VM 551 SAM - Urogenital System

• possible diagnoses for polyuria and polydipsia
• maintenance of water balance
• mechanisms behind polyuria and polydipsia
• a diagnostic approach to polyuria
• water deprivation and ADH-response tests
• protocol for performing a modified water deprivation test
• interpreting the results of the modified water deprivation test
• treating polyuric disorders

Polyuria, the production of a larger than normal volume of urine, is a common clinical complaint and is generally accompanied by polydipsia, an increase in water intake.

Pollakiuria, an increased frequency of urination is usually caused by lower urinary tract disease, such as cystitis.

Nocturia, urinating at night, is frequently associated with polyuria; or may reflect pollakiuria and be associated with lower urinary tract disorders.

Some causes of polyuria and polydipsia

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Maintenance of water balance

Water losses from dogs and cats include insensible losses (primarily through respiration) and urinary losses. Fecal losses are negligible in the absence of diarrhea. Water losses must be matched by water intake to maintain water balance. The kidney is primarily responsible for maintaining water balance by conservation under conditions of water deficiency or by excretion under conditions of water excess.

Conditions necessary for the kidneys to conserve water include:

• the presence of at least one-third functional nephron mass
• hypothalamic production of antidiuretic hormone (ADH) and release of ADH from the posterior pituitary gland
• the presence of renal tubular cells that are responsive to ADH
• the presence of a hypertonic renal medulla to allow passive reabsorption of water.

An absence of any of these conditions may result in polyuria. To maintain water balance, the polyuric animal must develop compensatory polydipsia.

The normal water intake for dogs and cats is 44 to 66 ml/kg/day. Water is consumed in the form of free water and water in canned and moist foods.

Mechanisms causing polyuria and polydipsia

Several pathologic processes may produce polyuria. Polydipsia is usually compensatory, with the exception of primary polydispsia. Polyuria may be due to water diuresis, solute diuresis or a combination of both mechanisms. Solute diuresis occurs when the solute load per nephron is increased. Solute diuresis often results in a urine specific gravity in the isosthenuric or minimally concentrated range (1.007 to 1.030), and the polyuria that results is milder than the polyuria that accompanies water diuresis. Diseases that induce solute diuresis include primary renal failure, diabetes mellitus, and renal glucosuria.

Water diuresis results in hyposthenuria (a urine specific gravity of 1.001 to 1.007). Conditions that induce water diuresis include central diabetes insipidus, congenital or acquired nephrogenic diabetes insipidus, and primary polydipsia.

Central (pituitary) diabetes insipidus is a defect in the production or secretion of ADH. It may be congenital, or acquired as a result of head trauma or space-occupying lesions in the brain. ADH deficiency may be complete or partial. Renal tubules remain responsive to exogenous ADH, although maximum renal concentration is often impaired by renal medullary solute washout.

Nephrogenic diabetes insipidus is a state in which the renal tubules are unresponsive to ADH. The congenital form is rare. Acquired nephrogenic diabetes insipidus may occur secondary to metabolic disorders such as hypercalcemia, hypokalemia, hyponatremia, hyperadrenocorticism, liver disease, and intrinsic renal disease, pyometra, pyelonephritis, and the administration of glucocorticoids or diuretics.

Both solute diuresis and water diuresis may contribute to polyuria in animals with pyelonephritis, hyperadrenocorticism, liver disease, renal failure, hypoadrenocorticism, hypercalcemia, and hyperthyroidism.

Primary polydipsia is a rare disorder resulting in compulsive water drinking. The increase in drinking is usually prompted by a stressful event. Primary polydipsia may contribute to PU/PD associated with hepatic failure and hyperthyroidism. Renal medullary solute washout perpetuates the PU/PD of primary polydipsia.

Renal medullary solute washout refers to a loss of the medullary hypertonicity responsible for passive reabsorption of water. It may be induced by any of the disorders that cause chronic polyuria. Circulatory disorders, such as hyperviscosity syndromes (polycythemia, hyperproteinemia), renal lymphatic obstruction (lymphosarcoma), and systemic vasculitis (septicemia, systemic lupus erythematosus), may result in renal medullary washout.

