Westjmed00244 0028

Medical Progress
Refer to: Weitzman RE, Kleeman CR: The clinical physiology of water metabolism-Part II: Renal mechanisms for urinary concentration; diabetes insipidus (Medical Progress). West J Med 131:486-515, Dec 1979
The Clinical Physiology of Water Metabolism

Part II: Renal Mechanisms for Urinary Concentration; Diabetes Insipidus
RICHARD E. WEITZMAN, MD, Torrance, California, and CHARLES R. KLEEMAN, MD, Los Angeles
The renal reabsorption of water independent of solute is the result of the coordinated function of the collecting duct and the ascending limb of the loop of Henle. The unique juxtaposition of the ascending and descending portions of the loop of Henle and of the vasa recta permits the function of a countercurrent multiplier system in which water is removed from the tubular lumen and reabsorbed into the circulation. The driving force for reabsorption is the osmotic gradient in the renal medulla which is dependent, in part, on chloride (followed by sodium) pumping from the thick ascending loop of Henle. Urea trapping is also thought to play an important role in the generation of a hypertonic medullary interstitium. Arginine vasopressin (A VP) acts by binding to receptors on the cell membrane and activating adenylate cyclase. This, in turn, results in the intracellular accumulation of cyclic adenosine monophosphate (AMP) which in some fashion abruptly increases the water permeability of the luminal membrane of cells in the collecting duct. As a consequence,
Renal Regulation of Water
THE ANATOMIC AND PHYSIOLOGIC concepts on which we based our earlier discussion143(pl459) of the kidney's maximal concentrating and diluting capacity have been confirmed and broadened by
Dr. Weitzman is Assistant Professor of Medicine, UCLA School of Medicine; Division of Nephrology and Hypertension, HarborUCLA Medical Center, Torrance, CA; and Dr. Kleemen is Factor Family Foundation Professor of Nephrology and Medicine, Emeritus Chief, Division of Nephrology, Department of Medicine, Director, Center for Health Enhancement, Education and Research, UCLA Center for the Health Sciences, Los Angeles. Part II of a three-part article. Part I appeared in the November 1979 issue. Part III will appear in a subsequent issue. Supported by a grant from the Greater Los Angeles Affiliate of the American Heart Association, and the James Fleming Fund. Reprint requests to: Charles R. Kleeman, MD, Director, Center for Health Enhancement, Education and Research, Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, CA 90024.
continuing investigations, and the results of these investigations have been analyzed and summarized recently in excellent reviews.144-'48 Improved *microdissection, microperfusion, micropuncture and microchemical techniques, combined with transmission and scanning electron microscopy used in these studies, have contributed to a better understanding of water excretion in normal humans and in those with various disorders.
Physiologic Anatomy The nephrons of a mammalian kidney arise

from the intralobular arteries and their afferent arterioles at varying depths within the cortex of the kidney, and are varying lengths. Their length
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water flows along an osmotic gradient out of the tubular lumen into the medullary interstitium. Diabetes insipidus is the clinical condition associated with either a deficiency of or a resistance to AVP. Central diabetes insipidus is due to diminished release of AVP following damage to either the neurosecretory nuclei or the pituitary stalk. Possible causes include idiopathic, familial, trauma, tumor, infection or vascular lesions. Patients present with polyuria, usually beginning over a period of a few days. The diagnosis is made by showing that urinary concentration is impaired after water restriction but that there is a good response to exogenous vasopressin therapy. Nephrogenic diabetes insipidus can be identified by a patient's lack of response to AVP. Nephrogenic diabetes insipidus is caused by a familial defect, although milder forms can be acquired as a result of various forms of renal disease. Central diabetes irisipidus is eminently responsive to replacement therapy, particularly with dDAVP, a long lasting analogue of AVP. Nephrogenic diabetes insipidus is best treated with a combination of thiazide diuretics as well as a diet low in sodium and protein.
is dependent on the length of the loop of Henle (Figure 22). The loop of Henle consists of the straight portion of the proximal tubule (pars recta), the thin limb, with descending and ascending segments, the ascending thick segment and a short straight portion of the distal tubule (pars recta) proximal to the macula densa. Basically, all nephrons in the mammalian kidney can be divided into two kinds: the outer cortical nephron with its short loop of Henle consisting of abbreviated thin limb segments penetrating, at most, to the inner strip of the outer zone of the medulla (Figure 22), and the juxtamedullary nephron with its long loop of Henle consisting of well-developed descending and ascending thin segments which
traverse the entire medulla and form their pin loops at varying depths within the inner medullary zone. The larger the number of these nephrons and the longer their loops of Henle, the greater is the concentrating capacity of the animal.* In humans,144,46 it has been estimated that there are approximately 1 million nephrons in each kidney and that approximately 15 percent of the nephrons have long loops of Henle.144"148 Of course, descending from the outer cortex to the juxtamedullary zone, there may be grada*While this relationship holds for most mammalian kidneys144 there are some striking exceptions. The macaque monkey, while capable of forming concentrated urine well above 1,000 mOsm per kg during fluid deprivation, has virtually no inner medulla or long loops of Henle. Other exceptions are the mountain beaver and the chinchilla.'"
THE WESTERN JOURNAL OF MEDICINE
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CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II ABBREVIATIONS USED IN TEXT AVP = arginine vasopressin cAMP = cyclic adenosine monophosphate CH20=free water clearance DI=diabetes insipidus GFR=glomerular ifitration rate NDI=nephrogenic diabetes insipidus PGE=prostaglandin E U/P-urine to plasma (ratio)
tions or variations between the two basic types of nephrons depending on their relative positions in the cortex.'48 In general, the pars recta changes to the thin descending limb at the outer strip of the outer medullary zone and the thick segment of the ascending limb is located in the outer medullary zone. The segment of the thick ascending limb of the loop of Henle, which begins at the point where it crosses from outer medulla to the cortex and extends to the macula densa, is called the cortical diluting segment, the cortical portion of the thick ascending limb or the straight (pars recta) segment of the distal tubule. The proximal and distal convoluted tubules of all nephrons are confined to the isotonic cortex where the distal convoluted tubule terminates or becomes the unbranched cortical collecting duct. The latter traverses the cortex to the junction with other cortical collecting tubules near the corticomedullary or outer strip of the outer medullary zone where it forms the medullary collecting duct which, in turn, traverses the eptire medulla and enlarges to terminate at the duct of Bellini near the tip of the medullary pyramid. The blood supply of the renal medulla is composed entirely of postglomerular vessels derived from the juxtamedullary glomeruli. These vessels (vasa recta) descend into the medulla, take a hairpin turn, and ascend to their level of origin. These vascular loops (capillaries) lie in the closest proximity with the loop of Henle and collecting ducts (Figure 22). However, Kriz and Lever149 described a tubulovascular relationship that must be of functional importance. The descending limb is juxtaposed to both descending and ascending vasa recta, while the ascending thin limb is adjacent to the collecting duct. The descending vasa recta, at various levels in the medulla, gives off branches that form a capillary plexus which surrounds the ascending limb and collecting duct, with blood flowing in a descending direction concurrent to collecting duct and
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*
Figure 22.-Diagrammatic representation of the cortical and juxtamedullary nephrons and their vascular supply. (From Pitts RR: Physiology of the Kidney and Body Fluids, 3rd Edition. Copyright e 1974 by Year Book Medical Publishers, Inc., Chicago. Used by permission.)
countercurrent to the ascending limb. As emphasized by Rector,144 this juxtaposition of limbs, collecting ducts and capillaries suggests that various elements are not exchanging equally with well-mixed interstitium and, therefore, constitute a countercurrent multiplier and exchanger system and, further, that none of the present models takes full consideration of these unique anatomic features. The loop of Henle (functioning as a countercurrent multiplier system) creates the hypertonicity of the renal medulla, essential to the production of a hypertonic urine, whereas the vascular loop (acting as a countercurrent exchanger) prevents the dissipation of the hypertonic gradient of the medulla. Throughout the entire nephron, the fundamental processes involved in the production of a dilute and concentrated urine are the active reabsorption of sodium chloride (NaCl) and the variable permeability of the nephron to the passive back diffusion of water and urea along their concentration gradients (Figure 23), the only possible exception being the passive permeability of the thin ascending segment of loop of Henle to salt.
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CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II
Solute and Water Reabsorption in the Nephron

In the average adult approximately 100 ml of glomerular filtrate is presented to the proximal tubules every minute. During its passage through this water-permeable segment (proximal convoluted and pars recta), approximately two thirds to three fourths of the glomerular ultrafiltrate is reabsorbed into the bloodstream. In this reabsorption process, the tubule fluid remains isosmotic with respect to plasma and there is usually no transepithelial concentration gradient for sodium. Therefore, the amount of isosmotic fluid delivered into the loop of Henle is dependent upon the filtered solute load and on the amount of solute reabsorbed in the proximal tubule. The fluid entering the descending limb of the loop of Henle becomes progressively more concentrated as it approaches the tip of the loop; as it moves up the ascending limb it becomes increasingly dilute until it enters the distal convoluted tubule as a distinctly hypotonic (150 to 200 mOsm per liter) fluid (Figure 23). These basic changes in the loop of Henle, while they may be modified from a quantitative point of view, occur under all circumstances regardless of the volume and composition of the final urine. This is the consequence of the unique transport and permeability characteristics of the loop of Henle which allow it to function as an efficient countercurrent multiplier
MAXIMAL ANTIDURESIS Ixm*I ADHM
system, the latter being primarily responsible for our capacity to produce a maximally hypertonic urine. In recent years the countercurrent hypothesis as applied to mammalian nephrons has been subjected to the most rigorous experimental verification and new models have been formulated to reconcile the observed facts. Many reviews have been published'44-'48 and we have drawn most heavily on the very lucid study of Jamison and Maffly146 for our discussion. Before discussing these investigations, which have greatly enhanced our understanding of the function of the loop of Henle, it will be helpful to review the concepts of countercurrent flow that enabled the physical chemist Werner Kuhn to recognize the fundamental implications of the Ushaped configuration of the long loops in which fluid flows in opposite directions in adjacent limbs.146 With respect to heat exchangers, he was well aware that large temperature gradients can be established in the longitudinal axis of such channels while the temperature differences between them at any given horizontal level can be very small. He applied this concept to the concentration or osmotic pressure differential in the loop of Henle and concluded that here, too, small differences in concentrations between ascending and descending limbs, at any given transverse level, could be responsible for great differences
MAXIMAL DIURESIS (Absnce of ADH)
TRANSPORT Poss.ve Actiew
molr
':.
Figure 23.-Countercurrent mechanism as it is believed to operate in the juxtamedullary nephron (A) and vasa recta (B). The numbers represent illustrative osmolality values during maximal antidiuresis (left) and maximal diuresis (right). No quantitative significance is to be attached to the number of arrows; only net movements are indicated. As with the vascular loops, not all loops of Henle reach the papillary tips and, hence, the fluid in them does not become so concentrated as that of the final urine, but rather only as concentrated as the medullary interstitial fluid at the same level. ADH=antidiuretic hormone. (Modified with permission from Gottschalk & Mylle: Am J Physiol 196:927, 1959.)
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CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11
in solute concentration along the long axis of the tubules and in the surrounding adjacent interstitial tissue. For such a system to function as a countercurrent multiplier, Kuhn proposed three basic requirements: (1) countercurrent flow, (2) differences in permeability between the tubules carrying fluid in opposite directions and (3) a source of energy. The loop of Henle provides the countercurrent flow, the descending limb has a very high level of permeability to water while the thin and thick ascending limbs are almost impermeable to water,144"150 and the active transport of NaCl out of the thick ascending limb to surrounding interstitium provides the basic energy source.'44"146 The impermeability of this latter segment to water means that the concentrations of NaCl transported into the surrounding interstitium must be distinctly hypertonic while the intraluminal NaCl concentration, at this level of the ascending limb, will be hypotonic. As the isotonic fluid from the pars recta of the proximal tubule enters the highly water-permeable descending limb of the loop of Henle, it becomes hypertonic as it loses water to the more concentrated (hypertonic NaCl) surrounding medullary interstitium. As it rounds the bend of the loop, and ascends, this intraluminal fluid-now considerably more concentrated (hypertonic) with respect to NaClis presented to the active transport site and pumped into the surrounding medullary interstitium, thereby elevating the NaCl concentration and osmolality of the interstitial tissue to an even higher degree of hypertonicity. Thus, the active transport process in the water-impermeable thick ascending limb, when augmented or multiplied by the countercurrent flow in the loop and the continued osmotic flow of water out of the de-
scending limb, results in the very large concentration difference in the longitudinal axis of the medulla between the isosmotic fluid entering the descending limb and the most hypertonic fluid at the tip of the loop and adjacent papillary interstitium (Figure 23). Note that this whole process, initiated by the active transport of NaCl into the outer medulla, occurs without the need to create a transepithelial concentration gradient for NaCl exceeding 100 mEq or 200 mOsm in the horizontal plane at any level of the medulla. "One of the most compelling features of the countercurrent mechanism is its biologic economy. When the urine is hyperosmotic, at no point along the renal tubule does the transepithelial osmotic gradient exceed 200 mOsm per kilogram of water."'146 As noted in Figure 23, the newly created hypotonic fluid (150 to 200 mOsm per liter) in the thick ascending limb enters the distal convoluted tubule. As it flows from this cortical segment into the cortical and medullary collecting ducts, its concentration is determined primarily by the level of arginine vasopressin (AVP) in the surrounding capillaries. When the amount is sufficient to create maximal permeability of the collecting ducts and, probably, the terminal portion of the distal convoluted tubule, the luminal fluid is reabsorbed until osmotic equilibrium is achieved with the surrounding isotonic cortical or increasingly hypertonic medullary interstitium. Therefore, the most concentrated urine equal to the osmolality of the interstitial fluid or the innermost medulla or papillary tip is created. Lesser amounts of AVP acting on the nephron create less than maximally concentrated urine. Essential prerequisites of the process described above appear to be an active reabsorption of salt throughout the ascending limb and that the fluid
TABLE 6.-Brief Summary of Permeability Characteristics of Different Segments of the Nephron (Rabbit)*
Segments of Nephron
Water
Sodium Ions
Urea
Descending limb ................ Very permeable Thin ascending limb ............. Impermeable Thick ascending limb ............ Impermeable
Distal tubule (or cortical
Impermeablet Very permeable Very permeable active chloride pump

Partial sodium-potassium exchange
Impermeablet Moderately permeable Impermeable

Impermeable
collecting duct, or both)
.......
