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Azathioprine (AZA) is characterized by a high interindividual variability in bioavailability and metabolism. AZA is converted into 6-thioguanine nucleotides (6-TGN) to which the immune modifier activity is attributed. The 6-TGN levels are known to be affected by the activity of the key enzyme, thiopurine methyltransferase (TPMT), which is under genetic dependence. The authors measured a significantly lower TPMT activity in 53 women with systemic lupus erythematosus (SLE) (12.2 +/- 2.4 pmol/h/ml RBC; P < 0.01) when compared with 30 healthy control participants (13.15 +/- 3.1 pmol/h/ml RBC) but not with 28 patients with other dysimmune diseases (non-SLE; 13.0 +/- 3.0 pmol/h/ml RBC; P = 0.10). To evaluate the impact of TPMT activity on the concentrations of AZA metabolites, we measured the TPMT activity and 6-TGN levels in a subgroup of 26 patients in remission and treated with a stable dose of AZA (mean value: 1.9 +/- 0.5 mg/kg/day) for at least six months (n = 13 with SLE and n = 13 with other dysimmune diseases, ie, non-SLE). In such a subgroup, no correlation between 6-TGN levels and TPMT activity was observed. However, patients with SLE presented lower TPMT activity and higher 6-TGN levels (215 +/- 123 versus 140 +/- 75 pmol/8 x 10(8) RBC in non-SLE patients; P < 0.04). It must be noted that transient increase in 6-methylmercaptopurine levels (6-MMP), a putative toxic metabolite (up to 21.7 nmol/8 x 10(8) RBC), was more frequently observed in the non-SLE group (P < 0.01). Even if a relationship was observed between low TPMT activity and 6-TGN levels in SLE, its clinical impact appears to be limited as far as regular hematologic controls are performed.

We evaluated in 110 consecutive elderly hyponatremic patients the value of traditional clinical and biochemical data and the place of a test infusion of 2 liters isotonic saline over 24 hours, in establishing the etiology of the hyponatremia. The causes of hyponatremia were as follows: 31% SIADH patients, 23% patients with hyponatremia due to diuretics, 18% potomania patients, 15% salt depleted patients, 5% salt depleted SIADH patients, 5% patients with a salt loosing syndrome and 3% patients with hyponatremia of unknown origin. Several salt depleted (SD) and SIADH patients could be confounded. Usually, adults with SIADH show plasma uric acid values 4 mg/dL. Eighty-two percent of SD patients appeared to have plasma urea levels >30 mg/dL, but this was also the case in 21% of SIADH patients. Twenty-nine of the SD patients presented a urinary sodium >30 mEq/L, but all had fractional sodium excretion (FENa) lower than 0.5%. However, in SIADH, 42% of the patients presented also FENa

Azathioprine (AZA) is characterized by high interindividual differences in bioavailability and metabolization. The aim of the present study was to analyze, in patients treated with AZA for various immune system disorders, whether the variation in red blood cell mean corpuscular volume (Delta MCV) could be used as an indirect estimation of the level of the active immune modifier metabolite 6-thioguanine nucleotides (6-TGN), In 43 consecutive patients treated with a stable dose of AZA for at least 6 months who were not initially anemic, the erythrocyte 6-TGN levels with routine hematologic parameters were determined two to four times at 1-month intervals. In most patients MCV significantly increased after 3 months of therapy and stabilized after 6 months. The correlation between the daily dose of AZA and the 6-TGN level was mild (r = 0.51; P < .001). A weak correlation was also found between the dose of AZA and the Delta MCV after at least 6 months of therapy (r = 0.36; P < .05), The correlation between Delta MCV and 6-TGN level, however, was much better (r = 0.74; P < .001), The lack of a significant increase in MCV after 3 to 4 months of AZA therapy reflects low 6-TGN levels, sometimes a result of undertreatment. A determination of the 6-TGN level during the first months after AZA therapy is begun will allow more accurate adaptation of the effective dose. We observed that Delta MCV could be used as an indicator of 6-TGN levels after 6 months of AZA treatment. An increase in MCV of at least 6 fL is expected to reflect a 6-TGN level of about 175 pmol/8 x 10(8) red blood cells (probably being within a therapeutic value).

(2000). Hyponatremia In The Intensive Care: From Diagnosis To Treatment. Acta Clinica Belgica: Vol. 55, No. 2, pp. 68-78.

Background A recent study has revealed that acute and chronic administration of the vasopressin V2 receptor (V2R) agonist dDAVP induced a marked increase of urinary albumin excretion (UAE) in healthy rats and humans (Bardoux P et al. Nephrol Dial Transplant 2003; 18: 497-506). The occurrence of an elevation of UAE among patients with chronic syndromes of inappropriate antidiuresis has not been reported. Methods We looked for the elevation of UAE in 24-h urine samples of the following patients: nine chronic SIADH patients, two patients with acute post-operative SIADH, three patients of the same family with nephrogenic syndrome of inappropriate antidiuresis (NSAID) and two patients with hyponatraemia due to surdosage of dDAVP in the setting of central diabetes insipidus. Results There was no elevation of UAE in our patients (whether they presented with hyponatraemia or not), apart from a patient treated with supra-physiological doses of dDAVP. When she received 80 microg/day of dDAVP, her UAE was 42 mg/day. In this patient, UAE returned to the normal range (21 mg/day) when doses of dDAVP were tapered (20 microg/day). Conclusion The present study shows that chronic V2R stimulation generally does not result in a rise in UAE. The discrepancy between our results and those of the above-mentioned study could be explained by a dose-dependent effect of V2R stimulation on UAE.

Resume Alors que la thrombose cave superieure est une manifestation rare mais bien connue de la maladie de Behcet, il n’existe, dans la litterature, qu’une seule observation de syndrome cave superieur par vasculopathie, sans thrombose. Nous decrivons deux nouvelles observations de ce tableau exceptionnel. Les manifestations inaugurales consistaient chez les deux malades en un œdeme du visage et une aphtose buccale. Une stenose cave superieure a ete mise en evidence par angiotomodensitometrie et par cavographie classique. Chez les deux malades, l’association d’un traitement anticoagulant et d’immunosuppresseurs (corticoides et azathioprine) a permis d’augmenter significativement le diametre de la lumiere cave superieure. Nous estimons qu’il existe un continuum entre la vasculopathie sans occlusion et l’occlusion par thrombose de la veine cave superieure. Les thromboses observees dans la maladie de Behcet sont attribuees principalement a des lesions vasculaires inflammatoires provoquees par la vascularite. L’epaississement de la paroi veineuse observee chez nos malades reflete probablement ces lesions inflammatoires. En conclusion, la maladie de Behcet doit faire partie du diagnostic differentiel du syndrome cave superieur d’origine non thrombotique.

