Kidney Function

a. Morphological immaturity. T h e kidneys of young rats have fewer glomeruli, and these are smaller and have thicker capsules t h a n in adults (Adolph, 1957). T h e number of nephrons doubles in the first 2 weeks and triples by the fourth week, while tubule length increases twenty times (Smith, 1951). Histological m a t u r i t y occurs in about 4 weeks (Baxter and Yoffey, 1948).

I n newborn pups the cortical zone of the kidney is very thin and the weight of the cortex is 6 0 % of t h a t of t h e medulla, as compared to 1 5 0 % in adult dogs (Capek and Kleinzeller, 1960).

I n Setonyx brachyurus, nephrons continue to develop in the nephrogenic zone until 100 days after birth; kidney growth then occurs b y enlargement of these nephrons. Glomerular diameter begins to increase a t 140 days, b u t a t 225 days is still only about 8 0 % of adult size (Bentley and Shield, 1962).

A t 113-135 days of age, S. brachyurus have reached t h e same ontogenetic point in kidney development as white rats a t 7-14 days after birth.

b. Urine flow. I n fetal guinea pigs, urine flow is maximum at 40 days, decreases toward full term, and then sharply increases after birth. At 4 days after birth urine flow is 5 0 % of the adult rate (Boylan et al., 1958).

Alexander et al. (1955) give d a t a for fetal sheep, which also show a maximum before full term, and Wells (1956) presents d a t a for fetal rats.

Fetal pigs show a remarkably high rate of urine formation. A t 45 days of age, when mesonephric parts are one-third of the total kidney weight, urine is formed a t the rate of 0.39 ml. per minute per kilogram of kidney tissue; this is higher t h a n the rate in h u m a n s with severe diabetes insipidus.

A t 67-71 days, after degeneration of the mesonephron, urine is formed a t a rate of 0.28 ml. per minute per kilogram (Perry and Stanier, 1962). R a b b i t fetuses a t 28 days weigh as m u c h as pigs a t 45 days, b u t form urine a t only one-tenth the rate of pig fetuses (Stanier, 1961).

c. Response to dehydration. R a t s 12^18 hours old show a 5 0 % reduction in urine flow when kept from nursing for 24 hours, probably due to hemo-concentration and reduced G F R . However, urine hemo-concentration does not increase, so t h a t electrolyte clearances are reduced (Heller, 1949). N o t until 2 weeks of age does the white r a t begin to concentrate its urine; by the third week, when weaning occurs and the individual first experiences variation in salt and water intake, the r a t handles saline loads in adult fashion (Falk, 1955).

T h e inability of newborn mammals to concentrate their urine is probably principally due to incomplete development of the countercurrent system.

I n young dogs the concentration gradient within medullary tissue fluid is not established until about the 10th day (Capek and Kleinzeller, 1960). I n

144 Robert Μ. Chew young white rats, the renal papilla develops within the first few days, and the loops of Henle elongate into the papilla during the 10th to 15th day after birth (Ginetzinsky, 1962). I n Setonyx brachyurus urine is not con­

centrated until the nephron tubules begin to elongate a t about 100 days after birth (Bentley and Shield, 1962). The newly formed nephrons m a y also be insensitive to A D H . Ginetzinsky (1962) finds t h a t the basement membranes and intercellular cement in the kidneys of newborn rats lack the mucopolysaccharides typical of adult kidneys before the 14th d a y ; morphological and physiological changes after injections of A D H do not occur until 20 days.

Reports vary as to the time of first appearance of A D H activity in t h e neurohypophysis. Roffi (1958) reports t h a t A D H activity first appears in the rat on the 18th-19th day of gestation. The dog shows distinct neuro­

secretory material 1 week before birth according to Scharrer (1954), but Rodeck and Caesar (1956) give much later dates for appearance of neuro­

