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International audience; BACKGROUND AND AIMS: Patients with inflammatory bowel diseases (IBD) are exposed to drug-related nephrotoxicity and kidney-related extra-intestinal manifestations (EIMs). Patients should be monitored but guidance is lacking in current international recommendations. The objective of the Kidney Function Monitoring in Inflammatory Bowel Disease (MONITORED) initiative was to achieve an expert consensus about monitoring kidney function in IBD. METHODS: A literature review was first conducted. Then, an expert consensus meeting, involving 28 attendees representing French-speaking gastroenterologists and nephrologists, was held as part of an academic initiative on May 28, 2021. An anonymous Delphi process was used to discuss and vote on statements. Agreement was defined as at least 75% of participants voting for any one statement. RESULTS: Experts reached consensus on 11 criteria for referral to the nephrologist. Concerning kidney function monitoring, participants unanimously validated the use of serum creatinine with estimation of the glomerular filtration rate via the MDRD or CKD-EPI equations. A blood ionogram and a urine sample with measurement of a protein-to-creatinine ratio were also broadly agreed validated. Experts recommended performing this monitoring at IBD diagnosis, prior introducing a new treatment, and annually for EIMs screening and evaluation of treatment tolerance. An evaluation 3 months after starting mesalamine and then every 6 months was felt necessary, while for biologics an annually monitoring was deemed sufficient. CONCLUSION: The MONITORED consensus proposed guidelines on how to monitor kidney function in IBD. These recommendations should be considered in clinical practice to preserve kidney function and ensure the best approach to our patients.

Hypercalciuria is the main risk factor for recurrent calcium urolithiasis. The goal of our study is to determinate how useful an oral calcium load test is for stone formers to classify different forms of hypercalciuria in pathogenetic categories defined as renal or absorptive according to the current knowledge. Between June 2013 and February 2016, a prospective study was carried out on 117 documented recurrent hypercalciuric stone formers undergoing an oral calcium load test modified from the original description by Pak. After 2 days of calcium-restricted diet, urine and blood were analyzed at baseline and 120 min after receiving orally 1 g of calcium. Total and ionized calcium, parathyroid hormone from serum and urine calcium and creatinine were assessed in order to divide patients in three groups as previously described: resorptive, absorptive, and renal hypercalciuria. This allowed the identification of 19, 39, 34 and 33 patients with normocalcemic primary hyperparathyroidism (NPHPT), renal hypercalciuria aka renal calcium leak (RCL), absorptive hypercalciuria (AH) and unidentified cause, respectively. Patients with NPHPT (who required parathyroidectomy) experienced a lower PTH decrease (41.41 ± 12.82 vs. 54.06 ± 13.84% p 0.01), higher beta-crosslaps, as well as lower TmP/GFR and distal third radius bone mineral density. RCL resulted in increased fasting urine calcium-to-creatinine ratio (Uca/Cr), i.e., 0.37 mmol/mmol), without hyperparathyroidism. AH was diagnosed by the presence of ΔUCa/Cr 0.60 mmol/mmol between baseline and 120 min without any other anomaly. For all remaining patients, results were inconclusive due to the lack of sufficient increase in serum calcium or because the cause of lithogenesis could not be clearly identified. The oral calcium load test is useful in nearly 80% of patients by identifying the different forms of hypercalciuria causing urolithiasis and by guiding treatment, including parathyroid surgery.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.

Simple Summary Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that affects individuals of African descent with sickle cell trait (SCT). The driver of RMC pathogenesis is thought to be renal medullary ischemia from red blood cell sickling in the setting of SCT. Currently, no modifiable risk factors for RMC have been identified that explain why certain individuals with SCT develop RMC. Prior studies have demonstrated that high-intensity exercise increases adverse events related to red blood cell sickling. We hypothesized that high-intensity exercise may increase the risk of RMC. We used multiple sources of evidence including retrospective and prospective review of RMC patient exercise activity, objective measurements of skeletal muscle surface area, and measurement of hypoxia levels in the renal medulla of mice with SCT following high or moderate-intensity exercise. Our results suggest that high but not moderate-intensity exercise may be associated with the development of RMC among individuals with SCT. Abstract Renal medullary carcinoma (RMC) is a lethal malignancy affecting individuals with sickle hemoglobinopathies. Currently, no modifiable risk factors are known. We aimed to determine whether high-intensity exercise is a risk factor for RMC in individuals with sickle cell trait (SCT). We used multiple approaches to triangulate our conclusion. First, a case-control study was conducted at a single tertiary-care facility. Consecutive patients with RMC were compared to matched controls with similarly advanced genitourinary malignancies in a 1:2 ratio and compared on rates of physical activity and anthropometric measures, including skeletal muscle surface area. Next, we compared the rate of military service among our RMC patients to a similarly aged population of black individuals with SCT in the U.S. Further, we used genetically engineered mouse models of SCT to study the impact of exercise on renal medullary hypoxia. Compared with matched controls, patients with RMC reported higher physical activity and had higher skeletal muscle surface area. A higher proportion of patients with RMC reported military service than expected compared to the similarly-aged population of black individuals with SCT. When exposed to high-intensity exercise, mice with SCT demonstrated significantly higher renal medulla hypoxia compared to wild-type controls. These data suggest high-intensity exercise is the first modifiable risk factor for RMC in individuals with SCT.