It has been widely accepted that there is little use for saline treatment in the syndrome of inappropriate secretion of ADH (SIADH). However, having observed that most SIADH patients increased their plasma sodium (PNa) after 2 l isotonic saline over 24 h, we investigated whether urine osmolality or the sum of urinary sodium and potassium (UNa + K) predicted this response, in 17 consecutive patients with chronic SIADH. The initial measure of urinary sodium plus potassium (UNa + K t0) was weakly correlated to the change in PNa (DPNa) after infusion (r = -0.51; p0.05), while initial urine osmolality (UOSM t0) was a much better predictor (y = -0.024x + 12.90; r = -0.81; p0.001). The lack of predictive value for UNa + K t0 was probably because urine electrolyte concentrations were not maximal for the corresponding initial UOSM. This reflects differences in salt intake between the patients. The theoretical maximal value for UNa + K t0 (th max UNa + K t0) for a given USOM t0, was as good a predictor as UOSM t0 (th max UNa + K vs. DPNa: r = -0.81; p0.001). A theoretical model describing the effect of 2 l isotonic saline infusion on DPNa as a function of UNa + K, produced values comparable to those observed in our patients. Only 6/17 patients, those with UOSM530 mOsm/kg, had their hyponatraemia aggravated by 2 l isotonic saline. Many SIADH patients have lower UOSM; in most such patients, 2 l of isotonic saline will improve PNa.

Hyponatremia is by far the commonest electrolyte disorder encountered in the clinical practice. The extracellular osmolarity is an important determinant of action potential conduction in neurons as well as glial cell volume. Neurological impairment is a widely recognised complication of hyponatremia and this occurs as a result of the failure of brain adaptative mechanisms to low serum osmolarity or abrupt osmotic changes. Because the brain is enclosed in a rigid skull, any changes in the brain volume induced by a decreased extracellular osmolarity could potentially result in severe symptoms like seizure or fatal brain herniation. On the other hand it has been established that rapid correction of hyponatremia is the principal risk factor for osmotic demyelination syndrome (ODS) which is a peculiar disorder characterised by loss of myelin in specific regions of the central nervous system.

DDAVP-related hyponatremia induces a blood volume expansion, but the analysis of fluid distribution in the vascular compartment has given controversial results in previous animal and human studies. In 5 healthy males, hyponatremia was induced by DDAVP and a free water intake during 3 days. Serum sodium concentration decreased from 138 +/- 0.8 mEq/L to 123 +/- 2.7 mEq/L on day 3. The plasma volume measured by dilution of marked albumin rose from 3033 +/- 230 ml to 3320 +/- 295 ml (p0.01). The mean corpuscular volume measured by microhematocrit increased slightly from 91.5 +/- 3.8 pl to 92.6 +/- 3.7 pl (p0.02). The red blood cell volume calculated with hematocrit and plasma volume did not change significantly (2565 ml to 2567 ml; not significant). In the present work, we demonstrated that in males the expansion of the plasma compartment almost completely amounted for the water retention in the intravascular volume. The erythrocyte volume increased only slightly, a finding that is consistent with an almost perfect adaptation of the erythrocyte cells to the hypoosmolality.

In hyponatremia related to syndrome of inappropriate antidiuretic hormone (SIADH), hypouricemia is explained primarily by the high uric acid clearance rate that results from the decrease in tubular uric acid reabsorption. This modification of tubular handling of uric acid is considered to be induced by the increase in the "effective vascular volume". This study was designed to determine if V1-receptor stimulation participates in the development of a high uric acid clearance rate as in SIADH, in which the antidiuretic hormone acts on V1 and V2 receptors. Therefore, the urate clearance rate was measured in seven volunteers with 1-desamino-8-D-arginine vasopressin (dDAVP)-induced hyponatremia, with dDVAP stimulating exclusively the V2 receptors (Group I), and in six patients with SIADH (Group II) during both normo- and hyponatremia. As expected, in both groups, the serum uric acid concentration decreased during hyponatremia, but did so to a larger extent in the patients with SIADH (-53% versus -29%, P < 0.02). Despite similar levels of hyponatremia (126 +/- 5 mmol/L and 125 +/- 5.5 mmol/L), of hypoproteinemia (64 +/- 5 g/L and 63 +/- 5 g/L) and of salt excretion (FENa, 0.66 +/- 0.28% and 0.73 +/- 0.25%), the urate clearance (8.3 +/- 3.3 mL/min) and the fractional excretion of filtered uric acid (5.7 +/- 2%) in Group I were not significantly different during hyponatremia than during normonatremia (6.4 +/- 1.5 mL/min and 5.4 +/- 0.9%). On the other hand, in Group II, both parameters were increased (17.8 +/- 2.9 mL/min and 19.6 +/- 5.3%; P < 0.001) and both values were higher than in the dDAVP-induced hyponatremia (P < 0.01). Additionally, the administration of a potent V1-receptor agonist (triglycyl-lysine-vasopressin) in a patient with central diabetes insipidus with preexisting dDAVP-induced hyponatremia produced a rapid increase of urate clearance. Because dDAVP acts only on the V2 receptors, these data suggest that the higher urate clearance observed during hyponatremia related to SIADH is not only the consequence of an increased "effective vascular volume," but that V1-receptor stimulation also contributes to it, by a mechanism that remains to be determined.