secretory material in the dog, rat, and guinea pig. Auer (1951) found t h a t the hypothalamic nuclei of hamsters do not appear until after birth, so this osmoregulatory system has a delayed development along with other structures in this mammal. Heller and Lederis (1959) found the A D H activity of pituitaries of newborn guinea pigs > h u m a n s > white rats, which is in agreement with the general development of these animals judged by other criteria. Neurosecretory material first appears in t h e neural lobe as very fine dustlike particles, and m a y be present before this in an undiscernible form. Dehydration of 1-8-day-old rats by withdrawal of milk results in a reduction in A D H activity of the pituitary, t h u s indicating t h a t release of A D H can occur before the kidneys are responsive to the hormone (Heller and Lederis, 1959). Falk (1955) found t h a t nicotine injections could cause release of A D H as early as the third day in the white rat. R a t s injected with A D H show no inhibition of diuresis until the third day (Falk, 1955), and rats 29-31 days old show only one-third the adult inhibition (Heller, 1952). T h e failure to adjust to water deficiency is not of much physiological importance since, as pointed out by Rodeck and Caesar (1956), the young m a m m a l is in a state of "physiological diabetes insipidus": its water intake in milk is equivalent to t h a t d r u n k by an adult with diabetes insipidus.

T h e low urine solute clearances of newborn mammals are partly counter­

acted in other ways. Most of the protein ingested goes into growth so t h a t there is less urea to be excreted, and NaCl surpluses can accumulate in t h e proportionately larger E C W (McCance and Widdowson, 1956).

d. Diuresis. Water diuresis is very poorly developed in infant r a t s ; this finding is surprising considering their high fluid intake. I n a 2-day-old rat, a water load of 5 % B⁰ causes a small diuresis, which is very slow in

developing. A 3-4-day-old rat with 1 5 % load has rates of diuresis equal to those of an adult with 5 % load, but the urine is not nearly as dilute in the young rat (Falk, 1955). Failure of diuresis is not due to inability of the kidney to handle large volumes of water since epinephrine diuresis and hypoxia diuresis do occur in infant rats, the former at rates equal to adult water diuresis (Adolph, 1957).

I n agreement with their greater development at birth, the guinea pig shows 5 0 % of adult diuresis at birth (Dicker and Heller, 1951) and the dog at 2 days shows a response two-thirds t h a t of the adult (McCance and Widdowson, 1955).

B. Sexual Cycle, Pregnancy, and Lactation 1. Water Balance and the Estrous Cycle

The swelling and regression of t h e vagina and uterus with each estrous cycle is to a large degree due to fluid changes. I n t h e white r a t , the water content of the uterus is very high near the end of proestrus and diminishes rapidly after estrus occurs (Astwood, 1938a). T h e different p a r t s of t h e tract do not necessarily undergo the same simultaneous changes. I n Macaca mulatta the vaginal mucosa undergoes changes inverse to those of the body of the uterus; the endometrium has a much higher water content t h a n the myometrium and responds to estrogen much more rapidly (van Dyke and Ch'en, 1936).

Certain primates have received special study because cyclical changes of t h e perineal sex skin involve much greater water storage and release t h a n in the reproductive tract. I n Papio ursinus the cyclical gain in body weight is usually almost exactly equal to t h e perineal increase; occasionally the increase in t h e sex skin is greater, indicating a shifting of body water into this region. T h e weight gain is a function of the basal body weight, amount­

ing to 1 1 - 1 6 % of the initial 12-21 kg. B⁰ (Gillman and Gilbert, 1956b).

I n 10-kg. Papio hamadryas swelling of the sex skin m a y amount to 5 0 % of the initial body weight, about 2 0 % of perineal weight being endogenous water (Clarke, 1940). Krohn and Zuckerman (1936) found a 1 7 % increase for 5-kg. Macaca nemestrina.

I n P. ursinus and Μ. nemestrina there is no obvious difference between water intake during the swelling and the deturgescent phases of the sex skin; t h e a m o u n t of swelling is not correlated with total water intake.

Clarke (1940) reports t h a t Papio hamadryas during swelling shows in­

creased thirst, hemoconcentration, and reduction of I C W , whereas during shrinking there is an almost complete stoppage of drinking. The important feature of the water exchanges is variation in urine volume. During the swelling of the perineum there is a slight positive water balance, which

146 Robert Μ. Chew allows the gradual accumulation of water in the perineum. Then, immedi­

ately after ovulation there is a sudden diuresis which coincides with rapid shrinking of the sex skin. For about 7 days after ovulation urine volume equals or exceeds drinking and the baboon is in negative water balance (Gillman and Gilbert, 1956b). I n the early postovulatory phase, movement of water from the sex skin increases plasma volume as much as 1 4 % and causes detectable hydremia (Cohen, 1954, 1955).

