Centre Hospitalier de Luxembourg 11th Annual Congress of the South African Society of Nuclear Medicine: Abstracts CSIR, Pretoria, South Africa, 1–4 October 2004

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 (deltaMCV) 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 deltaMCV after at least 6 months of therapy (r = 0.36; P<.05). The correlation between deltaMCV 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 deltaMCV 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/8x10(8) red blood cells (probably being within a therapeutic value).

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.

A 35-year-old patient with severe gout and mild renal insufficiency presented very low urinary urate excretion. Volume expansion induced by fludrocortisone combined or not with a uricosuric drug (Benzbromarone) was unable to significantly increase his urate excretion. A combined Probenecid (PB) and Pyrazinamide (PZA) test was performed. These drugs being considered to affect renal tubular reabsorption or secretion. No significant modification of uric acid fractional excretion (FE.uric acid) was observed after PB and PZA. When the same test was performed after the administration of Triglycyl-lysine vasopressine (TGLV), a potent V1 receptor stimulator, we observed a three fold increase in FE.uric acid after PB intake (from 6 to 18%) followed by a decrease after PZA (from 18 to 5.6%). When TGLV was administered alone their was no significant modification of uric acid fractional excretion. We propose that TGLV decrease proximal tubular urate reabsorption that could only be detected when postsecretory reabsorption is blocked by an uricosuric drug.

Severe hyponatremia may be chronic (days) or acute (hours), symptomatic or asymptomatic. Severe chronic symptomatic hyponatremia (serum sodium concentration < 110 to 115 mM/liter) occurs most commonly in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The treatment of this hyponatremia is a challenge to practicing physicians, in part because an overly rapid correction of hyponatremia may cause brain damage. The latter sometimes takes the form of central pontine myelinolysis (CPM). On the basis of available clinical and experimental literature, the rate of correction of this symptomatic hyponatremia should be no more than 0.5 mM per liter per hour, and the initial treatment should be halted once a mildly hyponatremic range of the serum sodium concentration has been reached (similar to 125 to 130 mM/liter). In contrast, severe chronic asymptomatic hyponatremia map be treated sufficiently by a fluid restriction. On the other hand, severe symptomatic acute hyponatremia should be treated promptly and rapidly, using hypertonic saline, to initially reach a mildly hyponatremic level.

PURPOSE:In the differential diagnosis of patients with polyuria-polydipsia one must distinguish usually between primary polydipsia (PP) and central diabetes insipidus (CDI). The first situation is a state of volume expansion and the second of volume contraction. We evaluate whether serum uric acid determination could help to differentiate between the two conditions. PATIENTS AND METHODS:We analyzed the score of 13 consecutive patients with CDI, 7 patients with PP, and 7 patients with nephrogenic diabetes insipidus (NDI). Serum uric acid concentration was available during normonatremia without treatment with 1-desamino-8-D-arginine vasopressin (dDAVP), during mild dehydration and during treatment with dDAVP. In 8 of these patients plasma renin activity (PRA), urate, urea and creatinine clearances were also available. These data were also obtained in the patients with NDI. In 1 patient with CDI, we studied the effect on urate clearance of dDAVP, which stimulates exclusively the V2 receptors, and of triglycyl-lysine-vasopressin (TGLV), a potent V1-receptor agonist. RESULTS:Normonatremic polydypsic patients with CDI presented an increase in uric acid concentration (7.1 +/- 2.2 mg/dL), whereas in the PP group the value was decreased (3 +/- 0.75 mg/dL; P <0.001). All the normonatremic PP presented a serum uric acid concentration lower than 5 mg/dL, whereas all the normonatremic CDI patients, exept 1, presented a value higher than 5 mg/dL. In both groups blood urea concentration was decreased as a consequence of high renal clearances. The hyperuricemia of CDI was related to low uric acid clearances. Patients with hypernatremia and NDI presented a lower increase in serum uric acid concentration than those with similar levels of hypernatremia and CDI (NDI: 5.7 +/- 0.8 mg/dL and CDI: 7.9 +/- 2.3 mg/dL; P <0.05) and the NDI patients presented an urate clearance corrected for creatinine clearance which was significantly higher than in CDI (9% +/- 3% and 4% +/- 1.1%; P <0.01). When the patients with CDI were treated with dDAVP and normalyzed their PRA (0.9 +/- 0.4 ng/mL/h) we observed still mild hyperuricemia compared to controls (5.5 +/- 1.4 mg/dL and 4.3 +/- 0.9 mg/dL; P <0.01) and a low fractional excretion of filtered uric acid (6.5% +/- 1.7% compared to 8.2% +/- 2% in controls; P <0.05). Acute administration of dDAVP, stimulating the V2 receptors, in one patient with CDI, had no effect on urate clerance, while TGLV, which stimulates the V1 receptor, increased urate clearance. CONCLUSION:The presence of an serum uric acid concentration higher than 5 mg/dL in polyuric polydipsic patients is highly suggestive of CDI. Even when these patients are treated with dDAVP many of them remain hyperuricemic, and this seems to be the consequence of a lack of V1 receptor stimulation.

