Extreme Hyponatremia Complicated by Osmotic Demyelination in a Previously Healthy Young Individual.

Rationale: Severe hyponatremia can lead to dramatic complications whether it is treated or not. At times, it may be very severe (serum Na concentration: NaS < 115 mmol/L) or even extreme (NaS < 105 mmol/L)a and its cause difficult to identify, especially in younger individuals with no history of water disorders. The case presented herein illustrates these points quite eloquently and leads us to believe that the current recommendations for the treatment of very severe hyponatremia require some fine-tuning. Presenting Concerns: A 26-year-old man was admitted to our intensive care unit for a NaS of 88 mmol/L in the absence of obvious extracellular fluid volume contraction. He had been experiencing vomiting, diarrhea, fatigue, and excessive thirst for the past 6 weeks and minor neurological symptoms just before admission. Laboratory tests at presentation also showed a urine osmolarity of 697 mOsm/L and urine Na of 40 mmol/L. Diagnoses: The presenting concerns were consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH) manifesting as extreme, yet mildly symptomatic hyponatremia. At the same time, they did not point toward a specific cause initially. Interventions: The patient was treated through water restriction, subcutaneous desmopressin, and various intravenous (IV) fluids. Our goal had been to increase NaS at a rate of 4 to 6 mmol/L/day and required the amount of NaCl and free water perfused hourly to be readjusted constantly. Access to water also had to be opposed as the patient was unable to tolerate his thirst. Outcomes: During the first 6 days, the rate of NaS correction achieved was ~6 mmol/L/day. The patient improved initially but at the end of day 6, he experienced severe extrapontine osmotic demyelination (with widespread pyramidal and extrapyramidal deficits) that did not respond to intravenous immunoglobulin and NaS relowering. A little more than 3 weeks later, he began to develop low blood pressure and a subfebrile state that revealed secondary to severe Addison disease. The water disorder and insatiable thirst subsided gradually upon replacing the deficient hormones but the neurological disorder went on to become permanent and highly disabling. Teaching points: (1) Very severe hyponatremia should always be handled as an emergency and monitored stringently in view of its potential to cause irreparable damage. (2) Because it is a major risk factor for osmotic demyelination, it should probably be corrected at a rate of less than 4 mmol/L/day especially if it is in the extreme range, chronic, or of unknown duration. (3) It can be a presenting manifestation of Addison disease.

Justification: Qu'elle soit traitée ou non, l'hyponatrémie grave peut entraîner des complications dramatiques. L'hyponatrémie peut être très grave (concentration de Na sérique : NaS < 115 mmol/L), voire extrême (NaS < 105 mmol/L)a, et sa cause peut être difficile à identifier, particulièrement chez les sujets plus jeunes sans antécédents de déséquilibres hydriques. Le cas présenté illustre ces points de façon éloquente et nous porte à croire que les recommandations actuelles pour le traitement de l'hyponatrémie très grave nécessitent un ajustement. Présentation du cas: Un homme de 26 ans a été admis à notre unité de soins intensifs pour une NaS de 88 mmol/L sans contraction évidente du volume liquidien extracellulaire. Le patient avait souffert de vomissements, de diarrhée, de fatigue et de soif excessive au cours des six dernières semaines, et de symptômes neurologiques mineurs juste avant son admission. Les analyses de laboratoire à la présentation montraient également une osmolarité urinaire à 697 mOsm/L et une concentration de Na urinaire à 40 mmol/L. Diagnostic: Les symptômes à la présentation étaient compatibles avec un SIADH se manifestant par une hyponatrémie extrême, bien que peu symptomatique. En même temps, ces symptômes ne pointaient pas initialement vers une cause spécifique. Intervention: Le patient a été traité par restriction liquidienne, desmopressine SC et divers liquides administrés par voie intraveineuse. L'objectif était d'augmenter la NaS entre 4 et 6 mmol/L/jour et il a requis que la quantité de NaCl et d'eau libre perfusée toutes les heures soit réajustée en permanence. L'accès à l'eau a également dû être restreint, car le patient était incapable de tolérer sa soif. Résultats: Au cours des six premiers jours, la correction atteinte pour la NaS "était" par "a été" d'environ 6 mmol/L/jour. L'état du patient s'est d'abord amélioré, mais à la fin du 6e jour, il a évolué vers une démyélinisation osmotique extrapontine sévère (avec déficits pyramidaux et extrapyramidaux étendus) qui n'a pas répondu à l'administration d'IVIG ni à la diminution de la NaS. Un peu plus de trois semaines plus tard, le patient a présenté une hypotension et a développé un état subfébrile qui se sont révélés secondaires à une maladie d'Addison sévère. Le déséquilibre hydrique et la soif insatiable se sont résorbés progressivement après le remplacement des hormones déficientes, mais les le désordre neurologique est devenu permanent et très invalidant. Enseignements tirés: 1) L'hyponatémie très grave devrait toujours être traitée comme une urgence et surveillée de façon continue en raison de son potentiel à causer des dommages irréversibles. 2) Parce qu'elle est un facteur de risque majeur pour la démyélinisation osmotique, l'hyponatrémie devrait probablement être corrigée à un taux inférieur à 4 mmol/L/jour, surtout si elle est jugée extrême, chronique ou de durée inconnue. 3) L'hyponatrémie peut être un symptôme inaugural de la maladie d'Addison.

