Diabetes insipidus

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Diabetes insipidus is an endocrine disease characterized by vasopressin dysregulation[1], excessive polyuria, polydipsia, and the absence of hyperglycemia and glucosuria.

Diabetes insipidus is entirely different to diabetes mellitus and has two presentations:

- results in lack of vasopressin (antidiuretic hormone) production
  • Nephrogenic diabetes insipidus - due to nephron impairment as a result of genetic or acquired disease
- results in lack of vasopressin sensitivity by nephrons

Central diabetes insipidus (CDI) results in absolute or partial loss of vasopressin (antidiuretic hormone; ADH) production by the central nervous system, causing persistent hyposthenuria (urine specific gravities ≤ 1.006) and severe diuresis, even with severe dehydration.

Nephrogenic diabetes insipidus (NDI), which may be primary (familial; X-linked in humans[8]) or secondary (acquired), results from impaired responsiveness of the nephron to the actions of vasopressin. Plasma vasopressin concentrations are normal or increased in animals with this disorder. Primary NDI is a rare congenital disorder of dogs resulting from a congenital defect involving the cellular mechanisms responsible for insertion of aquaporin-2 water channels into the luminal cell membrane.

Acquired secondary NDI includes a variety of renal and metabolic disorders which interfere with the normal interaction between vasopressin and its renal tubular receptors, affect renal tubular cell function, or decrease the hypertonic renal medullary interstitium, resulting in a loss of the normal osmotic gradient. These disorders are listed below as differential causes od secondary nephrogenic diabetes insipidus.

Clinical signs

Common clinical signs in dogs with diabetes insipidus is polyuria and polydipsia.

In dogs with primary (familial) NDI, clinical signs typically become apparent by the time the dog is 8 to 12 weeks of age, with symptoms of excessive thirst, urination and difficulty in house-breaking[9].

Neurological signs have been reported, due to electrolyte disturbances or pituitary neoplasia, with depression and seizures observed in rare cases[10].

Water consumption can often be extreme, sometimes exceeding 800 ml/kg/day, with compensatory urine production exceeding 50 mL/kg/day, .

Blood tests are usually within normal limits apart from a polydipsia-induced hyponatremia.

Urinalysis usually shows hyposthenuria or isosthenuria, and hematuria is not regularly observed unless underlying concurrent nephropathy present. Urine culture and sensitivity is required to eliminate underlying cystitis or pyelonephritis.

Diagnosis

Diagnosis is initially one of exclusion of other diseases (see list below), followed by low dose dexamethasone suppression test, water-deprivation tests, vasopressin therapy and central nervous imaging studies to diagnose central diabetes insipidus. The main diagnostic dilemma is differentiating between central diabetes insipidus, psychogenic polydipsia and nephrogenic diabetes insipidus.

Standard hematology and biochemistry assessments are usually unrewarding and in most cases, plasma concentrations of thyroid-stimulating hormone, thyroxine, growth hormone, insulin-like growth factor-1, adrenocorticotropic hormone and plasma α-melanocyte-stimulating hormone are within normal reference levels.

A response to synthetic vasopressin therapy (desmopressin; 0.1 - 0.2 mg orally every 8 hours) or urinary aquaporin-2 excretion testing may help clarify nephrogenic from central diabetes insipidus[11]. Other tests include vasopressin measurements during hypertonic saline infusion[12]. However, the occurrence of spontaneous vasopressin pulses may hamper the interpretation of the curve describing the relationship between plasma osmolality and plasma vasopressin concentration during osmotic stimulation[13].

An increase in urine specific gravity by 50% or more, compared with pre-treatment specific gravities, supports the diagnosis of CDI, especially if urine specific gravity exceeds 1.030. There should be only minimal improvement in dogs with primary NDI. Dogs with psychogenic water consumption may exhibit a mild decline in urine output and water intake because the chronically low plasma osmolality tends to depress vasopressin production.

Pituitary or hypothalamic neoplasia should be considered in older dogs diagnosed with CDI. A renal biopsy may be warranted in the older dog tentatively considered to have primary NDI.