Permeable with AVP
Medullary collecting duct ......... Permeable with AVP

AVP = arginine vasopressin *Modified from Britton et al.156 tVaries with different species.
Moderately permeablet
Impermeable except at collecting-duct junctions in inner medulla
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in this segment be rendered definitely hyposmotic to the adjacent interstitium. The low-level permeability to the osmotic flow of water has been clearly shown for both the thin and thick ascending limbs'44"150 and there is unquestioned active reabsorption of salt in the thick ascending limb.'44"146 However, studies in vitro of the thin segment have failed to disclose any evidence of active transport of sodium or chloride.'50 The contrast between the organelle-rich cuboidal epithelium of the thick ascending limb and the organelle-poor squamous epithelium of the thin ascending limb is consistent with this difference in active salt transport.148 If the in vitro studies of the transport and permeability characteristics of the entire ascending limb did not fulfill the essential prerequisites, how then could we explain the highly efficient countercurrent multiplier system obviously existing in the inner medulla and producing the most hypertonic interstitium at the tip of the pyramid? This dilemma may have been solved by the proposed models of Stephenson""52 and Kokko and Rector"53 which showed that passive transport of salt from lumen to interstitium of the thin ascending limb in the inner medulla could be brought about if certain assumptions about relative impermeabilities of various nephron segments to water, salt and urea were made. These impermeabilities have been observed"50"54-156 and are presented in Table 6. Furthermore, the models allowed the active transport of NaCl to be confined to the thick ascending limb, they provided a clear explanation for the role of urea in augmenting the urinary concentrating ability, and they explained the early important observations of Ullrich and Jarausch"17 that the sodium concentration gradient rose steeply along the axis of the outer medulla but only slightly along the axis of the inner medulla, whereas the urea gradient rose much more steeply along the axis of the inner medulla. These findings are inconsistent with the hypothesis that active salt transport is the local driving force in the inner medulla, favoring instead an important role for urea. The details of the models of Stephenson and Kokko and Rector are presented in Figure 24. The chloride pump"18 in the thick ascending limb of the loop of Henle, in the outer medulla, is the active source of energy for the whole medulla.'56 The active transport of salt from the lumen of the water- and urea-impermeable thick ascending limb leaves behind a hypotonic fluid rich in urea
which flows into the distal convoluted tubule and the cortical and outer medullary collecting ducts; segments which actively reabsorb salt are impermeable to urea but are freely permeable to water (at least the cortical collecting duct) in the presence of AVP or hydropenia. Here, the urea becomes progressively more concentrated in a smaller volume of fluid which enters the inner medullary collecting ducts. As the collecting ducts join they become increasingly permeable to urea, especially in the presence of AVP,'44 48"""'4 allowing the urea to flow along its concentration gradient and approach equilibrium with the adjaDISTAL TUBULE
LOOP OF HENLE
COLLECTING
TUBULE
Figure 24.-Recent modification of the countercurrent
hypothesis by Stephenson and Kokko and Rector. Both the thin ascending limb in the inner medulla and the thick ascending limb in the outer medulla, as well as the first part of the distal tubule, are impermeable to water, as indicated by the thickened lining in the thick ascending limb. Active chloride (Cl-) reabsorption, accompanied by passive sodium (Na+) movement (1), renders the tubule fluid dilute and the other medullary interstitium hyperosmotic. In the last part of the distal tubule and in the collecting tubule in the cortex and outer medulla, water is reabsorbed down its osmotic gradient (2), increasing the concentration of urea that remains behind. In the inner medulla both water and urea are reabsorbed from the collecting duct (3). Some urea reenters the loop of Henle (not shown). This medullary recycling of urea, in addition to trapping of urea by countercurrent exchange in the vasa recta (not shown), causes urea to accumulate in large quantities in the medullary interstitium (indicated by the large type), where it osmotically extracts water from the descending limb (4) and thereby concentrates sodium chloride (NaCI) in descending-limb fluid. When the fluid, rich in sodium chloride, enters the sodium-chloride-permeable (but water-impermeable) thin ascending limb, sodium chloride moves passively down its concentration gradient (5), rendering the tubule fluid relatively hyposmotic to the surrounding interstitium. (Reproduced with permission from Jamison & Maffly.1"(P'))
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cent interstitium of the inner medulla. The increase in medullary osmolality thus created draws water out of the adjacent tubules, the terminal collecting ducts and especially the descending limb of the loop. The NaCl in this relatively saltimpermeable descending limb becomes progressively more concentrated as the fluid approaches the hairpin turn, while the salt concentration in the adjacent interstitium is somewhat reduced by dilution. As the luminal fluid with its highest concentration of NaCl rounds the tip of the loop, it enters the water-impermeable, salt-permeable thin ascending limb, and immediately sodium and chloride ions diffuse down their concentration gradient into the surrounding interstitium, thus increasing its osmolality. The luminal fluid left behind becomes relatively hypotonic to the adjacent interstitial fluid (Figures 23 and 24). The rise in osmolality of the latter tends to draw more water into the interstitium from the collecting ducts and tends to dilute the interstitial urea. This process reestablishes the urea gradient from the terminal and inner medullary collecting ducts to interstitium. Urea now diffuses down its gradient from these ducts, thereby increasing the osmolality of the interstitium; more water moves in from the descending limbs and, in so doing, reestablishes the salt gradient and so on. The osmolality of the interstitium continues to rise and water reabsorption from the collecting duct is thus enhanced. Water that has entered the medulla from the descending limb and collecting ducts is carried away by the ascending vasa recta. Quoting from Britton and associates156:
The crux of the matter is that the osmolality of the interstitium depends on the sum of the salt and urea contributions whereas the diffusion of salt depends only upon the passive gradient of the ions from thin ascending limbs to interstitium. The model demonstrates how these two gradients are continuously but alternately reformed in an escalating manner as the diffusion of specific solute and water due to one gradient recreates the other. This is an example of the bootstrap concept
deprived rats and compared the results with similar studies in animals not given urea. Not only did urinary osmolality increase substantially in the urea-infused animals, but water extraction
from the descending limb also increased considerably. An additional finding of importance was that the urea concentration in the fluid at the end of the descending limb was appreciably higher than could be explained by simple osmotic flow of water from lumen to interstitium. This strongly suggests that part of the medullary recycling of urea involved its movement from interstitium to urine somewhere in the nephron segment between the end of the proximal tubule and the end of the descending limb. However, Rector'47 has stressed that if a substantial amount of urea is added to the thin descending limb, it will diminish water abstractions from this segment and actually impair the efficiency of the postulated passive model. To the extent that osmotic equilibrium in the thin descending limb occurs by solute entry, the ability of urea to enhance urine concentration will be diminished. The greater the solute urea entry, the lesser the amount of water abstracted and the lower the NaCl concentration in the loop fluid delivered to the thin ascending limb.2 An additional way in which urea may enter the papillary tips and inner medulla was suggested by Gertz and co-workers'6' and confirmed by Schiitz and Schnermann.'62 Because the papillary tips are bathed by pelvis urine containing the highest concentration of urea, the latter could diffuse across the pelvis epithelium into the adjacent medulla. Schiitz and Schnermann found, in rats, that when the renal pelvis was opened and maintained free of urine, the osmolality of urine emerging from the collecting ducts fell from 1,400 to 800 mOsm per kg. However, if they bathed the exposed papillae in increasingly hypertonic urea solutions, the urinary osmolality rose simultaneously to 2,000 to 2,500 mOsm per kg. Therefore, the pelvis urine appears to be an important source of urea and the absence of this intimate contact between papillae and pelvis urine could impair the function of the countercurrent system. Rector, in his excellent analysis of the renalconcentrating mechanisms,'44 concluded that not all the available micropuncture studies in rats, hamsters and Psammomys are consistent with the passive model for the production of a maximally concentrated urine, derived primarily from the permeability characteristics of the isolated perfused
before and after an infusion of urea to protein-
because the energy of the chloride pump in the cortex and outer medulla is transduced to the high urea concentration in the collecting ducts which primes the solute gradient interaction to increase the osmolality in the interstitium. The situation may be visualized as salt raising its own concentration by hauling on urea's bootstraps and vice versa.