Brain myelinolysis could develop after excessive correction (delta SNa > 20-25 mEq/1/24 hour [h]) of chronic hyponatremia; however, this neurological event is not recognized as a complication of hypernatremia when arising from a normonatremic baseline. Previous animal studies were unable to reproduce these brain lesions in hypernatremia after acute increase of serum sodium to moderately hypernatremic levels. We hypothesize that to produce brain dehydration and myelinolysis from normonatremic baseline requires a more important osmotic gradient than when starting from hyponatremic state. Rapid and sustained hypernatremia (at least > 6 to 12 h) was induced in male rats by i.p. administration of NaCl 2 M (3 injections at 6 h intervals). The NaCl doses were determined to define two groups of hypernatremic rats (moderate and severe hypernatremia) for further analysis of the neurological outcome. In group 1 (moderate hypernatremia, n = 26) 8 rats died early (< 12 h) after the beginning of the NaCl administration without specific neurologic manifestations. All the surviving rats fared well and were asymptomatic at time of death (day 8). They were submitted for at least 6 to 12 h to a serum sodium gradient of 28 +/- 6 mEq/l. Brain analysis was normal in all of them without brain demyelinating lesions. In group 2 (n = 51), 24 rats also died rapidly (< 12 h). The surviving rats developed severe neurologic symptoms as typically encountered in hyponatremic rats with myelinolysis. The majority of them died before day 8. The hypernatremic gradient in this group was significantly higher than rats in group 1 that completely recovered (mean delta SNa: 39 +/- 8 mEq/l, p < 0.001). In the 7 surviving rats (mean delta SNa: 33 +/- 3 mEq/l) brain analysis demonstrated severe demyelinating lesions similar to the histologic changes observed in hyponatremia-related myelinolysis. We demonstrated for the first time that high and sustained levels of hypernatremia could induce brain myelinolysis and that the osmotic gradient necessary to produce brain lesions is higher for normonatremic than for hyponatremic rats.

Patients with hyponatremia related to adrenocorticotropic deficiency are not easily distinguished by routine laboratory studies from patients with nonendocrine inappropriate secretion of antidiuretic hormone (SIADH). We wanted to investigate whether, in the routine biological analysis of such patients, some parameters could help to better identify this subgroup of hyponatremic patients. The biochemical profiles of 13 consecutive patients with hyponatremia related to ACTH deficiency were analyzed and compared with 30 consecutive patients with classical SIADH. Patients with adrenocorticotropic deficiency presented low uric acid and urea levels as in nonendocrine SIADH, but their total carbon dioxide was significantly lower (total CO(2), 20.5 +/- 3 vs. 25.5 +/- 2.4 mmol/liter; P < 0.001). Nine of the 13 patients presented a value lower than 22 mmol/liter, although this was not observed in the nonendocrine SIADH patients (P < 0.001). Arterial blood gas analysis was available in eight patients and showed a compensated respiratory alkalosis in most of them (pH 7.42 +/- 0.02; PCO(2), 30 +/- 5 mm Hg; HCO(3)(-), 20 +/- 2 mmol/liter; base excess, -3.4 +/- 1.8 mmol/liter). Aldosterone levels were much lower in ACTH deficiency patients during the hyponatremic state (33 +/- 40 pg/ml) when compared with the nonendocrine SIADH (120 +/- 60 pg/ml; P < 0.01). Correction of hyponatremia by cortisone therapy normalized total CO(2) and aldosterone levels. Low carbon dioxide level is a frequent observation in hyponatremia related to ACTH deficiency and could help to differentiate it from classical SIADH.

Delirium is common in older people. It is a crucial diagnosis because it raises the morbidity and the mortality. Diagnostic tools like Mini Mental State Examination (MMSE), the confusion assessment method (CAM), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV), can help with the diagnosis. We report a case of a woman with neurological symptoms which look like dementia. We diagnosed systemic lupus erythematosus (SLE). The apparition of late-onset SLE is more insidious, which leads to misdiagnosis. We will discuss about the difficulty of the differential diagnosis between delirium, depression and dementia in our patient and the difficulty to manage treatment of neurolupus in older people.

The vaptans are non-peptide arginine-vasopressin-receptor antagonists, that are orally and intravenously active. A few vaptans have undergone sufficient clinical development to be on the market. In the EU only tolvaptan is accepted to treat hyponatremia related to SIADH. The place of this new treatment is compared with water restriction, demeclocyclin, furosemide and urea.

Background Hyponatremia occurring as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome is a common complication in patients with subarachnoid hemorrhage (SAH). The efficacy and safety of urea as treatment for SIADH-induced hyponatremia has not been reported in this population. Methods This is a retrospective analysis of all patients admitted to our department for nontraumatic SAH between January 2003 and December 2008 (n = 368). All patients with SIADH-induced hyponatremia (plasma sodium < 135 mEq/L, urine sodium > 20 mEq/L, and osmolality > 200 mOsm/kg; absence of overt dehydration or hypovolemia; no peripheral edema or renal failure; no history of adrenal or thyroid disease) routinely received urea per os when hyponatremia was associated with clinical deterioration or remained less than 130 mEq/L despite saline solution administration. Results Forty-two patients developed SIADH and were treated with urea. Urea was started after a median of 7 (IQR, 5-10) days and given orally at doses of 15-30 g tid or qid for a median of 5 (IQR, 3-7) days. The median plasma sodium increase over the first day of treatment was 3 (IQR, 1-6) mEq/L. Hyponatremia was corrected in all patients, with median times to Na + >130 and >135 mEq/L of 1 (IQR, 1-2) and 3 (IQR, 2-4) days, respectively. Urea was well tolerated, and no adverse effects were reported. Conclusions Oral urea is an effective and well-tolerated treatment for SIADH-induced hyponatremia in SAH patients. © 2012 Pierrakos et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia. Aims: To review the long-term treatment of NSIAD. Methods: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports. Results: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient. Conclusions: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described entity, linked to gain-of-function mutations (R137C and R137L) in arginine vasopressin (AVP) gene leading to chronic activation of tubular V2 AVP receptor (V2R) and thus free water reabsorption. In addition to collecting duct cells, the V2R is also expressed in endothelial cells, where it mediates the rise in circulating levels of von Willebrand factor (vWF) and coagulation factor VIII (fVIII). Recent in vitro data showed that these mutant receptors are resistant to vasopressin-stimulated cAMP production. We aimed to explore by clinical observations the sensitivity to vasopressin of the R137C-V2R mutant in vivo.We performed a stimulation test with 1-desamino-D arginin vasopressin (dDAVP) 0·3 μg/kg of bodyweight in three patients (two hemizygous male and one heterozygous female) with NSIAD with R137C mutation and measured on the one hand the levels of vWF and fVIII and the other hand urine osmolality and albumin excretion (UAE).Whereas the female heterozygous patient displayed normal response to simulation by dDAVP (except for UAE), no increase in vWF, fVIII, urinary osmolality and UAE was observed among hemizygous male patients.Coherent with in vitro observation in transfected cells, our clinical observations demonstrate that the R137C-V2R mutant is resistant to vasopressin stimulation in its physiological sites of expression.

