Water Homeostasis and Diabetes Insipidus in Horses - Schott, VCNA 2011

What % of total adult body mass is water?

60-65%

What is the volume of total body water in a 500 kg horse?

300-325L

What is the volume of intracellular fluid in a 500 kg horse?

About 200-220 L

What is the volume of extracellular fluid in a 500 kg horse?

About 100-110 L

What is ECF divided into?

Plasma (5-6% of body weight, ~25L)

Interstitial fluid and lymph (8-10% of body weight, ~45L)

Transcellular fluid (6-8% of body weight, ~35L, majority in the lumen of the GI tract)

Plasma Osmolality in the Horse

270-300 mOsm/kg

What are the 3 sources that provide water?

Free water intake (drinking)

• ~85% of daily water for horses on a dry forage diet

Water in feed

• ~5% daily water

Metabolic water

• ~10% daily water

What are the 3 ways in which water can be lost?

Urine

Feces

Insensible losses (evaporation) across the skin and respiratory tract

What is the daily maintenance water requirement for a horse and how much is provided by drinking?

Daily maintenance water ~55-65 ml/kg/d

45-55 ml/kg provided by drinking

What % of daily water loss come from feces and urine?

Urinary losses from 20-55%

Fecal losses from 30-55%

What % of daily water loss is from insensible losses?

Up to 15-40$

What triggers thirst and renal water conservation?

Increases in plasma osmolality (P_osm)

Decreases in effective circulating volume and blood pressure

Response to an Increase in P_osm

Initial response is secretion of arginine vasopressin from the neurohypophysis → enhanced renal water conservation

Secondary response to even greater increases in plasma tonicity is thirst → drinking

What are the two main stimuli for thirst in mammals?

Increased Posm

• Mediated through osmoreceptors in the anterior hypothalamus

Hypovolemia/hypotension

After a period of water deprivation, how long does it take horses to replace water deficits after gaining access to water?

15-30 minutes

Why don’t horses that become dehydrated as a consequence of prolonged exercise or diarrhea sweat?

These conditions produce loss of body water and electrolytes

• With loss of electrolyte-containing body fluids, the increase in Posm is smaller and the osmotic thirst stimulus is blunted compared with water deprivation

Effect of Diets High in Nitrogen (Protein) and Calcium on Urine

Typically increase urine volume and are associated with a similar increase in urinary excretion of nitrogen and calcium

These diets are also more digestible so fecal water excretion generally decreases, consequent to a decrease in total fecal material

Where is AVP produced?

Neurohypophysis (pars nervosa or posterior pituitary) in the distal axons of magnocellular neurons that comprise the neurohypophysis

• Cell bodies of these neurosecretory neurons are located in the paired supraoptic and paraventricular nuclei within the hypothalamus

• Once synthesized, AVP is stored in granules within these axons until stimuli result in release

How is secretion of AVP from the granules triggered?

By propagation of an action potential along the axon, influx of calcium, and a calcium-dependent exocytotic process

What are the stimuli for AVP release?

Increases in Posm

Hypovolemia/hypotension

Where are osmoreceptors located?

In the anterior hypothalamus, likely in or near the circumventricular organ, organum vasculosum or the lamina terminalis, but outside the blood brain barrier

Responsiveness of Osmoreceptors to Different Plasma Solutes

Increases in plasma sodium concentration and infusion of mannitol are potent stimuli

Increases in plasma glucose and urea concentrations are weak stimuli

Occurs because osmoreceptor activation is caused by an osmotic water shift that produces cell shrinkage → activates a stretch inactivated noncationic membrane channel that initiates depolarization of the osmoreceptor

Difference in Response of AVP to Changes in Posm vs Hemodynamic Changes

Osmoreceptors are higihly sensitive to changes in Posm with each 1 mOsm/kg increase leading to an increase in plasma AVP concentration of 0.5-1.0 pg/mL

Hemodynamic changes are weaker stimuli for AVP release

• Little release in response to modest hemodynamic changes

• Progressively larger hemodynamic changes lead to exponential increases in plasma AVP concentration

What mediates hemodynamic influences on AVP secretion?

Afferent baroreceptor neural pathways

Where is AQP1 found?

