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.

Hyponatremia is a common disorder associated with higher mortality in hospitalized patients, but its impact in an ambulatory setting remains unclear. Here we used data from the Dallas Heart Study, a prospective multiethnic cohort study that included ambulatory individuals, to determine the prevalence and determinants of hyponatremia (serum sodium <135 mEq/l), and its impact on mortality. The analysis included 3551 individuals with a median age of 43 years followed up over a median of 8.4 years. The sample weight-adjusted prevalence of hyponatremia was 6.9%. Hyponatremia was mild (median serum sodium: 133 mEq/l), and was significantly associated with age, black ethnicity, presence of cirrhosis or congestive heart failure, and use of selective serotonin reuptake inhibitors. By the end of the follow-up period, there were 202 deaths including 29 in hyponatremic individuals. The unadjusted hazard ratio for hyponatremia and death was 1.94. Hyponatremia remained significantly associated with mortality after adjustment for age, gender, ethnicity, diabetes, hypertension, dyslipidemia, smoking, alcohol use, renal function, plasma C-reactive protein, use of antiepileptic drugs and selective serotonin reuptake inhibitors, and history of congestive heart failure, cirrhosis, and cancer (hazard ratio of 1.75). Thus, mild hyponatremia is associated with an increased risk of death in a young and ethnically diverse community population.

SummaryBackground 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, 12563 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, 13563 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, 13562 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.

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.

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the bloodbrain barrier, inhibited microglial activation, decreased both the expression of IL1␣ and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans. Osmotic demyelination syndrome (ODS) is a severe neurologic condition that is characterized by severe demyelination in the central nervous system (CNS) secondary to osmotic imbalance. In a clinical setting, this syndrome often occurs after too rapid correction of chronic hyponatremia. [1][2][3][4][5] In ODS, demyelination is widespread in the brain, with predominance in hippocampus, basal ganglia, and subcortical regions. The physiopathology of this disorder is not yet fully understood, and an experimental murine model has been developed to better understand the mechanisms leading to myelin damage after an osmotic injury. 2,5,6 Previous experiments have suggested that ODS might share key characteristics with other models of central nervous system demyelination in which both opening of the blood-brain barrier (BBB) and microglia-macrophage activation are involved in the genesis of demyelinative changes. [7][8][9][10][11] Minocycline is a second-generation tetracycline that has been well studied in various models of brain pathology including autoimmune or ischemic myelin damage, and others have reported that administration of minocycline in CNS injury was associated with a striking reduction in BBB permeability, inhibition of microglia-macrophage activation, and inflammatory

Myoglobinuric acute kidney injury (AKI) is a severe condition requiring early therapeutic strategies. Early recognition and treatment are crucial to reduce morbidity and mortality rate. Here, we report a kidney recipient with severe rhabdomyolysis and AKI secondary to parvovirus B19 infection. Initiation of hemodialysis with the super high-flux filter Theralite^® (Gambro, cut-off 45 kDa, 2.1 m²) resulted in the clearance of myoglobin from 61 to 71% after 3 hours. Elimination rates of IL-6 and β2-microglobulin were ~ 30 - 64% and 55 - 71% after 3 hours, respectively. Renal graft function rapidly recovered. The place of this effective but expensive procedure still needs to be defined and validated in high-risk patients.
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International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. Based on the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in 9 countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

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