par CRISPR-Cas9. Des femelles ont ete etudiees en cage a metabolisme a 3 mois. L’expression des Cldn dans la BLAAH et l’existence d’une nephrocalcinose ont ete etudiees. Resultats A 3 mois, le poids, les ingestats et les parametres sanguins (Na, Cl, Ca, Mg, Pi, creatinine) etaient similaires chez les souris Cldn16+/+ et Cldn16L151F/L151F. Les souris Cldn16L151F/L151F ont une excretion urinaire augmentee de Ca, Mg et de Pi et un pH urinaire plus bas ; le volume, l’osmolalite, le Na, le K et l’aldosterone urinaires n’etaient pas modifies. A 6 mois, le calcitriol etait augmente chez les Cldn16L151F/L151F. Il n’y avait pas de nephrocalcinose a 12 mois. La Cldn16 n’etait quasiment jamais vue a la JS et la Cldn19 semblait etre moins exprimee a la JS chez les Cldn16L151F/L151F suggerant que la Cldn16L151F a un effet negatif sur l’expression de la Cldn19. Conclusion Les souris Cldn16L151F/L151F ont une perte renale de Ca et de Mg, comme les patients FHHNC, sans perte renale de NaCl. L’etude des mâles, de la fonction renale, de la PTH, du phenotype osseux et dentaire est en cours.

Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO 2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1–4. All patients had measured glomerular filtration rate (mGFR) by 51 Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m 2 . Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06–3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98–3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO 2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes.

Muscle wasting predicts mortality in patients with end-stage renal disease (ESRD), but its role in the progression of chronic kidney disease (CKD) is uncertain. We studied CKD outcomes associated with low muscle mass, assessed by urinary creatinine excretion (UCr).The NephroTest cohort included 1429 patients with CKD stages 1-4 and both measured glomerular filtration rate (mGFR) (by (51)Cr-EDTA) and estimated glomerular filtration rate (eGFR) (by CKD-Epidemiology Collaboration equation). We used cause-specific Cox models to estimate hazard ratios (HRs) for the competing risks of ESRD and death associated with gender-specific UCr quartiles.UCr was 13.6 ± 3.2 mmol/24 h (0.17 ± 0.05 mmol/kg/24 h) in men and 9.2 ± 2.1 (0.14 ± 0.05) in women. It was positively associated with mGFR, but not with eGFR. Over a median follow-up of 3.6 (2.1-5.8) years, 229 patients developed ESRD and 113 patients died before ESRD. Compared with patients in the highest UCr quartile, those in the lowest quartile had a higher crude HR (95% confidence interval) for pre-ESRD death: 4.3 (2.4-7.7), which was weakened, but remained statistically significant, independent of demographics, mGFR and several other factors: 2.1 (1.04-4.3). Their crude ESRD risk was not higher: HR: 0.95 (0.65-1.4), and even tended to be lower after adjusting for mGFR and log-proteinuria: HR: 0.70 (0.45-1.1). Adjustment for eGFR instead of mGFR reversed this relationship: HR: 1.7 (1.1-2.7).In early stage CKD, low UCr is associated with higher risk for mortality, but not for ESRD. Using creatinine-based equation to adjust for GFR may bias the relationship of UCr with ESRD risk.

