Introduction

Hyponatremia, a common electrolyte disturbance in humans and animals, can result from a variety of underlying conditions.^1,2 One such condition is the syndrome of inappropriate antidiuretic hormone (SIADH), which is characterized by the excessive release of antidiuretic hormone (ADH) despite decreased plasma osmolality, leading to inappropriate water retention and hypo-osmotic hyponatremia.³ The diagnosis of SIADH is based on the presence of hyponatremia, urine osmolality that is inappropriate in relation to the low plasma osmolality, persistent renal sodium (Na⁺) excretion, and the exclusion of other conditions that could potentially cause hyponatremia, such as renal, hepatic, or adrenal disorders, diuretic use, thyroid dysfunction, or the administration of fluids with low sodium content.^1,3

In contrast to human medicine, in which SIADH is a relatively common cause of hyponatremia, the condition is infrequently reported in veterinary patients. In animals, SIADH has been associated with various underlying conditions, such as hepatic dysfunction, congenital disorders, and traumatic injuries.^4–6 Idiopathic SIADH, in which no underlying cause can be identified, is even more rarely described in veterinary literature, with only a limited number of documented cases.^7,8

This case report describes an unusual presentation of idiopathic SIADH in a dog, with polyuria and polydipsia as the only clinical signs. The diagnosis was supported by biochemical findings, measurement of ADH and copeptin concentrations, and the exclusion of other potential causes of hyponatremia. The case is notable for the use of diagnostic tests not commonly employed in veterinary medicine and the patient’s good long-term outcome without specific treatment.

Case Report

An approximately 3 yr old female Chihuahua, weighing 4.32 kg, was presented to the University of Florida Small Animal Hospital for evaluation of polyuria, polydipsia, hyponatremia, and hypochloremia. The dog was noted to consume a substantial volume of water (approximately 218 mL/kg/day) and had a normal appetite (commercially available adult canned and dry food) since the time of adoption. Initial diagnostics were performed by the primary veterinarian 12 wk after adoption. A urinalysis at that time was unremarkable except for a specific gravity of 1.019. She was negative for heartworm, Lyme, Anaplasma spp, and Ehrlichia spp on 4Dx SNAP test^a. A fecal evaluation showed hookworm ova, which was treated with pyrantel pamoate/praziquantel. Blood work performed at that visit included a complete blood count, thyroxine level, and chemistry panel, which were unremarkable except for hypochloremia (93 mmol/L, reference range 109–122 mmol/L) and hyponatremia (126 mmol/L, reference range 144–160 mmol/L), as shown in Table 1. Mathematical correction of serum chloride concentration ([Cl⁻]) using the formula calculated [Cl⁻] = (mid-reference range [Na⁺] / measured [Na⁺]) × measured [Cl⁻] resulted in corrected normochloremia (112.2 mmol/L). The dog was considered normovolemic based on normal hydration status assessed by physical examination and complete blood count, which showed normal hematocrit (0.42, reference range 0.38–0.57) and total protein (62 g/L, reference range 55–75 g/L). A urine culture obtained by cystocentesis was negative for bacterial growth. An ACTH stimulation test was performed 2 wk later, measuring plasma cortisol levels, and the results were within normal limits.

TABLE 1 Serial Serum Biochemistry Values

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Blood work at that time showed persistent hypochloremia and hyponatremia (Table 1). An abdominal ultrasound revealed a mildly hyperechoic, coarse liver at the lower end of normal size, bilateral mild nephrocalcinosis, and low normal adrenal gland size.

Physical examination during the University of Florida Small Animal Hospital evaluation 17 wk after adoption was unremarkable with normal hydration status and stable body weight (4.35 kg). The dog’s urination posture was normal, and there were no signs of pollakiuria, dysuria, or pigmenturia. A serum biochemistry panel was notable for mild hypercalcemia (10.5 mg/dL, reference range 8.70–10.4 mg/dL), persistent hypochloremia (93.3 mmol/L, reference range 107.8–117.1 mmol/L), upward correction of serum [Cl⁻] concentration of 14.2 mmol/L (to almost within the reference range at 107.5 mmol/L), and persistent hyponatremia (127.1 mmol/L, reference range 141.9–150.6 mmol/L). Serum osmolality by freezing point depression^b was 252 mmol/kg H₂O (reference range 297–307 mmol/kg H₂O).⁹ Urine osmolality was 219 mmol/kg H₂O (reference range for young and adult dogs 369–2416 mOsm/kg).¹⁰ The urinalysis was unremarkable except for hyposthenuria (specific gravity 1.006), and urine [Na⁺] of 41.6 mmol/L. Fractional excretion of Na⁺ was 0.9%, and fractional excretion of Cl⁻ was 1.4%.¹¹ The owner declined further diagnostics, such as brain imaging. Fasted serum ADH concentration was measured on protease-inhibited plasma collected at the same visit, using an enzyme immunoassay kit^c as previously described.¹² Serum ADH concentration in this dog was 5.54 pg/mL, which was above the reported range for healthy dogs (3.22–5.03 pg/mL).¹² Fasted serum copeptin concentration measured using an enzyme-linked immunosorbent assay test kit^d was 135.40 pg/mL which was higher than the 75th percentile for 19 healthy dogs (58.52 pg/mL; unpublished data from a recently performed study in Dr. Harris’s laboratory at the University of Florida). Copeptin units were converted from pg/mL to pmol/L to allow for expressing copeptin as a ratio to urinary [Na⁺], which was 0.81 pmol/mmol.

