Water Intoxication in Dogs Treated with Desmopressin for Diabetes Insipidus

I'm writing about Jazz, a 5-year-old, F/S, Labrador retriever with a working diagnosis of  diabetes insipidus. This dog presented just over a year ago with a history of marked polyuria and polydipsia (PU/PD) but otherwise felt well.  She displayed persistent isosthenuria to hyposthenuria, with urine specific gravities ranging from 1.004 to 1.008 on multiple urine checks (at least 5 at random times during the day, including early morning).

Her initial serum chemistry panel showed no abnormalities. The serum alkaline phosphatase (ALP) was within reference range limits, as were serum electrolytes and calcium concentrations. Serum T4 determination was also normal. An initial urine culture, collected by cystocentesis, grew Klebsiella, so she was treated with an appropriate antibiotic; a subsequent culture 4-weeks later was negative.

An abdominal ultrasound revealed nodule in the right adrenal gland, but subsequent CT showed that both adrenals were of normal size and shape.   Repeat blood work was also normal (including the serum ALP), so I didn't pursue a workup for Cushing’s syndrome.

To rule out diabetes insipidus (DI) as a causes of Jazz's PU/PD, a desmopressin response trial was performed. After 2 days of desmopressin, the low urine specific gravity increased to 1.038. On this basis of this excellent response, a diagnosis of central DI was made. Initially, we administered the desmopressin in the form of eye drops; after a few months, we switched the route of administration to subcutaneous injections (5 μg, given twice daily) when she developed an ocular reaction to the drops. We had been able to keep her urine specific gravity measurements around 1.020-1.025. However, after about 6 months of successful desmopressin treatment, the urine specific gravity has decreased again —down to 1.102-1.015, with recurrence of her PU/PD.

I recently rechecked her routine blood tests, which were all within normal range, except her serum sodium and chloride concentrations, which were both markedly reduced at 123 mEq/L and 95 mEq/L, respectively. I was concerned that she may have developed medullary washout, so I added sodium chloride to her diet and gradually increased the daily desmopressin dose. This has helped her serum electrolytes a bit, with her sodium and chloride rising to 135 mEq/L and 101 mEq/L, respectively. Her urine specific gravity has come up to 1.020, but she remains very PU/PD despite an increased in her subcutaneous desmopressin dose from 5 μg to 30 μg, twice daily.

Jazz also has episodes where she seems to lose awareness, gazes into space, and then paces compulsively. After a few minutes, she appears to return to normal. I haven’t witnessed an episode, but it sounds cerebral-based, petit mal like seizure events.

My queries are the following:

• Do you ever perform urine and plasma osmolalities to help in your diagnostic workup for DI?
• How can you explain the dog's neurologic signs?
• Should I workup this dog for Cushing's disease, bearing in mind normal ALPs over at least the last 12 months, Labrador breed, young age, and no secondary skin changes?
• Do you agree with my presumptive diagnosis?
• Can you add any hints for management, presuming you do agree with my diagnosis?

Thank you very much in advance for your help.

My Response:

There are many potential causes of polyuria and polydipsia (PU/PD). Primary disorders of water balance (i.e. central diabetes insipidus, primary nephrogenic diabetes insipidus and primary polydipsia), although uncommon, should always be considered in the differential diagnoses of polyuria and polydipsia. Clinically, patients with DI have intense thirst and failure to concentrate urine (1-5).

Confirming the diagnosis of DI
In general, animals with DI have only one laboratory abnormality: a low urine specific gravity (SG) or urine osmolality (1-6). To answer your first question, I do not generally use urine and plasma osmolalities for diagnosis of DI — I routinely depend on measurement of urine specific gravity, which is much more practical in clinical practice (7). Measured urine osmolality provides similar information to urine specific gravity, but it can sometimes be easier to interpret changes in osmolality after water deprivation testing or desmopressin (ADH) response testing.

In dogs with DI, a urinary specific gravity of 1.005 or less and a low urinary osmolality (less than 200 mOsm/kg, but sometimes as low as 50 mOsmol/kg) are the hallmarks of DI (2,4,6).  As long as thirst mechanism is intact and access to water/fluids is not denied, plasma osmolality in dogs with DI is near or above the upper limit of the reference range (greater than 300 mOsm/kg).  In contrast, dogs with psychogenic polydipsia usually have serum osmolality measurements that are in the low- to low-normal range (remember that thirst is not driven by osmolality).

In addition to plasma and urine osmolality measurements, which may not be readily available, a number of other diagnostic approaches can be used to confirm central DI, nephrogenic DI or primary (psychogenic) polydipsia. The water deprivation test is generally considered by most authorities to be the best diagnostic test for differentiating between these disorders (1-4). However, it is labor-intensive, difficult to perform correctly, unpleasant for the animal, relies heavily on repeated emptying of the bladder, and can lead to untoward complications and misdiagnosis in some animals.