Introduction La BLAHC est un site majeur de reabsorption renale de Na et Ca. Le Ca est exclusivement transporte par la voie paracellulaire ; la permeabilite paracellulaire au Ca (PCa) necessite l’expression dans les jonctions serrees de la claudine (cldn)16. La voie paracellulaire permet egalement un transport passif de Na et la permeabilite paracellulaire au Na (PNa) necessite l’expression de la Cldn10b [1] . La perte de fonction de Cldn16 entraine le syndrome d’hypomagnesemie familiale avec hypercalciurie et nephrocalcinose [2] ; celle de Cldn10b cree le syndrome HELIX, caracterise par une perte renale de NaCl [3] . Dans la BLAHC, le voltage transepithelial (Vte) lumiere-positive, dependant de la Cldn10b, constitue la force motrice de la reabsorption de Ca [1] . Finalement, la PTH augmente le transport de Ca [4] mais les mecanismes en cause sont imprecis. Notre but est de determiner si la Cldn16, qui determine PCa, et la Cldn10b, qui determine Vte et PNa, sont impliquees dans l’effet de la PTH dans ce segment et d’identifier les mecanismes impliques. Patients/materiels et methodes Des BLAHC murines ont ete microperfusees in vitro pour mesurer les flux transepitheliaux de Ca et Na, Vte et les permeabilites ioniques paracellulaires a l’etat basal, et/ou apres ajout de PTH (10−10 M), de phorbol 12-Myristate 13-Acetate (PMA 10−6 M), de dibutyryl cAMP (dbcAMP 5 × 10−4 M), de ionomycine (10−7 M), ou d’H89 (inhibiteur de PKA) (10−5 M). Le rapport PNa/PCl est obtenu par l’equation de Goldman–Hodgkin–Katz. Resultats La PTH augmente la reabsorption de Ca par la BLAC de souris Cldn16+/+ (+44 %) et Cldn16−/− (+60 %) sans modifier Vte, indiquant une augmentation de PCa independante de la presence de Cldn16. La PTH augmente la reabsorption de Na (+15 %) par la BLAC sauvage et le rapport PNa/PCl (+22 %). Le dbcAMP et la ionomycine augmentent PNa/PCl. L’H89 inhibe l’effet de la PTH sur PNa/PCl. Le PMA n’a pas d’effet sur PNa/PCl. Discussion Contrairement au modele classique, la Cldn16 n’est pas necessaire a l’effet de la PTH sur la reabsorption de Ca dans la BLAHC. La PTH augmente PNa/PCl en activant la proteine kinase A et la Ca/Calmoduline kinase. Conclusion Les proprietes des jonctions serrees intercellulaires peuvent etre directement controlees par des voies de signalisation intracellulaire sur tissu intact.

Introduction La creatinine est un metabolite de la creatine, un derive d’acide amine d’origine musculaire. Les principales formules d’estimation du debit de filtration glomerulaire (DFG) utilisent la valeur de creatininemie et dependent donc de la masse musculaire. La myosite a inclusions est une myopathie acquise responsable d’une amyotrophie. Elle touche exclusivement les sujets âges, une population ou l’incidence des nephropathies est elevee. Notre objectif est de tester si l’estimation du DFG grâce a la creatininemie mesestime le DFG chez les patients atteints de myosites a inclusions. Patients et methodes Chez 20 patients suivis dans le service de medecine interne de l’hopital Pitie-Salpetriere, Paris, le DFG a ete simultanement mesure par la clairance renale du 51Cr-EDTA (DFGm) et estime (DFGe) par les formules MDRD, CKD-EPI creatinine et CKD-EPI cystatine C. La creatininemie a ete mesuree par technique enzymatique (CrE) et les urines des 24 heures ont ete recueillies la veille de l’examen. La composition corporelle (masse maigre appendiculaire non osseuse) a ete mesuree par absorptiometrie biphotonique a rayons X (DXA), exprimee en Z-score pour chaque patient. Resultats Huit hommes et 12 femmes âges de 65 ± 9 ans ont ete inclus. Leur masse maigre appendiculaire moyenne se situait dans les valeurs basses de la normale −1,85 [−2,50 ; −1,18] DS. La valeur de CrE etait situee dans les valeurs basses 43,5 μM [35,3–56,8]. Le DFGm etait 78 ± 18 mL/min/1,73 m2, 8 patients (40 %) avaient une maladie renale chronique selon les criteres KDIGO 2012 dont 4 avec un DFG Discussion Chez les patients etudies ayant une masse musculaire dans les valeurs basses de la normale, l’estimation du DFG utilisant la creatininemie ou la cystatine C est biaisee, en particulier avec la formule du MDRD. Ce biais de mesure empeche le diagnostic et le classement de la maladie renale chronique chez ces patients. L’utilisation des formules d’estimation du DFG dans la myosite a inclusions peut entrainer un retard dans la prise en charge de la maladie renale chronique mais egalement des surdosages pour les medicaments a elimination renale. Dans notre population, en utilisant un seuil de DFG estime par le CKD-EPI creatinine de 100 mL/min/1,73 m2, la sensibilite pour depister une maladie renale chronique stade ≥ 3 est de 100 %, la specificite de 87,5 % (Chi2 = 11,67). De maniere etonnante, le biais entre les DFG estimes et mesures n’etaient pas statistiquement correles avec la masse maigre appendiculaire exprimee en Z-score. Cela s’explique probablement par la faible taille de l’echantillon, mais peut etre egalement par la qualite du muscle qui n’est pas prise en compte par cette mesure contrairement a la mesure de la masse musculaire par IRM (resultats en cours d’analyse). Conclusion Au cours de la myosite a inclusions, le DFG est largement surestime par les formules habituelles malgre une masse musculaire moderement inferieure aux valeurs normales. Les formules d’estimation du DFG ne permettent pas de depister les insuffisances renales chroniques de facon satisfaisante dans cette population. Nous proposons qu’une mesure du DFG soit realisee chez les patients atteints de myosite a inclusion en cas de DFG estime par le CKD-EPI creatinine