Two recent studies from Jamison's labora-
tory'59'60 lend added weight to the passive models of Stephenson'51'152 and Kokko and Rector.'44"153 In one study,'59 they examined the contents of the
collecting tubule, loop of Henle and vasa recta
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rabbit nephron. It may well be that there are important species differences in the intimate mechanism(s) responsible for the optimum function of the renal medullary countercurrent system. In the other study from Jamison's laboratory,'60 the differences in sodium concentration between fluid in the thin limb of Henle and that in adjacent vasa recta plasma in normal hydropenic rats were examined. Assuming that the vasa recta plasma was an accurate indicator of the sodium concentration in the interstitial fluid, they found a clearcut gradient favoring passive reabsorption or diffusion of sodium. The results of both of these studies fulfill key requirements of the passive models. The anatomic arrangement of the vasa recta and their function as a countercurrent exchanger greatly facilitates the function of the loop in the maintenance of the hypertonic interstitium (Figures 22, 23 and 25) and, at the same time, allows water from the descending limb and collecting duct to be removed from the medulla by way of the ascending vasa recta. The endothelium of the vasa recta is freely permeable to water, much less permeable to plasma proteins, and its permeability to smaller solutes, such as electrolytes, lies between these extremes. As blood in the vasa recta descends in the capillary loop, it approaches osmotic equilibrium with the surrounding hypertonic environment by the passive diffusion of sodium salts and other solutes, notably urea, into the capillary lumen while water diffuses out along its osmotic and hydrostatic pressure gradient. The rapidity of blood flow creates an osmotic disequilibrium in which the osmotic pressure of the interstitial fluid and the hydrostatic pressure in the capillary together oppose the oncotic pressure exerted by the plasma proteins. This generates the net force. As the blood doubles back on itself and flows toward the corticomedullary junction in the ascending vasa recta, urea and sodium salts return to the interstitium while water diffuses into the blood. In the ascending limb plasma, the concentration of the small solutes now exceeds that in the adjacent interstitium and this osmotic force, plus the now additive oncotic pressure of the proteins, cause a net fluid entry into the blood. The quantity of water entering exceeds that lost from the descending vasa recta and is equal to the volume of fluid reabsorbed from the collecting tubule and descending limb of the loop of Henle. The net effect is the free diffusion of salt and urea from
ascending to descending, and of water from descending to ascending limb of the vascular loop, and return to the bloodstream of the water that has diffused into the medulla from the descending limb of the loop of Henle and the collecting ducts. Therefore, the vascular loop, as a countercurrent exchanger, minimizes the loss of excess sodium
Figure 25.-Countercurrent exchange by the vasa recta. The medullary circulation, unlike the loops of Henle, consists of a network of channels with main thoroughfares (the vasa recta) and branch connections. Pr denotes plasma protein. The size of type indicates the relative concentrations of each solute with respect to its location in the medulla but not necessarily with respect to other solutes. The progressive rise in the concentration of sodium chloride (NaCI) and urea in the medullary interstitium is due to the loop of Henle and collecting tubule. Because the capillaries are permeable to sodium chloride and urea, these solutes enter descending vasa recta and leave ascending vasa recta. This transcapillary exchange helps trap the solutes in the medulla. Conversely, water leaves the descending vasa recta, causing the plasma protein concentration to increase. In the ascending vasa recta the sum of oncotic (that due to plasma protein) and osmotic (that due to nonprotein solutes) pressures results in capillary fluid uptake. Thus, water reabsorbed from the collecting tubule and the descending limb of Henle is removed from the medulla and returned to the general circulation. The vasa recta function in a dual capacity-trapping solute and removing water-in order to preserve the hyperosmolality of the renal medulla. (Reproduced with permission from Jamison & Maffly.14(pI6))
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and urea from the medulla and maintains the hypertonic gradient which would be dissipated if the vasa recta blood did not double back on itself (Figures 22, 23 and 25). The "trapping" and recycling of urea in the medulla creates the surprising phenomenon in which the net resorption of urea into the bloodstream (normally 40 percent to 50 percent of the filtered urea) occurs only in the cortical parts of the nephron. The urea which is resorbed from the collecting ducts, and which approaches the same concentration in medullary water and collectingduct fluid, is trapped in the medullary interstitium from which an amount approximating proximal resorption diffuses into the loop (? descending limb) of Henle (Figures 23 and 25). As urea, during antidiuresis, approaches diffusion equilibrium across the collecting duct (equal concentration in medullary water and collecting-duct fluid), it contributes equally to the total osmolality of the medulla and urine. Therefore, it increases the osmotic pressure of the urine beyond that attained by the osmotic equilibrium of collecting-duct fluid with the hypertonic NaCl in the interstitium. In summary, the hypertonicity in the medulla and the magnitude of the hypertonic gradient from corticomedullary junction to papilla at any given moment during both diuresis and antidiuresis will be directly proportional to the number and length of the loops of Henle, the rate of salt delivered to and actively transported across the ascending limb and the load of urea presented to the collecting duct; they will be inversely proportional to the velocity of medullary blood flow, the flow of tubular fluid in the loop of Henle and the rate of water transport into the medulla from the collecting ducts and descending limb of the loop. Role of AVP and the Control of Urine Concentration and Dilution Although solutes are actively resorbed in the distal part of the distal convoluted tubule and the cortical segment of the collecting duct, the resorption of water in these segments is dependent primarily on the presence of AVP (Figure 23). In the absence of AVP, there is a minimal transport of water into the surrounding capillary beds, and the dilute fluid from the ascending limb and the more proximal segment of the distal convoluted tubule is made progressively- more hypotonic by continued active solute resorption. Therefore, when AVP is absent, the fluid in the distal portion
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of the cortical collecting duct approaches the lowest osmolality observed throughout the nephron, possibly between 15 and 20 mOsm per liter. This is the situation seen during maximal sustained water diuresis, in diabetes insipidus (DI) or in any physiologic state that prevents AVP from acting on this segment of the nephron. Although the medullary collecting ducts are also relatively impermeable to water in the absence of AVP, the pronounced gradient between the hypotonic luminal fluid and hypertonic interstitium allows some back diffusion of water, the magnitude of which is determined by the volume per minute delivered to the collecting duct during water diuresis. If this volume is small enough, a moderately hypertonic urine can be formed in the absence of AVP.'63 When a maximal amount of AVP is available, the cortical collecting duct is freely permeable to water and, as the solutes are actively resorbed, the tubular fluid in this segment will approach isotonicity. If less than maximal amounts of AVP are available, the permeability of this segment will be proportionately decreased, lesser amounts of water will back diffuse with the solute, and the tubular fluid will not reach isotonicity. Therefore, AVP simply permits the back diffusion of water to occur along established concentration gradients. Because approximately 90 percent of the solute delivered into the distal convoluted tubule and cortical collecting duct is resorbed, at least 90 percent of the water delivered to it will back diffuse. It is apparent that a reduction in the resorption of solutes in these segments, such as may occur during an osmotic diuresis, will increase the volume of residual isosmotic tubular fluid delivered into the medullary collecting tubules during the maximal AVP activity. As a consequence of the alterations taking place in the thick ascending limb, distal convoluted tubule and cortical collecting duct, the fluid delivered into the medullary collecting duct may be of minimal osmolality and approximately the same volume as that delivered into the distal convoluted tubules, or the luminal fluid may decrease to the smallest volume necessary to excrete the remaining urinary solutes in isotonic or isosmotic concentration. The isotonic fluid entering the medullary collecting duct courses down through the hypertonic medulla. In the hydropenic animal (maximal AVP activity), this small volume of fluid is maximally concentrated by the back diffusion of water along
its osmotic gradient into the hypertonic interstitium. The maximal concentration of urine that is usually achieved in the moderately hydropenic human is approximately 1,000 to 1,100 mOsm per liter. However, in circumstances of a prolonged water deficit, such as may occur during complete abstinence from water for 72 hours, the urinary concentration may attain values of 1,300 to 1,400 mOsm per liter. As stated earlier, the attainment of these maximal values is not due to a further increase in circulating AVP or in the permeability of the collecting duct but, rather, to the continued decrease in medullary blood flow and increase in medullary tonicity. The volume abstracted in the final concentrating process is ordinarily quite small, being below 1.5 ml per minute. This water is returned to the circulation via the vasa recta. The exact cellular mechanism(s) by which AVP creates a physicochemical change in certain epithelial membranes to allows the differential passage of water, urea and salt is still unknown. However, the recent reviews by Andreoli and Schafer'45'.64 and Hays'65 have added greatly to our understanding. It is of great interest that in mammalian cortical medullary collecting ducts AVP enhances the transcellular movement of water without any effect on urea or sodium transport.45" 64 This is in contrast to its effect on amphibian skin and bladder where water, urea and sodium permeate the hormone-responsive apical membranes through what appear to be parallel but dissociated routes.'45"164 In fact, there may even be separate membranebound adenyl cyclases controlling the hormone's stimulation of water and sodium transport. In both species, the initial step in the action of AVP is its binding to receptors in the basal lateral membrane of the responsive cells. As mentioned earlier, this receptor-hormone interaction may not only initiate the cellular processes responsible for water and solute transport, but its magnitude and saturation may also determine the metabolic turnover and degradation of the hormone. Exactly how the spatial configuration and physicochemical structure of AVP determine its binding to the receptor is beyond the scope of this chapter, but an in-depth analysis of the available information can be found in the review of Walter and associates.'66 Once AVP is bound to its receptor on the basal (peritubular) surface of the cell, it initiates a series of reactions which lead to the increased apical (luminal) permeability to water and en-
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sin in control rats (o-o) and in rats treated with colchicine on three to six experimental days (----). Each group consisted of six animals. Asterisks indicate values significantly different from controls (P<0.05 in t test). (Reproduced with permission from Douzsa and
Barnes."')
hanced transcellular hydraulic flow along osmotic gradients. First in this series is the activation of the membrane-bound adenyl cyclase. The latter stimulates the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (3'5'-cAMP), the intracellular concentration of which is regulated by phosphodiesterase. The more active or the greater the amount of the latter, the greater the inactivation and breakdown of cAMP. These initial steps, proposed by Handler and Orloff'67 to be fundamental to the action of AVP, have been widely confirmed and accepted. The subsequent intracellular steps are actively being investigated, and have been discussed in detail by Dousa and Valtin168 and Andreoli and Schafer.'69 Based on the current concepts of the intracellular role of cAMP in various tissues,'69 it appears that cAMP, in turn, activates one or more protein kinases in the cell, thus regulating the level of phosphorylation of specific cell proteins which may be bound or involved in the intracellular formation, aggregation and translocation of certain unique intracellular organelles. These organelles are known as microtubules and microfilaments, the formation of which accompanies and may be essential for the hydro-osmotic
495
effect of AVP.'70 Whatever the role of microtubules and microfilaments in the action of AVP, it is clear that acute and chronic administration of colchicine (the classic antimitotic agent) and the related plant alkaloid vinblastine can substantially impair the hormone's hydro-osmotic effect on mammalian collecting ducts (Figure 26) without themselves altering glomerular filtration rate (GFR), solute excretion or urine flow. Furthermore, this inhibitory effect did not involve an action of these alkaloids on the activity of the enzymes involved in cAMP metabolism and cAMP-dependent phosphorylation.'17 It is well established that these antimitotic agents interfere with intracellular microtubule assembly in vitro and exert disruptive effects on cytoplasmic microtubules in vivo.170
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Figure 27.-Above, Fracture face of the luminal membrane of a granular cell from toad urinary bladder not stimulated with vasopressin. Ridgelike microvilli are prominent and intramembranous particles are distributed randomly over the entire membrane face (reduced from x47,500). Below, Fracture face of granular cell membrane from toad bladder stimulated with vasopressin (20 mU per ml) in the absence of an osmotic gradient. Aggregates (arrows) appear identical to those found after vasopressin stimulation in the presence of an osmotic gradient (reduced from X60,000). (Reproduced with permission from Kachadorian et al.173)
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Numerous morphologic studies have shown a temporal and spatial relationship between the presence of microtubules or microfilaments, or both, and a variety of cell processes involving the movement of cellular components (such as pigment granules), phagocytosis, release of secretions, mobility of membrane receptors, pinocytosis and exocytosis.'70 How this tubular aggregation and assembly can be related to water transport across AvP-responsive epithelium is unknown. As suggested by Taylor,170 it is possible that it may be related to the dramatic structural or organizational change in the (epithelial cell) luminal membrances of amphibian bladders in response to AVP as described recently by Kachadorian and associates.172"173 By using freeze-fracture electron microscopy, they were able to consistently show that in the presence or absence of an osmotic gradient vasopressin and dibutyryl, cAMP induced a reversible organized aggregation of intramembranous particles (presumably representing intramembranous proteins) in epithelial cell luminal membranes (see Figure 27). Taylor speculated that microtubules and microfilaments may play a role in determining the distribution of intramembranous particles in the amphibian bladder. These organelles may play an anchorage role or may be the effectors of movement of intramembranous particles in the plane of the plasma membrane, thereby controlling the surface topography of the luminal membrane and, in turn, its permeability characteristics. In summary, AVP binds to high-affinity receptors on the basolateral or contraluminal surface of responsive epithelial cells which results in an adenyl cyclase-mediated generation of cAMP from ATP. The cAMP, in turn, mediates the kinetics of apical or luminal membrane-bound protein phosphorylation-dephosphorylation reactions which somehow interact with the formation and assembly of the microtubules. These permeability steps are associated with or followed by the permeability change(s) in the luminal membrane which cause increased hydro-osmotic flow of water, antidiuresis and a more concentrated urine. The luminal surfaces of the cortical and medullary collecting ducts constitute the rate-limiting site for water transport and the final locus of action of AVP-mediated effects on transepithelial water permeation.'45 Schafer and Andreoli'41 "64 recently reviewed in depth various studies contributing to an understanding of the physicochemical factors involved
496
DECEMBER 1979 * 131