INTRODUCTION AND OBJECTIVE:Renal medullary carcinoma (RMC) is a rare and aggressive malignancy that primarily affects young patients of African descent with sickle cell trait. No targeted therapies...

Resume En 2017, la reforme du 3e cycle des etudes medicales a pose les bases de 3 nouvelles phases dans la formation des medecins : « socle », « approfondissement » et « mise en responsabilite ». Cette derniere a ete particulierement discutee puisqu’elle semble tres proche du statut d’assistant specialiste. La nephrologie, qui a toujours ete une discipline tres attractive, s’est vue maintenir sa maquette a 4 ans de formation lorsque de nombreuses autres specialites ont vu une augmentation de leur duree initiale. Une mobilisation generale de la specialite a amene a s’interroger sur les differents aspects de cette maquette. A travers 3 questionnaires menes conjointement entre les associations representatives des jeunes nephrologues et des nephrologues titulaires, nous avons interroge les principaux concernes afin de connaitre leurs souhaits actuels et ce qu’ils connaissaient de la reforme. Ces resultats originaux montrent un fort mecontentement de l’ensemble de la profession, quelle que soit la generation interrogee, mais aussi une volonte globale de modification de la formation. Une majorite de la communaute nephrologique s’accorde sur la necessite de l’extension de la maquette a 5 annees ; les plus jeunes sont egalement demandeurs de davantage de souplesse dans la formation via la creation d’options et de formations specialisees transversales. Dans tous les cas, les associations representatives des nephrologues doivent agir conjointement afin de porter leur voix et de diffuser l’information sur cette reforme.

BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m(2) from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH

Resume La maladie de Fabry est une maladie genetique systemique due a un deficit enzymatique en α-galactosidase A, provoquant une accumulation de sphingolipides dans les lysosomes. Il s’agit d’une maladie rare et peu connue. L’objectif de cette etude etait de decrire la formation des nephrologues, d’evaluer leurs connaissances ainsi que leurs habitudes de depistage et de prise en charge de cette maladie. Les reponses de 152 nephrologues ont ete analysees. Seulement 22 % suivent des patients atteints de maladie de Fabry et 18 % en ont deja fait le diagnostic eux-memes. Une majorite d’entre eux (76 %) juge leur formation insuffisante : ils connaissent les symptomes de facon incomplete. Les moyens deja mis en œuvre autour de la pathologie (associations, bases de recueil, etc.) semblent egalement insuffisants. Certaines indications de traitement sont mal maitrisees, notamment en ce qui concerne l’insuffisance renale terminale ; les principaux fournisseurs d’informations sont les industriels du medicament. Le calcul d’un score de competence a montre que l’atteinte renale est mal connue (moins de 50 % de reponses correctes) et seuls 50 % des medecins connaissent la conduite a tenir pour le depistage et la confirmation de la maladie. Une partie des interroges (65 %) connait bien les symptomes, les indications du traitement ainsi que les generalites de la maladie, mais des ameliorations restent a attendre. La maladie de Fabry demeure une maladie meconnue, pour laquelle il existe des outils diagnostiques precoces et des armes therapeutiques permettant de limiter la survenue des complications. La communaute nephrologique doit s’investir en termes de formations concernant les symptomes, le depistage et la prise en charge de cette maladie rare.

Oral alkalization with sodium bicarbonate (NaHCO3 ) or citrate is prescribed for conditions ranging from metabolic acidosis to nephrolithiasis. Although most nephrologists/urologists use this method routinely, extracellular volume (ECV) increase is the main feared adverse event reported for NaHCO3 . Thus far, no trial has specifically studied this issue in a real-world setting. AlcalUN (NCT03035812) is a multicentric, prospective, open-label cohort study with nationwide (France) enrollment in 18 (public and private) nephrology/urology units. Participants were adult outpatients requiring chronic (>1 month) oral alkalization by either NaHCO3 -containing or no-NaHCO3 -containing agents. The ECV increase (primary outcome) was judged based on body weight increase (ΔBW), blood pressure increase (ΔBP), and/or new-onset edema at the first follow-up visit (V1). From February 2017 to February 2020, 156 patients were enrolled. After a median 106 days of treatment, 91 (72%) patients reached the primary outcome. They had lower systolic (135 (125, 141) vs. 141 (130, 150), P = 0.02) and diastolic (77 (67, 85) vs. 85 (73, 90), P = 0.03) BP values, a higher plasma chloride (106.0 (105.0, 109.0) vs. 105.0 (102.0, 107.0), P = 0.02) at baseline, and a less frequent history of nephrolithiasis (32 vs. 56%, P = 0.02). Patients experienced mainly slight ΔBP (