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A diagnostic approach to polyuria

Evaluation of an animal that may have PU/PD should proceed in a series of logical steps:

• Verify the PU/PD exists
• Inspect the initial database for diagnostic clues
• Perform specific diagnostic tests that are indicated by the initial database
• Perform urine concentration tests

The first step is to verify that polyuria and polydipsia exist. The perceived increase in water intake or urine output may be a physiological response to alterations in the environment temperature, dietary changes (from moist to dry food or visa versa), or unrecognized water deprivation. It is also possible that the pet’s owner has misinterpreted the clinical signs. Clients may confuse polyuria with dysuria, pollakiuria, or nocturia. Polydipsia may manifest itself as drinking from sources other than the water bowl, such as from toilets.

Initial evaluation should include collection of a thorough medical history (including information on a previous drug administration), a complete physical examination, an accurate determination of body weight and hydration status, measurements of the PCV and total plasma protein concentration, and an assessment of urine specific gravity. Dogs with a urine specific gravity above 1.030 and cats with a urine specific gravity above 1.035 are probably not polyuric.

PU/PD can be verified by quantitation of urine output and water intake. Water consumption and, in some cases, urine output can be measured at home. Owners should be given explicit instructions on how to perform these measurements. They should also be instructed to make sure that the measured source of water is the only source available and that the patient is the only animal drinking from that source. If the animal is hospitalized, urine output can be measured by placing the pet in a metabolic cage, by performing multiple catheterizations, or by collecting multiple samples of voided urine. During the measurement period, the animal should be fasted or fed dry foods to avoid the contribution of water from canned foods (70% water). If PU/PD is mild, 48-72 hour determinations are necessary to document PU/PD. When PU/PD is severe, 24 hour determinations are usually sufficient. Specific gravity should be measured on each aliquot of urine collected.

Once PU/PD is confirmed, the next step is to search for diagnostic clues in the history, physical examination, CBC, serum biochemical profile (including the BUN, creatinine, glucose, calcium, phosphorus, ALP, ALT, sodium, potassium, and chloride measurements), and urinalysis. A history that includes polyphagia and weight loss suggests diabetes mellitus or hyperthyroidism. Complaints of anorexia, depression, and vomiting are compatible with diabetic ketoacidosis, hyperthyroidism, renal failure, hyperadrenocorticism, hepatic disease, or pyometra. Bilaterally symmetrical alopecia, comedo formation, hyperpigmentation, increased panting, and abdominal distention are frequently associated with hyperadrenocorticism. In addition to the signs detected by owners, dogs with hyperadrenocorticism may have palpable hepatomegaly, calcinosis cutis, testicular atrophy, clitoral hypertrophy, or vascular fragility, which results in bruising after venipuncture.

In patients with hypercalcemia of malignancy, the physical examination may reveal generalized lymphadenopathy (supportive of lymphoma) or perirectal masses (apocrine gland adenocarcinoma of the anal sac). Palpably enlarged or small, irregular kidneys may implicate renal failure or pyelonephritis as the underlying cause of PU/PD. Palpable cervical masses are detected in up to 95% of cats with hyperthyroidism. Palpable uterine enlargement in an intact diestrous bitch, with or without vaginal discharge or systemic signs of illness, is highly suggestive of pyometra. Enlargement of the limbs, feet, head, and abdomen, thickened skin, and inspiratory stridor may be detected in dogs or cats with excessive growth hormone (acromegaly, hypersomatotropism). The catabolic effects of growth hormone result in insulin resistance and may lead to diabetes mellitus.

Patients with primary polydipsia or diabetes insipidus are generally normal on physical examination. A complete neurologic and fundic examination should be performed in patients with primary polydipsia or central diabetes insipidus. The presence of neurologic abnormalities in dogs and cats with pituitary or hypothalamic neoplasia is variable. Many of these animals have no perceptible neurologic abnormalities, but some show mild to severe signs that include depression, blindness, weakness, ataxia, circling, and proprioceptive deficits.

Urinalysis is a valuable diagnostic aid. Determination of urine specific gravity is essential, and the specific gravity of at least three urine samples from each patient, collected at least one day apart, should be measured. Hyposthenuric urine (a specific gravity below 1.007) indicates normal renal diluting ability, reducing the likelihood that the patient has renal failure. A specific gravity below 1.007 can be normal if the animal needs to excrete water, but is abnormal if the animal is dehydrated. Most polyuric disorders result in urine specific gravities in the isosthenuric range (1.007 to 1.017) because of solute diuresis.