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in the hormone-regulated movement of water across the luminal membrane, such as the way in which water traverses this hormone-regulated membrane. A brief summary of their conclusions is presented and the reader is referred to their excellent analysis for additional information. (1) Water probably traverses the luminal membrane through hydrophilic sites having the characteristics of narrow aqueous channels (effective radius 1.8 to 2.0 A) and AVP increases water permeability by increasing the number of such hydrophilic sites ("pores") in these membranes rather than increasing pore radii. (2) The primary process for hormone-dependent water movement is diffusion rather than laminar net volume; that is, bulk flow through aqueous channels, pores or cylinders as originally proposed by KoefoedJohnsen and Ussing.174 (3) The experimental observation that AVP enhances not only the diffusion of water but also certain small lipophilic (high oil/water partition ratios) molecules such as butyramide, isobutyramide and antipyrine across the isolated, perfused cortical collecting duct of the rabbit is best explained by assuming parallel diffusion pathways influenced by the hormone. (4) The water permeation pathways virtually exclude the diffusion of small hydrophilic molecules such as urea and thiourea as well as the electrolytes sodium and chloride. Under normal physiologic conditions, the maximal urinary osmolality is determined by the magnitude of the hypertonicity of the medullary interstitial fluid bathing the collecting tubules and by their permeability to water. The available data suggest that in certain circumstances the concentrating process is limited by a maximal rate at which free water can be abstracted from the tubular urine. Because the volume of the water resorbed ordinarily may exceed considerably the volume delivered to the collecting tubule, it is obvious that the maximal rate of back diffusion of free water can be measured only when a large volume of isotonic fluid is delivered to this segment in the hydropenic animal. This can be achieved by the adrhinistration of an osmotic diuretic. Figure 28 illustrates the effects of increasing solute excretion on maximal urinary osmolality in the hydropenic human being administered a continuous infusion of vasopressin. It is readily apparent that as the solute load increases, the maximum concentration of the urine falls in an asymptotic fashion toward the plasma osmolality
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Figure 28.-The effect of a progressive increase in solute excretion on the maximal urinary osmolality in the hydropenic animal (above horizontal line which represents plasma osmolality) and minimal urinary osmolality during water diuresis (below horizontal line). (Reproduced with permission from Kleeman & Vorherr. 143(pl4S))
(285 mOsm per liter). Under these circumstances, increasing amounts of isosmotic fluid are delivered to the concentrating segment of the nephron, and it can be calculated that the maximal amounts of water abstracted from these relatively large volumes as they pass through the collecting tubule approach 5 to 8 ml per minute. This rate may be altered by many factors, including, of course, renal functional mass. Minimal osmolality and maximal volume of the urine during a water diuresis (absence of AVP) may also be influenced by the rate of solute excretion. Figure 28 illustrates that as solute excretion is increased during a maximal diuresis, the osmolality of the urine increases in an asymptotic manner toward isotonicity. These alterations would, of course, be the result of the decreased fractional solute resorption in the diluting segment of the nephron (thick ascending limb and distal convoluted tubule). The residual urine leaving this segment durinig maximal water diuresis would approach isotonicity as proportionately less and less of the solute delivered to it is reabsorbed. If the back diffusion of free water in the cortical and medullary collecting tubule is a passive process, what are the factors limiting its maximal rate? During osmotic diuresis the back diffusion of increasing quantities of water into the hypertonic interstitium would, of course, reduce the hypertonicity of the interstitium, and this, in turn, would decrease the maximal concentration of the urine if the interstitial fluid and urine are in osmotic equilibrium. The model earlier described for the production of maximal medullary hypertonicity requires that urea be progressively conTHE WESTERN JOURNAL OF MEDICINE
497
centrated in the distal convoluted tubule and collecting duct and, therefore, in medullary interstitium, and, in turn, that sodium chloride be maximally concentrated by water abstraction in the descending limb of the loop of Henle. As progressively more water is obligated or held back in the lumen during an increasing osmotic diuresis, it would progressively lower tubular urea concentration in the distal nephron and NaCl concentration in the descending limb, further reducing the medullary interstitial concentration of those solutes responsible for its hypertonicity. Also of importance in limiting the final back diffusion of free water is the fact that the volume and velocity of flow of the fluid passing down the medullary collecting duct progressively increase during osTABLE 7.-Sequence of Events in Water Diuresis
* Ingestion of water load (1,000 to 1,500 ml) * Dilution of all body fluids, hydration of cells of supraoptic nuclei, inhibition of secretions of antidiuretic hormone (arginine vasopressin) from the neurohypophysis * Destruction of circulating arginine vasopressin (half-life approximately 9 to 16 minutes) requires 60 to 90 minutes to reach peak water diuresis * No action of arginine vasopressin in distal nephron (cortical and medullary collecting ducts) permits maximal impermeability of these segments to water so that almost all water delivered to them appears in the urine (approximately 10 percent to 15 percent of the filtered water) * Continued normal resorption of salts; therefore, urine of minimal solute concentration and maximal volume
TABLE 8.-Sequence of Events in Maximal Antidiuresis * Moderate negative water balance, such as rigid water restriction for 24 hours * Negative water balance of approximately 1,500 ml or 1 percent to 2 percent of body weight * Hyperosmolality of all body cells with dehydration of cells of the supraoptic nuclei * Release of impulses down neurohypophyseal stalk to posterior pituitary gland; release of arginine vasopressin (AVP) into circulation on sustained basis * AVP acts on cortical and medullary collecting duct to make these segments freely permeable to water and the latter flows along concentration gradients established by continued solute resorption * Approximately 80 percent to 90 percent of solute reaching distal convoluting tubule is actively resorbed here; 80 percent to over 90 percent of water is resorbed, leaving small volumes of isotonic fluid to be delivered into medullary collecting duct * In collecting duct water continues to passively back diffuse into hypertonic interstitial tissue of medulla until urine and medulla reach maximal and equal concentrations; small volume reaching collecting duct is reduced from a third to a fourth of its volume and is maximally concentrated (1,100 to 1,300 mOsm per
motic diuresis, leaving less and less time for contact between the tubular urine and the cells of the collecting tubule. It also should be pointed out that efficiency of any countercurrent multiplier (including the loop of Henle) mechanism is inversely related to the velocity of flow. Osmotic diuretics may also reduce the hypertonicity of the renal medulla by increasing medullary blood flow which, in turn, decreases the "trapping" efficiency of the countercurrent exchange function of the medullary circulation. Therefore, during an osmotic diuresis maximal hypertonicity of the medullary interstitium cannot be achieved because of the decreased efficiency of the countercurrent exchange and multiplier mechanisms. This would contribute materially to limiting the maximal rate of free water resorption and urinary concentration during osmotic diuresis. It is apparent then that active reabsorption of water need not be invoked to explain its movement anywhere in the nephron. Water diffuses passively along osmotic gradients, its movement being limited only by the magnitude of the gradient and the relative permeability of various segments of the nephron. Therefore, the maximal urine to plasma (u/P) concentration ratios during oliguria and the maximal rate of back diffusion of free water during osmotic diuresis, although of considerable physiologic importance in the homeostatic regulation of water, do not denote any form of tubular maxima limited by an active transport process. Although the collecting tubule is relatively impermeable to water in the absence of arginine vasopressin, if the volume of fluid delivered to this segment is small enough, a moderately hypertonic urine can be produced. This phenomenon is most strikingly seen in the production of a substantially hypertonic urine during hydropenia in rats with congenital diabetes inspidus.175,176 Tables 7 and 8 summarize the physiologic events responsible for a maximal water diuresis and antidiuresis after an acute water load or period of hydropenia.
Concept of Free Water Clearance

For functional purposes, Homer Smith and his associates conceived of urinary water as being divided into two moieties: that volume necessary to excrete all urinary solutes in isosmotic proportion, and that volume resorbed from the urine without solute during the concentrating process or "freed" of solute during the diluting process.
liter; specific gravity, 1.037)

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DECEMBER 1979 *
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TABLE 9.-Physiologic Factors Altering Maximal Renal Concentrating Capacity (in Presence of Maximal Arginine Vasopressin)
Rate of solute excretion or osmotic diuresis (such as sodium chloride, urea, glucose, mannitol) Glomerular filtration rate Rate of medullary blood flow Protein content of the diet Water intake and the state of hydration Salt (NaCl) intake and salt depletion Presence or absence of an adequate amount of adrenal glucocorticoid and mineralocorticoid Altered renal medullary prostaglandin synthesis by interstitial cells of the renal medulla Diuretics with the exception of aminophylline
AVP activity 90 percent of the remaining solutes were resorbed and enough water back diffused to bring the urine to isotonicity by the end of the cortical collecting duct, 1.5 ml of isotonic fluid would be delivered to the medullary collecting duct. Here, fluid would be withdrawn until 0.3 ml maximally concentrated urine of 1,400 mOsm per liter was formed. If we assume plasma osmolality to be 285 mOsm per liter, then
1,400 x 0.3 = 420 28s 285
=
1.5 ml per minute= Cosm
V-CoSm=CH2O 0.3-1.5= -1.2 ml per minute
Homer Smith called these two moieties of urinary water Cosm (osmolar clearance) and CH20 (free water clearance), respectively. As mentioned, the osmolar clearance represents the volume of urine necessary to excrete all the urinary solutes in an isosmotic solution. This would include the solutes remaining after all proximal and distal nephron segments had acted upon them. It is calculated as follows:
Cosm=-Posm
Uosm V
Uosm =urinary osmolality (mOsm per liter) V=urinary flow (ml per minute) Posm = plasma osmolality (mOsm per liter) Uosm V = solute excretion (mOsm per minute)
The magnitude of the negative free water clearance, or the fluid back diffusing in the ultimate concentrating process, equals 1.2 ml per minute. Conversely, if 15 ml of hypotonic fluid were delivered into the distal tubule in the absence of AVP and 90 percent of the solute were reabsorbed without water, approximately 15 -ml of a dilute fluid (osmolality of 28.5 mOsm per liter) would be delivered into the final segment. Here, a minimal amount of fluid would be removed in the absence of AVP (2 ml per minute), leaving 14 ml of urine with a final concentration of 30 mOsm per liter. CH20=V-Cosm
14X30 14 Cosm= 285 = 1.5 ml per minute CH20= 14-1.5 =12.5 ml per minute
When Uosm is hypertonic to plasma, the ratio Uosm/Posm will exceed 1. Therefore, (Uosm/ Posm) X V will exceed urinary volume, or Cosm will exceed urinary volume. Thus: V = Cosm + CH20
CH20 = V -Cosm Therefore, the free water clearance will have a negative value when the urine is hypertonic and a positive value when the urine is hypotonic. Expressed another way, free water clearance is that quantity of water excreted which is virtually freed of solutes during the process of urinary dilution. An example of the calculation of osmolar clearance and positive and negative free water clearance will assist in clarifying these terms. Assume that 100 ml of glomerular filtrate is being formed per minute and that 80 percent of this filtrate is resorbed in isosmotic proportions by the beginning of the descending limb of the loop of Henle. In the descending limb, an additional 5 ml of water is reabsorbed. Assuming that no water is resorbed in the ascending limb, 15 ml of hypotonic (150 mOsm per liter) fluid is delivered into the distal convoluted tubule. If during maximal
In recent years, the generation of a positive
C1120 during a maximally sustained water diuresis in dogs and humans has been used as an index of NaCl reabsorption in the diluting segment of the nephron.'77 Maximal urine volume (V), under these conditions, has been used as an index of NaCl delivery to this site(s). The exact anatomic location of this segment is not actually designated. In the state of physiologic diabetes insipidus (no apparent circulating AVP), it includes at least the thick ascending limb, the distal convoluted tubule, the cortical collecting duct, and some have even included the medullary collecting duct. To use CH20 and V in this manner as an approximation of distal nephron NaCl reabsorption, one must assume little or no back diffusion of water in this segment. It is clear from the micropuncture study of Jamison and colleagues178 in rats with hereditary diabetes insipidus that even in the absence of AVP at least 2 percent of the filtered load of water is reabsorbed in the medullary collecting duct. In Table 9 are listed the physiologic factors
499
altering the maximal renal-concentrating capacity during hydropenia or when there is a maximal effect of AVP on the kidney.
Solute Excretion Rate The effect of the rate of solute excretion, or

osmotic diuresis has been described above.
capacity except by its effect on total solute excretion. The greater the protein content of the diet, therefore, the greater would be the back diffusion of urea during the concentrating process, and the more hypertonic the medullary interstitium.
Glomerular Filtration Rate When the glomerular filtration rate (GFR) iS functionally decreased by more than 25 percent, insufficient NaCl and urea are delivered to the ascending limb and collecting duct, respectively, to provide maximal interstitial hypertonicity and, therefore, maximal urinary concentration. However, a decrease in GFR of less than 25 percent has been shown to enhance slightly the maximal urinary osmolality of the hydropenic animal.
Medullary Blood Flow Rate The effect of change in medullary blood flow has been discussed earlier. However, it may be emphasized that if other factors remain relatively constant, a decrease in medullary blood flow increases maximal urinary concentration; an increase in medullary blood flow will decrease the maximal osmolality.
Dietary Protein
An increase in the protein content of the diet increases the maximal capacity of the concentrating mechanism. Although it is possible that a low-protein diet may impair slightly the ability of the kidney to concentrate nonureal urinary solutes, the primary effect of protein on the concentrating mechanism is due rather to the resultant variations in urea excretion. It has been shown that increased urea excretion enhances the concentrating mechanism.'144"46 From micropuncture studies and analysis of the medullary tissues of hydropenic animals, it is evident that urea exists in equal and high concentration in the urine, in the tip of the vascular loop and in the interstitium of the surrounding medulla.144"146 Thus, in the hydropenic animal under the maximal influence of AVP, urea appears able to be diffused freely across the cells of the collecting tubule; as water is resorbed in this segment, urea follows it passively along its own concentration gradient. This, of course, adds to the hypertonicity of the interstitium and enhances the maximum concentrating ability of the nephron. The protein content of the urea formed from the diet does not appear to alter the maximal diluting
Hydration Prolonged overhydration impairs the concentrating mechanism, whereas chronic dehydration enhances it.179 This effect of chronic overhydration may be of clinical significance, particularly in patients with psychogenic polydipsia. A mild qencentriting defect may be evident after a few L Ays of cnronic overhydration. However, polydipsia of months or years' duration may impair the concentrating mechanism substantially. These persons may be unable to form urine with a concentration greater than isotonicity. The observation of this concentrating defect may lead to the mistaken diagnosis of polyuria and polydipsia secondary to a primary renal tubular lesion. Rigid water restriction for several days in these patients, although difficult to maintain, will definitely enhance the maximal concentrating capacity. These persons are capable of producing a normal maximal water diuresis, and their kidneys can respond to the administration of AVP with the production of an isotonic or only slightly hypertonic urine. There is evidence that this concentrating defect is due to a reduction in medullary hypertonicity rather than any decrease in tubular responsiveness to AVP.180 The prolonged water ingestion in some way diminishes the efficiency of the countercurrent exchange and multiplier mechanisms. The augmentation in concentrating capacity associated with prolonged water restriction, conversely, is associated with an increase in medullary tonicity. The impaired responsiveness to AVP and the production of an increasingly concentrated urine in congenital diabetes insipidus rats during water restriction is a most striking example of this phenomenon.