The mechanisms responsible for the increased renal clearance of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are not fully clarified. Studies using either pyrazinamide or probenecid, or both drugs but at an interval of several days, could not undoubtedly distinguish the 'hypersecretory theory' from the one favoring a defect in either post- or presecretory reabsorption. We decided to do a combined pyrazinamide and probenecid test in 5 patients with hyponatremia due to SIADH in order to evaluate more clearly the respective importance of these different pathways. Our results allow the conclusion of a diminished presecretory and mainly postsecretory reabsorption (80 +/- 4.6 and 14 +/- 3% of filtered load, respectively). As far as the secretion of uric acid is concerned (17 +/- 10% of filtered load), we may say that this pathway is adapted to the amount of hypouricemia.

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 blood–brain barrier, inhibited microglial activation, decreased both the expression of IL1α 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.

In cirrhotic patients without renal failure, salt retention could result from a decreased effective intravascular volume or could be a primary event leading to increased intravascular volume. Clearance of urea and uric acid depend on an effective intravascular volume. In the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)--a state of increased intravascular volume--uric acid clearance is increased and that of urea is increased only when salt excretion is low. The intravascular volume of 60 consecutive cirrhotic patients without renal failure was estimated indirectly by studying the relationship between fractional excretion of filtered (FE) sodium, urea, and uric acid. Forty five per cent had a high FE uric acid (> 12%), which could mean a high intravascular volume, and presented with an FE urea that was inversely correlated with FE sodium (r = 0, 62; p < 0.001) as in SIADH, while in the controls the FE urea was positively correlated with FE sodium (r = +0, 46; p < 0.01). In patients who had a normal FE uric acid and low FE sodium (< 0.2%), the FE urea was significantly lower (40 (13)%, n = 20) than in subjects with high FE uric acid and a low FE sodium (61 (9)%, n = 16, p < 0.001); this last group also presented with lower mean blood urea concentrations (3.1 (1.2) mmol/l and 4.0 (1.8) mmol/l; p < 0.05) and a lower supine renin activity (p < 0.01). As observed in the SIADH, cirrhotic patient with high FE uric acid have raised FE urea only when salt excretion is low. It is believed that the low salt excretion is not caused by a decrease in effective intravascular volume and that this is increased in cirrhotic patients with raised FE uric acid.

Treatment of chronic hyponatremia in rats by intravenous saline: Comparison of rate versus magnitude of correction. The role of the rate of correction in the development of demyelinating brain lesions after correction of chronic severe hyponatremia is controversial. It has been recently suggested in rats treated by intravenous (i.v.) hypertonic saline (NaCl) that both the rate and the absolute change in serum sodium represent critical risk factors. However, we previously demonstrated in rats treated by intraperitoneal (i.p.) injections of NaCl that below a threshold of serum sodium rise of 20 mEq/liter/24 hr, only 5% of the brain lesions were recorded, even in rats submitted to a rapid (1 hr) serum sodium increment following the i.p. injection. Working below this threshold (serum sodium rise < 20 mEq/liter/24 hr) in the present work, allowed us to independently determine the role of the rate in the outcome of the correction. This was done by submitting the rats to a rapid (1 hr) intravenous infusion of NaCl. As a difference between the i.p. and i.v. route in the degree of volume expansion produced by the NaCl administration could also play a role in the pathogenesis of the brain lesions, rats treated with rapid i.v. infusion of NaCl (associated with volume expansion) were compared to a group of rats treated with water restriction (associated to volume contraction) to evaluate the role of volemia on the incidence of neurological damage. Hyponatremia was induced over three days with d-glucose in water and vasopressin. The group 1 was corrected by intravenous (i.v.) infusion of hypertonic saline over one hour. Rats achieved a serum sodium correction of 12 ±0.5 mEq/liter (8 to 17 mEq/liter) at the end of the infusion and of 13.5 ±0.6 mEq/liter (8 to 19 mEq/liter) after the first 24 hours. Group 2 was submitted to spontaneous correction with water restriction over 48 hours. The maximum daily increment in serum sodium observed during this period in this group was 14.8 ±0.5 mEq/liter (9 to 19 mEq/liter). No difference could be observed in the incidence of brain lesions between both groups. Only one rat (1 of 25) was damaged in group 1 and two rats (2 of 24) in group 2, an incidence similar to our previous results. We conclude that: (1) A rapid (1 hr) and large (12 mEq/liter, range 8 to 17 mEq/liter in 1 hr) rise in serum sodium after NaCl administration is well tolerated provided that the limit of daily absolute change in serum sodium (20 mEq/liter/24 hr) is not exceeded. In these conditions, the rate of the correction is not important; (2) In the same conditions, a correction associated with an acute (1 hr) volume expansion (NaCl i.v.) is not more toxic for the brain than water restriction (volume contraction) alone.

(1992). Abstracts of the meeting of the Belgian Society of Internal Medicine (23 May 1992) Acta Clinica Belgica: Vol. 47, No. 4, pp. 290-295.

Objective:S100A8 and S100A9 are calcium binding proteins of the S100 family highly expressed in neutrophils and monocytes. S100 proteins are novel ligands of TLR4 important in modulating inflammation. High levels of S100A8/A9 found in human inflammatory diseases are a marker of disease activity in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). We determined levels of S100A8/A9 in sera of patients with systemic lupus erythematosus (SLE) and analyzed their relation to clinical variables of disease activity.Methods.A group of 93 patients with SLE were studied over a period of 3 years, and 143 serum samples were analyzed. S100A8/A9 serum concentrations were determined by a sandwich ELISA. Sera from 10 primary Sjögren’s syndrome (pSS) patients and 50 healthy volunteers were used as controls. Correlations to SLEDAI, ANA, anti-dsDNA, WBC, CH50, C4, and CRP were made. In addition, infections were recorded in all SLE patients.Results.Serum levels of S100A8/A9 were significantly (p = 0.04) higher in SLE patients (1412 ± 664 ng/ml) versus healthy controls (339 ± 35 ng/ml) and pSS patients (400 ± 85 ng/ml). The only significant correlation (r = 0.219; p = 0.015) was found was between S100A8/A9 and SLEDAI. Further, SLE patients with concomitant infections had higher serum levels of S100A8/A9 (39300 ± 13375 ng/ml) than those without infections (1150 ± 422 ng/ml).Conclusion.Serum levels of S100A8/A9 are significantly raised in SLE versus pSS patients and healthy controls and can be correlated to a disease activity index. S100A8/A9 is a more relevant marker of infection in SLE patients.

