Bruno Couturier

Efficacy and Tolerance of Urea Compared with Vaptans for Long-Term Treatment of Patients with SIADH

BACKGROUND AND OBJECTIVES Vaptans (vasopressin V(2)-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been evaluated. This prospective, long-term study compared the efficacy, tolerability, and safety of two oral vaptans with those of oral urea in patients with SIADH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with chronic SIADH of various origins were treated first with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Serum sodium was measured every 2 months, and drug doses were adjusted accordingly. RESULTS Thirteen participants were initially included in the study (serum sodium, 125±3 mEq/L); 12 completed the 2-year treatment period. Treatment with vaptans (satavaptan, 5-50 mg/d, n=10; tolvaptan, 30-60 mg/day, n=2) increased natremia (serum sodium, 135±3 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the natremia with the same efficacy (serum sodium, 135±2 mEq/L) as vaptans during the 1-year urea treatment period. One participant treated with tolvaptan withdrew from the study early because of excessive thirst. Another patient receiving urea developed hypernatremia without complications. CONCLUSIONS Urea has efficacy similar to that of vaptans for treatment of chronic SIADH. Tolerance is generally good for both agents.

Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.

Pericarditis Revealing Large Vessel Vasculitis

Large vessels vasculitis and more specifically, Giant cell arteritis, is characterized by increased inflammatory markers, headaches and altered clinical status. Diagnosis is confirmed by biopsy of temporal arteries showing the presence of granuloma and vasculitis. We hereby report the case of a patient presenting initially as pericarditis and revealing large vessel vasculitis using FDG-PET.

Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment.

Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.

Actual Therapeutic Indication of an Old Drug: Urea for Treatment of Severely Symptomatic and Mild Chronic Hyponatremia Related to SIADH.

Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done.

Weight loss, fever and arthralgia in a 43-year-old man treated for follicular lymphoma.

Service de médecine interne. hôpital Erasme, université Libre-de-Bruxelles (ULB), 808, route de Lennik, 1070 Bruxelles, Belgique Service d’hématologie, institut Jules-Bordet, université Libre-de-Bruxelles (ULB), 121, boulevard de Waterloo, 1000 Bruxelles, Belgique Service d’anatomo-pathologie, CHU de Bordeaux, place Amélie-Raba-Léon, 33000 Bordeaux, France Service de dermatologie, hôpital Saint-Pierre, université Libre-de-Bruxelles (ULB), 121, boulevard de Waterloo, 1000 Bruxelles, Belgique Service d’anatomo-pathologie, hôpital Erasme, université Libre-de-Bruxelles (ULB), 808, route de Lennik, 1070 Bruxelles, Belgique Service de médecine interne, CHU de Côte-de-Nacre, avenue de la Côte-de-Nacre, 14033 Caen cedex, France

From Polyuria to Renal Mass: An Unexpected Link

From Polyuria to Renal Mass: An Unexpected Link Frédéric Vandergheynst, MD, Paraskevi Kazakou, MD, PhD, Bruno Couturier, MD, Nicolas Dumarey, MD, Rose Ghanooni, MD, Agnieszka Pozdzik, MD, PhD, Sandrine Rorive, MD, PhD, Daniel Van Gansbeke, MD, Agnès Burniat, MD, PhD Department of Internal Medicine, Department of Endocrinology, Department of Nuclear Medicine, Department of Otorhinolaryngology, Department of Nephrology, Department of Pathology, and Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Belgium.

Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood-brain barrier disruption in a murine model of osmotic demyelination syndrome.

The osmotic demyelination syndrome (ODS) is a non‐primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post‐correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post‐correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood–brain barrier (BBB) leakages. Expression levels of IL‐1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post‐correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS.

Œdème facial matinal, insuffisance rénale et anémie : petite cause, grands effets

Une femme, âgée de 39 ans, sans antécédent médical notable si e n’est une chirurgie de réduction mammaire à l’âge de 20 ans et ne opération des ligaments du genou consultait pour un œdème u visage. Elle ne prenait aucun médicament et avait un stérilet ormonal. Elle ne mentionnait aucune assuétude ni allergie. Elle xerç ait un travail administratif et ne possédait pas d’animaux omestiques. Neuf jours avant l’admission, elle constatait, au éveil, l’apparition d’un œdème palpébral qui allait s’étendre en jours à l’ensemble du visage ainsi qu’au dos des mains et des ieds, associé à une prise de poids de 6 kg (Fig. 1). Elle signalait une rofonde asthénie et des céphalées holocrâniennes à prédomiance occipitale. Une biologie sanguine ne révélait qu’une anémie ormocytaire normochrome (Hb : 9,3 g/dL). De l’ibuprofène 400 mg) était prescrit mais elle ne consommait au total que deux omprimés. De retour en Belgique, elle était admise dans un autre

Fièvre et syndrome inflammatoire prolongé d'origine obscure : le PET mène au diagnostic.

Service de médecine interne générale, université libre de Bruxelles, hôpital Erasme, 808, route de Lennik, 1070 Bruxelles, Belgique Service de médecine nucléaire, université libre de Bruxelles, hôpital Erasme, 808, route de Lennik, 1070 Bruxelles, Belgique Service d’imagerie médicale, université libre de Bruxelles, hôpital Erasme, 808, route de Lennik, 1070 Bruxelles, Belgique Service de gastroentérologie médicale, université libre de Bruxelles, hôpital Erasme, 808, route de Lennik, 1070 Bruxelles, Belgique Service d’anatomopathologie, université libre de Bruxelles, hôpital Erasme, 808, route de Lennik, 1070 Bruxelles, Belgique Service de médecine interne A, CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France