Sodium Chloride Balance It is readily apparent from the discussion of the function of the loop of Henle and the production of a hypertonic interstitium that if the active reabsorption of chloride accompanied by passive reabsorption of sodium in the thick ascending limb is defective or altered, or if the amount of sodium chloride delivered to this site is diminished, the critical force for initiating a hypertonic medullary interstitium will be inadequate, the
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"bootstrap" effect mentioned earlier will be blunted, water will not adequately diffuse out of the descending limb, and the build-up of the NaCl concentration in the loop and ascending thin limb essential for the passive step of the countercurrent multiplier will not occur. Thus, for pathologic or physiologic reasons, we are left with a less hypertonic inner medulla and an inability to form a maximally concentrated urine in the terminal collecting ducts. It is often observed clinically that patients who are severely salt depleted may, in spite of their pronounced oliguria, continue to produce an isotonic or only slightly hypertonic urine. This phenomenon may be secondary to a reduced sodium content of the interstitial tissues of the medulla.
ship indicate that any physiologic or pathophysiologic change which alters the renal response to AVP must engender the possibility that the deviation from normal is caused by a change in the synthesis of PGE. It is also of great interest that recent studies have shown that vasopressin can increase renal PGE biosynthesis in rabbits, normal rats and the strain of Brattleboro rat.183
Diuretics
Diuretic agents (such as ethacrynic acid, furosemide and mercurials) impair maximal concentrating capacity by inhibiting active chloride resorption in the thick ascending limb of the loop of Henle and by producing chronic potassium depletion.'87 It is of great interest that the xanthine diuretic aminophylline actually enhances both maximal diluting and maximal concentrating capacity of mammalian nephrons.'88 It seems to act by increasing the delivery of sodium and water to the loop of Henle and distal nephron without interfering with NaCl resorption in any segment other than the proximal tubule. It is obvious that the concentrating capacity of the kidney cannot be evaluated while the patient is receiving a "loop" diuretic.
Adrenal Corticoids Both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) seem necessary for the production of a maximally concentrated urine during hydropenia.'8' A distinct concentrating defect has been repeatedly observed in patients with adrenal insufficiency. This defect is probably due to a decrease in the delivery of NaCl to the loop of Henle and impaired active resorption of NaCl in the ascending limb of the loop. The possibility that glucorcorticoids, through their permissive role, are essential for the normal action of AVP on the nephron has not been ruled out as a factor contributing to the concentrating defect of adrenal insufficiency. Recent studies suggest that glucocorticoids may enhance the hydroosmotic effect of AVP on the epithelial membranes by inhibiting the generation of prostaglandins.'82
Pathologic Factors Altering Maximal Concentrating Capacity

All the clinical syndromes listed in Table 10 impair the kidney's ability to form a concentrated, or maximally concentrated, urine by producing singly or in combination the following lesions: (1 ) A progressive destruction of renal mass, leaving a reduced number of functional nephrons, which would cause an increased GFR or increased osmotic (primarily urea and NaCl) load per nephron, or both. The ensuing osmotic diuresis in each tubule could reach enormous proportions, thus causing the same "defect" in concentrating capacity that we see during an osmotic diuresis in normal animals and humans (Figure 28), and for the same reasons. (2) Organic lesions of the renal medulla that disrupt the anatomic arrangement of the loop of Henle and the vasa recta or produce a specific defect in the active transport capacity of the thick ascending limb of the loop, which would seriously interfere with the countercurrent exchange and multiplier functions of this part of the kidney. The maximal osmolality of the urine would be equal to or less than the reduced hyperosmolality of the medullary (or papillary) interstitium. (3) Organic lesions in the cortical
Prostaglandins
Secretion of prostaglandin E (PGE) by the interstitial cells of the renal medulla or the cells of the medullary collecting duct clearly modulates the action of AVP on mammalian nephrons.'83-'85 A local increase in PGE concentration inhibits the action of AVP (decreases maximal urinary concentration) while a decrease in PGE enhances the antidiuretic effect of AVP.184"185 This modulating capacity of PGE appears to be exerted through its ability to alter the AVP activation of adenyl cyclase. For example, the concentrating defect caused by potassium depletion is associated with an increased renal medullary generation of PGE and the defect can be ameliorated substantially by the inhibition of PGE synthesis in dogs.'86 These observations on the AVP-PGE interrelation-
501

TABLE 10.-Clinical States That Impair Maximal Renal Concentrating Capacity
Chronic renal failure (pyelonephritis, glomerulonephritis, nephrosclerosis, gout, polycystic and medullary cystic kidneys, analgesic nephropathy and other causes of interstitial nephritis Diuretic phase of acute tubular necrosis of any etiology Hypokalemic nephropathy Hypercalcemic nephropathy Hyperaldosteronism (primary) Multiple myeloma, amyloid disease and the Sjogren syndrome Postobstructive uropathy Postrenal transplantation Sickle-cell anemia Congenital nephrogenic diabetes insipidus (failure to respond to antidiuretic hormone) Chronic ingestion of high doses of lithium Methoxyflurane anesthesia Psychogenic polydipsia Chronic glucocorticoid and mineralocorticoid deficiency (Addison disease)
evidence in favor of the currently accepted view that the neural lobe, although the major site for storage and release of the hormone, is not involved in its synthesis, and that in the absence of the posterior pituitary the newly formed hormone can still be released into the circulation.
pituitary stalk. The simple removal of the posterior lobe, although at times associated with a short period of DI, has never been capable of producing the sustained disorder. This is strong
Pathophysiology
All the clinicopathologic lesions associated with involve the supraoptic and paraventricular nuclear areas or a major portion of the stalk. it is generally concluded today that a primary functional abnormality in the thirst mechanism is not an important factor in the polydipsia, but that the latter is a response to the profound renal water loss. However, it is not inconceivable that the associated hypothalamic lesions might at times produce a specific disorder of the thirst mechanism. In fact, the authors have had the opportunity of observing a patient with well-documented DI who, on recovery from this illness, was left with a severe thirst in spite of the fact that his renal-conserving mechanism for water was normal. Over the period of a year there was a gradual reduction in the thirst of this patient, aqd he was able to do well with increasingly smaller oral intakes of water. This may be a conditioning defect of the thirst center, secondary to the excessive water ingestion of DI. After experimental injury to the neurohypophyseal system, the development of the DI syndrome frequently follows a characteristic triphasic pattern (Figure 29). This pattern, which may also occur clinically after acute surgical or traumatic injury to this area, is as follows: After the acute injury the initial effect is the immediate development of a polyuric, polydipsic syndrome incistinguishable from the full-blown disorder. Within hours to days this polyuric syndrome is replaced by a progressive reduction in urinary volume approaching the control level in both concentration and value, and the animal appears to be normal once again. During this normal interphase, however, the administration of an acute or sustained water load will not cause a noralp water diuresis. The animal will continue to excrete little and inappropriately concentrated urine. If one persists in administering water, a state of profound hyposmolality and water intoxication will ensue. In
DI
Dichlormethyltetracycline (Declomycin)
or medullary collecting ducts, or both, which would impair their response to AVP. Such lesions would cause a polyuric syndrome associated with the persistence of a hypotonic urine despite hydropenia with high circulating levels of AVP or the administration of vasopressin (Pitressin).
Diabetes Insipidus Diabetes insipidus (DI) is a syndrome that results from failure of the neurohypophyseal system to produce or to release a quantity of AVP sufficient to bring about the normal homeostatic
renal conservation of free water. In recent years this disorder has been called vasopressin-sensitive DI to distinguish it from the rare congenital and familial disorder nephrogenic diabetes insipidus (NDI), in which greater than normal amounts of AVP are produced; the latter has no observable effect on the diluting segments of the nephron. It is obvious that the disturbance in water metabolism would be identical in both states, each characterized by the continuous production of an inappropriately large volume of hypotonic urine (specific gravity usually less than 1.005 and osmolality less than 200 mOsm per liter). Diabetes insipidus may be complete or partial, permanent or temporary. This syndrome has been produced experimentally in many mammals over several decades. In general, to produce a persistent abnormality in the production or release of AVP, it has been necessary to destroy either the supraoptic nuclei or a major part of the neurohypophyseal tract or
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DECEMBER 1979 * 131
* 6
a matter of days the normal interphase will be replaced by a progressive increase in polyuria and polydipsia until a sustained state of DI is attained. The latter may be permanent or temporary, complete or partial. It is difficult to be certain about the exact cause of the first and second phases of this triphasic response. The initial, temporary DIlike state probably represents a physiologic lesion comparable to spinal shock; that is, as a consequence of the sudden injury to the axons or nerve cell bodies, all impulses responsible for discharge of the hormone from the neurohypophysis are eliminated and the hormone is not discharged into the circulation. On the basis of chemical analysis of the hypothalamus and neural lobe, it appears that during the normal interphase there is a slow "leak" of AVP from the injured axons and the neurohypophysis itself into the circulation as the neurohypophysis undergoes atrophy and its hormone content disappears.189 Extensive lesions also produce a progressive disappearance of the hormone content of the hypothalamus itself.189 If at the time of the initial experimental injury the stalk, posterior lobe and median eminence are removed, the normal interphase will not develop.190 Finally, in the third phase the sustained state of DI is attained. In those instances in which the lesion does not destroy or lead to the degeneration of the supraopticohypophyseal nuclei, the animal or patient may be left with the incomplete DI syndrome. This condition may manifest itself as a less severe polyuria (3,000 to 6,000 ml per day), with an impaired but not necessarily absent response to various ostotic and nonosmotic stimuli. At times this type of patient may fail to respond to hypertonic saline, but will develop a distinct antidiuresis after administration of acetylcholine or methacholine chloride (Mecholyl) .38,191,192 The triphasic response may be seen in many instances of pituitary stalk section, total hypophysectomy,
Volume (ml)
Specific gravity
6 7 Days
9 10
11
12 13 14
Figure 29.-Typical triphasic cycle produced by section of the hypophyseal stalk and damage to the median eminence. The interphase extends from day 6 to day 10 or 11. (Reproduced with permission from Hollinshead WH: Proc Mayo Clin 39:95, 1964.)
normal interphase will persist and only rigid water restriction will correct it.
cryohypophysectomy or even yttrium implantation. Figure 30 is a summary of metabolic changes in a patient who developed water intoxication and severe hyponatremia during the normal interphase of a mild DI which followed pituitary stalk section. This syndrome can be quickly differentiated from the impaired water excretion of acute glucocorticoid deficiency by giving the patient liberal amounts of cortisol or its equivalent. This therapy will immediately correct the water retention and hyponatremia if a glucocorticoid deficit
exists. If it does not, the water retention of the
Etiology The following are the major causes of DI in their relative order of frequency: (1) idiopathic (approximately 50 percent), which may appear in a congenital and familial form; (2) posthypophysectomy (surgical, yttrium implants, cryohypophysectomy or stalk section); (3) basal skull fractures; (4) suprasellar and intrasellar tumors, either primary or metastatic, such as suprasellar cysts, craniopharyngioma, pinealoma, carcinoma of the breast and leukemia; (5) histiocytosis, such as eosinophilic granuloma and Schiiller-Chnrstian disease; (6) granulomatous disease, such as sarcoidosis and tuberculosis; (7) vascular lesions, such as aneurysms and atherosclerotic thrombosis; (8) encephalitis or meningitis, and (9) intraventricular hemorrhage.193 Idiopathic or primary DI may be a familial disease; the hereditary form has been described as autosomal dominant with incomplete female penetrance, or else an X-linked recessive. This form may appear at any time during the lifetime of a person. Although few postmortem investigationis have been carried out, a recent study by Brav4man and his associates has shown that this disorder was due to a substantial decrease in the number of nerve cells of the supraoptic and paraventricular nuclei with increased gliosis (Figure 31) and decreased size of the posterior pituitary.'94 The histologic changes observed in patients with idiopathic DI are in striking contrast to the intact and enlarged supraoptic nuclei withTHE WESTERN JOURNAL OF MEDICINE
503
out gliosis seen in rats with hereditary congenital DI. In rats there is a defect in hormone synthesis and in humans, a degeneration of the hormoneproducing cells. The cause of this degeneration and gliosis is completely unknown. These cases do not show any associated abnormality of anterior pituitary function. The various types of therapeutic hypophysectomy are becoming an increasingly common iatrogenic cause of DI. Of the primary tumors, in the region of the neurohypophysis the adenomas of the anterior pituitary almost never cause DI. This is consistent with the experimental observation that removal of the posterior lobe per se does not result in DI. Those tumors that do create such a state must do so by involving the supraoptic and paraventricular nuclei or a major part of the neurohypophyseal stalk. The most classic examples of this are craniopharyngiomas and suprasellar cysts. On rare occasions, an acute DI state will develop as a result of metastases to the neurohypophyseal system. By far, the most common of
2 40 -"- .1, '-C t 1 70 It
these malignancies is carcinoma of the breast. Usually the DI develops late in the course of the disease and is almost always associated with other
metastatic lesions. However, it may be the first subjective evidence of metastases. With this or
10 1120
Figure 31.-Photomicrograph of supraoptic nucleus of a normal 52-year-old man (A) and of a patient with diabetes insipidus (B). Note, in the normal subject, the large number of nerve cells with prominent peripheral distribution of Nissl substance. In the patient with diabetes insipidus there is a loss of nerve cells, a loss of Nissl substance and moderate gliosis (reduced from x200). (Reproduced with permission from Braverman et al.'9)
180 ts 60 t
40 vt 20 At
C ASE I
CASE 4
CASE 2
200
-
CASE 5
loot-
~~~~~~~~~~~~200 1~~~~~~~~~~~~~00
Uine
4-
volume-6
W aler
intake
CASE 3
CASE 6
10 It 12
13
14
15
16 17
19 20
Day
Figure 30.-Metabolic changes after pituitary stalk section in a 39-year-old woman. Asterisk shows period of confusion, headache and lethargy. Double dagger indicates intravenous administration of 385 mEq of sodium chloride as a 5 percent solution. (Reproduced with permission from Gastineau CF, et al: Proc Mayo Clin 42:406, 1967.)
