The Effect of Hypercalcemia Induced by Calciferol Upon Renal Concentrating Ability1

Abstract

Polyuria and loss of renal concentrating ability have frequently been observed in patients with hypercalcemia (1-8). It has not been clear whether the capacity of the kidneys to concentrate urine is selectively impaired by hypercalcemia or whether it is depressed together with many other renal functions as a result of substantial injury to and encroachment upon active renal parenchyma (9). In the present experiments the effects of hypercalcemia on renal function and morphology were studied in rats given large doses of calciferol (vitamin D2) for several days. The results suggest that hypercalcemia and renal damage produced in this manner specifically impair renal concentrating ability. This functional defect is associated with alterations in the structure of the collecting tubules of the renal medulla. METHODSEighteen male albino rats of the Sprague-Dawley strain, weighing about 300 Gm., were maintained on a measured diet of Purina Lab Chow and allowed to drink tap water ad libitum. Following initial determinations of blood urea nitrogen, urea clearance, phenolsulfonphthalein (PSP) excretion and maximum urinary osmolality, 200,-000 units or 400,000 units of vitamin D2 in peanut oil was injected subcutaneously daily for four days. At the end of this time, the same tests were repeated. The animals were then sacrificed by exsanguination from the abdominal aorta during pentobarbital anesthesia and the kidneys removed for morphologic examination. Eight rats served as controls, receiving only peanut oil for four days, with food intake limited to that taken by matched animals receiving vitamin D2.For the measurement of urea clearance, 0.2 to 0.3 ml. of heparinized blood was obtained from the tail. Rats

On the Mechanism of Impairment of Renal Concentrating Ability in Hypercalcemia*

“…As previously reported (2), maximum urinary osmolality was greatly diminished in rats injected with vitamin D (control = 3,036 mOsm per kg; vitamin D = 1,724 mOsm per kg). This could not be ascribed to a solute diuresis, since the total solute output of the hypercalcemic animals did not differ significantly from that of controls.…”

“…It must be appreciated that this is only a rough approximation of the actual osmotic activity of tissue water. the distal tubules and loops of Henle (2). The present data indicate that one reason for the decrease in maximal urinary concentration observed under these circumstances is a diminished ability of the kidneys to create and maintain a high concentration of sodium in the interstitial fluids of the medulla and papilla.…”

“…Vitamin D intoxication in rats (2) and large doses of parathyroid extract in dogs (3,4), in addition to producing hyposthenuria, have been shown to cause morphological changes which are most marked in the epithelial cells lining the collecting ducts but are also present in the distal convoluted tubules and the loops of Henle. Such lesions might impair renal concentrating capacity by interfering with the accumulation and concentration of sodium in the interstitial fluids of the medulla and papilla, or by impairing the back-diffusion of water from the lumen of the collecting duct into a hypertonic interstitium (5).…”

On the Mechanism of Hyposthenuria in Hypercalcemia*

“…In 50-to 75-g golden hamsters, hypercalcemia was induced by subcutaneous injection of 100,000 U of calciferol daily for 4 (2). At all rates of osmolar clearance, however, TCH20 was lower in the experimental animals.…”

Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors.

“…The association of hypercalcemia with disturbances in renal concentrating ability, water intake, and loop of Henle function has been widely recognized in both humans (1,2) and experimental animals (3,4). Studies in rats show that chronic hypercalcemia is associated with inhibition of thick ascending limb NaCl reabsorption (5).…”