Howard Levitin

ON THE MECHANISM OF IMPAIRMENT OF RENAL CONCENTRATING ABILITY IN POTASSIUM DEFICIENCY

A decrease in the ability of the kidneys to excrete a highly concentrated urine is one of the earliest hallmarks of potassium depletion in animals and in humans (1). According to present views of the mechanism of the renal concentrating process (2), this might be the result of a) impairment of the countercurrent multiplier system by which a high concentration of sodium (and urea) is created and maintained in the interstitial space of the renal papilla, and/or b) decreased permeability of the walls of the collecting ducts and distal tubules to the back-diffusion of water. If the first alternative were correct, analysis of the renal papilla from potassium-deficient animals excreting a maximally concentrated urine should reveal a lower concentration of sodium than that present in the papilla of normal animals. Should the second mechanism be operative, the fall in maximum urinary osmolality observed in potassium deficiency might be entirely unassociated with a decrease in papillary sodium, or else would be out of proportion to it. In the present experiments samples of maximally concentrated urine and renal papilla, medulla and cortex from potassium-depleted rats and dogs were analyzed. By placing all animals on a sodium-free diet prior to sacrifice, difficulties in the interpretation of tissue analyses consequent to high concentrations of sodium in the urine were avoided. The results indicate that the

COMPOSITION OF THE RENAL MEDULLA DURING WATER DIURESIS

During antidiuresis, sodium is concentrated in the papilla and medulla of mammalian kidneys as a result of active sodium reabsorption from medullary tubules and countercurrent flow through the loops of Henle and the medullary capillaries. It is clear from chemical (1) and cryoscopic (2, 3) analysis of sections of kidney, and from direct micropuncture (4-6), that under these circumstances the osmolality of medullary interstitial fluid is approximately that of collecting-duct urine and that sodium concentration rises progressively along a gradient from cortex to medulla. The precise role of antidiuretic hormone (ADH) in establishing and maintaining this gradient is not entirely clear, partly because comparable studies in the absence of vasopressin (i.e., during water diuresis) have been more difficult to accomplish. Ullrich, Jarausch and Drenckhahn demonstrated that the osmolality and sodium concentration of papillary water approached that of peripheral plasma in dogs during water diuresis (1, 7). That medullary interstitial fluid is actually hypertonic to plasma in the absence of ADHwas suggested by the demonstration (8) that compression of the renal artery of one kidney during water diuresis led to production of hypertonic urine by that kidney. Recently, Bray reported that the melting point of the contents of small medullary

ON THE MECHANISM OF IMPAIRMENT OF RENAL CONCENTRATING ABILITY IN HYPERCALCEMIA

A decrease in the ability of the kidneys to concentrate the urine is characteristic of many varieties of experimental and clinical hypercalcemia, hypercalciuria and nephrocalcinosis (1). 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). In the present studies the composition of renal cortex, medulla and papilla was compared with that of plasma and urine in hydropenic rats in which hypercalcemia had been induced by large doses of vitamin D. The results indicate that the hyposthenuria observed in such animals results at least in part from a diminished concentration of sodium in renal medulla and papilla.

CHANGES IN RENAL CONCENTRATING ABILITY PRODUCED BY PARATHYROID EXTRACT

Polyuria is a frequent symptom of hyperparathyroidism. Impairment of renal concentrating ability, often out of proportion to other signs of renal insufficiency, has been noted in patients with hyperparathyroidism (1-3) as well as in patients and animals with hypercalcemia due to other causes (4-6). In many patients with hyperparathyroidism, extensive deposits of calcium in the renal parenchyma, secondary fibrosis, superimposed pyelonephritis and vascular disease have combined to destroy considerable amounts of renal substance. The mechanism of the reported decrease in renal concentrating ability in such patients is not clear, since fixation of urinary specific gravity is a well-known accompaniment of the simple ablation of renal tissue (7). In the present experiments, renal concentrating capacity was found to be depressed in dogs in which hypercalcemia had been induced for only 24 hours by injecting parathyroid extract. This functional defect was associated with morphologic changes in the distal portions of nephrons and the collecting ducts.

Effect of Route of Administration on Protective Action of Corticosterone and Cortisol Against Endotoxin

Summary 1. Both cortisol and corticosterone were effective in protecting rats against endotoxin when the steroid hormones were given intracardially at the time of administration of endotoxin. 2. Cortisol was more protective than corticosterone when both were given subcutaneously 24 hours before endotoxin; as the interval between the time of injection of steroid and the time of challenge with endotoxin was decreased, corticosterone was increasingly protective. 3. The rates of disappearance of corticosterone and cortisol from the blood of rats after intracardiac administration of steroid were similar. 4. The evidence indicates that corticosterone is more rapidly mobilized from local tissue sites of deposition than is cortisol and that the difference in the activity of these 2 substances after subcutaneous administration is due in large part to this difference. By inference, the many published differences in the biologic activities of cortisol and corticosterone may be subject to revision when control of this variable has been achieved. 5. Corticotropin and lipoadrenal extract were protective against endotoxin but desoxycorticosterone was not.