Renal medullary carcinoma (RMC) predominantly occurs in individuals with sickle cell trait (SCT). We found that patients with RMC more frequently participated in high-intensity exercise than matched controls, and renal medullary hypoxia significantly increased predominantly in the right kidney of mice with SCT following high-but not moderate-intensity exercise, consistent with the distinct predilection of RMC toward the right kidney. These results establish high-intensity exercise as a risk factor for RMC in individuals with SCT.

Epigenetic effectors "read" marks "written" on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy.

The chromatin modifier SETD2 was recently shown to be a dual-function methyltransferase that “writes” methyl marks on both chromatin and the mitotic spindle, revealing α-tubulin methylation as a new posttranslational modification of microtubules. Here, we report the first cytoskeletal “reader” for this SETD2 methyl mark: the polybromo protein PBRM1. We found PBRM1 directly binds the α-Tub-K40me3 mark on tubulin, and localizes to the mitotic spindle and spindle pole during cell division. PBRM1 can assemble a PBAF complex in the absence of chromatin as revealed by mass spectrometry, and can recruit other PBAF complex components including SMARCA4 and ARID2 to α-tubulin. In addition to PBRM1, other PBAF components were also localized to the mitotic spindle and spindle pole. This PBAF localization was dependent on recruitment to microtubules by PBRM1, and loss of spindle-associated PBRM1/PBAF led to genomic instability as assessed by increased formation of micronuclei. These data reveal a previously unknown function for PBRM1 beyond its role remodeling chromatin, and expand the repertoire of chromatin remodelers involved in writing and reading methyl marks on the cytoskeleton. The results of this study lay the foundation for a new paradigm for the epigenetic machinery as chromatocytoskeletal modifiers, with coordinated nuclear and cytoskeletal functions.

Introduction Anion exchanger 1 (AE1) (SLC4A1 gene product) is a membrane protein expressed in both kidney and red blood cells (RBCs): it exchanges extracellular bicarbonate (HCO3–) for intracellular chloride (Cl–) and participates in acid−base homeostasis. AE1 mutations in kidney α-intercalated cells can lead to distal renal tubular acidosis (dRTA). In RBC, AE1 (known as band 3) is also implicated in membrane stability: deletions can cause South Asian ovalocytosis (SAO). Methods We retrospectively collected clinical and biological data from patients harboring dRTA due to a SLC4A1 mutation and analyzed HCO3– and Cl– transports (by stopped-flow spectrophotometry) and expression (by flow cytometry, fluorescence activated cell sorting, and Coomassie blue staining) in RBCs, as well as RBC membrane stability (ektacytometry). Results Fifteen patients were included. All experience nephrolithiasis and/or nephrocalcinosis, 2 had SAO and dRTA (dRTA SAO+), 13 dominant dRTA (dRTA SAO−). The latter did not exert specific RBC membrane anomalies. Both HCO3– and Cl– transports were lower in patients with dRTA SAO+ than in those with dRTA SAO− or controls. Using 3 different extracellular probes, we report a decreased expression (by 52%, P < 0.05) in dRTA SAO+ patients by fluorescence activated cell sorting, whereas total amount of protein was not affected. Conclusion Band 3 transport function and expression in RBCs from dRTA SAO− patients is normal. However, in SAO RBCs, impaired conformation of AE1/band 3 corresponds to an impaired function. Thus, the driver of acid−base defect during dominant dRTA is probably an impaired membrane expression., Graphical abstract

Resume Rationnel L’impact de l’insuffisance renale chronique (IRC) sur l’elan vital des patients non dialyses est mal connu, et la perception des patients peut etre differente de celle des medecins. Methodes Un auto-questionnaire a ete adresse a 1282 nephrologues et un second auto-questionnaire en « miroir » a ete transmis aux patients (stade 3, 4 ou 5) par leur nephrologue. Les donnees ont ete recueillies de facon prospective et anonyme. Resultats Au total, 261 nephrologues et 172 patients ont participe. Soixante-six pour cent des patients decrivaient un effet deletere de l’IRC sur leur qualite de vie (egalement identifie par les nephrologues) : impact evalue comme important pour 22 % vs 27 %, modere ou inconstant pour 44 % vs 47 %, faible ou nul pour 34 % vs 31 %, respectivement pour les patients et les nephrologues. La perception des facteurs favorisant un meilleur elan vital etait egalement differente, les nephrologues sous-estimant leur role (soutien psychologique) : l’optimisme et les encouragements des nephrologues etaient majeurs pour le maintien de l’elan vital pour 60 % des patients vs 20 % des nephrologues (p Conclusion Les nephrologues ont une connaissance relative de l’impact de l’IRC sur l’elan vital des patients atteints d’une IRC non dialyses, mais il existe des differences de perception. Elle pourrait etre amelioree au cours d’une formation specifique.

