REVIEW SIADH and other hyponatremic disorders: diagnosis and therapeutic problems

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1 REVIEW SIADH and other hyponatremic disorders: diagnosis and therapeutic problems Toshikazu SAITO Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Tochigi, Japan Hyponatremia is more frequently observed in elderly patients associated with exaggerated response of ADH release and attenuated response of renin-aldosterone system. Differentiation of SIADH and hyponatremia other than SIADH is essential in anticipating the therapeutic effect of water restriction to correct hyponatremia. Serum concentration of uric acid and urinary excretion of kallikrein are significant parameters in biochemical discrimination index to differentiate these two types of hyponatremia. In addition to sodium replacement, water restriction and mineral corticoid, newly developed nonpeptide ADH V2 receptor antagonist, OPC-31260, seems to be a useful tool to correct hyponatremia. Jpn J Nephrol 38: , 1996 Key words: Hyponatremia, aged subjects, SIADH, non-peptide ADH antagonist, mineral corticoid Introduction Hyponatremia, serum concentration of sodium below 135 meq/1, is clinically most frequently observed among the disorders of electrolytes. Its incidence is approxi mately 8 times of that of hypernatremia (Fig. 1). The occurrence of hyponatremia increases along with the age and pathophysiological basis and selection of its therapeutic procedures in elderly subject is different from the young. Recently, non-peptide ADH V2 receptor antagonist that induces marked aquaresis after oral administration has been developed. As hyponatremia is usually associ ated with relative excess of ADH in plasma, this agent is expected to be useful to correct hyponatremia. For the choice of treatment, especially the water restriction or administration of ADH antagonist, the discrimination of SIADH and hyponatremia other than SIADH (non- SIADH) seems to be important, since decrease in total body water by these treatments would be effective to correct hyponatremia without any hazardous side effect in case of SIADH. In this paper the recent clinical implications of diag nosis and therapeutic problems of SIADH and non- SIADH will be reviewed. Accepted August 29, 1996 Hyponatremia o f the elderly patients In the study of patients admitted to the hospital, the incidence of hyponatremia in the elderly patients is higher than the young. Its incidence increases along with the age in the study of 4214 patients admitted to Jichi Medical School Hospital (Fig. 1). At the age be tween 70 and 79 years old, the highest incidence is observed. The high incidence of hyponatremia in the elderly patients has been reported by several authors [1, 2]. As the serum concentration of sodium is controled by negative feed back mechanisms, the pathogenesis inducing hyponatremia should be considered in relation with the hormonal factors. Antidiuretic hormone (ADH, arginine vasopressin) is especially important in deter mining the serum sodium concentration as this hormone is involved in the feed back loop controlling serum osmolality. Secretion of ADH is finely controled by serum osmolality and its antidiuretic action results in the dilution of serum sodium concentration. Influence of aging on the control of ADH secretion has been studied in the elderly and young subjects. The secretion of ADH in response to tilting was studied in young, 20 to 34 years old, and elderly, 65 to 80 years old, subjects. The tilting position at 60 for 15 minutes resulted in the increase in plasma ADH concentration. This response is, however, more exaggerated in the elderly subjects as compared with the young (Fig. 2) [3]. The facilitation of ADH release in the aged is also

2 430 Toshikazu Saito Fig. 2. ADH release in response to tilting for 15 minutes in elderly and young subjects. ( œ): Elderly group, 65 to 80 years old, ( Z): Young group, 20 to 34 years old. *p <0.05 vs. the value before the head-up tilt. + p < 0.05 vs. the respective value of the young subjects. Values are the mean } SEM, n = 6. (Ref. 3) Table 1. Guide for the diagnosis of SIADH Fig. 1. Effect of aging on the incidence of hypernatremia and hypo natremia. The incidence of patients showing serum sodium con centration higher than 150 or lower than 135 meq/l was studied in 4214 subjects admitted to the hospital. observed by Helderman et al. [4]. The release of ADH in response to infusion of hypertonic saline was higher in the elderly person in their report. As the hyponatremia is essentially a relative excess of water to sodium in plasma, the facilitated response of ADH release seems to be closely related with the high incidence of hypo natremia in the aged. The second factor to be considered which is involved in the development of hyponatremia is renin-aldosterone system. In the aged, plasma