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Differential Diagnosis of Polyuria/Polydipsia

Often it is difficult to differentiate patients who have diabetes insipidus from patients who have a primary disorder of polydipsia, that is, who habitually ingest water in excessive quantities. Psychogenic polydipsia is a neurotic disorder in which the patient feels compelled to drink excessive amounts of water. In severe cases, the amount of water ingested (above 15 L/day!) can exceed the capacity of the kidneys to excrete it, resulting in severe and even lethal hyponatremia. Typically, patients with psychogenic poly-dipsia are secretive about their drinking behavior or believe they are drinking only when very thirsty.

The problem in the differential diagnosis is a classic example of which came first, the chicken or the egg: Does the patient have polydipsia because he or she has diabetes insipidus resulting in polyuria, or does the patient have polyuria because he or she has psychogenic polydipsia? In the first case, one might expect that the plasma osmolality would be elevated because of the urinary water loss and this would drive thirst. In the latter case, one might expect that the plasma osmolality would be low because of the water ingestion that is suppressing vasopressin secretion and leading to urine dilution. However, determination of plasma vasopressin levels alone usually does not provide a definitive diagnosis. Because of the large flux of water into and out of the body, the plasma vasopressin level may vary markedly depending on whether the patient has just drunk a lot of water, or whether she or he has been without water for a while.

To make a diagnosis, it is helpful to withhold water for at least a 12-hr test period. This water deprivation test requires a hospital stay with close monitoring of potential water sources (no flower vases in the room, etc.!). After water deprivation, it is found that patients with poly-dipsia have significant vasopressin levels in the plasma, and they excrete hyperosmotic urine. On the other hand, a patient with central diabetes insipidus still does not have detectable plasma vasopressin levels and does not concentrate urine despite the water deprivation, but will concentrate the urine if given vasopressin. The patient with nephrogenic diabetes insipidus develops high plasma vasopressin levels with water deprivation, but does not concentrate the urine even when given exogenous vasopressin. However, it should be recognized that even in the presence of vasopressin and normal kidney function, the urine osmolality might be only slightly above isosmotic in patients who have had polyuria and polydipsia before the water deprivation test. The reason is that diuresis reduces medullary hypertonicity (see next section), and it takes several hours or days for the kidneys to reestablish their medullary concentration gradient.

consequent concentration of the plasma, the thirst mechanism drives compensatory water ingestion. As long as the individual with diabetes insipidus has access to water, normal plasma osmolality can be maintained, the only inconvenience being thirst and polyuria day and night. However, individuals with diabetes insipidus can become critically dehydrated very rapidly when their water intake is impaired.

In some cases, the kidney fails to respond to vaso-pressin, although release of the hormone is normal. These instances are referred to as nephrogenic diabetes insipidus. The collecting duct may not respond appropriately to vasopressin for a variety of reasons. The disease may be congenital, or may be acquired due to the effects of toxins and some drugs such as derivatives of the antibiotic tetracycline, and lithium, which is used for treatment of bipolar disorder. Hypokalemia and hypercalcemia are also associated with a decreased response to vasopressin. Congenital nephrogenic diabetes has been shown to be due to genetic mutations of two types. In some pedigrees, the V2 receptors have mutations that decrease vasopres-sin binding or prevent the receptor from increasing intracellular cAMP. In other pedigrees, mutations in the aquaporin-2 gene reduce the ability of the channel protein to transport water or interfere with its insertion into the luminal membrane of the collecting duct.

Loss of Medullary Concentrating or Diluting Ability

The concentration of the urine ultimately depends on the presence of a concentrated medullary interstitium, and dilution of the urine depends on active NaCl reabsorption without water in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. These processes can be compromised in a variety of conditions. First, the loop diuretics such as furosemide directly inhibit active NaCl absorption by the medullary and cortical regions of the thick ascending limb of the loop of Henle. Consequently, they result in a reduction in medullary interstitial hypertonicity and impairment in the ability of the kidney to concentrate the urine. The thiazide diuretics inhibit NaCl cotransport in the distal convoluted tubule and result in a diminished ability to dilute the urine.

Medullary hypertonicity can also be compromised by an excessive delivery of fluid to the loop of Henle from the proximal tubule. For example, with saline diuresis (produced by excessive intake of salt and water and decreased proximal tubule reabsorption; see Chapter 29) or with osmotic diuresis, an increased amount of water is delivered to and reabsorbed by the descending limb of the loop of Henle. This dilutes the medullary hyperto-nicity and reduces the concentrating ability. Volume expansion and increased renal blood flow also increase medullary blood flow, which ''washes out'' the medullary hyperosmolality.

On the other hand, the development of a hyperos-motic medullary interstitium also depends on the delivery of adequate amounts of salt to the thick ascending limb in order to provide sufficient solute to produce the hyperosmolality. Therefore, when delivery from the proximal tubule is diminished by excessive volume reabsorption in that segment, medullary hyper-tonicity is compromised.

The passive countercurrent multiplication mechanism in the inner medulla also depends on urea recycling, as described in the previous section. This mechanism requires the delivery of adequate amounts of urea to the medullary collecting duct so that urea will diffuse into the medullary interstitium and contribute to the hyperosmolality that concentrates NaCl in the thin descending limb of the loop of Henle. Therefore, conditions of decreased urea production (as associated with malnutrition, especially with a deficit in dietary protein) result in decreased plasma levels of urea and a consequent decrease in the filtered load of urea. Thus, a smaller amount of urea is delivered to the medullary interstitium and the maximum urinary osmolality is reduced. It should, however, be noted that the decreased intake of food and production of urea reduces the necessity of maximal urinary concentration.

A decrease in concentrating and diluting ability is also associated with both age and renal failure. The ability to concentrate the urine maximally is reduced in infants because of their lower protein intake and relatively anabolic metabolism. Urinary concentration in the infant depends primarily on active NaCl absorption with little contribution of medullary urea. With old age and with renal failure, the number of functioning nephrons decreases and, consequently, there are fewer thick ascending limbs to concentrate NaCl in the medulla. The result is a decrease in both concentrating and diluting ability. Thus, a common presenting symptom associated with an elderly patient or a patient with compromised renal function is nocturia due to an impaired ability to concentrate the urine.

Suggested Readings

Agre P, Nielsen S, Knepper MA. Aquaporin water channels in mammalian kidney. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 1, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 363-377.

Berliner RW. Formation of concentrated urine. In Gottschalk CW, Berliner RW, Giebisch GH, eds. Renal physiology. People and ideas. Bethesda, MD: American Physiological Society, 1987, pp 247-276.

Morello J-P, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev Physiol 2001;63:607-630.

Robertson GL. Vasopressin. In Seldin DW, Giebisch G, eds. The kidney: Physiology andpathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1133-1152.

Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders, 5th ed. New York: McGraw-Hill, 2001, pp 285-298.

Valtin H. "Drink at least eight glasses of water a day.'' Really? Is there scientific evidence for "8 x 8''? Am J Physiol 2002;283: R993-R1004.

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