Osmotic demyelination syndrome is a devastating neurologic disorder often seen after the rapid correction of chronic hyponatremia. The permeability of the blood-brain barrier is increased in experimental osmotic demyelination, and some have suggested that corticosteroids protect against this disorder by keeping the permeability of the blood-brain barrier low. We previously reported that re-lowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h). Here we compared mortality, blood-brain barrier permeability, and microglial activation in rats after the rapid correction of chronic hyponatremia. We studied three groups of rats after correction of chronic hyponatremia: and treated them with sodium chloride, with or without dexamethasone; or with sodium chloride followed by re-induction of hyponatremia. We found that treatment with dexamethasone or re-induction of hyponatremia effectively prevented the opening of the blood-brain barrier, reduced neurological manifestations, and decreased microglial activation; however, only re-induction of hyponatremia resulted in a significant decrease in mortality 5 days after the correction of chronic hyponatremia. Restoring the permeability of the blood-brain barrier to normal levels did not decrease mortality. Our results suggest that after inadvertent rapid correction of hyponatremia, treatment options should favor re-lowering serum sodium. The increased permeability of blood-brain barrier seen in osmotic demyelination syndrome may not be a primary pathophysiologic insult of this syndrome.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of water balance characterized by hypotonic hyponatremia and impaired water excretion. The diagnosis of SIADH is based on the exclusion of other hyponatremic conditions, the presence of hyposmolality with inappropriate urine osmolality and a urine sodium concentration usually above 30 mEq/L. Some simple and readily available biologic parameters can be helpful in the diagnosis of SIADH (low urea and uric acid levels). The recent syndrome of nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is also discussed and the association of asymptomatic hyponatremia with falls and bone fractures.

1. At present there is no consensus about the optimal management of hyponatraemia to prevent demyelinating brain lesions. We have evaluated in a large series of rats (n = 136) the protective role of urea for the brain in the treatment of severe chronic hyponatraemia. Urea (group I, n = 51) was compared with hypertonic saline in boluses (group II, n = 46) and with hypertonic saline in divided doses (group III, n = 39). Treatment was administered intraperitoneally over 48 h. The severity of brain lesions was assessed by histological scoring. 2. For 95% of the injured animals treated with hypertonic saline, brain lesions appeared for an absolute increment in serum Na+ concentration (δSNa+) of 20 mmol day−1 l−1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (δSNa+ 20–23 mmol day−1 l−1) 89% (group III) to 100% (group II) of the animals were injured. This limit can be reached rapidly, as attested by the comparable severity of brain lesions observed in group II (mean δSNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean δSNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily δSNa+. 3. A correction above the threshold of 20 mmol day−1 l−1 is as toxic during the first 24 h as during the second day of the treatment. This can be deleterious even if a mildly hyponatraemic level (>120 4. We have confirmed the protective effect of urea against the development of brain damage when used to correct hyponatraemia. The threshold of tolerance to daily δSNa+ after urea is identical to the limit defined for hypertonic saline, but a further rise in serum Na+ concentration (range of daily δSNa+ >23 >30 mmol/l) leads to a significantly lower incidence (47%, P

We report the case of a 57-year-old man, presenting with bilateral panuveitis, bilateral sacroiliitis, intermittent pyrexia and a pulmonary nodule. The patient had been under immunosuppressive treatment for 2 years for Behcet’s disease. However, he did not fulfill the diagnostic criteria of Behcet’s disease. Blood analysis showed a very high C reactive protein (CRP at 34 mg/dl).In view of severe intra-ocular inflammation, the anterior chamber was punctured. Polymerase chain reaction (PCR) on the aqueous humour and on the blood revealed the presence of Tropheryma whippelii DNA, an agent responsible for Whipple’s disease. The patient was treated with ceftriaxone followed by trimethoprim-sulfamethoxazol for 1 year with good clinical and biological evolution.This case illustrates the difficulty to diagnose an atypical Whipple’s disease.In cases of uveitis with atypical signs and/or not responding to the treatment, the internist must consider to perform an analysis of the ocular fluids.

Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a frequent cause of hypotonicity. Although the differential diagnosis with other causes of hypotonicity such as salt depletion is sometimes challenging, some simple and readily available biologic parameters can be helpful in the diagnosis of SIADH. In SIADH, urea is typically low; this is less specific for elderly patients, for whom lower clearance of urea accounts for higher values. Low levels of uric acid are more often seen in SIADH (70%) compared with salt-depleted patients (40%). Typically, patients with SIADH will show a lower anion gap with nearly normal total CO2 and serum potassium, this despite dilution. In patients with hyponatremia secondary to hypocorticism, total CO2 is usually lower than in nonendocrine SIADH despite low urea and uric acid levels. Urine biology can also be helpful in diagnosis of SIADH because patients with SIADH have high urine sodium (Na; >30 mEq/L), and most of them will have a high fractional excretion of Na (>0.5% in 70% of cases), reflecting salt intake. Conversely, low urine Na in patients with SIADH and poor alimentation is not rare. Finally, measurement of urine osmolality is useful for the diagnosis of polydipsia and reset osmostat and could further help in the choice of therapeutic strategy because patients with low urine osmolality will benefit from water restriction or urea, whereas those with high urine osmolality (>600 mOsm/kg) would be good candidates for V2 antagonist.