Acid-base regulation is essential to maintain homeostasis in humans. Carbonic acid/bicarbonate (H2CO3/HCO3-) couple is the most predominant extracellular buffer to keep plasma pH within a physiological range. The ability to (re)generate such a buffer is a key milestone that necessitates to understand a precise physiology of both renal tubule and digestive tract. Here, we first reviewed renal and digestive cycles of bicarbonate in physiology. We also reviewed pathological findings where acid-base disequilibrium is involved and nutritional and/or alkali therapy could be necessary. Secondly, data from clinical trials were synthesized. Alkali therapy, oral and parenteral, from mineral-based water, masterful preparations or pharmaceutics drugs, is regularly used in a wide range of clinical findings, even if supporting data are (often) of a low level of evidence. Bicarbonate is primarily used during contrast-induced nephropathy, metabolic acidosis in chronic kidney disease or nephrolithiasis in which alkaline urine is necessary. Cast nephropathy, rhabdomyolysis and tumor lysis syndrome make usually physicians prescribe alkali therapy even if this prescription is only supported by physiopathological data without any proven clinical results. Finally, bicarbonate is essential in the composition of dialysate in both hemodialysis and peritoneal dialysis.

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. Methodes 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 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 Discussion 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 forme probablement plus moderee de SIAD.

Introduction Peu d’informations existent sur la prise en charge de l’hypoparathyroidie chronique en vie reelle. Notre objectif est d’etudier l’adequation des pratiques (suivi et objectifs du traitement) avec les recommandations internationales. Methodes Nous utilisons les donnees d’un sous-groupe de la e-cohorte francaise Epi-Hypo (118 medecins et 107 patients, 09/2016-12/2019) et celles d’une enquete en ligne (110 ePatients, 11/2019). Les participants devaient etre i) medecin prenant en charge des patients avec hypoparathyroidie chronique ou ii) patient participant a la cohorte Epi-Hypo ou iii) patient de l’association Hypoparathyroidisme France (ePatients). Resultats Endocrinologues et nephrologues representent 89 % des medecins mais d’autres specialites sont aussi impliquees. L’association vitamine D active/sels de calcium est donnee a 58-59 % des patients. La majorite (85-87 %) des medecins suit la calcemie au moins 2 fois/an a l’etat stable. Les recommandations internationales conseillent de controler les symptomes, les valeurs de calcemie, de phosphatemie et de calciurie : un controle simultane de tous ces facteurs est rapporte par 32 % des ePatients et 26 % des medecins. La majorite (80 %) des ePatients rapportent que leurs symptomes sont insuffisamment controles par le traitement en cours alors que leur suivi est similaire a ceux dont les symptomes sont controles. Leur traitement est similaire en dehors des sels de magnesium qu’ils recoivent plus frequemment que les autres. Discussion De nombreuses specialites sont impliquees dans la prise en charge des patients avec hypoparathyroidie chronique en France : les recommandations devraient les cibler car l’adherence est encore faible. De nouveaux traitements sont necessaires pour mieux controler les symptomes.

Introduction Peu d’informations existent sur la prise en charge de l’hypoparathyroidie chronique en vie reelle. Notre objectif est d’etudier l’adequation des pratiques (suivi et objectifs du traitement) avec les recommandations internationales. Description Nous utilisons les donnees d’un sous-groupe (118 medecins et 107 patients, entre 09/2016 et 12/2019) de la e-cohorte francaise Epi-Hypo (> 1100 patients) et celles d’une enquete en ligne (110 ePatients, 11/2019). Les participants devaient etre : – medecin prenant en charge des patients avec hypoparathyroidie chronique ; – patient participant a la cohorte Epi-Hypo ; – patient de l’association Hypoparathyroidisme France (ePatients). Methodes Nous comparons les habitudes de prescriptions rapportees par les medecins participant a l’etude aux reponses des ePatients et aux resultats renseignes dans la cohorte Epi-Hypo pour la meme periode. Nous analysons ces resultats par rapport aux dernieres recommandations internationales. Resultats Endocrinologues et nephrologues representent 89 % des medecins mais d’autres specialites sont aussi impliquees. L’association vitamine D active/sels de calcium est donnee a 58-59 % des patients. La majorite (85-87 %) des medecins suit la calcemie au moins 2 fois/an a l’etat stable. Les recommandations internationales conseillent de controler les symptomes, les valeurs de calcemie, de phosphatemie et de calciurie : un controle simultane de tous ces facteurs est rapporte par 32 % des ePatients et 26 % des medecins. La majorite (80 %) des ePatients rapportent que leurs symptomes sont insuffisamment controles par le traitement en cours alors que leur suivi est similaire a ceux dont les symptomes sont controles. Leur traitement est similaire en dehors des sels de magnesium qu’ils recoivent plus frequemment que les autres. Conclusion De nombreuses specialites sont impliquees dans la prise en charge des patients avec hypoparathyroidie chronique en France : les recommandations devraient tous les cibler car l’adherence est encore faible. De nouveaux traitements sont necessaires pour mieux controler les symptomes.