Molecular mechanisms, physiological roles, and therapeutic implications of ion fluxes in bone cells: Emphasis on the cation-Cl- cotransporters.

Bone turnover diseases are exceptionally prevalent in human and come with a high burden on physical health. While these diseases are associated with a variety of risk factors and causes, they are all characterized by common denominators, that is, abnormalities in the function or number of osteoblasts, osteoclasts, and/or osteocytes. As such, much effort has been deployed in the recent years to understand the signaling mechanisms of bone cell proliferation and differentiation with the objectives of exploiting the intermediates involved as therapeutic preys. Ion transport systems at the external and in the intracellular membranes of osteoblasts and osteoclasts also play an important role in bone turnover by coordinating the movement of Ca2+ , PO4 2- , and H+ ions in and out of the osseous matrix. Even if they sustain the terminal steps of osteoformation and osteoresorption, they have been the object of very little attention in the last several years. Members of the cation-Cl- cotransporter (CCC) family are among the systems at work as they are expressed in bone cells, are known to affect the activity of Ca2+ -, PO4 2- -, and H+ -dependent transport systems and have been linked to bone mass density variation in human. In this review, the roles played by the CCCs in bone remodeling will be discussed in light of recent developments and their potential relevance in the treatment of skeletal disorders.

Genetic abnormalities in biopsy-proven, adult-onset hemolytic uremic syndrome and C3 glomerulopathy.

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. KEY MESSAGES: The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.

Anatomophysiology of the Henle's Loop: Emphasis on the Thick Ascending Limb.

The loop of Henle plays a variety of important physiological roles through the concerted actions of ion transport systems in both its apical and basolateral membranes. It is involved most notably in extracellular fluid volume and blood pressure regulation as well as Ca2+ , Mg2+ , and acid-base homeostasis because of its ability to reclaim a large fraction of the ultrafiltered solute load. This nephron segment is also involved in urinary concentration by energizing several of the steps that are required to generate a gradient of increasing osmolality from cortex to medulla. Another important role of the loop of Henle is to sustain a process known as tubuloglomerular feedback through the presence of specialized renal tubular cells that lie next to the juxtaglomerular arterioles. This article aims at describing these physiological roles and at discussing a number of the molecular mechanisms involved. It will also report on novel findings and uncertainties regarding the realization of certain processes and on the pathophysiological consequences of perturbed salt handling by the thick ascending limb of the loop of Henle. Since its discovery 150 years ago, the loop of Henle has remained in the spotlight and is now generating further interest because of its role in the renal-sparing effect of SGLT2 inhibitors. © 2022 American Physiological Society. Compr Physiol 12:1-21, 2022.