This study confirms in humans an age-related increase in plasma urea levels (r = 0.62; P < 0.001; y = 0.229x + 18.26) and no correlation between plasma creatinine and age (r = 0.06; NS). Fractional urea excretion (FE urea) decreases with age (r = -0.41; P < 0.001; y = -0.226x + 55). Comparing urea and creatinine clearances, measured in 19 young and in 15 old women, a larger decrease of urea clearance (-56%) compared with the creatinine clearance (-43%) was observed as expected, explaining the lower FE urea in the elderly. In old women, the daily urea excretion was 27% and the daily creatinine excretion was 42% lower than in young women. An age-related decrease of same magnitude in both creatinine production and creatinine clearance explains why plasma creatinine remains stable with increasing age. The observation of a more important decrease in urea clearance (56%) than in urea production (27%) in older women led to an expected increase in plasma urea of 29%. These observations incited a comparison of biochemical profiles from younger and older patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Young patients with SIADH present lower mean plasma urea (18 +/- 8 mg/dl) and higher mean FE urea (58 +/- 14%), compared with both young control subjects (mean plasma urea 27 +/- 7 mg/dl; mean FE urea 46 +/- 10%) and old patients with SIADH (mean plasma urea 29 +/- 8 mg/dl; mean FE urea 44 +/- 15%). Physicians must realize that frankly low plasma urea values and high FE urea values can be expected only in young patients with SIADH, whereas old patients with SIADH will present values of plasma urea and FE urea in the same range than young control subjects. However, old patients with SIADH show still lower mean plasma urea values and higher mean FE urea values, compared with old control subjects (mean plasma urea 39 +/- 8 mg/dl; mean FE urea 36 +/- 9%), in whom plasma urea values between 40 and 50 mg/dl must be considered as usual.

Superior vena cava (SVC) thrombosis is a rare but well-recognized manifestation of Behcet's disease, whereas SVC syndrome due to vasculopathy, without evidence of thrombosis, has only been described a single time in the literature. We report two cases of this exceptional association. The two patients presented with swelling of the face and oral aphtosis, the SVC stenosis was evidenced by angio-CT and classical cavography. In each case, a combination of anticoagulant and immunosuppressive (corticosteroids and azathioprine) treatments allowed a significant improvement of SVC diameter. In one of the patients, an angioplasty of SVC was also performed. We believe there is a continuum between non-obstructive and obstructive vasculopathy (thrombosis) of SVC. Inflammatory vascular injury secondary to vasculitis is considered to be the primary reason for thrombosis in Behcet's disease. Thickening of the venous wall observed in our patients probably reflects this inflammatory vascular injury. In conclusion, Behcet's disease should be considered in the differential diagnosis of SVC syndrome not related to thrombosis.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology and pathogenesis. The disease usually presents with high spiking fever, evanescent rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, lymphadenopathy, polynuclear leukocytosis, liver cytolysis, and a high serum level of ferritin with a low glycosylated fraction [1]. Abnormalities in liver tests, like a moderate elevation of transaminases and cholestasis, are common but usually resolve either spontaneously or rapidly under medical treatment [2]. However, rare cases of severe liver dysfunction in AOSD have been reported [2]. We describe a case of fulminant liver failure (FLF) in a patient with a recently diagnosed AOSD who was successfully treated with molecular absorbent recirculating system (MARS), followed by urgent liver transplantation (LT).

Consequences of hyponatremia are generally mild and remain unnoticed by both physician and patient. When water restriction, usually prescribed to avoid water intoxication, fails to normalize serum sodium values, clinicians will tolerate mild stable hyponatremia (especially when serum sodium is >125 mEq/L [1 mEq/L = 1 mmol/L]). In a recent study, we observed that mild chronic hyponatremia contributes to an increased rate of falls, probably due to impairment of attention, posture, and gait mechanisms. Eight attention tests were used to assess 16 patients with asymptomatic hyponatremia (mean serum sodium, 128 +/- 3 mEq/L) due to syndrome of inappropriate antidiuretic hormone secretion. On attention tests for visual and auditory stimuli, there was an increase in mean response latency of 58 msec (P

OBJECTIVE The polydipsiahyponatremia syndrome is difficult to control in patients with severe mental illness, and there is no established effective therapeutic approach. We investigate the effect of oral daily intake of large amounts of urea to prevent hyponatremic episodes. METHOD Seven patients were treated during 4 to 18 months with urea (0.3-0.9 g/kg/day). Five of these patients had schizophrenia. Body weight variation between morning and evening was determined before and during the course of therapy in 5 patients. The dose of urea was increased if morning serum sodium level (SNa) was lower than 132 mmol/L. RESULTS Urea therapy increased mean +/- SD morning SNa (from 127.5 +/- 3.4 mmol/L before initiation of urea treatment to 136.5 +/- 2.4 mmol/L during the second month of urea treatment; p < .01) and mean +/- SD urine osmolality (from 86 +/- 39 mOsm/kg H(2)O to 159 +/- 58 mOsm/kg H(2)O; p < .05), probably without changes in water intake or urine volume excretion as attested by the level of urinary creatinine concentration. Mean +/- SD body weight variation decreased from 4.5% +/- 1.0% before initiation of urea treatment to 2.8% +/- 1.0% during the second month of urea treatment (p < .05). Two patients stopped urea treatment after 1 year and subsequently developed symptomatic hyponatremia. CONCLUSION These preliminary data show that urea appears to be an effective therapeutic approach for the polydipsiahyponatremia syndrome.

We recently read with interest the article by Dupond et al. about a case of oncogenic osteomalacia (OO) [1]. The originality of this case lies in the fact that the tumor responsible for phosphatonin hyperproduction could only be detected by 18F fluorodeoxyglucose (FDG) PET-scan. An interesting feature of this case was that octreotide scintigraphy–like total body CT and MRI–was not able to localize the tumor. Cases of mesenchymal tumors responsible for OO, as evidenced by octreotide scintigraphy, have been reported in the literature. This finding supports successful treatment of OO in some cases with subcutaneous analogues of somatostatin [2]. We report herein a case of a 46-year-old man with dorsal vertebral hemangioma who was admitted to the Department of Neurosurgery of our hospital for exacerbation of paraparesia. This patient had undergone vertebral laminectomy for this hemangioma, located in the ninth dorsal vertebra, 2 years earlier. Recently, he had developed progressively increasing weakness, mainly of the lower limbs. Remarkable findings of the physical examination were hyporeflexia at the level of the lower limbs and the absence of Babinski sign. This was unexpected, given the suspicion of medullar compression by the hemangioma. The finding of a dramatic hypophosphoremia (0.6 mg/dl, normal range 2.5–4.5 mg/ dl), combined with an elevated phosphaturia (1380 mg/day) and increased phosphate clearance (64 ml/min, N