Glucosuria results in polyuria due to osmotic diuresis. Diabetes mellitus is the most frequent cause of glucosuria in dogs; renal glucosuria occurs infrequently. Hyperglycemia induced by stress (glucocorticoid-induced) or by fear and excitement (catecholamine-induced) is common in cats and may result in glucosuria. Repeated evaluations of blood and urine glucose concentrations and observation for characteristic clinical signs are indicated to distinguish between stress-induced or fear/excitement-induced hyperglycemia and diabetes mellitus in cats. Ketonuria may occur with stress or diabetes mellitus, thus it is not a distinguishing feature. Glucosuria is present in about 10% of dogs with hyperadrenocorticism and indicates concurrent diabetes mellitus. Hyperadrenocorticism occurs infrequently in the cat, but glucosuria is common in cats with hyperadrenocorticism and reflects concurrent diabetes mellitus. Excessive amounts of growth hormone (acromegaly) may also result in glucosuria because of diabetes mellitus induced by insulin resistance. Additional diagnostic tests are indicated to confirm the presence of hyperadrenocorticism or excessive growth hormone concentrations.

The result of concurrent blood and urine glucose analysis can be used to differentiate primary renal glucosuria (normoglycemia) from diabetes mellitus (hyperglycemia [>200 mg/dl]). Glucosuria is not a reliable indicator of acquired renal tubular dysfunction and is not often associated with renal disease. Pyuria and bacteriuria may support a diagnosis of pyelonephritis, pyometra, or a lower urinary tract infection secondary to hyperadrenocorticism or diabetes mellitus.

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Water deprivation and ADH-response tests

If the initial diagnostic evaluation fails to identify the cause of PU/PD, water deprivation and ADH-response tests are indicated to differentiate among renal medullary washout, psychogenic water consumption, and central or nephrogenic diabetes insipidus. Dehydration results in the release of endogenous ADH from the posterior pituitary gland. ADH promotes water reabsorption from the distal tubules and collecting ducts of the kidneys, resulting in a concentrated urine if the renal medulla is hypertonic and the renal response is normal. The modified water deprivation test assesses the dehydration-induced release of endogenous ADH, the renal response to endogenous ADH, and the renal response to exogenous ADH.

Water deprivation is contraindicated in azotemic or dehydrated patients and in those suspected or known to have renal disease. Animals must be monitored closely because severe dehydration can develop rapidly, especially in animals with central diabetes insipidus or congenital nephrogenic diabetes insipidus. A gradual reduction in water intake allows the patient to partially re-establish a hypertonic renal medulla before it is completely deprived of water.

The modified water deprivation test should be started in the morning so that animals can be observed and evaluated frequently. Most dogs with complete central diabetes insipidus or nephrogenic diabetes insipidus will become dehydrated and lose 5% of their body weight within 3 to 10 hours. Dogs with primary polydipsia may require more than 24 hours of water deprivation before a concentrated urine specific gravity can be demonstrated. There is no time restriction with the modified water deprivation test, as long as the animal does not become dehydrated or azotemic. Repeated determinations of body weight, skin elasticity, PCV, total plasma protein, BUN concentration, and serum creatinine are important parameters to monitor for dehydration; none of the parameters alone is a completely reliable indicator of dehydration.

At each sampling period during the test, the urinary bladder must be emptied completely to ensure that the urine specific gravity values or osmolality represent recently formed urine. Urine osmolality is determined by the number of particles in solution. Urine specific gravity (weight of a given volume of urine compared with the weight of the same volume of water) is dependent on particle size and particle weight, as well as particle number. Urine specific gravity is much simpler to measure and is a valid reflection of osmolality. This measurement of urine osmolality, although the most accurate way to assess urine concentrating ability, is not essential for interpreting the results of the modified water deprivation test.

Sampling intervals during Phase 2 of the modified water deprivation test are determined by the patient’s status.

Measurement of circulating ADH levels improves the accuracy of the modified water deprivation test. Samples for plasma ADH measurement should be collected at the conclusion of Phase 2 of the modified water deprivation test and before the administration of exogenous ADH.