Proximal tubular and thin descending limb of Henle epithelial cells

Where are AQP3 and 4 found?

Constitutively expressed in the basolateral membranes of collecting duct epithelium

Where is AQP2 found?

Inserted into the apical membrane of principal cells as a result of AVP action

What does stimulation of the V2 receptors on the basolateral membrane of tubular epithelial cells in the thick medullary ascending limb lead to?

Enhanced reabsorption of NaCl

What is the action of AVP on urea?

Stimulates transepithelial movement of urea in the inner collecting ducts which is an important factor in generating and maintaining a hypertonic medullary interstitium

How do V2 receptors work?

V2 receptors are coupled to a transmembrane G protein that stimulates adenyl cyclase → increase in cAMP concentration → activates protein kinase A → phosphorylation and translocation of AQP2-containing vesicles

What antagonizes V2 receptor activation?

Activation of adjacent a2-adrenoceptors and PGE2-mediated effect on an inhibitory G protein

• Likely that diuresis associated with administration of a2-agonists is caused by antagonism of V2 receptor activation

How much urine do horses produce a day?

5-10 L of urine

How many more times concentrated is equine urine compared to plasma?

3-4 times more concentrated

What is considered PU/PD in a 500 kg horse?

More than 20-25 L of urine production

More than 50L of water consumption

What are the major causes of PU/PD in horses?

Renal insufficiency

PPID

Primary or psychogenic PD

Less common causes

• Excessive salt consumption

• Central and nephrogenic DI

• DM

• Sepsis and/or endotoxemia

• Iatrogenic causes (sedation with a2-agonists, corticosteroid therapy, diuretic use)

PU Associated with AKI

In horses with AKI, there may be a transient period of anuria or oliguria

• If horses survive the primary disease and acute phase of renal injury, glomerular and tubular damage results in a period of impaired concentrating ability and PU

Congenital Causes of Central DI in the Horse

Cerebral malformations, hydrocephalus

Hypoxic-ischemic encephalopathy

Acquired Causes of Central DI in the Horse

Head trauma

Brain or pituitary gland mass

Infection (viral encephalopathy, protozoal encephalopathy, pituitary abscess)

Postoperative

Drug-induced

Idiopathic

Congenital Causes of Nephrogenic DI

X-linked recessive (suspected)

Acquired Causes of Nephrogenic DI in the Horse

Renal disease

• After AKI

• With chronic kidney failure

• Postobstructive uropathy

• Medullary washout

Drug-induced

Idiopathic

Causes of Primary PD in the Horse

Behavior problem

Altered thirst

Excessive salt consumption

What fraction of horses with PPID can be affected with PU/PD?

1/3 or more

Potential Causes of PU/PD in PPID

PU has been attributed to hyperglycemia and an associated osmotic diuresis

• Glucosuria found in small numbers of affected horses in reports

• Horses with hyperglycemia and glucosuria may still be able to concentrate their urine in response to water deprivation of exogenous AVP

Antagonism of the action of AVP on the collecting ducts by cortisol

• Evidence to support this mechanism is lacking

Growth of a pituitary macroadenoma may lead to impingement of the neurohypophysis, the site of AVP storage

• Central DI is not the cause of PU in all cases because some horses can concentrated their urine when deprived of water

What is probably the most common cause of PU/PD in adult horses?

Primary of psychogenic PD

How to Diagnose Primary PD

By exclusion of other disorders

• Neurogenic and nephrogenic DI are excluded by showing urine concentrating ability after water deprivation

  • Specific gravity should exceed 1.025 after water deprivation of 12-24 hours to produce a 5% loss in body weight

  • In long-standing PU, the osmotic gradient between the lumen of the collecting tubule and the medullary intestitium may be diminished (medullary washout)

    • AVP activity may not lead to an increase in urine specific gravity greater than 1.020

    • If horse’s with PD for more than a few weeks duration fail to concentrate their urine after 24 hours of water deprivation, a modified water deprivation test can be performed

Modified Water Deprivation Test in Horses

Restrict water intake to approximately 40 ml/kg/d for 3-4 days

USG should exceed 1.025 in a horse with medullary washout

If the USG remains isosthenuric (1.008-1.014), the horse should be further evaluated for early CKD

Treatment for Primary PD

Water restriction

• Initially restrict to twice the maintenance needs and then reduce to maintenance over the following weeks

Improve the attitude by reducing boredom

What causes hereditary central DI?