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.

Background: Tributyltin (TBT) is a persistent and bioaccumulative environmental toxicant. Developmental exposure to TBT has been shown to cause fatty liver disease (steatosis), as well as increased adiposity in many species, leading to its characterization as an obesogen. Objective: We aimed to determine the long-term effects of developmental TBT exposure on the liver. Methods: C57BL/6J mice were exposed to a dose of TBT (0.5mg/kg body weight per day; 3.07μM) below the current developmental no observed adverse effect level (NOAEL) via drinking water, or drinking water alone, provided to the dam from preconception through lactation. Sires were exposed during breeding and lactation. Pups from two parity cycles were included in this study. Animals were followed longitudinally, and livers of offspring were analyzed by pathological evaluation, immunohistochemistry, immunoblotting, and RNA sequencing. Results: Developmental exposure to TBT led to increased adiposity and hepatic steatosis at 14 and 20 weeks of age and increased liver adenomas at 45 weeks of age in male offspring. Female offspring displayed increased adiposity as compared with males, but TBT did not lead to an increase in fatty liver or tumor development in female offspring. Liver tumors in male mice were enriched in pathways and gene signatures associated with human and rodent nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). This includes down-regulation of growth hormone receptor (GHR) and of STAT5 signaling, which occurred in response to TBT exposure and preceded liver tumor development. Conclusions: These data reveal a previously unappreciated ability of TBT to increase risk for liver tumorigenesis in mice in a sex-specific manner. Taken together, these findings provide new insights into how early life environmental exposures contribute to liver disease in adulthood. https://doi.org/10.1289/EHP5414

The number of new patients with chronic kidney diseases strongly increases while the one of nephrologists does not: this is developing new challenges, in which e-health will take a special part. This field is poorly investigated: so, we developed a dedicated survey. Telenephrology is a new approach that includes all what nephrologists can do in their routine practice: especially, telehealth with teleconsulting, telesurvey, and helpline. We also studied their relationship with m-health. The questionnaire was developed and validated by members from the Club des Jeunes Nephrologues and the Societe Francophone de Nephrologie, Dialyse et Transplantation: it was then broadcast to all french nephrologists, thru web media. From June to July, 2017, we collected 175 answers: they represented all kinds of practices of the profession. Results show that French nephrologists are connected: most of them are present on social network(s) and/or uses connected objects, mostly for personal reasons. They communicate a lot, between them and/or with patients, mainly via email. Computerized medical records are mostly used in the follow-up of patients on renal dialysis or with chronic kidney diseases. Most of French nephrologists are satisfied by telenephrology but there are still obstacles to its deployment: mainly, technical, administrative, and/or billing difficulties. All should be taken into account to help telenephrology developing. In conclusion, French nephrologists are yet connected but they really need more help again to face new challenges raised by e-health.

2017 was the year during which France has seen the amendment of the 3rd cycle of medical education. Three new steps have been uploaded: "basement", "in depth", and "liability". The latter has been particularly discussed as it is really close to the former post-graduate state. Nephrology has always been a very attractive discipline. While most others have been increased in terms of length in initial medical education, nephrology has been assigned to 4 years. Altogether, nephrologists whatever their generation have led a series of questionnaires we report here. From 3 of them, we had new data providing insights regarding both their feeling and knowledge about this amendment. Globally, they dissatisfy whatever the considered generation and they propose different modifications. The upcoming generation especially wants more options and tailored initial formation when older nephrologists are more prone to require one additional year for all. Whatever is chosen by state institutions, representative associations such as SNIN, CJN, and CUEN should act together as spokeperson to disseminate both nephrologists' wishes and information about what is coming.