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Protocal for performing a modified water deprivation test

Phase 1: Gradual water restriction

• Seventy-two hours before beginning Phase 2, limit the patient's water intake to 120 ml/kg/day, divided into small amounts.
• Fourty-eight hours before beginning Phase 2, decrease the patient's water intake to 90 ml/kg/day, divided into small amounts.
• Twenty-four hours before beginning Phase 2, decrease the patient's water intake to 60-80 ml/kg/day, divided into small amounts.

Phase 2: Water deprivation

During this phase, water is withheld altogether, and the animal is offered only dry food

• At the beginning of Phase 2, empty the bladder completely. Then determine the patient's body weight, hydration status, PCV, total plasma protein, BUN, serum creatinine concentration, serum osmolality, and urine osmolality or urine specific gravity.
• Every 30 to 60 minutes during Phase 2, empty the bladder completely and again determine the patient's body weight, hydration status, mental state, urine osmolality, urine specific gravity, PCV, and total plasma protein. Recheck the BUN and serum creatinine concentrations and the serum osmolality as often as practical.

The endpoints of water deprivation are:

• A loss of more than 5% of the initial body weight
• Clinical dehydration, systemic signs of illness, or serum osmolality above 320 mOsm/kg
• Azotemia
• A urine specific gravity above 1.030, or a urine osmolality above 1,100 mOsm/kg

Phase 3: Response to exogenous administration of ADH

This phase of the test should be performed if the patient's urine specific gravity is less than 1.030 at the end of Phase 2.

• Continue to withhold water
• Intramuscularly inject the animal with aqueous vasopressin (Pitressin)
• Empty the bladder at 30, 60, 90, and 120 minutes after the ADH injection.
• At each interval, assess the patient's hydration status and mental state and measure the urine osmolality and/or urine specific gravity.

Phase 4: Completion of the test

• To avoid water intoxication, provide the animal with small amounts of water every 30 minutes.
• Monitor the animal's hydration status and mental state.
• After two hours, allow the animal free access to water.

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Interpreting the results of the modified water deprivation test

Normal Animals

• Urine specific gravity at the end of Phase 2 is above 1.048.
• Urine osmolality at the end of Phase 2 is above 1,700 mOsm/kg
• The test should be discontinued at this point; ADH need not be administered. Little change in urine concentration would be seen in response to exogenous ADH.

Animals with primary polydipsia

• Urine specific gravity at the end of Phase 2 is above 1.030.
• Urine osmolality is above 1,100 mOsm/kg at the end of Phase 2.
• The test should be discontinued at this point; ADH need not be administered. Little change in urine concentration would be seen in response to exogenous ADH.

Animals with complete central diabetes insipidus

• There is little change in urine specific gravity or urine osmolality in response to water deprivation.
• There is a large increase in urine specific gravity and urine osmolality (greater than 200% increase) following ADH administration.

Animals with partial central diabetes insipidus

• Urine specific gravity is 1.008 to 1.018 at the end of Phase 2.
• Urine osmolality is 310 to 1,000 mOsm/kg at the end of Phase 2.
• There is an additional 10 to 50% increase in urine osmolality following ADH administration. Urine specific gravity will also increase after ADH administration.

Animals with congenital nephrogenic diabetes insipidus

• There is little change in urine specific gravity or urine osmolality at the end of Phase 2.
• There is little change in urine specific gravity or urine osmolality following ADH administration.

Animals with acquired nephrogenic diabetes insipidus

• There is little change in urine specific gravity or urine osmolality at the end of Phase 2.
• There is little change in urine specific gravity or urine osmolality following ADH administration.
• Disorders that cause acquired nephrogenic diabetes insipidus should be identifiable with screening tests, which will make it unnecessary to perform a modified water deprivation test.

Animals with hyperadrenocorticism

• Animals with this disorder may respond similarly to the way those with partial central diabetes insipidus or primary polydipsia respond.
• Adrenocortical function studies are necessary to distinguish among these conditions.

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Treating polyuric disorders

Therapy for polyuric disorders is directed at the causative disease. If the polyuria cannot be resolved by specific therapy, compensatory polydipsia must be allowed to prevent dehydration and subsequent prerenal azotemia. In patients with primary polydipsia, water consumption should be gradually restricted over 3 to 10 weeks. Frequently, the self-perpetuating PU/PD cycle will be broken by the water deprivation test. Untreatable polyuric disorders may necessitate a change in the way the animal is housed in order to allow it to remain an acceptable pet.