Figure 32.-Diagram of neural and vascular connections between hypothalamus and pituitary gland (center) and of the location of carcinomatous deposits (solid black) in six cases. The metastases are mainly in neural tissue at the sites of the primary capillary beds. In case 6, the stalk had been transected and the hatched area indicates the extent of infarction of the anterior lobe. A = anterior lobe; AC = anterior commissure; IHA=inferior hypophyseal artery; M=mammillary body; OC=optic chiasma; P=posterior lobe; PV=paraventricular nucleus; SHA = superior hypophyseal artery; SO=supraoptic nucleus; T=tubular nucleus; III V= third ventricle. (Reproduced with permission from
Duchen."92)
504
DECEMBER 1979 * 131 * 6
other malignant tumors metastasizing to the area, DI always precedes the development of anterior pituitary insufficiency, if the latter occurs. The tumor involves the anterior pituitary by contiguous spread from the neurohypophyseal system rather than by direct bloodstream metastasis to the adenohypophysis. As illustrated in Figure 32 (from the excellent study by Duchen'92), the anterior lobe receives its blood supply through a portal circulation, whereas the neurohypophyseal system is supplied by the systemic circulation. Tumor cells would not readily gain entrance to this portal circulation. When DI develops in a given patient, every effort should be made to determine its cause, as it may be amenable to specific therapy. The DI may be accompanied by symptoms of the causative disorder, such as sarcoidosis, central nervous system tumor or xanthomatosis.
Clinical Features Diabetes insipidus may occur at any age, and there is no sexual predilection. Because of the rare familial nature of the disorder, other family members should be evaluated if a patient develops the idiopathic type. Almost all cases of true DI are of abrupt onset. These patients often recall that the polyuria and thirst started suddenly and reached a peak in a day or two. The history of a gradually increasing urinary flow, over weeks to months, generally suggests some other polyuric disorder. Continuous thirst is, of course, a classic symptom of the disease-the patient showing a predilection for very cold or iced water. This desire for very cold water is not characteristic of other polyuric syndromes, including psychogenic polydipsia. The urinary volume may range between 3,000 and 15,000 ml per day, and a prominent nocturia is almost invariably present. Patients with psychogenic polydipsia are rarely bothered with nocturnal polyuria. It must be remembered, however, that with DI of long duration the patients may develop an incredibly large caliceal, ureteral and bladder capacity with frank hydronephrosis and hydroureter. The muscular wall of the bladder becomes thinned and decreased in tone. These patients may void as much as 1,000 ml at a time, and the absence of nocturia, or the presence of only a mild nocturia, may be due to these alterations in the character and capacity of the urinary drainage system. On rare occasions, the hydronephrosis may lead to definite impairment of kidney function with elevated levels
of blood urea nitrogen (BUN) and serum creatinine.'96 Diabetes insipidus may occasionally present in an atypical fashion. In one instance, the earliest symptom of DI in a young boy was the presence of severe night sweats. Nocturia did not occur because of dilatation of the urinary collecting system.'95 Characteristically, the withdrawal of water from a patient with severe DI will lead to an extremely rapid weight loss, profound thirst and the rapid development of hypertonic dehydration. However, as long as the patient can satisfy this thirst, he or she will experience little but the inconvenience of the polyuria, and the state of hydration will remain close to normal.
Diagnosis One must differentiate DI from all other important polyuric syndromes (Table 11). In DI, with the exception of mild plasma hyperosmolality (5 percent above normal), and unless pronounced dehydration is present, the blood and urinary chemistries are normal. This will not be the case in many of the syndromes listed in Table 11. A knowledge of the physiologic basis for polyuria is most helpful when one is confronted with this symptom. True polyuria invariably means a decrease in the percentage of the filtered water that is absorbed by the renal tubules. This decrease may be secondary to an alteration in the tubular handling of water per se, to an impaired resorption of solutes with the development of an osmotic type of diuresis or, finally, as in most acquired renal diseases, to a combination of both of these
functional abnormalities. The classification in Table 11 is relatively self-explanatory, and when physicians are confronted with a polyuric syndrome, they should consider most of the disorders listed. Polyuria may be the consequence of excessive water ingestion. Compulsive water drinking may be seen as a reflection of an underlying psychiatric disorder. Severe water intoxication to the point of death has been observed on occasion in severely disturbed or psychotic patients. The precise cause of this disturbance is not known. It is also possible that selective lesions in the hypothalamus can produce enhanced thirst such as those that occur after experimental stimulation of the hypothalamus in goats. Indeed, primary polydipsia has been reported in a patient with histiocytosis, which may reflect the influence of an organic lesion on water balance.'97 AltemaTHE WESTERN JOURNAL OF MEDICINE
505
tively, endogenous dipsogens such as angiotensin 11198 or PGE may play a role in some of these patients. Thus, compulsive water drinking could have a psychologic, structural or neurochemical cause. Nephrogenic diabetes insipidus (NDI) or vasopressin-resistant DI is a rare congenital and familial disorder in which, in the homozygous form, the renal tubules are totally refractory to the antidiuretic effect of vasopressin.'99-202 It is fascinating that although spontaneous mutation may rarely be the cause of this disorder,200,201 all
TABLE 11.-Major Polyuric Syndromes Due to a Decrease in Tubular Reabsorption of Water and Solutes
Water Excessive water ingestion-minimal circulation of arginine vasopressin (AVP) Psychogenic polydipsia Polydipsia due to injury to hypothalamic thirst centers (rare) Potassium depletion and hypercalcemia Pronounced hyperreninemia (uncommon) Inability to reabsorb adequate amounts of filtered water Inadequate circulation of AVP equals complete or partial AVP-responsive diabetes insipidus (DI) Renal tubular failure to respond normally to AVP * Nephrogenic DI (congenital and familial) * Nephrogenic DI (acquired) Usual chronic renal diseases that do not primarily involve the glomerulus, such as chronic pyelonephritis, polycystic kidneys, analgesic nephropathy, gouty nephropathy, medullary cystic disease, all acute and chronic interstitial nephropathies Obstructive uropathy Multiple myeloma Amyloid disease The Sjogren syndrome Potassium deficiency Hyperaldosteronism or mineralocorticoid excess Nephrocalcinosis or renal damage secondary to hypercalcemia Unilateral renal artery occlusion (acute) with pronounced hyperreninemia Diuretic phase of acute tubular necrosis (ATN) or nonoliguric ATN Postrenal transplantation Prostaglandin E excess acting on distal nephron may contribute to any of the above Sickle-cell anemia Ingestion of high doses of lithium Methoxyflurane anesthesia
Dichlormethyltetracycline (Declomycin)
Solutes Inability to reabsorb adequate quantities of filtered solutes (osmotic-type diuresis) Glucose-diabetes mellitus Salts-Primarily sodium chloride Urea-tissue catabolism or excess production of urea from hyperalimentation * Various types of chronic renal disease, particularly chronic pyelonephritis * After various diuretics, including mannitol
affected persons may have been of common genetic origin, descendants of an Ulster Scotsman.202 In the heterozygous form or in the absence of complete penetrance, there may be varying degrees of responsiveness to AVP and, in turn, varying degrees of polyuria. When basal plasma AVP and osmolality are measured in these patients, they are usually found to be above normal,94'203 suggesting a state of mild water depletion. The patient with NDI is clinically indistinguishable from one with DI until a complete, or almost complete, lack of response to Pitressin is observed. The exact cause of this defect in the nephron is unknown. Any step, from the initial binding of vasopressin to its receptor sites to the final metabolic event responsible for the maximum increase in the permeability of the distal nephron to water, could be defective. When the GFR and renal blood flow of patients with NDI are reduced to a degree comparable to that of patients with DI, the former are unable to produce a urine hypertonic to the plasma.199 This suggests that in NDI the collecting duct is truly impermeable to water or that the renal medulla of these patients is either isotonic or even less hypertonic than the reduced medullary osmolality observed in the animal with DI. The diagnosis of acquired nephrogenic diabetes insipidus should be restricted to patients with an acquired renal disorder whose polyuria is associated with a persistently hypotonic urine unresponsive to Pitressin or hydropenia. In general, the disorders (Table 12) do not attain the degree of polyuria observed in DI or NDI because, in most, the overall functioning renal mass is reduced by the basic disease process. In DI a moderate concentration defect is usually present which can be corrected by the continuous administration of Pitressin. Valtin72 found that the correction of the defect in congenital DI rats receiving Pitressin was associated with a return of the medulla to its maximally hyperosmolar state. The latter was due especially to a rise in urea concentration and, to some extent, NaCl. Invariably, in the DI patients or animals, urine volume will decrease substantially following a single injection of Pitressin, even though urinary osmolality, at first, may only slightly exceed isotonicity (that is, 450 mOsm per liter). The diagnosis of DI is assured when it has been shown that one or more of the major stimuli to the release of AVP, such as carefully controlled water restriction, hypertonic saline infusions and
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DECEMBER 1979 * 131
* 6
CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II TABLE 12.-Primary Water Depletion and Other Hyperosmolar States
=3 URINE
Hypematremia and hyperosmolality with dehydration secondary to water loss in excess of sodium: Polyuric states with failure of renal conservation of water in association with inadequate water intake * Diabetes insipidus (DI), nephrogenic DI (congenital and acquired) * Osmotic diuresis with unreplaced loss of hypotonic urine; pronounced glycosuria, mannitol diuresis (may be hyperosmolar and hyponatremic), high-protein gavage to comatose patients (urea diuresis), chronic renal failure Primary water depletion in excess of sodium with normal renal-concentrating mechanisms; comatose or disoriented patients with inadequate water intake, primary disorders of thirst regulation, diabetic coma, excess sweating and diarrheal disorders in children, hypothalamic lesions causing adipsia or hypodipsia in which forced fluid administration corrected the hyperosmolar syndrome Hypertonic peritoneal dialysis Hypernatremia and hyperosmolality with possible normal hydration: Reset of osmoregulatory center with or without hypodipsia (idiopathic, hydrocephalus, brain tumor, histiocytosis X, postconcussive hyperosmolality) Hypernatremia and hyperosmolality with overhydration: Primary aldosteronism, the Cushing syndrome, congestive heart failure with tracheostomy, pneumonia; hypertonic saline enemas to infants, hypertonic saline given orally to infants, iatrogenic hypertonic saline administration to patients with chronic renal failure, inadvertent dialysis with hypertonic sodium solution, hypertonic (glucose) peritoneal dialysis
em PLASMA
6001
mOsm/t
500- :,
Con trols
Patients after
hypopMysectom y
Figure 33.-Comparison of maximal urinary osmolality of normal controls with that of patients with varying degrees of diabetes insipidus following ten hours of water restriction. (Reproduced with permission from Lipsett & Pearson.2W')