The dog underwent an ovariohysterectomy to rule out a potential influence of reproductive hormones on her condition. Serum electrolytes were measured 4 wk after surgery (22 wk after adoption), revealing persistent hyponatremia and hypochloremia, as shown in Table 1. Intracranial disease was considered unlikely because of the dog’s age, absence of other localizing clinical signs, and the prolonged duration of clinical laboratory abnormalities. However, MRI and computed tomography were not performed. Therefore, the possibility of intracranial disease cannot be excluded entirely. A diagnosis of SIADH was made based on persistent hyponatremia and hypochloremia, marked upward mathematical correction of serum [Cl⁻], serum osmolality <275 mmol/kg H₂O, urinary osmolality >100 mmol/kg H₂O, clinical euvolemia, urinary [Na⁺] >40 mmol/L, no evidence of liver disease, normal thyroid and adrenal function, no diuretic use, and elevated ADH concentrations.^1,3 Because no underlying cause for inappropriate ADH production was identified, a diagnosis of idiopathic SIADH was presumed. Water restriction was recommended.

One year after adoption, the dog returned for a recheck evaluation at the University of Florida Small Animal Hospital. Although water restriction had been recommended, it was not instituted because of impracticability. The owner was supplementing the dog’s diet with a small, unmeasured amount of salt sprinkled on the food. The dog was reported to be in good health and free from clinical signs other than polyuria and polydipsia. However, persistent hyponatremia, hypochloremia, and marked upward mathematical correction of serum [Cl⁻] were again noted (Table 1). The calculated serum osmolality remained low, indicating a continued hypo-osmolar state due to SIADH but without overt clinical manifestations aside from polyuria and polydipsia. Two years after adoption, the dog was rechecked by the primary veterinarian for routine examination. Hyponatremia and hypochloremia persisted with no change in clinical status (Table 1).

Informed consent was obtained from the owner of this dog for publication of this case report. The dog described in this study was clinically managed according to contemporary standards of care.

Discussion

SIADH is a disorder of water balance characterized by hypo-osmotic hyponatremia and impaired urinary dilution in the absence of appropriate physiologic stimuli, resulting in inappropriate water retention.¹ It is a common cause of hyponatremia in humans, accounting for approximately one-third of all cases of hyponatremia in euvolemic patients.² This syndrome is characterized by excessive release of ADH (also known as vasopressin) despite decreased plasma osmolality (which should suppress ADH release) or increased renal tubule sensitivity to ADH.³ It can be caused by various conditions that disrupt ADH regulation, including neurologic disorders, neoplasia, some medications, and other miscellaneous conditions.¹ If an underlying cause of SIADH is not identified, it is considered idiopathic.¹³ Although SIADH is common in humans, it appears to be uncommon in animals, with reported causes including liver failure, congenital abnormalities, and trauma.^4–6 Only three reported cases in veterinary medicine were considered idiopathic.^7,8