My test of choice for diagnosis of DI is to consider a therapeutic trial with the arginine vasopressin analogue desmopressin (5,8), as you have done in this dog. However,DI can be a difficult problem to confirm, especially when a dog doesn't completely respond to low-dose desmopressin treatment or relapses on treatment.

Development of neurologic signs in dogs treated with desmopressin
In this case, I am worried that Jazz is being overdosed with desmopressin, with some degree of water intoxication. The dose of 30 μg, administered subcutaneously twice daily, is very high — in fact, I've never used that high of a dose in any dog. I would consider stopping the drug for a few days to see if the neurological signs improve and serum electrolytes remain normal off the salt supplementation. Remember that the added salt will only make the PU/PD worse.

If the neurologic signs do improve or resolve after stopping the desmopressin, then we know that the clinical signs of mental dullness and pacing are likely due to water intoxication. If the signs continue then further workup for a primary neurological disease or seizure diorder should be undertaken.

Differentials for PU/PD in dogs that develop "resistance" to desmopressin
Given the fact that this dog is no longer responding well to low "phyiologic" doses of desmopressin, I would start looking for another problem leading to PU/PD. DI is rare and we haven't completely ruled out all of the more common causes (see Table 1). Many of these other causes of PU/PD will initially respond, at least to some degree, to desmopressin so it's very likely that Jazz is suffering from another disease process other than DI.

I know that that you have excluded diabetes mellitus, hypercalcemia, and hyperthyroidism. If you haven't done a urine culture in awhile, I would do a complete urinalysis and culture. You might want to consider performing an antibiotic trial to help exclude occult pyelonephritis (5).

Table 1—Differential rule outs for polyuria and polydipsia in dogs, listed from most to least common

Since Cushing's syndrome is the most common cause of PU/PD in dogs, the next step would be to certainly do a Cushing's workup. Not all of these atypical cases look cushingoid, especially if they are a large-breed dog like Jazz. If you see leptospirosis in your area (Table 1), that should also be excluded (5,9,10)

If everything else is ruled out and you are left with a diagnosis of DI, I'd consider doing brain imaging to rule out a pituitary or brain mass, especially if the neurologic signs don't resolve.

Other nonspecific treatments for PU/PD
You could also evaluate the use of an NSAID (COX-2 inhibitors), which may help reduce urine output & improve urine concentrating ability in dogs with nephrogenic diabetes insipidus. These drugs act independent of vasopressin secretion and work by inhibiting renal prostaglandin synthesis (11-13). They can allow circulating vasopressin to work better.

References:

1. Barsanti JA, DiBartola SP, Finco DR. Diagnostic approach to polyuria and polydipsia. In: Kirk’s Current Veterinary Therapy XIII. Small Animal Practice, WB Saunders, Philadelphia. 2000; 831–835.
2. Feldman EC, Nelson RW. Water metabolism and diabetes insipidus. In: Canine and Feline Endocrinology and Reproduction, 3rd edition, WB Saunders, Philadelphia. 2004; 2–44. 
3. Harb MF, Nelson RW, Feldman EC, et al. Central diabetes insipidus in dogs: 20 cases (1986– 1995). J Am Vet Med Assoc 1996;209:1884-1888.
4. Shiel RE. Disorders of vasopressin production In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;15-27.
5. Nichols R, Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth edition. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;215-220.
6. Waldrop JE. Urinary electrolytes, solutes, and osmolality. Vet Clin North Am Small Anim Pract 2008;38:503-512. 
7. Watson ADJ. Urine specific gravity in practice. Australian Vet J 1998; 76: 392-398. 
8. Nichols R. Clinical use of the vasopressin analogue DDAVP for the diagnosis and treatment of diabetes insipidus. In: Kirk’s Current Veterinary Therapy XIII. Small Animal Practice, WB Saunders, Philadelphia. 2000; 325–326. 
9. Greene CE, Sykes JE, Brown CA et al. Leptospirosis. In: Infectious Diseases of the Dog and Cat, 3rd edn. Elsevier, Philadelphia. 2006;402–417. 
10. Van De Maele I, Claus A, Haesebrouck F, et al. Leptospirosis in dogs: a review with emphasis on clinical aspects. Vet Rec 2008;163:409–413.
11. Vanherweghem JL, Ducobu J, D'Hollander A. Effects of indomethacin on renal hemodynamics and on water and sodium excretion by the isolated dog kidney. Pflugers Arch 1975;357:243-252. 
12. Kim GH, Choi NW, Jung JY, et al. Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. Am J Physiol Renal Physiol 2008;294:F702-709. 
13. Anderson RJ, Berl T, McDonald KD, et al. Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest 1975;56:420-426.