level of aldosterone is lower in the aged subject as compared with the young [5]. SIADH in hyponatremia disorders The SIADH is diagnosed by criteria based on the clinical data including physical findings [6] (Table 1). According to this criteria, laboratory findings were analysed in 48 hyponatremic patients showing serum sodium concentration below 135 meq/1 in our hospital. Twenty four patients were diagnosed to have SIADH and approximately half of the patients with moderate or severe hyponatremia may be categorized as SIADH. In order to elucidate whether pathophysiological state named SIADH is an independent clinical entity from other hyponatremic disorders, non-siadh, endocrino logical findings were studied in the hyponatremic subjects with or without SIADH. The correlations between serum sodium concentration and plasma ADH in hyponatremic 1. Chief symptom 1) General malaise, anorexia 2) Lack of physical findings of dehydration 2. Laboratory findings 1) Hyponatremia: Serum sodium concentration lower than 135 meq/l 2) Low plasma osmolality: Plasma osmolality lower than 270 mosm/kg 3) Concentrated urine: Urinary osmolality higher than 300 mosm/l 4) Natriuresis: Urinary sodium concentration higher than 20 mosml 5) Normal renal function: Serum creatinine lower than 1.2 mg/dl 6) Normal adrenal function: Serum consentration of cortisol higher than 6 ƒêg/dl 3. Reference findings [Diagnostic 1) Plasma renin activity lower than 5 ng/ml/h 2) Serum uric acid concentration lower than 5 mg/dl 3) Increase in urinary excretion of kallikrein 4) Correction of hyponatremia by water restriction in prior to dehydration 5) Increase in plasma concentration of ADH criteria] Definite diagnosis: Laboratory findings 1) ` 6) in the absence of dehydration Suspicious diagnosis: Laboratory findings 1) ` 6) in the presence of slight dehydration subjects are shown in Fig. 3. There is no significant difference in plasma ADH concentration between these two groups of hyponatremic subjects, SIADH and non- SIADH. The slope of the correlation between serum sodium concentration and plasma ADH is, however, negative in SIADH group and positive in non-siadh. This reverse correlation of two groups of hyponatremia

3 SIADH and other hyponatremic disorders 431 Fig. 3. Correlation of serum sodium and plasma ADH concentrations in normal and hyponatremic subjects. Upper panel: hyponatremic subjects associated with SIADH, lower panel: hyponatremic subjects other than SIADH. seems to be resulted from difference of fluid volume in these hyponatremic subjects. In SIADH there is no depletion in circulating blood volume, whereas the effective blood volume is often decreased in non-siadh. These include dehydration with sodium depletion and edematous states associated with nephrotic syndrome, liver cirrhosis or congestive heart failure. The correlation line of serum sodium concentration and plasma ADH level and its point of intersection with abscissa shift leftwards in case of fall in the effective blood volume [7]. Biochemical findings of SIADH The concentration of norepinephrine reflects the activity of sympathetic nerve and it is increased in the hyponatremic subjects without SIADH [8]. In the study of author's laboratory, there was no significant difference between SIADH group and group with hyponatremia other than SIADH in the plasma concentration of norepinephrine. As reported by Beck [9], serum concentration of uric acid is lower in SIADH as compared with hyponatremic subjects without SIADH. The urinary excretion of kallikrein is higher in hyponatremic subjects with SIADH than those without SIADH (Fig. 4). This finding seems to confirm the results of Tomita et al. [10]. In the study of human, Fig. 4. Urinary excretion of kallikerin in subjects with SIADH, hyponatremia other than SIADH (non-siadh) and normal. significant correlation was seen between urinary excretion of ADH and kallikerin [11]. The renal action of ADH under the presence of fluid volume expansion is reported to increase the urinary excretion of kallikrein. These findings seem to indicate the significance of measurement of urinary kallikrein excretion in the discrimination of SIADH from non-siadh. In order to elucidate the discriminating index of SIADH from non-siadh, the stepwise regression analysis was applied to the biochemical parameters. Among the serum concentrations of creatinine, uric acid, plasma levels of ADH, atrial natriuretic polypeptide and norepinephrine, plasma renin activity and urinary excretion of kallikrein, serum con centration of uric acid and urinary excretion of kallikrein turned out to be determinant parameters. Based on the factors obtained by this regression analysis, an index discriminating two hyponatremic states, SIADH and non-siadh was determined as follows: Y = X X2, where Y is discriminating index, X1 is urinary excretion of kallikrein ( Đg kallikreinlmg creatinine), X2, is serum concentration of uric acid (mg/dl). In this equation, Y is expected to be 1 in a typical case of SIADH and it is 0 in a hyponatremic subject other than SIADH. The overlap of this index discriminating SIADH and non- SIADH was observed in only one case (Fig. 5). The different distribution of the index based on the bio-