Criteria for the diagnosis of SIADH in humans include hyponatremia, inappropriately high urine osmolality (>100 mmol/kg H₂O) in the face of plasma hypo-osmolality (<275 mmol/kg H₂O), continued renal excretion of Na⁺ (urine [Na⁺] >40 mmol/L), and exclusion of other potential causes of hyponatremia, such as renal disease, liver disease, adrenal disease, diuretic administration, thyroid dysfunction, or Na⁺-poor fluid administration.^1,3 The diagnosis for the dog in this report was idiopathic SIADH. In addition to biochemical findings indicative of SIADH, we had other supporting findings including high ADH concentrations, high copeptin concentrations, normal urine electrolyte excretions, and urine osmolality >100 mmol/kg H₂O, all of which were considered inappropriate for the degree of serum hypo-osmolality and hyponatremia. Because copeptin is co-secreted with ADH, is released in equimolar concentrations, and is more stable in circulation than ADH, it is considered a surrogate marker of ADH in humans.¹⁴ In humans with hyponatremia and hypo-osmolarity, copeptin and urine osmolality differentiates primary polydipsia from other causes of hyponatremia, such as SIADH.¹⁵ Additionally, in one study in humans, a copeptin to urinary [Na⁺] ratio of <30 pmol/mmol was 85% sensitive and 87% specific for a diagnosis of SIADH.¹⁴ The copeptin concentration for the dog in this case report was high, the urine osmolarity was inappropriately high, and the copeptin to urinary [Na⁺] ratio was <30 pmol/mmol, all consistent with a diagnosis of SIADH. Additionally, upward mathematical correction of serum [Cl⁻] in this dog supported relative free water retention, which is consistent with ADH excess.¹⁶ Finally, the measured ADH in this dog was 5.54 pg/mL, which was higher than reported value for healthy dogs¹² and inappropriate for the degree of hyponatremia and hypo-osmolality, supportive of SIADH. The diagnosis of SIADH does not require increased plasma levels of ADH because osmostat resetting or genetic mutations of the vasopressin receptor in the renal collecting duct can cause hypoosmolality; however, in the absence of these abnormalities, ADH should be low or undetectable in response to serum hypo-osmolality.^3,6,17 Therefore, when ADH is measurable, or in this case mildly above values reported in healthy dogs in conjunction with serum hypo-osmolality, it is inappropriate.¹ Another consideration for interpretation of ADH concentrations is that episodic secretion could affect measured values depending on the time of day or relation to food intake.¹⁸ Additionally, measurement of ADH is challenging because of its instability and the limited sensitivity of available tests that could impact measured values.¹⁷

The clinical signs of hyponatremia are related more to the rapidity of onset than to the severity of the associated plasma hypo-osmolality. The dog in this report had chronic hyponatremia, which might have been present for longer than 2 yr because her history before adoption was unknown. However, even clinically asymptomatic chronic hyponatremia in humans has been associated with gait abnormalities, falls, and attention deficits.¹⁹ Interestingly, humans with SIADH do not usually exhibit polydipsia.⁸ In contrast to humans, polydipsia was one of the most common presenting clinical signs in reports of dogs with SIADH, along with a variety of other clinical signs, ranging from neurological abnormalities, such as altered mental state and seizures,^4,7 to behavioral changes, including restlessness, and vocalization.^4,7 Only one other reported dog with SIADH (congenital hydrocephalus) had polyuria and polydipsia as the sole clinical sign.⁶ That dog was initially referred for surgical intervention to address a suture granuloma in the abdominal cavity, and hyponatremia developed as a postsurgical complication. Unlike many dogs and humans with ADH excess, the dog reported here maintained a stable condition 2 yr after diagnosis. While polyuria and polydipsia persisted, the dog did not develop additional clinical signs. Current management of canine SIADH involves water restriction as the primary therapy. This approach aims to induce a negative water balance and restore body fluid homeostasis.²⁰ Other treatment options, such as dietary manipulations to increase the solute load through Na⁺ administration, urea supplementation, and vasopressin V2 receptor antagonists, can be considered if water restriction alone is ineffective.^1,6,20 In the present case, water restriction was not feasible for the owners. Instead, they opted to sprinkle a small amount of salt on the dog’s food. This approach did not result in a noticeable improvement in the polyuria and polydipsia; however, the degree of mathematical [Cl⁻] correction slightly decreased over time. The significance of this decrease is not known because the amount of upward correction remained larger than normal.¹⁶

One limitation of this case report is the lack of brain MRI or computed tomography scans, which could have provided valuable information to support or rule out the diagnosis of idiopathic SIADH; however, a hypophyseal/hypothalamic lesion was considered unlikely based on clinical examination and history. Another limitation is the lack of serial ADH measurements, which could have provided insights into the dynamics of ADH secretion related to time of day, feeding, or postovariohysterectomy because the reference range used for comparison was established in neutered dogs.

Conclusion

In this case report, we present an approximately 3 yr old female Chihuahua diagnosed with idiopathic SIADH, exhibiting polyuria and polydipsia as the sole clinical sign. The diagnosis was supported by biochemical findings, measurement of ADH and copeptin concentrations, and the exclusion of other potential causes of hyponatremia. Despite the persistent hyponatremia and hypo-osmolar state, the dog remained asymptomatic during a 2 yr postdiagnosis follow-up period and was reported to be in good health. This case emphasizes the importance of considering SIADH as a potential cause of hyponatremia in dogs, even when neurological or behavioral signs are absent. The use of novel diagnostic tests, such as copeptin measurement, highlights the potential for advancing the understanding and diagnosis of SIADH in veterinary medicine. Additionally, the stable long-term outcome in the absence of treatment is notable and in contrast to much of the published literature, suggesting that further research is needed to better understand the prognosis and management of idiopathic SIADH in dogs.

The authors wish to thank Molly Pearson, DVM, at Micanopy Animal Hospital for collaborative care of the dog and Shirley Graves-Modell, MD, the owner of the dog.