nicotine administration (rapidly smoking three or four cigarettes), do not cause a pronounced antidiuresis or the production of hypertonic urine, and that the kidney is responsive to exogenous AVP or Pitressin. Probably the most important and reliable test to show endogenous secretion of AVP is simple water restriction. This will lead to mild or moderate dehydration, and if complete DI is present, a hypotonic urine (specific gravity below 1.005). or osmolality substantially below the simultaneously measured plasma osmolality will continue to be formed in spite of the dehydration. Restriction of water intake in a patient with probable DI should be done only with great care while the patient is observed closely. A patient with a severe case may lose as much as 0.5 kg of body water per hour, and the test should be stopped if the patient loses 3 percent of body weight. It must be remembered that if the dehydration causes a major drop in GFR and solute excretion, oliguria and a slightly hypertonic urine may be formed even in the absence of AVP secretion. If a sensitive bioassay or immunoassay for
AVP is available, it is possible to show that during water restriction the rise in plasma osmolality does not cause an appropriate rise in the level of AVP in the plasma94'203'204 (see Figure 9 in Part I). It has been generally thought that DI was an "all-or-nothing" disorder and that mild to moderate forms of DI did not exist. However, over 15 years ago Lipsett and Pearson205 clearly illustrated that incomplete failure of production or release of AVP occurred clinically. Their patients developed DI after surgical procedures involving the region of the neurohypophyseal system; this form is most apt to be seen following such operations. Figure 33 shows maximal concentration of the urine compared with simultaneous plasma osmolality in subjects with varying degrees of posthypophysectomy DI following mild dehydration (ten hours of water restriction). It is apparent that a hypertonic urine can be formed by some of
these patients, although they are not capable of producing a urine with an osmolality in the normal range for this test. The diagnosis of DI iS obvious in those patients whose urine was distinctly hypotonic at the end of the water restriction, but the presence of a moderately hypertonic urine after this period of water restriction does not rule out the diagnosis of partial DI. These patients, therefore, had a quantitative decrease in the release or production of AVP. Recently, Miller and associates206 studied the
507
maximal concentrating capacity, during standardized conditions of dehydration, for normal volunteers, normal subjects admitted to hospital and a wide variety of patients with diabetes insipidus. They clearly confirmed the observations of Lipsett and Pearson205 as well as showing that the patients with partial and complete DI, after attaining their maximal but subnormal urinary concentration, still responded with a further increase in urinary osmolality after an injection of AVP (Figure 34). The normal subjects and patients with psychogenic polydipsia did not show this response to exogenous AVP at the end of their dehydration. Thus, the production of a mildly to moderately hypertonic urine during water restriction, followed by a further significant increase in urinary osmolality (greater than 9 percent) with an injection of Pitressin, indicates the presence of incomplete DI. The response of patients with DI to the sulfonylurea chlorpropamide indicates that incomplete DI is far more common than ever suspected. Rarely, a patient with a syndrome indistinguishable from DI may be unable to form a concentrated urine during simple dehydration or after the administration of hypertonic salt, but is able to produce a hypertonic urine after the
vI II
administration of nicotine, a strong nonosmotic stimulus to the release of AVP. This would suggest that the subject is incapable of responding to an osmotic stimulus but may respond to a nonosmotic one. However, it should be stressed that nicotine frequently produces such reactions as nausea, vomiting and, at times, a substantial drop in blood pressure. Such an intense nonosmotic stimulus to the neurohypophyseal system would be quantitatively a far greater signal to its receptor and releasing function than the standard dehydration or hypertonic saline test. Therefore, we may not be dealing with a truly qualitative difference but, rather, with degrees of quantitative unresponsiveness. Furthermore, this pronounced reaction to nicotine may produce a considerable alteration in renal hemodynamics. If the patient does have such a subjective reaction in association with a definite antidiuretic response, a substantially concentrated urine (greater than 450 mOsm per liter) might also be formed even if the patient had not released AVP with this stimulus. This type of patient will still be polyuric because the total secretion of AVP per day is less than that necessary to bring about normal homeostatic renal conservation of free water, and would be classified as incomplete DI with the ability to
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patients with vasopressin-sensitive (pituitary) diabetes insipidus (DI) and with vasopressin-insensitive (nephrogenic) diabetes insipidus and the change in urinary osmolality after an injection of antidiuretic hormone. (From Miller et al.'m)
as in
MAXIMUM URINE OSMOLALITY AFTER DEHYDRATION, mOsm/Kg Figure 34.-The relationship between maximal urinary osmolality after dehydration in normal subjects
100
1200
1300
1400
1500
as
well
508
DECEMBER 1979
131
release AVP in response to a strong nonosmotic stimulus. It is possible that if every patient with DI were tested for his or her response to various nonosmotic (see Table 3 in Part I) as well as to the usual osmotic stimuli (dehydration and hypertonic saline), we would find many more patients with qualitative as well as quantitative defects in the ability to release AVP. De Rubertis and associates38 described in remarkable detail another type of qualitative abnormality in AVP secretion in which a patient had little or no response to osmotic stimuli, but had an excellent response to various nonosmotic volume or baroreceptor stimuli. Enough AVP was secreted to prevent polyuria, but the patient had sustained hypernatremia and a deficit in thirst regulation. In most patients with DI antidiuresis will not develop during or after the administration of hypertonic saline (5 grams per dl of NaCl) (Figure 35). For reasons cited earlier, subjects should not have too great a positive water load (that is, in excess of 500 ml) as they begin the test and probably should not receive more than 300 ml of 5 percent saline during the testing period. In normal subjects a distinct antidiuresis with hypertonic urine will develop within 30 to 60 minutes after starting the hypertonic saline infusion. Although the absence of an antidiuresis strongly suggests DI, it must be remembered that on rare occasions, in persons in whom a pronounced augmentation of salt excretion develops, the osmotic diuresis may be so great that there will be little or no drop in total urinary volume despite a distinct fall in free water clearance. The drop in free water clearance with the production of a hypertonic urine is a true measure of either a significant increase in permeability of the distal nephron or the presence of an effective amount of circulating AVP. The failure of a normal response to hypertonic saline, simple water withdrawal or nicotine (rapid smoking of three or four cigarettes) should be followed by the intravenous administration of Pitressin over two to three hours. If a hypertonic urine is formed, the diagnosis of DI is assured. A failure to produce a hypertonic urine after Pitressin administration does not absolutely rule out the diagnosis of DI, but suggests the possible presence of some functional or organic disorder of the renal tubules as the primary diagnosis. The absence of significant polyuria does not necessarily rule out the diagnosis of DI. When GFR and solute excretion are substantially reduced
(as in combined anterior and posterior pituitary insufficiency or severe water and salt depletion), and back diffusion of water occurs even in the absence of AVP, the urinary volume may be less than 3,000 ml per 24 hours, and urinary osmolality may approach or slightly exceed isotonicity. In recent years several attempts to devise more simplified tests for the diagnosis of DI have appeared.207 Basically, these have consisted of a standard period of rigid water restriction, varying
n
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30 60 90 120 IS M INUT ES Figure 35.-Composite of 15 osmotic threshold studies in ten subjects with diabetes insipidus, of whom six had combined pituitary deficiency. No osmotic threshold was attainable even though the experiments were continued until the highest plasma osmolality in each instance ranged from 298 to 332 mOsm per kg. Time intervals are expressed in relation to the beginning of rapid saline infusion. V=vQlume; Co., =osmolar clearance; CH2.,=free water clearance; Posm=plasma osmolality; U('rV=creatinine excretion; U.NaVV=sodium excretion. (Reproduced with permission from Moses AM, et al: Am J Med 42:368-377, 1967.)
.2
509
from six to eight hours, with a measure of plasma and urinary osmolality at the beginning and end of this period. Normal persons will have little or no change in their plasma osmolality; they will frequently begin with a moderately hypertonic urine which will become more concentrated by the end of the period of water restriction; that is, the u/P osmolality ratio will always significantly exceed 1 and, frequently, 2. A patient with complete DI will initiate the test with a plasma osmolality that on a random specimen usually exceeds that of the normal subject; the patient's initial urine osmolality will be less concentrated than plasma, and after six to eight hours of water restriction, the plasma osmolality may rise significantly with little or no change in urinary osmolality. Therefore, the u/P ratio does not go up and may actually fall. This test, if unequivocally positive, is strong presumptive evidence for the diagnosis of DI. However, the authors prefer in any given case to carry out the more extensive procedures described earlier. Too many patients have been misdiagnosed as having DI and have needlessly taken injections of Pitressin for months or sometimes years. In patients with psychogenic polydipsia, as a consequence of the profound and sustained primary ingestion of water, the random plasma osmolality is usually significantly below that of normal persons and certainly lower than that of patients with DI. In patients with psychogenic polydipsia, in whom water is restricted under careful observation for 12 to 18 hours, urine volume will always be reduced to a low level (1 to 2 ml per minute) and urinary osmolality will increase at least to isotonicity. On occasion, however, a compulsive water drinker may be so overhydrated that it may require longer than 24 hours for the positive water load to be excreted and, therefore, a longer time for the urine volume to be reduced to a low level. This patient can usually be suspected because initial plasma osmolality and sodium concentration values will be considerably below normal. Patients with psychogenic polydipsia when given an infusion of hypertonic saline will respond like normal subjects with the single exception that maximal urinary osmolality will be less hypertonic. In the authors' experience, despite the concentrating defect resulting from months and years of excessive water ingestion, patients with psychogenic polydipsia can invariably concentrate at least to isotonicity. This response to dehydration and hypertonic saline ad510
DECEMBER 1979 * 131
ministration readily differentiates these patients from those with complete DI. Incomplete DI may cause a problem in differential diagnosis, but the clinical picture, as described previously, the response to Pitressin after a period of dehydration,201 and the progressive improvement in concentrating ability with modest water restriction in patients with psychogenic polydipsia will usually confirm the true diagnosis. The authors have observed that patients with DI, under the influence of a maximal sustained water diuresis, do not generally produce a urine quite so dilute or so high in volume as normal subjects under similar circumstances, and random samples of their urine obtained when they are not receiving AVP are usually less dilute than during a sustained intravenously infused water load. This suggests that in patients with DI some new mechanism develops for either delivering a smaller volume of salt and water to the diluting segments of the nephron, or, less likely, for allowing a greater degree of back diffusion of water in these segments even in the absence of AVP.