BACKGROUND: The treatment of hyponatremic patients requires physicians to make a therapeutic choice between saline infusion and water restriction. Therefore, they need readily available and reliable parameters to facilitate making that choice. This study was designed to determine whether the use of clearance ratios can help clinicians recognize saline-responding hyponatremic patients.PATIENTS AND METHODS: Thirty-five nonedematous, hospitalized, hyponatremic patients were classified according to their history and saline response into four groups: diuretic-taking patients, polydipsic patients, saline responders, and saline nonresponders. Within these four groups, clinical and biochemical volume-related parameters, including clearance ratios, were prospectively evaluated before infusion of 2 L isotonic saline. Clearance ratios as well as usual clinical and biochemical parameters were tested for their accuracy in predicting saline responsiveness.RESULTS: Both positive (70%) and negative (54.5%) predictive values for hypovolemia were unsatisfactory; clinical prediction of hypovolemia was also characterized by low sensitivity (41.1%), but acceptable specificity (80%). In the polydipsia and saline-nonresponder groups, plasma urea and uric acid values tended to be lower than in the diuretic and saline-responder groups. However, the usefulness of these parameters was limited by too large an overlap among the different groups. In both polydipsic patients and saline responders, urinary sodium concentration was low. The combined amount of urinary sodium and potassium in relation to plasma sodium did not discriminate among the different groups. Most helpful in distinguishing among the groups was a combination of several clearance ratios (fractional excretions of sodium, potassium, urea, and uric acid), since the predictive use of each parameter on its own was restricted. The best indicator of saline responsiveness was a low fractional excretion of filtered sodium (< 0.5%) combined with a low fractional excretion of urea (< 55%).CONCLUSION: The accuracy of clinical evaluation for predicting the state of extracellular fluid volume in hyponatremia is low. The combination oi: low fractional sodium excretion (< 0.5%) and low fractional urea excretion (< 55%) is the best biochemical way to predict saline response, whereas high fractional potassium excretion (> 20%) indicates diuretic intake.

Prolactin is known to have renal sodium retention properties in animals. In man, only two studies have suggested a similar effect in healthy volunteers or in patients with microprolactinoma. Since hyperprolactinemia is frequently observed in liver disease, this prospective study of 19 patients evaluated the influence of prolactin on urinary electrolytes excretion in cirrhosis. Basal hyperprolactinemia was found in 14 out of 19 cases. The effect of serum prolactin elevation on renal sodium and potassium excretion was studied in all patients after thyrotropin-releasing hormone stimulation (200 micrograms), with seven consecutive hourly urinary samples. Patients were separated into two groups according to amount of prolactin discharge after thyrotropin-releasing hormone injection. Group I included patients with "low prolactin release", defined as the difference between basal and peak prolactin values (delta prolactin) < 1000 mu u/ml (n = 8), and no change in natriuresis could be observed. In contrast, in group II with a "high PRL release" (delta prolactin > 1000 mu u/ml, n = 11), significant reductions in urinary sodium (p < 0.01) and potassium (p < 0.02) excretion were observed, which lasted until the third hour after thyrotropin-releasing hormone injection. A significant correlation was found between peak prolactin values and the decrements of natriuresis (r = 0.70, p < 0.02). The pattern of urinary electrolyte changes and the stability of the ratio UK/UK+Na suggest a possible sodium-retaining effect of prolactin localized proximally to the distal tubule.

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.

Our purpose was to compare the effect of urea and indomethacin on solute excretion in hyponatremic patients with inappropriate secretion of antidiuretic hormone (SIADH). In 6 patients (serum Na: 126 +/- 3 mmol/l), the intake of urea (0.1 g/kg) induced a decrease in sodium excretion while urine osmolality, urine flow and osmotic clearance (Cosm) did not change. In the control group, the urinary flow and Cosm were increased as expected, while sodium excretion tended to increase. In the SIADH group, the decrease in the fractional excretion (FE) of Na+ (FE.Na+) (or FE.Cl-) after urea intake was negatively correlated with urinary urea concentration while the FE.K+ was positively correlated with FE.Na+ (or FE.Cl-), which suggests that the effect of urea on sodium excretion takes place proximally to the distal tubule, probably at the thin ascending limb. After indomethacin intake, FE.Na+ (or FE.Cl-), FE.K+, Fe.osm and Fe.urea decreased in the normal and hyponatremic groups. The mean free water reabsorption relatively to osmolar delivery was lower in SIADH (p < 0.05), and did not change significantly after indomethacin intake. The fact that the decrease of FE.Na+ (or FE.Cl-) after indomethacin was associated with a decrease in FE.K+ suggests that the increase in sodium (or chloride) reabsorption occurred more proximally to the distal tubule (probably a the medullary segment of the thick ascending limb of the loop of Henle).

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.