Decreased numbers of magnocellular neurons int he supraoptic nuclei of the hypothalamus

• Mutations result in production of an abnormal precursor protein that accumulates and eventually kills magnocellular neurons because it cannot be correctly processed, folded, and transported out of the endoplasmic reticulum

• Only 1 allele is affected, allowing some production of AVP production in the first few years of life

  • Results in delayed onset of PU/PD

  • 80-90% of magnocellular neurons must be destroyed before significant PU develops

What causes acquired neurogenic DI?

Degeneration of magnocellular neurons in the supraoptic nuclei secondary to trauma, vascular abnormalities, infection, or tumors

• PU/PD is usually not manifested until 80-90% of the neurosecretory neurons are destroyed

What causes nephrogenic DI?

Results from failure of AVP activity on cortical- and medullary-collecting ducts

What are the four functional abnormalities in nephrogenic DI?

The mutant receptor is not inserted into the cell membrane

The mutant receptor is inserted into the cell membrane but it does not bind AVP

The mutant receptor is inserted into the cell membrane and binds AVP but does not activate adenyl cycalse

The mutant receptor is inserted into the cell membrane and binds AVP but with subnormal stimulation of adenyl cyclase activity

Diagnostic Evaluation of Horses with Suspected DI

Rule out azotemia

Ensure renal size and structure are normal ultrasonographically

Document the magnitude of PD by isolating the horse and measuring water intake over 3-5 days

Once PD has been documented, perform water deprivation test

• Document baseline USG

• Deprive the horse of water for 12-24 hours

• Collect a second urine sample

• Increase in USG to 1.025 or greater is the goal after a body weight loss of about 5%

If USG increases to 1.025 or greater after overnight water deprivation, diagnosis of primary PD is supported

IF USG does not exceed 1.020, overnight water deprivation test can be performed after 3-5 days of limiting water intake to about 75 ml/kg/d (modified water deprivation test) with body-weight monitoring to prevent losses exceeding 5%

• Must monitor carefully because horses with DI may continue to excrete excess water in the face of water deprivation and can become substantially dehydrated within the first 12 hours of water deprivation

If there is failure to achieve a significant increase in urine concentrating ability after water deprivation, measurement of Posm and plasma AVP concentration in samples collected at the start and end of the water-deprivation test are the next steps

• An appropriate increase in plasma AVP concentration is to a value greater than 10 pg/mL when Posm exceeds 300 mOsm/kg

  • Supports a diagnosis of nephrogenic DI

  • Lack of significant AVP response establishes a diagnosis fo central DI

Final test to confirm nephrogenic DI in a patient that fails. to concentrate urine in response to water deprivation is administration of exogenous AVP

Hickey-Hare Test

Infusion of hypertonic saline to induce a rapid increase in Posm

Can be performed when there are concerns about water deprivation in an individual patient

Appropriate urinary response is an increase in urine output to excrete the sodium load but the effect on USG and Uosm can be variable

Treatment of Neurogenic DI

Hormone replacement with desmopressin acetate

• Dilutional hyponatremia is the only significant adverse effect if excessive doses are administered over a prolonged course

Treatment of Nephrogenic DI

Dietary sodium restriction

Administration of thiazide diuretics

• Inhibit sodium reabsorption in the distal tubule (diluting segment of the nephron) and when combined with dietary sodium restriction, may cause mild hypovolemia

• Limiting the ability to produce hyposthenuric urine in the diluting segment decreases free water clearance (or enhances water reabsorption) and hypovolemia reduces renal blood flow and GFR and enhances proximal tubular solute and water reabsorption

• Thiazide diuretics seem to directly enhance water reabsorption in the inner medullary collecting ducts via a mechanism independent of AVP

Can combine thiazide diuretics with prostaglandin inhibitors (indomethacin) to further decrease renal blood flow and GFR

Amiloride (a potassium-sparing diuretic) can be used in combination with a thiazide diuretic to further diminish PU

Treatment may reduce PU by 50%