The study objective was to determine the eventual consequences (falls, unsteadiness, and cognitive impairment) of mild chronic hyponatremia, which is generally considered as asymptomatic.In a case-control study, we focused on the incidence of falls among 122 patients (mean age 72+/-13 years) with asymptomatic chronic hyponatremia (mean serum sodium concentration [SNa] 126+/-5 mEq/L), who were admitted to the medical emergency department, compared with 244 matched controls. To explore the mechanisms of the excess of falls, we prospectively asked 16 comparable patients (mean age 63+/-15 years; SNa+/-2 mEq/L) to perform 8 attention tests and a gait test consisting of 3 steps "in tandem," in which we measured the "total traveled way" by the center of pressure or total traveled way. Thereafter, the patients were treated and tested again (50% of the patients were tested first with normal SNa to avoid learning biases).Epidemiology of falls: Twenty-six patients (21.3%) of 122 were admitted for falls, compared with only 5.3% of the control patients (adjusted odds ratio: 67; 95% confidence: 7.5-607; P.001). The frequency of falls was the same regardless of the level of hyponatremia. Gait: The total traveled way by the center of pressure significantly increased in hyponatremia (1336+/-320 mm vs 1047+/-172 mm with normal SNa; P=.003). Attention tests: The mean response time was 673+/-182 milliseconds in hyponatremia and 615+/-184 milliseconds in patients with normal SNa (difference: 58 milliseconds, P.001). The total error number in hyponatremia increased 1.2-fold (P=.001). These modifications were comparable to those observed after alcohol intake in 10 volunteers.Mild chronic hyponatremia induces a high incidence of falls possibly as the result of marked gait and attention impairments. Treating these patients might prevent a considerable number of hospitalizations.

Nous rapportons le cas d’un patient presentant une maladie de Paget osseuse associee a un diabete phosphate (phosphate :1,6 mg/dl (2.5-4.4 mg/dl), la clearance du phosphate est de 29 ml/’ (nl 85 %). Nous avons teste l’hypothese (comme recemment demontree lors de diabete phosphate associe aux tumeurs) d’une amelioration du diabete phosphate lors de l’administration d’analogue de la somatostatine. Le patient a beneficie d’une scintigraphie a l’octreotide marque a l’Indium-111 demontrant une captation dans l’os pagetique. Sous Lanreotide (40 mg IM), le patient a presente une amelioration des douleurs osseuses avec diminutions du taux de phosphatase alcaline. La clearance de phosphate et le taux de reabsorption tubulaire de phosphate ne sont pas modifies. Nous rapportons egalement les autres cas associant une maladie de Paget et un diabete phosphate.

As discussed by Karen Yeates and associates[1][1] in their review of hyponatremia, evaluation of extracellular volume is sometimes difficult. In a patient with hyponatremia, a trial of saline infusion may be useful in clarifying the diagnosis; however, contrary to information in the review, most

BACKGROUND: Periostitis, usually seen on X-ray, may be diagnosed on bone scan as non-nodular cortical bone hyperactivity. Both the complete form (including clubbing, arthritis and periostitis) and the incomplete form have been described in association with chronic pulmonary disease, neoplasm, hepatopathy and inflammatory bowel disease. It is not known whether the bone scan pattern of non-nodular cortical bone hyperactivity varies with the etiology. METHODS: We conducted a retrospective study to analyze the etiologies and bone scan patterns of 115 cases of non-nodular cortical bone hyperactivity. RESULTS: Eighty percent of our patients were asymptomatic. Thirty-four percent of all cases of periostitis (all bilateral) were associated with cancer. The rate of cancer in cases of periostitis involving both lower limbs was 28.5%; it was 61.3% when both lower and upper limbs were involved. The duration of the disease was not correlated with either the distribution of periostitis or the intensity of uptake. Moreover, the intensity of uptake was not correlated with the importance of the symptomatology. Bone scan pattern (regular versus heterogenous uptake, localized versus diffuse uptake) was not correlated with the etiology. CONCLUSIONS: Bilateral upper and lower uptake should alert the clinician to the risk of association with neoplasm. Bone scan pattern and intensity of uptake are not necessarily correlated with etiology.

Background: Polydipsia-related hyponatraemia is generally considered an acute dilutional state. Aim: To determine whether solute loss plays a role in the pathogenesis of polydipsia-related hyponatraemia. Design: Prospective uncontrolled study Methods: We studied routine biochemical volume-related parameters before and after 2 l isotonic saline infusion over 24 h, in 10 consecutive hyponatraemic polydipsia patients (mean age 55 ± 11 years; 6 beer drinkers and 4 compulsive water drinkers) with initial urinary osmolality

Dilutional hyponatremia is a frequent complication of cirrhosis partly because of nonosmotic vasopressin release. No effective therapy exists for this complication. Therefore, we investigated the effects of VPA-985, an orally active vasopressin V2 receptor antagonist, in patients with cirrhosis and dilutional hyponatremia. Primary endpoint was normalization of serum sodium (serum sodiumor=136 mmol/L).Sixty patients with cirrhosis and dilutional hyponatremia were randomly assigned to 100 or 200 mg/day of VPA-985 or placebo in a double-blind study. Treatment was given with fluid restriction (1000 mL/day) until normalization of serum sodium or for 7 days.Normalization of serum sodium concentration was achieved in 27% and 50% of patients in the VPA-985 100 mg/day and 200 mg/day groups, respectively, but in none of the patients in the placebo group (P0.05 and P0.001, respectively). Treatment with VPA-985 was associated with a significant reduction in urine osmolality and body weight. Thirst sensation increased significantly in the VPA 200 mg group but not in the VPA 100 mg or placebo group. Serious adverse events were similar among the 3 groups.An orally active vasopressin receptor antagonist can correct hyponatremia in patients with cirrhosis and ascites. This represents a novel therapy of water retention in cirrhosis.