4 432 Toshikazu Saito Fig. 5. Distribution of discrimination index to differentiate SIADH and hyponatremia other than SIADH in each group of hyponatremia. Definition of the index is shown in the text. chemical parameters in these two hyponatremic states seems to confirm the significance as an independent clinical entity of SIADH hitherto diagnosed by clinical criteria including physical findings. Treatment of hyponatremia As hyponatremia is a secondary symptom due to various primary disorders, the treatments of such causa tive disease are essential. Hyponatremia is often associ ated with manifestations related to neuromuscular system, however, including fatigue, anorexia, nausea, muscle spasms and sometimes convulsion or coma [12]. The severerity of the symptoms is closely related to the degree of hyponatremia and velosity of its development. Apart from the treatment of original deseases, therefore, the correction of hyponatremia is occasionally essential. As the emergency procedure to correct severe hypona tremia, infusion of hypertonic saline in combination with furosemide elevates serum concentration of sodium rapidly. The development of central pontine myelinolysis should be avoided [13] by keeping the velosity of daily serum sodium elevation slower than 10 meq/1. The treatment of SIADH is principally based on the restriction of water intake as this hyponatremia resulted from water retention due to inappropriate antidiuresis. Fifteen to 20 ml/kg is prescribed as daily fluid intake for the patient with SIADH. The attenuators of renal ADH action such as demeclocyline or lithium carbonate are effective to strengthen the effect of water restriction [14] although their effect is expected to appear in several days after the start of therapy. In cases with SIADH due to intracranial disease, diphenylhydantoin suppresses release of ADH and correct hyponatremia [15]. As diphenylhydantoin is used as anticonvulsant, it is often prescribed to correct chronic hyponatremia due to SIADH associated with head trauma or intracranial surgery. In cases with SIADH, saline infusion or administration of mineralocorticoid is sometimes not very effective to correct hyponatremia as urinary excretion of sodium is exaggerated in response to sodium and fluid adminis tration in cases with expansion of circulating blood volume. However, SIADH is sometimes associated with sodium depletion due to attenuation of sodium intake and prolonged natriuresis due to suppression of renin aldosterone system in the presence of elevated or normal glomerular filtration rate. To correct such sodium depletion, more than 200 meq/day of sodium should be administered, orally or intravenously. Further, adminis tration of mineralocorticoid, 9a fludrocortisone acetate, is effective to intensify the effect of water restriction to elevate serum sodium concentration. Treatment of hyponatremia other than SIADH varies depending on the original diseases. Sodium depletion due to decreased salt intake associated with anorexia, vomiting or diarrea is corrected by oral or intravenous administration of sodium chloride. Especially in elderly subjects associated with relative decrease in regulatory function through renin-aldosterone system, hyponatremia is corrected by the administration of mineralocorticoid [16]. In some cases of hyponatremic patients admitted to hospital, their hyponatremia has resulted from excess ive fluid administration and is corrected by restriction of fluid intake. Hyponatremia associated with the depletion of effective blood volume as observed in liver cirrhosis or nephrotic syndrome is effectively corrected by infusion of plasma volume expander like albumin solution and administration of furosemide by causing water diuresis. Hyponatremia is often a single recognizable symptom in hypopituitarism especially in isolated ACTH de ficiency. Measurement of cortisol and ACTH levels in plasma is essential to diagnose hypopituitarism. There have been arguments whether hyponatremia due to hypopituitarism should be included in the category of SIADH. As the absence of adrenal insufficiency is one of the criteria to diagnose SIADH, hypopituitarism has not been included in the category of SIADH. As cortisol suppresses biosynthesis of ADH in supraoptic nucleus in hypothalamus, however, cortisol deficiency with normal aldosterone level may have primary ADH excess under the absence of decrease in effective blood volume. Oelkers et al. [17] claimed that hypopituitarism could be included in SIADH as no sign of dehydration were observed in their patients. Correction of hyponatremia with ADH antagonist In the treatment of hyponatremia associated with relative excess of plasma ADH, ADH V2 receptor antagonist has been expected. The peptide V2 receptor antagonist has been difficult to use clinically. The peptide antagonist developed by Manning et al. [18] is not so effective to block V2 receptor in primates as compared with its effect in rats. The peptide antagonist should be administered intravenously and oral route is not ad-