Swelling and deturgesence of the sex skin is obviously controlled by changing titers of estrogen and progesterone during each cycle. Normal cycles can be simulated in castrated female baboons by hormone injections.

Swelling of the perineum can be reproduced by daily injections of estradiol;

massive excretion of water follows suspension of estradiol injections and, if progesterone is given at the height of turgescence, against the background of previous high estrogen, there is even more rapid shrinking of the sex skin. I n normal baboons turgescence can be prolonged by exogenous estrogen and premature shrinking produced by progesterone (Gillman and Gilbert, 1956b). I n Macaca rhesus mulatto,, daily estradiol injections cause first edema of the anus and base of tail, then swelling of the genital region, followed by swelling over extensive surfaces of the pubic region, perineum, and proximal part of the tail. General edema of the skin m a y also occur (Marois, 1954).

The water metabolism of the sex skin of the female baboon represents a very specialized p a t t e r n which persists independently of changes in the general water balance of the body. Injections of Pitressin t a n n a t e at 5-hour intervals reduce urine output by half, but there is still normal deturgescence and typical negative water balance (Gillman and Gilbert, 1956c). Normal diuresis following ovulation neither impairs nor stimulates diuresis of water given by stomach tube (Gilbert and Gillman, 1955).

Repeated injections of thyroxine cause a loss of weight to a certain point, but cyclical fluctuations of water in the perineum are unaffected (Gillman and Gilbert, 1956a). Neither thyroidectomy, adrenalectomy, or hypo-physectomy prevent water retention induced by estrogen, nor delay excre­

tion of water after withdrawal of estrogen, although the general water metabolism is greatly disturbed (Gillman and Gilbert, 1956a).

I n the white rat 0.1 ^g. of estradiol injected into 21-23-day-old pre­

pubertal females causes an increase of 6 0 % in weight of the uterus in 6 hours (Astwood, 1938b). I n spite of cyclical accumulations of water in the reproductive tract, the daily water intake of female Peromyscus is not significantly different from t h a t of male mice (Lindeborg, 1952). Hisaw (1959) has investigated the effects of five different natural estrogens on fluid imbibition and growth of rat uteri; Bitman et al. (1959) compared the effects of estrogen and progesterone on rabbit uteri.

2. Pregnancy and Lactation

T h e development of fetal tissues, embryonic fluids, and the production of milk obviously increase the water requirements of the female. In habitats where water is seasonally in short supply, reproduction is restricted to the wetter seasons. Adjustment of the breeding season to coincide with periods when sufficient water is available to bring the young through to weaning age is an especially important evolutionary adaptation to xeric habitats (Lindeborg, 1950). Peromyscus maniculatus bairdi shows a midsummer lull in breeding when temperature is high and moisture low, as do several other species of wild mice (Lindeborg, 1950). T h e ground squirrels, Citellus tereticaudus and C. nelsoni produce litters only during the season when green feed is abundant (Vorhies, 1945; Hawbecker, 1947). I n the Siberian marmot a dry summer induces retardation and prolongation of reproduction the following spring (Orlova, 1955). Reproductive success of the desert bighorn sheep m a y vary with precipitation (Jones, 1955).

Gestational and lactational water requirements have been measured for several small mammals. Lindeborg (1950) found t h a t the water intake of Peromyscus maniculatus bairdi increases 3 5 % during the last 10 days of pregnancy, by 1 1 1 % on the fourteenth day after birth, and by 1 5 8 % at weaning. Dice (1922) found a 2 1 7 % increase in drinking of P. m. bairdi before birth and 1 7 1 % while nursing; P. leucopus noveboracensis showed increases of 360 and 370%, respectively, and Microtus ochrogaster showed a

140% increase while nursing.

Morrison (1956) found t h a t water balance became markedly positive in the hooded rat on the 12th-15th d a y of gestation and remained so until birth. T h e amount of water retained is not in excess of t h a t required for formation of fetal tissues and fluids. Successful pregnancy can occur when there is considerable maternal dehydration.