A differential diagnosis would include:

Treatment

With hypophyseal tumors, a transsphenoidal hypophysectomy is usually recommended. In dogs which develop CDI secondary to hypophysectomy may spontaneously resolve within 2 - 4 weeks[18][19].

Prophylactic use of desmopressin at 4 μg twice daily has been shown effective at minimizing onset of CDI[20].

In dogs with primary NDI, long-term therapy with low sodium diet, unlimited water access, hydrochlorothiazide (used to increase urine osmolality)[21] or desmopressin tablets or nasal spray.

References

  1. Tavernier G et al (1993) A study of alpha 1- and alpha 2-adrenoceptor responsiveness in diabetic insipidus dogs. Fundam Clin Pharmacol 7(6):275-80
  2. Foley C et al (2009) Hypothalamic-pituitary axis deficiency following traumatic brain injury in a dog. J Vet Emerg Crit Care (San Antonio) 19(3):269-274
  3. Teshima T et al (2011) Central diabetes insipidus after transsphenoidal surgery in dogs with Cushing's disease. J Vet Med Sci 73(1):33-39
  4. Meij BP et al (2012) Lymphocytic hypophysitis in a dog with diabetes insipidus. J Comp Pathol 147(4):503-507
  5. Goossens MM et al (1995) Central diabetes insipidus in a dog with a pro-opiomelanocortin-producing pituitary tumor not causing hyperadrenocorticism. J Vet Intern Med 9(5):361-365
  6. Goossens MM (1994) Diabetes insipidus in a dog with an αMSH-producing pituitary tumor. Vet Q 16(1):61
  7. Nielsen L et al (2008) Central diabetes insipidus associated with primary focal B cell lymphoma in a dog. Vet Rec 162(4):124-126
  8. Van den Ouweland AM et al (1992) Mutations in the Vasopressin Type-2 Receptor Gene (Avpr2) Associated with Nephrogenic Diabetes-Insipidus. Nat Genet 2:99–102
  9. Greco DS (2001) Diagnosis and treatment of juvenile endocrine disorders in puppies and kittens. Vet Clin North Am Small Anim Pract 31(2):401-409
  10. Harb MF et al (1996) Central diabetes insipidus in dogs: 20 cases (1986-1995). J Am Vet Med Assoc 209(11):1884-1888
  11. van Vonderen IK et al (2004) Urinary aquaporin-2 excretion in dogs: a marker for collecting duct responsiveness to vasopressin. Domest Anim Endocrinol 27(2):141-153
  12. van Vonderen IK et al (2004) Vasopressin response to osmotic stimulation in 18 young dogs with polyuria and polydipsia. J Vet Intern Med 18(6):800-806
  13. van Vonderen IK (2004) The role of vasopressin in dogs with polyuria. Tijdschr Diergeneeskd 129(22):751-755
  14. Ramsey IK et al (1999) Concurrent central diabetes insipidus and panhypopituitarism in a German shepherd dog. J Small Anim Pract 40(6):271-274
  15. Schwedes CS (1999) Transient diabetes insipidus in a dog with acromegaly. J Small Anim Pract 40(8):392-396
  16. Cohen M & Post GS (1999) Nephrogenic diabetes insipidus in a dog with intestinal leiomyosarcoma. J Am Vet Med Assoc 215(12):1818-1820
  17. Henderson SM & Elwood CM (2003) A potential causal association between gastrointestinal disease and primary polydipsia in three dogs. J Small Anim Pract 44(6):280-284
  18. Taoda T et al (2006) Functional and morphological changes in the hypothalamus-pituitary posterior lobe system after hypophysectomy in the dog. J Vet Med Sci 68(1):1-7
  19. Hanson JM et al (2005) Efficacy of transsphenoidal hypophysectomy in treatment of dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 19(5):687-694
  20. Hara Y et al (2003) Prophylactic efficacy of desmopressin acetate for diabetes insipidus after hypophysectomy in the dog. J Vet Med Sci 65(1):17-22
  21. Takemura N (1998) Successful long-term treatment of congenital nephrogenic diabetes insipidus in a dog. J Small Anim Pract 39(12):592-594