The chromatin modifier SETD2 often mutated in clear cell renal cell carcinoma (ccRCC), was recently shown to be a dual-function methyltransferase that “writes” methyl marks on both chromatin and microtubules, revealing α-tubulin methylation as a new posttranslational modification of the mitotic spindle. Here, we report that the polybromo protein PBRM1, the 2nd most mutated gene in ccRCC, is a “reader” for this SETD2-dependent methyl mark on α-tubulin. PBRM1 is a component of the PBAF (Polybromo BRG1 associated factor) chromatin remodeler complex. Our western and immunocytochemistry data in multiple kidney-derived cell lines, including HEK293T, HKC and 786-O, revealed that PBRM1 binds to methylated α-tubulin and localizes to the mitotic spindle and spindle pole during cell division. PBRM1 has six bromo domains, two bromo-associated homology (BAH) domains and one HMG domain. While PBRM1 is known to bind acetylated histones via its bromo domains, our GST pull down assays showed that PBRM1 binds methylated α-tubulin via its two BAH domains. Additional western and immunocytochemical experiments following knockout or re-expression of PBRM1 revealed that PBRM1 recruits other PBAF components to the mitotic spindle to maintain genomic stability. Two clinically established ccRCC mutations (P1048R and C1233W) in PBRM1 BAH domains result in loss of microtubule binding, mislocalization of PBAF, and the inability of PBRM1 to maintain genomic stability, as assessed by increased lagging chromosomes, chromosome bridges, multipolar spindles and micronuclei count. A third pathogenic ccRCC mutation (T1202K) in the PBRM1 BAH domain did not affect microtubule binding and consequently was not associated with mitotic spindle defects or genomic instability. Mass spectrometry and RNASeq confirmed BAH domain mutant PBRM1 still assembled a transcriptionally competent PBAF complex, clearly distinguishing the cytoskeletal from the chromatin impact of these mutations. These data reveal a previously unknown function of PBRM1 beyond reading acetylated histones, and expand the repertoire of chromatin remodelers acting on the cytoskeleton to maintain genomic stability. Citation Format: Menuka Karki, Rahul Jangid, Ramakrishnan Anish, Riyad N. Seervai, Jean-Philippe Bertocchio, Takashi Hotta, Pavlos Msaouel, Sung Y. Jung, Sandra L. Grimm, Cristian Coarfa, Bernard E. Weissman, Ryoma Ohi, Kristen J. Verhey, Courtney H. Hodges, Ruhee Dere, In Young Park, B. V. Venkataram Prasad, W. Kimryn Rathmell, Cheryl L. Walker, Durga N. Tripathi. A cytoskeletal function for PBRM1: reading methylated microtubules to maintain genomic stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2042.

Renal medullary carcinoma (RMC) is a rare and highly aggressive malignancy that affects primarily young patients of African descent with sickle cell trait. No targeted therapies are currently approved for patients with RMC and the median survival from diagnosis is only 13 months with the current standard of care therapy consisting of platinum-based cytotoxic chemotherapy. New therapeutic targets are urgently needed for this lethal disease. We previously identified proteotoxic and replication stress as hallmarks of RMC (Carugo et al. Cancer Cell, 2019; Msaouel et al. Cancer Cell, 2020). The neddylation pathway is a critical regulator that protects cells from proteotoxic and replication stress. We therefore hypothesized that inhibition of neddylation will produce antitumor responses in RMC. We accordingly tested the efficacy of the neddylation activating enzyme inhibitor pevonedistat (MLN4924) in vitro in the platinum-naïve RMC2C and the platinum-experienced RMC219 cell lines, as well as in vivo in the platinum-naïve RMC2X and the platinum-experienced RMC32X patient-derived xenograft (PDX) models. Cell viability was evaluated using MTT assays. To determine the effects of pevonedistat in combination with platinum-based cytotoxic chemotherapy (carboplatin + paclitaxel) in vivo, immunodeficient mice bearing subcutaneous RMC tumors were divided into 4 treatment arms (n=5-8 per arm) which consisted of vehicle control, pevonedistat (30mg/kg), carboplatin (80mg/kg) + paclitaxel (20mg/kg), and pevonedistat+carboplatin+paclitaxel. Synergy between pevonedistat and chemotherapy was determined based on the Bliss definition of drug independence. Pevonedistat showed potent in vitro antitumor efficacy against both RMC2C (IC50 0.199 μΜ) and RMC219 (IC50 0.551) cell lines. In the RMC2X in vivo model, mean tumor volumes were 2164±835mm3 for control, 433±250mm3 for pevonedistat, 339±44mm3 for chemotherapy, 75±46mm3 for pevonedistat + chemotherapy. The combination of pevonedistat with chemotherapy significantly reduced tumor volumes compared to vehicle control (p=0.02) and chemotherapy alone (p=0.008). A similar pattern was demonstrated with RMC32X tumor volumes, whereby pevonedistat combined with chemotherapy again significantly reduced tumor volume compared to control (p=0.006) and chemotherapy alone (p=0.02). A significant synergistic therapeutic effect of pevonedistat combined with chemotherapy was found for both RMC2X (p=0.008) and RMC32X (p=0.002). Our results identify the neddylation pathway as a targetable vulnerability of RMC tumors, and provide in vitro and in vivo preclinical rationale for a clinical trial testing the combination of pevonedistat with carboplatin + paclitaxel to improve the outcomes of patients with this deadly malignancy. Citation Format: Daniel D. Shapiro, Niki Millward Zacharias, Durga N. Tripathi, Jean-Philippe Bertocchio, Melinda Soeung, Priya Rao, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir, Christopher G. Wood, Jose A. Karam, Pavlos Msaouel. Targeting neddylation in combination with cytotoxic chemotherapy for the treatment of renal medullary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1247.

