Effect of tolvaptan on hyponatremia in a dog with syndrome of inappropriate secretion of antidiuretic hormone

Abstract

A 1-year-old spayed female Miniature Schnauzer had chronic hyponatremia, accompanied by polyuria and polydipsia. Blood tests and urinalysis revealed severe hyponatremia, low plasma osmolality with euvolemia, and increased sodium excretion in urine. Hypothyroidism and hypoadrenocorticism were ruled out as causes. These findings led to the diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Magnetic resonance imaging (MRI) showed dilation of the lateral ventricles, indicating severe hydrocephalus. Tolvaptan, a vasopressin V2 receptor antagonist commonly used in human SIADH, was administered along with water restriction. This treatment resulted in a consistent increase in plasma sodium levels without any adverse effects. This case report represents the first documented evidence of the therapeutic efficacy of tolvaptan in treating SIADH in a dog.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder characterized by the excessive release of antidiuretic hormone (ADH), regardless of decreased plasma osmolality or increased renal tubule sensitivity to ADH [6]. Inappropriate ADH secretion leads to increased water reabsorption, resulting in hyponatremia due to increased circulating fluid volume. Clinical manifestations of SIADH include chronic hyponatremia and euvolemia. In humans, SIADH can be caused by central nervous system disorders like encephalitis and cerebral hemorrhage, pulmonary diseases, ectopic ADH-producing tumors, and certain medications [6]. While treatment primarily targets the underlying condition, interventions such as water restriction, intravenous fluids, high-dose salt tablets, and medication may be utilized when managing the underlying disease becomes challenging [16].

To diagnose SIADH in dogs, several criteria need to be met: normal circulating fluid volume; presence of hyponatremia; low plasma osmolality (<275 mOsm/kg); increased urinary sodium concentrations (>40 mEq/L) despite hyponatremia; higher urine osmolality compared to plasma osmolality; normal kidney, adrenal, and thyroid function; and normal acid–base and plasma phosphorus levels [7, 8].

Tolvaptan, an antagonist of vasopressin V2 receptor, is commonly used to treat SIADH in humans. It selectively blocks vasopressin, leading to reduced water reabsorption and diuresis, while maintaining electrolyte balance [16]. SIADH cases in dogs are rarely reported, and apart from addressing the underlying condition, treatment has mainly involved water restriction and intravenous fluids [1, 3, 17]. While a previous report mentioned the use of the V2 receptor antagonist Mozavaptan (OPC-31260), there is no established pharmacological treatment for dogs [7]. The previous study found that tolvaptan demonstrated a higher affinity and stronger binding to the human V2 receptor compared to mozavaptan, which may lead to higher pharmacological effects [21]. In this study, we present a case of SIADH caused by hydrocephalus in a dog, successfully treated with oral tolvaptan, a V2 receptor agonist.

A 1-year-old spayed female Miniature Schnauzer weighing 6.3 kg was referred to the surgical department of Yamaguchi University Animal Medical Center (Yamaguchi, Japan). The reason for referral was the treatment of a suture granuloma in the abdominal cavity. Following the surgery, the dog developed chronic hyponatremia [125 mEq/L; reference interval (RI), 141–152 mEq/L]. Subsequently, the dog was transferred to the Department of Veterinary Internal Medicine for further examination of the hyponatremia. The only clinical symptom observed was polyuria/polydipsia (water intake, 110–125 mL/kg/day) beginning at five months old, with no signs of neurological issues. The dog had not received any medications since the surgery.

On the initial visit to the Department of Veterinary Internal Medicine (day 0), the dog underwent various tests including a complete blood cell count (CBC), blood biochemistry, urinalysis, measurement of thyroid hormone levels, and an adrenocorticotropic hormone (ACTH) stimulation test. The CBC indicated mild leukopenia (4.58 × 10³/µL; RI, 6–17 × 10³/µL) without abnormalities in the proportions of different blood cell types. Blood biochemistry revealed electrolyte imbalances, including hyponatremia (124 mEq/L), hypochloremia (88 mEq/L; RI, 102–117 mEq/L), and hypokalemia (3.0 mEq/L; RI, 3.8–5.0 mEq/L) (Table 1). Blood urea nitrogen was decreased (6.7 mg/dL; RI, 9.2–29.2 mg/dL). Urinalysis showed a urine specific gravity of 1.010, urine sodium concentration of 54 mEq/L, and urine osmolality of 372 mOsm/L (Lintec Inc., Fukuoka, Japan). Thyroid hormone levels were normal (Table 1). Furthermore, the dog exhibited increased endogenous ACTH levels and hyperreactivity of cortisol during the ACTH stimulation test (Table 1). Chest radiography and abdominal ultrasonography did not reveal any significant abnormalities. The maximum diameters of the left and right adrenal glands were 2.6 mm and 4.3 mm, respectively. To determine the type of hyponatremia (true hyponatremia [hypotonic], pseudohyponatremia [hyperlipidemia or paraproteinemia], hypertonic hyponatremia, or iatrogenic hyponatremia), classification based on plasma osmolarity levels was initially performed. The calculated plasma osmolality (formulae=2Na⁺ [mEq/L] + Glucose [mg/dL]/18 + BUN [mg/dL]/2.8 [5]) was hypo-osmolar (259 mOsm/L; RI, 290–315 mOsm/L), confirming true hyponatremia in this case. The hyponatremia occurred in a state of euvolemia, indicating neither hypovolemia (dehydration) nor hypervolemia (edematous state). Based on the increased urinary sodium excretion and the absence of hypothyroidism or Addison’s disease, we diagnosed the case as SIADH. However, the underlying condition remained unknown.