Magnesium's most important role is in the release of chemical energy. Although most magnesium is stored outside of the extracellular fluid compartment, the regulated value is blood magnesium concentration. Cellular magnesium and bone magnesium do not play a major role in the defense of blood magnesium concentration; the major role is played by the kidney, where the renal tubule matches the urinary magnesium excretion and the net entry of magnesium into the extracellular fluid. In the kidney, magnesium is reabsorbed in the proximal tubule, the thick ascending limb of the loop of Henle, and the distal convoluted tubule. Magnesium absorption is mainly paracellular in the proximal tubule and in the thick ascending limb of the loop of Henle, whereas it is transcellular in the distal convoluted tubule. Several hormones and extracellular magnesium itself alter the distal tubular handling of magnesium, but the hormone(s) regulating extracellular magnesium concentration remains unknown.

For the past 40 years, primary hyperparathyroidism has been recognized as a common endocrine disease which is, most often, “non-symptomatic”, without the occurrence of nephrolithiasis or osteitis fibrosa cystica. Our knowledge in the pathophysiology has increased largely and diagnosis of primary hyperparathyroidism is usually easy. The only radical treatment is surgery and the surgical indications have been codified by several consensus conferences. For patients who do not undergo surgery, prolonged medical monitoring is needed.

Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling.

Ammonia secretion by the collecting duct (CD) is critical for acid-base homeostasis and, when defective, causes distal renal tubular acidosis (dRTA). The Rhesus protein RhCG mediates NH3 transport as evident from cell-free and cellular models as well as from Rhcg-null mice. Here, we investigated in a Rhcg mouse model the metabolic effects of Rhcg haploinsufficiency, the role of Rhcg in basolateral NH3 transport, and the mechanisms of adaptation to the lack of Rhcg. Both Rhcg+/+ and Rhcg+/− mice were able to handle an acute acid load, whereas Rhcg−/− mice developed severe metabolic acidosis with reduced ammonuria and high mortality. However, chronic acid loading revealed that Rhcg+/− mice did not fully recover, showing lower blood HCO3− concentration and more alkaline urine. Microperfusion studies demonstrated that transepithelial NH3 permeability was reduced by 80 and 40%, respectively, in CDs from Rhcg−/− and Rhcg+/− mice compared with controls. Basolateral membrane permeability to NH3 was reduced in CDs from Rhcg−/− mice consistent with basolateral Rhcg localization. Rhcg−/− responded to acid loading with normal expression of enzymes and transporters involved in proximal tubular ammoniagenesis but reduced abundance of the NKCC2 transporter responsible for medullary accumulation of ammonium. Consequently, tissue ammonium content was decreased. These data demonstrate a role for apical and basolateral Rhcg in transepithelial NH3 transport and uncover an incomplete dRTA phenotype in Rhcg+/− mice. Haploinsufficiency or reduced expression of RhCG may underlie human forms of (in)complete dRTA.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, recommendations for RB procedures are still lacking. Our working group, appointed by the scientific commission of the Societe de nephrologie in France, aimed to depict the main aspects of the practice of RB in adults in France, before establishing some guidelines. METHODS: Members of the Societe de nephrologie in France were asked to participate to a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals, and 12 in private centers) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to less than ten per year. Transjugular RB was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of hemorrhagic risk factors, care of patients with antiplatelet agents and hemorrhagic risk factors, and radiological guidance. Early discharge (