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.

The value of estimated glomerular filtration rate (eGFR) in living kidney donors screening is unclear. A recently published web-based application derived from large cohorts, but not living donors, calculates the probability of a measured GFR (mGFR) lower than a determined threshold. Our objectives were to validate the clinical utility of this tool in a cohort of living donors and to test two other strategies based on chronic kidney disease epidemiology collaboration (CKD-EPI) and on MDRD-eGFR. GFR was measured using 51 Cr- ethylene-diamine tetraacetic acid urinary clearance in 311 potential living kidney donors (178 women, mean age 50 ± 11.6 years). The web-based tool was used to predict those with mGFR < 80 mL/min/1.73 m2 . Inputs to the application were sex, age, ethnicity, and plasma creatinine. In our cohort, a web-based probability of mGFR

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 Hyperphosphatemia and cardiovascular mortality are associated particularly with end-stage renal disease. Available therapeutic strategies (i.e., diet restriction, calcium [or not]-based phosphate binders, calcimimetics) are associated with extrarenal blood purification. Compartmentalization of phosphate limits its depuration during hemodialysis. Several studies suggest that plasmatic pH is involved in the mobilization of phosphate from intracellular to extracellular compartments. Consequently, the efficiency of modified bicarbonate conductivity to purify blood phosphate was tested. Methods Ten hemodialysis patients with chronic hyperphosphatemia (>2.1 mmol/L) were included in the two three-sessions-per week periods. Bicarbonate concentration was fixed at 40 mmol/L and 30 mmol/L in the first and second periods, respectively. Phosphate depuration was evaluated by phosphate mobilization clearance (KM ). Findings Although bicarbonatemia was lower during the second period (21.0 ± 2.7 vs. 24.4 ± 3.1 mmol/L, P

Renal medullary carcinoma (RMC) is a rare but highly lethal renal cell carcinoma (RCC) that predominantly afflicts young African Americans with sickle cell hemoglobinopathies. There are currently no approved targeted therapies for RMC and the median survival from diagnosis is 13 months despite best available treatments. New biomarkers and therapeutic targets are therefore urgently needed for this very aggressive disease. No studies to date have profiled the long noncoding RNA landscape of RMC. We performed RNA sequencing in untreated primary tumor samples obtained from 11 patients with RMC. The lncRNA expression profile of RMC was compared to that of adjacent normal kidney (n = 6 patients with RMC), upper tract urothelial carcinoma (UTUC), and closely related RCCs including collecting duct carcinoma (CDC), clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC). We performed principal component analyses as well as hierarchical clustering of the lncRNA expression levels using the Pearson correlation coefficient as the distance metric and the ward's linkage rule. The read counts of each lncRNA were fitted using a negative binomial model and a Wald test was used in DESeq2 to compare expression levels. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. We found that the lncRNA signature of RMC is clearly distinct from that of ccRCC, pRCC, and chRCC, but substantially overlaps with CDC. Urothelial cancer associated 1 (UCA1) was the highest upregulated lncRNA (305-fold increase, FDR < 0.001) in RMC compared with adjacent normal kidney. This dramatic upregulation of UCA1 was similar to that seen in UTUC and not found in any of the other RCCs, including CDC. UCA1 is known to be associated with chemotherapy resistance and was previously considered to be highly specific for urothelial carcinoma. Our findings now suggest that UCA1 is also a hallmark of RMC. Future studies will focus on elucidating the functional consequences of UCA1 expression in RMC pathobiology. Citation Format: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Jianjun Gao, Priya Rao, Jean-Philippe Bertocchio, Jose Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir. Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4815.