5 SIADH and other hyponatremic disorders 433 equate. Further, the repetitive administrations of peptide antagonist result in the fall of its antagonistic action. From these points, non-peptide ADH V2 receptor antag onist has long been expected. Potent nonpeptide antagonist for ADH V2 receptor, OPC-31260, has been developed by Otsuka group, and its utility to correct hyponatremia is being confirmed (Fig. 6). This compound is orally appliable and induces marked aquaresis in human [19]. In rats even after water restriction of 24 hours, urinary volume greatly increased associated with fall in its osmolality from 2404 mosm/kg to 213 mosm/kg in response to oral administration of the antagonist [20]. Hyponatremia in rats with experimental SIADH induced by administration of desmopressin and liquid chaw was corrected 24 hours after the treatment with the antagonist (Fig. 7) [21]. Rats with liver cirrhosis made by chronic injection of carbon tetrachloride show blunted excretion of water in response to oral water load associ ated with high concentration of plasma ADH. This impaired water diuresis in cirrhotic animals is strikingly improved after administration of the antagonist [22]. Effects of non-peptide ADH V2 receptor antagonist on the ADH induced antidiuresis observed in rats suggest the striking utility of this compound to correct hypona tremia in human. Actually, the preliminary clinical data of this compound in hyponatremic subjects seem to promise its effect to correct hyponatremia due to various causes including SIADH. Summary Hyponatremia is the most frequently observed electro lyte disorder which is more common in elderly subjects. The occurrence of hyponatremia in the aged may be related to the exaggerated release of ADH in response to circulatory change resulting in the relative water excess through its antidiuretic action. The attenuated response of renin-aldosterone system may be involved in the hyponatremia of the aged through the impaired function to retain sodium. Differentiation of hypona tremia into SIADH and non-siadh is important in anticipating the therapeutic effect of water restriction. Among the biochemical parameters, serum concen tration of uric acid and urinary excretion of kallikrein seem to be essential in discriminating index to differen tiate the two types of hyponatremia. Water restriction is essential in the treatment of SIADH. Administration of mineral corticoid, 9a fludrocortisone acetate, is useful to fortify the sodium retaining action in hyponatremic subjects, especially in elderly subjects. In addition to these treatments, recently developed non-peptide ADH V2 receptor antagonist seems to be of striking clinical utility to correct hyponatremia. Address to: Dr. Toshikazu Saito, Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Tochigi , Japan Fig. 6. Structure of non-peptide ADH V2 receptor antagonist, OPC Fig. 7. Alteration in serum osmolality in the experimental SIADH rats in the presence and absence of OPC For the preparation of SIADH rats, DDAVP was infused, and OPC was orally applied for the correction of hyponatremia. Symbols are: ( ) Vehicle/vehicle, ( ) Vehicle/OPC-31260, ( œ) DDAVP/Vehicle, ( ) DDAVP/OPC-31260, ( ) DDAVP/OPC vehicle References 1. Miller M, Morley JE, Rubenstein LZ: Hyponatremia in a nursing home population. J Am Geriatr Soc 43: , Sunderam SG, Mankikar GD: Hyponatremia in the elderly. Age Aging 12: 77-80, Ishikawa S, Fujita N, Fuijisawa G, Tsuboi Y, Sakuma N, Okada K, Saito T: Involvement of arginine vasopressin and renal sodium handling in pathogenesis of hyponatremia in elderly patients. Endocrine J 43: , Helderman JH, Vestal RE, Rowe JW, Tobin JD, Andres R, Robertson GL: The response of arginine vasopressin to intravenous alcohol and hypertonic saline in man: The impact of aging. J Gerontol 33: 39-47, Zodik Z, Kowarski AA: Normal integrated concentration of aldosterone and plasma renin activity: Effect of age. J Clin Endocrinol Metab 50: , Saito, T: Guide for the diagnosis of SIADH. Annual report: Study Group of Japanese Minister of Health and Welfare about hypothalamo-pituitary disorders, p. 210, (in Japanese) 7. Robertson GL, Shelton RL, Athar S: The osmoregulation of vasopressin. Kidney Int 10: 25-37, Anderson RJ, Chung HM, Kluge R, Schner RW: Hyponatremia:

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