SummaryThe insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.

Resume Les connaissances sur la vitamine D ont beaucoup progresse ces dernieres annees. La vitamine D ne peut plus etre consideree comme uniquement necessaire a la prevention du rachitisme/osteomalacie. Son role dans la prevention des fractures osteoporotiques peripheriques du sujet âge est maintenant bien demontre (en association avec du calcium) et de tres nombreuses donnees epidemiologiques et experimentales sont en faveur d’un role dans la prevention de nombreuses affections (certains cancers et maladies auto-immunes, evenements cardio-vasculaires et hypertension, sarcopenie du sujet âge….). Deja, quelques etudes d’intervention confirment certains de ces effets. L’evaluation du statut vitaminique D peut etre aisement realisee par le dosage de la 25OHD serique. Toutefois, la plupart des revues recentes sur le sujet suggerent que les valeurs de reference de la 25OHD obtenues dans des populations apparemment en bonne sante sont beaucoup trop basses et que la concentration de 25OHD au-dessous de laquelle il existe une insuffisance en vitamine D se situe entre 50 et 100 nmol/L (20 et 40 ng/mL) avec une franche tendance a cibler des valeurs > 75 nmol/L (30 ng/mL). Les supplementations habituellement recommandees sont insuffisantes pour atteindre ces concentrations.

The European patents for epoetin alpha recently expired. Biosimilars (i.e. "a medicine which is similar to a biological medicine that has already been authorized" [EMEA 2007]) of epoetins have thus been released on the market in Europe. Because of the complexity of the processes that are required to produce medicinal products containing biotechnology-derived proteins as active substances and to characterize the physicochemical properties of these compounds, the guidelines that have been developed for generic drugs cannot be used for approval of biosimilar products. The EMEA guidelines do not answer all questions that have been raised for the development of biosimilars, and in some cases, decisions will have to be taken at a national level. This is why the Society of Nephrology (Societe de nephrologie), the French-speaking Society of Dialysis (Societe francophone de dialyse) and the Pediatric Society of Nephrology (Societe de nephrologie pediatrique) established guidelines for the usage of biosimilar epoetins concerning approval, identification, substitution of an innovator drug, post-marketing surveillance, extension of indication and pharmacovigilance plan.

Contains fulltext : 81402.pdf (Publisher’s version ) (Open Access) BACKGROUND: Kidney stone formation is a major socioeconomic problem in humans, involving pain, recurrent treatment and renal insufficiency. As most renal precipitates contain calcium as a major component, hypercalciuria is the main risk factor for renal stone formation. Different forms of hypercalciuria can be classified, which primarily arise from defects in the main organs involved in calcium homeostasis. A distinction can be made between renal, absorptive and resorptive hypercalciuria, originating from disturbed calcium handling in kidney, intestine and bone, respectively. A positive family history predisposes individuals to an increased risk of stone formation, which strongly indicates the involvement of genetic susceptibility factors. TRPV5 is the renal epithelial calcium channel that is the gatekeeper protein in active calcium reabsorption in the kidney. TRPV5 gene ablation in mice leads to severe hypercalciuria, implying that TRPV5 is an interesting candidate gene for renal hypercalciuria in humans. This study aims to identify and functionally characterize TRPV5 gene aberrations in patients with renal hypercalciuria. METHODS: The TRPV5 coding region and intron-exon boundaries were screened for gene mutations in 20 subjects displaying renal hypercalciuria after which identified non-synonymous polymorphisms were functionally characterized by patch-clamp analysis. Wild-type and TRPV5 channels including polymorphisms were transiently expressed in human embryonic kidney (HEK) 293 cells and functionally characterized by path-clamp analysis. RESULTS: Genotyping TRPV5 in renal hypercalciuria patients revealed three non-synonymous and five synonymous polymorphisms. Electrophysiological characterization of the TRPV5 mutants did not reveal significant functional changes compared to wild-type TRPV5 channel recordings. CONCLUSIONS: In this specific patient cohort, our data do not support a primary role for TRPV5 in the pathogenesis of renal hypercalciuria. However, TRPV5 cannot be excluded as a candidate gene in hypercalciuria.