Volume overload has been shown to be an independent risk factor for mortality in patients receiving chronic dialysis, but data in non-dialysis patients are scarce. Therefore we evaluated the prognostic value of extracellular fluid (ECF) volume for chronic kidney disease (CKD) progression and mortality in a prospective hospital-based cohort with CKD stage 1-4 (NephroTest Study). ECF (scaled to body surface area) and the measured glomerular filtration rate (mGFR) were determined using the distribution volume and clearance of 51Cr-EDTA, respectively. Cause-specific Cox and linear mixed-effect regression models were used to analyze the association of ECF with end-stage kidney disease (ESKD) and mortality, and with mGFR decline, respectively. The 1593 patients were mean age 58.8 years, 67% were men, mean mGFR of 43.6 mL/min/1.73m2 and mean ECF 15.1 L/1.73m2. After a median follow-up of 5.3 years, ESKD occurred in 324 patients and 185 patients died before ESKD. In multivariable analysis, ECF was significantly associated with the risk of ESKD (hazard ratio per 1L/1.73m2 increase: 1.14; 95% confidence interval [1.07; 1.21]) and with a faster GFR decline (adjusted mean difference in mGFR slope per 1L/1.73m2 increase -0.14 [-0.23; -0.05] mL/min/year). The relationship of ECF with mortality was non-linear and not significant (per 1L/1.73m2 increase 0.92, [0.73; 1.16]), below 15L/1.73m2, but significant (1.28; [1.14-1.45]) above 15L/1.73m2. Thus, in this large cohort of carefully phenotyped patients with CKD, ECF was an independent risk factor of CKD progression and mortality. Hence, close monitoring and treatment of fluid overload are important for the clinical management of patients with non-dialysis CKD.

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy.

Urolithiasis: assessment and metabolic management. Nephrolithiasis is a very common and recurrent disease. A minimal biological assessment is indicated in all patients. A more detailed biological investigation can be required according to the results of the first biological screening, or in case of recurrence, or in first intention depending on the medical history or on the consequences of renal calculi. Stone analysis (morphologic and using infra-red spectrophotometry) is the cornerstone for the understanding of the underlying pathophysiological processes. An appropriate imaging modality should be performed in order to detect urinary tract malformation in case of multiple or recurrent renal calculi. A medical treatment including at least dietary modifications must be prescribed to prevent stone recurrence and the potential risk of chronic kidney disease. Medical and dietary management should be individualized according to each type of stones.Lithiase urinaire : bilan et prise en charge métabolique. La maladie lithiasique rénale est une pathologie fréquente qui peut récidiver. Une évaluation biologique minimale est indiquée dès sa découverte. Selon ses résultats, ou en cas de récidive, ou en première intention selon le terrain, ou en raison du retentissement de la maladie lithiasique, une exploration biologique plus approfondie est indiquée. Dans tous les cas, l’analyse morpho-constitutionnelle du calcul est indispensable à la compréhension de la physiopathologie du processus lithiasique. Une uropathie malformative doit être recherchée par la réalisation d’une imagerie adaptée en cas de calculs multiples et/ou de récidives. Un traitement médical préventif comportant au minimum des règles diététiques doit être initié en raison du risque de récidive et de maladie rénale chronique. La connaissance de la nature des calculs permettra d’adapter ces mesures préventives.

The number of new patients with chronic kidney diseases strongly increases while the one of nephrologists does not: this is developing new challenges, in which e-health will take a special part. This field is poorly investigated: so, we developed a dedicated survey. Telenephrology is a new approach that includes all what nephrologists can do in their routine practice: especially, telehealth with teleconsulting, telesurvey, and helpline. We also studied their relationship with m-health. The questionnaire was developed and validated by members from the Club des Jeunes Néphrologues and the Société Francophone de Néphrologie, Dialyse et Transplantation: it was then broadcast to all french nephrologists, thru web media. From June to July, 2017, we collected 175 answers: they represented all kinds of practices of the profession. Results show that French nephrologists are connected: most of them are present on social network(s) and/or uses connected objects, mostly for personal reasons. They communicate a lot, between them and/or with patients, mainly via email. Computerized medical records are mostly used in the follow-up of patients on renal dialysis or with chronic kidney diseases. Most of French nephrologists are satisfied by telenephrology but there are still obstacles to its deployment: mainly, technical, administrative, and/or billing difficulties. All should be taken into account to help telenephrology developing. In conclusion, French nephrologists are yet connected but they really need more help again to face new challenges raised by e-health.

Alkali therapy is frequently used during chronic kidney disease and nephrolithiasis: nephrologists and urologists are the key operators. Very few is known about the underlying conditions of such a prescription: the aim of this study was to delineate those determinants. We conducted a prospective survey where French nephrologists and urologists were involved. Responders were without gender distinction and principally nephrologists. Prescription frequency was associated with gender (women), specialty (nephrologists), indications and perceived efficiency. Urologists prescribe more often during nephrolithiasis and nephrologists during chronic kidney disease. Urologists were more expert (by scoring on mineral-based alkaline waters compositions knowledge). By multivariate analysis, prescription frequency is associated with gender (women), indications and perceived efficiency by prescribers, which is itself influenced by feedback from patients. These results could have been influenced by a huge representation of nephrologists but foster physicians to go on listening to feedback from patients, due to a lack of clinical trials on the efficiency of mineral-based alkaline waters in such a field. Finally, physicians' education (especially young nephrologists) on mineral-based alkaline waters should be intensified.