Table 1. The results of blood examinations at initial visit.

Parameters	Units		Reference interval
Blood biochemistry
Glucose	mg/dL	156.0	75–128
Total protein	g/dL	6.8	5.0–7.2
Albumin	g/dL	3.4	2.6–4.0
Alanine aminotransferase	U/L	24.0	17–78
Alkaline phosphatase	U/L	53.0	<89
Total cholesterol	mg/dL	195.0	115–337
Blood urea nitrogen	mg/dL	6.7	9.2–29.2
Creatinine	mg/dL	0.38	0.4–1.4
Calcium	mg/dL	9.5	9.3–12.1
Sodium	mEq/L	124.0	141–152
Potassium	mEq/L	3.0	3.8–5.0
Chloride	mEq/L	88.0	102–117
Phosphate	mg/dL	3.0	1.9–5.0
Others
Endogeneous ACTH	pg/mL	86.7	5–36
Baseline cortisol	µg/dL	11.6	1.0–7.8
Cortisol 1hr post-ACTH stimulation	µg/dL	28.8
T4	µg/dL	3.63	1.1–3.6
Free T4	ng/dL	2.8	0.9–2.6
Thyroid-Stimulating Hormone	ng/mL	0.105	0.08–0.32

CRP, C-reactive protein; ACTH, adrenocorticotropic hormone.

Although no neurological symptoms were observed in the present case, given the frequent occurrence of SIADH associated with intracranial conditions in dogs [1, 4, 8, 17], magnetic resonance imaging (MRI) of the head was conducted on day 28. This revealed thinning of the brain parenchyma, indicating severe ventricular enlargement (Fig. 1), with no indications of tumor or inflammation. The ventricle/brain (VB) index, which is the criterion for discrimination between hydrocephalus and ventriculomegaly [10], was 0.74 (VB index >0.6), indicating internal hydrocephalus. As in a previous report [20], we measured plasma ADH concentration using the double antibody radioimmunoassay (Lintec Inc.). Despite low plasma osmolality, inappropriate secretion of ADH was observed at 3.5 pg/mL (RI, 1.4–9.9 pg/mL [9]). Based on these findings, the present case was diagnosed as SIADH resulting from congenital hydrocephalus.

Fig. 1.

Transverse and sagital T2-weighted magnetic resonance imaging of the brain at the temporomandibular joint level indicated the dilation of lateral ventricles.

The case was started on treatment with tolvaptan (Samsca, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), and regular monitoring of physical examinations, blood tests, and urinary electrolytes was conducted. Initially, a dosage of 1 mg/kg twice daily was administered for 5 days, leading to an increase in plasma sodium levels from 126 mEq/L to 133 mEq/L (Fig. 2). However, the owner’s difficulty in continuing treatment at the initial dosage due to the high cost of Samsca, then the dosage was subsequently reduced to 0.5 mg/kg after 3 days, along with the implementation of water restriction. Water restriction was gradually reduced from 90 mL/kg/day to 60 mL/kg/day, and blood sodium levels remained stable at around 126 mEq/L. On day 231, tolvaptan was resumed after the release of a generic version by Towa Pharmaceutical Co., Ltd. (Osaka, Japan), which offered a more affordable option. The dog is currently receiving tolvaptan at a dosage of 1 or 1.5 mg/kg twice daily, alongside water restriction, resulting in an increased plasma sodium level of up to 134 mEq/L. No adverse effects associated with tolvaptan have been observed in this case.

Fig. 2.

Change in plasma sodium (Na) concentration (mEq/L) from day 0 (first day of admission to our department) to the last day of follow-up.