Berkshire sows increase water intake by 5 4 % before farrowing and by 120% by the eighth week of nursing young (Bond et al., 1952). Pregnant Odocoileus hemionus drink more water and drink oftener t h a n other deer (Clark, 1953). D r y cows, particularly of the B r a h m a n breed, show lower evaporative losses t h a n lactating cows (Thompson et al., 1953), and high-producing cows drink about twice as much as low producers (Woodward and M c N u l t y , 1931).

Water conservation m a y be increased during lactation because of suckling antidiuresis due to release of A D H under the stimulus of nursing young.

Cross (1951) found t h a t in rabbits, suckling inhibited forced diuresis J to 1 hour. Stimulation of the t e a t s is alone sufficient to evoke release of oxy-tocin, b u t actual passage of milk out of t h e glands is required to cause t h e additional release of A D H . Probably t h e distinctive p a t t e r n of sensory

148 Robert Μ. Chew impulses from the m a m m a e occasioned by t h e outward passage of milk is the effective stimulus. If t h e teats are coated with celloidin so t h a t milk cannot be withdrawn, or if lesions are produced in the supraopticohypo-physeal tract, suckling antidiuresis does not occur. Similarly, Peeters and Coussens (1950) observed up to 4 0 % inhibition of normal urine flow, lasting J to 1 hour, when cows are milked.

C. Aging and Water Balance

I n male white rats the daily water intake declines from y o u t h to middle age and then increases with old age and senility; urine volumes change similarly (Everitt, 1958). Since daily t r e a t m e n t of aged rats with Pitressin t a n n a t e tends to reduce their urine output to values equal to those for young rats, their high urine output m a y be due to neurosecretory failure (Friedman et al, 1960). However, the results of Rodeck et al. (1960) indicate t h a t regression of renal function is more important. In camels, water intake per day increases progressively with age from 3 to at least 20 years (Gauthier-Pilters, 1961).

The longevity of rats is not reduced by causing t h e m to chronically take in three to five times the normal amount of water per day. Nor is a high rate of water turnover inducive to kidney disease (Saxton et al., 1953).

The greater diuretic response of old rats after fluid loading m a y be due to their inability to temporarily store p a r t of the load because E C W is typically expanded in older animals (Friedman and Friedman, 1957).

D. Stress

Water deficits and excesses, with accompanying tonicity changes, are in themselves stresses. I n addition, the water-regulatory mechanisms are involved in adrenal responses to nonspecific stress.

Within a few minutes after the application of a nonspecific painful or frightening stimulus, the neurohypophysis of the white rat becomes notice­

ably depleted of neurosecretory material (Rothballer, 1953). This depletion persists in adrenalectomized and demedullated individuals, but occurs only in conscious rats (Rothballer, 1956). Posterior lobe hormones m a y be involved in the release of A C T H and t h u s A C H . Some neurons from hypothalamic nuclei terminate on portal vessels t o t h e anterior pituitary, rather t h a n in the posterior pituitary. I n congenital absence of the hypo­

thalamic-hypophyseal tissue, the adrenal cortex does not develop normally, although the anterior pituitary is present, possibly owing to inadequate A C T H (Scharrer and Scharrer, 1954).

The d a t a of Arimura (1955) suggest t h a t exogenous A D H inhibits the rc l a s e c f A C T H t h a t normally occurs in response to stimuli of epinephrine,

histamine, or cold. However, A D H does not influence depletion of adrenal ascorbic acid, once A C T H is released. I t o h et al. (1957) found t h a t adrenal response t o epinephrine, histamine, cold, and A C T H is greater in over-h y d r a t e d r a t s t over-h a n in n o r m a l ; response t o epinepover-hrine a n d A C T H is less after 48 hours without water. However, these a u t h o r s conclude t h a t A D H h a s no direct effect on A C T H release a n d t h a t d e h y d r a t i o n directly in­

fluences t h e adrenal cortex.

A cknowledgments

I wish gratefully to acknowledge the help of my wife, Alice Eastlake Chew, who assisted in the preparation of illustrations and in other aspects of the manuscript. Thanks are due also to Dr. Andrew Starrett for translations of Russian articles and to the National Library of Medicine for providing photocopies of hard-to-get articles. Support by National Science Foundation Grant No. G-5570 made time available for writing the review.

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In document Water Metabolism of Mammals (Pldal 101-136)