It is well known that during low diuresis or low effective circulating volume, salt excretion is low. The aim of this study was to find out whether salt excretion, expressed as either urinary sodium concentration (UNa) or fractional sodium excretion (FENa), and the combined use of FENa and fractional urea excretion (FEurea) still differentiate between hyponatremic SIADH and hyponatremic salt depletion (SD) patients when diuresis is low. The relationships between UNa, FENa and diuresis, indirectly estimated by the urinary to plasma creatinine ratio (U/P creat), were studied in 42 hyponatremic SIADH patients, 21 hyponatremic SD patients and 66 normonatremic controls (CO) of similar age and sex ratio. There was no significant relationship between UNa and U/P creat either in SIADH or in SD or CO patients. FENa and U/P creat were inversely correlated, both in CO (r = –0.72; p < 0.001) and in SIADH (r = –0.68; p < 0.001). SIADH and SD patients can be fairly well differentiated from one another using FENa and U/P creat. Even with high U/P creat values, SIADH patients, despite a sharp decrease in their FENa values, presented still higher FENa values than SD patients did (mean FENa = 0.3 ± 0.2% in SIADH and 0.1 ± 0.04% in SD; p < 0.05). However, FENa values of SIADH patients with low diuresis (mean FENa = 0.3 ± 0.2% for a mean U/P creat = 191 ± 40) are indistinguishable from those of SD patients with normal urine volumes (mean FENa = 0.2 ± 0.2% for a mean U/P creat = 92 ± 30). The combined use of FENa and FEurea remains a reliable way to discriminate SD patients and SIADH patients, as far as the differential limit value for FENa is narrowed to a value of 0.15%, for hyponatremic patients with U/P creat >140. Conclusion: In SIADH, FENa values are lower than 0.5%, as soon as U/P creat exceeds a value of 180. In SD patients with U/P creat values exceeding 140, FENa is lower than 0.15% and FEurea lower than 45%.

It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.

We report the case of a patient with an idiopathic syndrome of inappropriate secretion of ADH for more than 6 years. Water restriction was effective only during hospital care but was socially difficult to maintain at home, so that the patient presented frequent symptoms of water intoxication. Normal natremia was also obtained with a high salt intake (9 g/day) but this induced leg edema mild dyspnea and gastric intolerance. The patient was however successfully treated for more than 5 years without any side effects with oral urea (30 g/day) allowing her a normal fluid intake (1-1.5 liters/day). Oral urea, even during long periods, is a safe and effective therapeutic approach for patients with chronic SIADH which is not controlled by water restriction alone.

The high fractional excretion (FE) of uric acid observed in hyponatremia associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is commonly attributed to the volume-expanded state, although volume expansion in normonatremic volunteers is unable to increase urate clearance to a degree similar to that in SIADH. The goal of the present study is to analyze whether hyponatremia by itself could influence the FE of uric acid, as well as the effects of intravascular volume and glomerular filtration rate on FE of uric acid in SIADH. This study examines the effects of a 2-L infusion of isotonic saline over 24 hours on FE of uric acid in 9 normonatremic volunteers and 17 hyponatremic patients with SIADH. We also studied the FE of uric acid in 6 patients with SIADH with only mild water retention and the urate and creatinine clearances in 18 hyponatremic patients with SIADH before and after normalization of serum sodium levels by water restriction. When infusing 2 L of isotonic saline over 24 hours in healthy subjects, there was a decrease in plasma protein concentration of 8%, suggesting a similar degree of volume expansion than in patients with SIADH. The FE of uric acid did not increase to the same extent (9% +/- 1.5% versus 17% +/- 1.5%; P: < 0.01). Conversely, in 6 hyponatremic patients with mild water retention (1 L), the FE of uric acid was still high despite indirect signs of only a small increase in plasma volume. The mainstay of these observations is that chronicity of hyponatremia by itself could affect urate excretion. We also observed that in the patients with SIADH, high FE of uric acid inversely correlated with glomerular filtration rate (r = -0.66; P: < 0.01) only during the hyponatremic state. These data suggest that hyponatremia by itself, combined with mild volume expansion and glomerular filtration rate, has a role in the high FE of uric acid in the SIADH.

Brain myelinolysis complicates excessive correction of chronic hyponatremia in man. Myelinolysis appear in rats for correction levels deltaSNa) > 20 mEq/l/24 h. We previously showed in rats that when chronic hyponatremia was corrected with urea, the incidence and the severity of brain lesions were significantly reduced compared to hypertonic saline. In man, hyponatremia is frequently associated with azotemia and hemo-dialysis usually corrects rapidly the serum sodium (SNa) but only few patients apparently develop demyelination. We hypothesize that uremic state protects brain against myelinolysis. This hypothesis was evaluated in rats developing azotemia by administration of mercuric chloride (HgCl2, 1.5 mg/kg). Severe (SNa < 120 mEq/l) hyponatremia (3 days) was induced by S.C. AVP and i.p. 2.5% D-glucose for 3 days. HgCl2 was injected on day 2. Hyponatremia was corrected on day 4 by i.p. injections of 5% NaCl in order to obtain a correction level largely above the toxic threshold for brain (deltaSNA approximately 30 mEq/l/24 h). Surviving rats were decapitated on day 10 for brain analysis. In the group with renal failure (Group I, n = 15, urea 59 mmol/l) the outcome was remarkably favourable with only three rats (3/15) dying before day 10 and only one of them (1/3) presenting myelinolysis-related neurologic symptoms. The 12 other rats (80%) survived in Group I without symptoms and brain analysis was normal in all of them despite large correction level (deltaSNa: 32 mEq/l/24 h). On the contrary in nine rats in which HgCl, did not produce significant azotemia (control 1, n = 9, urea: 11 mmol/l), all the rats developed severe neurologic symptoms and eight of them died before day 10. Similar catastrophic outcome was observed in the non-azotemic controls (control 2, no HgCl2 administration, n = 15, urea: 5 mmol/l). All of them developed myelinolysis-related neurologic symptoms and only four of them survived with severe brain lesions (survival 12/15 in Group I vs. 5/24 in pooled controls 1 and 2, p < 0.001). In conclusion, we showed for the first time that chronic hyponatremic rats with azotemia (48 h) tolerated large increases in SNa (approximately 30 mEq/l/24 h) without significant brain damage.