We present a case of congenital hydrocephalus accompanied by hyponatremia resulting from SIADH. In humans, SIADH often manifests as a secondary condition associated with various pathological factors, predominantly neoplasms [6]. Although less common in dogs, SIADH cases secondary to intracranial neoplasms, encephalitis, and other central nervous system disorders have been documented [1, 4, 8, 17]. Hydrocephalus, characterized by abnormal accumulation of cerebrospinal fluid (CSF) in the brain ventricles, is known to be an underlying cause of SIADH in humans [11]. Previous reports suggest that mechanical pressure exerted on the ventricles may trigger ADH release from the pituitary gland [11, 17]. In our case, plasma ADH levels remained within the normal range despite low plasma osmolality, similar to a previous report [7]. While ADH measurement is not commonly utilized for diagnosing SIADH in humans due to ADH instability and limited test sensitivity [13], these findings hint at a potential association between hydrocephalus and SIADH. However, the reference interval for canine ADH has not yet been established across testing facilities, and further investigation is required.

There has been one report of a dog with SIADH caused by congenital hydrocephalus; however, treatment in that case did not involve shunt surgery or the administration of V2 receptor antagonists such as tolvaptan [17]. In our case, we proposed ventriculoperitoneal shunting surgery to alleviate CSF accumulation [2], but the owner declined this option. Acetazolamide was avoided due to potential risks of exacerbating hyponatremia. Corticosteroids and isosorbide dinitrate were also avoided due to exacerbation of polydipsia or diuresis. Therefore, we opted for tolvaptan to inhibit water reabsorption, resulting in increased plasma sodium levels. Although literature on the effect of tolvaptan in dogs with SIADH is limited, the dosage in our case was determined based on a previous pharmacokinetic study [12]. Healthy beagles administered a single oral dose of tolvaptan ranging from 0.3 mg/kg to 10 mg/kg in exhibited dose-dependent increases in urine volume and decreases in urinary osmolality for up to 6 hr. Key concerns with tolvaptan include overly rapid correction of serum sodium concentrations leading to osmotic demyelination of neurons and its relatively short half-life in plasma. The lower dosage of 1 mg/kg of tolvaptan significantly increased free water clearance. Hence, we initiated treatment with 1 mg/kg twice daily. Since plasma sodium concentration could not be normalized at the final dosage (Fig. 2), further dose escalation would ideally be necessary. Even in humans, the appropriate administration of tolvaptan remains controversial [18], underscoring the need for additional clinical studies to evaluate its clinical efficacy and safety profile in dogs with SIADH. Nevertheless, our case suggests that tolvaptan may hold a clinical utility as a treatment option for the prevention of symptoms caused by severe hyponatremia when the underlying disease cannot be treated.

To rule out hypoadrenocorticism, we measured endogenous ACTH and basal/ACTH-stimulated cortisol concentrations. Hypoadrenocorticism was effectively ruled out, while elevated levels of endogenous ACTH and cortisol were observed. Conversely, there were no clinical signs of adrenal gland enlargement, alopecia, or elevated alkaline phosphatase, eliminating the possibility of hyperadrenocorticism. Previous human studies have demonstrated the influence of ADH on the hypothalamic-pituitary-adrenal (HPA) axis, where ADH regulates ACTH secretion from corticotropic cells in the anterior pituitary gland, either independently or in synergy with corticotropin-releasing hormone (CRH) [15, 19]. Therefore, the increased levels of ACTH and cortisol in this case may be attributed to HPA axis stimulation caused by the inappropriate secretion of ADH, despite the absence of prior reports on dogs with SIADH.

Unlike in human SIADH, dogs with SIADH due to intracranial diseases exhibit polydipsia and polyuria [8, 14, 17]. The following four reasons are considered as possible causes for polydipsia and polyuria observed in this case: 1) the region of the posterior pituitary is close to that of the thirst center. Structural changes in the hypothalamus may simultaneously affect both areas, 2) pressure diuresis due to increased circulating blood volume may be present, 3) prolonged secretion of ADH may lead to desensitization of vasopressin receptors in kidneys, 4) disruption of the glomerular tubular balance may lead to impaired reabsorption of sodium in the tubules, resulting in natriuresis and polyuria. However, the reason for this discrepancy between humans and dogs remains uncertain.

In conclusion, this case report provides the initial evidence of the therapeutic efficacy of tolvaptan in a dog with SIADH. When dealing with hyponatremic dogs, it is important to consider the possibility of SIADH after ruling out cardiac, renal, or adrenal diseases, by assessing intracranial imaging.

Conflict of Interest

The authors have no conflict of interest to disclose.