An inverse relationship exists between urinary tissue kallikrein (TK) excretion and blood pressure in humans and rodents. In the kidney TK is synthesized in large amounts in the connecting tubule and is mainly released into the urinary fluid where its function remains unknown. In the present study mice with no functional gene coding for TK (TK-/-) were used to test whether the enzyme regulates apically expressed sodium transporters. Semiquantitative immunoblotting of the renal cortex revealed an absence of the 70-kDa form of gamma-ENaC in TK-/- mice. Urinary Na+ excretion after amiloride injection was blunted in TK-/- mice, consistent with reduced renal ENaC activity. Amiloride-sensitive transepithelial potential difference in the colon, where TK is also expressed, was decreased in TK-/- mice, whereas amiloride-sensitive alveolar fluid clearance in the lung, where TK is not expressed, was unchanged. In mice lacking the B2 receptor for kinins, the abundance of the 70-kDa form of gamma-ENaC was increased, indicating that its absence in TK-/- mice is not kinin-mediated. Incubation of membrane proteins from renal cortex of TK-/- mice with TK resulted in the appearance of the 70-kDa band of the gamma-ENaC, indicating that TK was able to promote gamma-ENaC cleavage in vitro. Finally, in mouse cortical collecting ducts isolated and microperfused in vitro, the addition of TK in the luminal fluid increased significantly intracellular Na+ concentration, consistent with an activation of the luminal entry of the cation. The results demonstrate that TK, like several other proteases, can activate ENaC in the kidney and the colon.

International audience; Apical bumetanide-sensitive Na(+)-K(+)-2Cl(-) co-transporter, termed NKCC2, is the major salt transport pathway in kidney thick ascending limb. NKCC2 surface expression is subject to regulation by intracellular protein trafficking. However, the protein partners involved in the intracellular trafficking of NKCC2 remain unknown. Moreover, studies aimed at under-standing the post-translational regulation of NKCC2 have been hampered by the difficulty to express NKCC2 protein in mammalian cells. Here we were able to express NKCC2 protein in renal epithelial cells by tagging its N-terminal domain. To gain insights into the regulation of NKCC2 trafficking, we screened for interaction partners of NKCC2 with the yeast two-hybrid system, using the C-terminal tail of NKCC2 as bait. Aldolase B was identified as a dominant and novel interacting protein. Real time PCR on renal microdissected tubules demonstrated the expression of aldolase B in the thick ascending limb. Co-immunoprecipitation and co-immunolocalization experiments confirmed NKCC2-aldolase interaction in renal cells. Biotinylation assays showed that aldolase co-expression reduces NKCC2 surface expression. In the presence of aldolase substrate, fructose 1,6-bisphosphate, aldolase binding was disrupted, and aldolase co-expression had no further effect on the cell surface level of NKCC2. Finally, functional studies demonstrated that aldolase-induced down-regulation of NKCC2 at the plasma membrane was associated with a decrease in its transport activity. In summary, we identified aldolase B as a novel NKCC2 binding partner that plays a key role in the modulation of NKCC2 surface expression, thereby revealing a new regulatory mechanism governing the co-transporter intracellular trafficking. Furthermore, NKCC2 protein expression in mammalian cells and its regulation by protein-protein interactions, described here, may open new and important avenues in studying the cell biology and post-transcriptional regulation of the co-transporter.