Treatment Once the diagnosis of DI has definitely been established, every effort should be made to find and treat the underlying causative disorder. Although newer modes of therapy are now available for treating DI some form of AVP administration frequently remains the mainstay of therapy; at present, the most common form is Pitressin Tannate in Oil (5 units per ml). There is a general tendency among physicians to use excessive doses of this drug. As little as 0.5 ml every two days, given as a deep intramuscular injection, is usually adequate for optimal control. Unfortunately, Pitressin Tannate is packed in 1-ml ampules, but the residual 0.5 ml may be covered with an alcohol sponge and adhesive and stored in the refrigerator for use later. If one looks carefully at an ampule of Pitressin Tannate, one can see a patch of dirty-brown material on the bottom of the ampule-this is the hormone. The ampule must be warmed in the hand and thoroughly shaken until this material is suspended in a slightly discolored emulsion. The importance of doing this cannot be emphasized too greatly. A small percentage of patients will have an occasional allergic or local reaction to this preparation. If this occurs, a period of desensitization may be instituted, beginning with a dosage of 0.01 ml per day or less, and gradually increasing it in step-
* 6
wise fashion. Antihistaminics may be administered simultaneously. During the first days of treatment, and for emergency or acute use, aqueous Pitressin (20 units per ml) may be administered subcutaneously, particularly when DI complicates an acute disorder such as basal skull fracture or surgical (or nonsurgical) hypophysectomy. Use of Pitressin Tannate in Oil, with its effect taking place 24 to 48 hours after administration, makes it difficult to follow the unpredictable course of the DI complication. Also, water intoxication is more likely to develop in patients treated with the combination of the long-acting preparation and parenteral water administration. Recently, the authors observed a 30-year-old man who had been given Pitressin Tannate in Oil (1 ml three times a day) for acute DI associated with a basal skull fracture, a dosage which he then continued to take for two years. On his admission to hospital, laboratory studies gave the following values: serum sodium was 120 mEq per liter with a proportionate decrease in plasma osmolality and urine osmolality was 300 mOsm per liter. When administration of Pitressin Tannate was stopped, the patient had a profound diuresis of very hypotonic urine and lost 20 pounds in 24 hours. Values for serum sodium and osmolality tests returned to normal. He was shown on subsequent testing to have recovered completely from the DI, and the only abnormality was a functional concentrating defect resulting from the prolonged overhydration. This defect was corrected after four days of moderate water restriction (1,000 ml per day). The usual dosage of aqueous Pitressin is 0.1 to 0.3 ml every four to six hours. One should be careful in administering these amounts to patients with known coronary artery disease because of the vasoconstrictive effect of this hormone. Diapid, a nasal spray of synthetic lysine-8vasopressin (50 units per ml, in isotonic saline) has been available for clinical use for almost a decade.208 In contrast to arginine-8-vasopressin, lysine-8-vasopressin is remarkably stable; therefore, although not quite as potent as arginine-8vasopressin, it lends itself admirably to use as a nasal spray. Studies indicate that this preparation is both stable and nontoxic, and when used approximately every four hours may cause a 50 percent to 75 percent reduction in urinary flow in the average case of DI. The nonirritating saline solution is sprayed deeply into the nasal passages from a plastic squeeze bottle, one to two sprays
in each nostril. In the most severe cases of DI, it has been necessary to combine the nasal spray with the far less frequent use of Pitressin Tannate in Oil. A newly developed synthetic analogue of vasopressin, dDAVP (1-desamino, 8-D-arginine vasopressin), in which the L-arginine in position 8 has been replaced by D-arginine, and the free amino group in position 1 has been removed. This remarkable analogue has greater antidiuretic degree and duration potency than the natural hormone or any other known analogue, whereas pressor activity in therapeutic doses has been reduced to very low values.209-21' The reduced pressor activity of this compound permits administration of high doses via the nasal passages without the smooth muscle constricting effects of either AVP or LVP that often lead to abdominal cramps or hypertension. It appears to be six to ten times more potent than aqueous Pitressin, depending on the dose, is very stable and can be administered as nasal drops. A dose of 5 to 20 ,ug of dDAVP given as a nasal spray will result in 8 to 20 hours of antidiuresis in patients with central DI. The introduction of this highly potent, long-lasting AVP analogue dramatically changes the therapeutic options for patients with diabetes insipidus. It is certain that it will become the drug of choice for this disorder, and will thus eliminate the necessity for nonhormonal forms of therapy. In recent years two nonhormonal forms of therapy have been developed for the treatment of DI: (1) various diuretics, primarily thiazides and (2) oral hypoglycemic agents such as chlorpropamide (Diabinese). The former has also made a major contribution to the treatment of NDI as no other successful treatment for this disorder had existed in the past. Crawford and Kennedy212 first showed that chronic administration of thiazide diuretics to patients with NDI and DI could reduce urinary volume by approximately 50 percent in 24 hours and cause a comparable amelioration of thirst as well. The reduced urine volume, although less hypotonic, was never hypertonic. This suggested that the thiazides did not act by substantially increasing the permeability of the distal convoluted tubule or collecting duct. Recent studies have clearly shown, however, that other diuretics, as well as rigid sodium restriction, may cause a comparable degree of antidiuresis in these patients. Conversely, when a thiazide or other diuretic agent is administered with enough sodium chloride to prevent a negative salt balance
511
or a reduction in extracellular volume, the antidiuretic effect does not occur.9'199 This implies that the mild negative salt balance and reduction of GFR, created by the diuretic, lead to enhanced reabsorption of isosmotic fluid in the proximal nephron. This, in turn, leads to a decrease in the amount of fluid delivered to the water-impermeable segments and, therefore, to a reduced urinary volume. Although diuretic therapy, particularly the use of thiazides, is now the specific form of therapy for NDI, it is at most an adjunct in the treatment of DI. The authors recommend this form of therapy in DI, either alone or in combination with the sulfonylureas, when a pronounced sensitivity to available vasopressins is present or if the polyuria is so severe that the AVP preparation must be administered too frequently to be practical as a form of therapy in itself. It is important to instruct the patient to restrict oral intake of sodium while on diuretics as the antidiuretic effectiveness of these agents is substantially reduced by ad libitum sodium. While treating diabetes mellitus with the sulfonylurea chlorpropamide (Diabinese) in a patient with DI, Arduino and associates213 noted that the nonglycosuric polyuria was considerably ameliorated. They clearly showed that this compound had an AVP-like effect and could be used successfully in the treatment of vasopressin-sensitive DI. It had no effect in nephrogenic DI. Since publication of these astute observations, numerous investigators have confirmed both the antidiuretic effect of chlorpropamide, which mimics small to moderate doses of AVP, and the therapeutic efficacy of chlorpropamide in many patients with DI.21422' Chlorpropamide acts through a mechanism(s) clearly different from that of the thiazides or other diuretics. The antidiuresis caused by the diuretics is secondary to their effect on sodium metabolism, and it is never accompanied by the production of a hypertonic urine. In contrast, when effective, a mild to moderate hypertonic urine is almost always produced by chlorpropamide and it has no known effects on sodium metabolism. It also does not alter the polyuria of nephrogenic DI, and the diuretics are as effective in NDI213,214 as in DI. The use of another sulfonylurea hypoglycemic agent, tolbutamide, has, on rare occasions, also been associated with hyponatremia, but it is not as effective as chlorpropamide for the treatment of DI.222 An interesting clinical observation that may bear directly on the mechanism of the action of
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chlorpropamide is that some patients with DI do not respond to oral or parenteral administration of chlorpropamide. These patients appear to be those with the most severe or "complete" DI (patients who release no AVP from the neurohypophysis and, therefore, have none in the circulation). This suggests that the antidiuretic effect of these agents requires a minimal concentration of AVP in the circulation, a level which by itself has little, if any, antidiuretic action in the DI patient. In most clinical studies,213-221 50 percent to 80 percent of patients with DI respond in varying degrees to chlorpropamide therapy. Many of these patients, from the magnitude of their polyuria and failure to respond to antidiuretic stimuli, were considered to be patients with complete DI. Chlorpropamide responsiveness greatly broadens the spectrum and number of patients with incomplete DI. It further indicates that a maximal sustained water diuresis may be present in these patients and water-loaded, normal subjects,221 despite the presence of minimal amounts of AVP in the circulation. These observations and the fact that chlorpropamide has no antidiuretic effect, but, rather, potentiates the action of nonantidiuretic doses of AVP in congenital DI rats,223 indicate that chlorpropamide acts through a mechanism that augments or enhances the action of AVP on the distal nephron. Ingelfinger and Hays224 have carried out in vitro experiments on the toad bladder that also strongly suggest this conclusion. They found that chlorpropamide alone at concentrations as high as 3 X 102 mol had no effect on water movement across the toad bladder. This concentration is almost six times the mean blood level attained in patients on long-term therapy with 0.5 gram chlorpropamide. However, when vasopressin in a low concentration (6 mU per ml) was added to the bladders that had been incubated with the chlorpropamide, water movement was substantially greater than that of the paired controls receiving vasopressin alone. This enhancement was not seen when a high concentration of vasopressin (60 mU per ml) was used. Although chlorpropamide enhanced the action of vasopressin, it did not augment the effect of cAMP on water movement across the toad bladder. These observations led Ingelfinger and Hays to question whether the sulfonylureas exert a direct AVP-like effect on the kidney in DI, and to suggest that they acted by increasing the sensitivity of the distal tubule to trace amounts of vasopressin or vasopressin-like
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peptides that persist in some patients with DI. They concluded from their observations that vasopressin and chlorpropamide share at least one site of action, and that this common site may precede cAMP within the receptor cell. This is supported by several in vitro studies in which chlorpropamide was shown to increase the activation of adenylate cyclase in the presence of submaximal concentrations of AVP.225'226 More recently, however, Brooker and Fichman227 in an in vitro system found that sulfonylureas inhibit the cAMP phosphodiesterase, and thereby could increase the steady-state level of cAMP in tissues, depending on the tissue concentration achieved after oral or parenteral administration. As might have been anticipated from the present state of the art, Zusman and associates'83 most recently showed that chlorpropamide enhances the hydro-osmotic effect of AVP by inhibiting the AVP-stimulated tissue synthesis of PGE, a step proximal to and independent of the stimulation of the adenyl cyclase-cAMP system. As mentioned earlier, PGE appears to modulate the action of AVP on the nephron; for example, a rise in local PGE decreases the effectiveness of AVP while a fall increases the antidiuretic response to AVP. Conversely, AVP stimulates PGE synthesis from the kidneys of the rabbit, normal rat, the Brattleboro rat and in the toad urinary bladder183 by increasing the rate of release of the PGE precursor arachidonic acid from intracellular storage pools.'83 That the chlorpropamide has no antidiuretic effect in patients with congenital nephrogenic DI,213'214 is consistent with Ingelfinger and Hays' concept224 that vasopressin and chlorpropamide share a common site of action. In NDI patients, this site in the tubular epithelium is nonresponsive to these agents. Miller and Moses221 found a significant correlation between the ability of the patients with DI to reduce free water clearance in response to water deprivation and the ability to reduce the free water clearance in response to subsequent chlorprQpamide treatment. Both ethanol and water loading were able to overcome the chlorpropamide-induced antidiuresis. Water deprivation while the patients were receiving chlorpropamide resulted in a further increase in urine concentration. Their data lend further insight to the concept that for chlorpropamide to produce an antidiuresis, some low level of endogenous antidiuretic hormone must be present. The single best explanation for its action is that chlorpro-
pamide is capable of augmenting the action of nonantidiuretic or low submaximal levels of endogenous or exogenous AVP. No evidence for direct AvP-like action of chlorpropamide has been found, because the ability to respond to the drug appears to depend on the presence of the residual AVPreleasing capacity of the neurohypophyseal system. Available data have not ruled out the additional possibility that chlorpropamide can enhance the release of AVP from a normal or an abnormal neurohypophyseal system. Such a central action is suggested by the effect of chlorpropamide in restoration of thirst in patients with adipsia.228 Miller and Moses22' concluded from their observations that the response to water deprivation in a patient with DI may serve as a useful test to predict which patients are most likely to be benefited by treatment with chlorpropamide. In adults, the dosage should be 250 mg once or twice per day and in children, a half to a third of this dosage, depending on the child's age. The antidiuretic effect should begin within the first day after ingestion of the drug, reaching peak effectiveness within three to four days.213-22' However, the authors have observed an occasional patient who requires as long as seven days to attain maximal antidiuretic benefit. Urine flow may fall to as little as a third of the predrug level with the production of a moderately (300 to 600 mOsm per liter) hypertonic urine. When the response is optimal, chlorpropamide can be used as the sole form of therapy. In other patients it may be an important adjunct to the various forms of vasopressin. Because its mechanism of action differs from the thiazides, the two drugs will have additive effects and thereby complement each other therapeutically. An occasional patient, primarily one who appears to have complete DI, will not respond to maximal doses (500 to 750 mg per day) of chlorpropamide, and the drug should not be continued in such a patient. It is extremely important to remember that hypoglycemia may accompany the antidiuretic dose, especially during periods of fasting. The patient must be made aware of the hypoglycemic symptoms, and it is recommended that small between meal and bedtime feedings be taken. Excess water ingestion in patients with DI and even in non-DI patients with diabetes mellitus, ingesting sulfonylureas may cause hyponatremia and water intoxication;68219"29 this is because of the sustained effect of those agents on the distal nephron. Clofibrate (Atromid) has also been shown to
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exert an antidiuretic action in patients with DI who have some residual neurohypophyseal function.230 This action appears to be mediated by enhanced secretion of endogenous AVP.231 Clofibrate has the advantage of having considerably fewer side effects than chlorpropamide. Carbamazepine (Tegretol), a potent anticonvulsant also used for the treatment of tic douloureux, has been shown to be very effective in the oral therapy of DI.232 Rado233 has shown that this agent has a synergistic action when used along with chlorpropamide in patients who show an inadequate response to chlorpropamide alone.23' Combined use of both agents permits lower doses of each agent to be used with less likelihood of dose-related toxicity. Kimura and co-workers have shown significant increases in bioassayable plasma AVP that were not fully suppressed by oral water loading after treatment with carbamazepine.234 This suggested that the drug acted centrally to release AVP independently of osmotic stimulation. In contrast, Meinders and co-workers were unable to detect plasma AVP by immunoassay during the period of maximal antidiuresis after carbamazepine therapy in both patients with DI and in control subjects.235 The explanation for this discrepancy is unclear. Carbamazepine does not appear to have any intrinsic antidiuretic activity nor does it augment submaximal doses of AVP.236 Needless to say, the well-treated patient with DI may lead a normal life in every respect. Untreated patients, as long as water is available and can be taken ad libitum, despite the inconvenience of the frequent day and night voidings, will suffer no basic ill effects and do remarkably well. However, if for any reason they are unable to ingest water or have it readily available, profound dehydration, water depletion and hyperosmolar syndrome may develop in a very short period of time. A patient with DI who is receiving adequate amounts of vasopressin, other forms of therapy, or both, need not alter his or her diet in any manner. During the first few days or weeks of treatment the patient should be warned against continued excessive water ingestion because of the danger of water intoxication. In those cases in which the DI is frequently of a temporary nature, the therapy should be discontinued at intervals to note the patient's water turnover and possible recovery.
REFERENCES 1-142, see Part I, Nov 1979 issue.
143. Kleeman CR, Vorherr H: Water metabolism and the neurohypophyseal hormones, In, Bondy PK, Rosenberg L (Eds): Duncan's Diseases of Metabolism. Philadelphia, WB Saunders Co, 1974 144. Rector FC Jr: Renal concentrating mechanisms, In Andreoli TE, Grantham JJ, Rector FC Jr, (Eds): Disturbances in Body Fluid Osmolality. Bethesda MD, American Physiology Society, 1977, chap 8, p 179 145. Schafer JA, Andreoli TE: Action of antidiuretic hormone on water and nonelectrolyte transport processes in mammalian collecting tubules, In Andreoli TE, Grantham JJ, Rector FC Jr (Eds): Disturbances in Body Fluid Osmolality. Bethesda MD, American Physiology Society, 1977, chap 3, p 57 146. Jamison RL, Maffly RH: The urinary concentrating mechanism. N Engl J Med 295:1059-1067, 1976 147. Hays RM, Levine SD: Pathophysiology of water metabolism, chap 1, In Brenner BM, Rector FC Jr (Eds): The Kidney. Philadelphia, WB Saunders Co, 1976, p 553 148. Tisher CC: Anatomy of the kidney, In Brenner BM, Rector FC Jr (Eds): The Kidney. Philadelphia, WB Saunders Co, 1976 149. Kriz W, Lever AF: Renal countercurrent mechanisms: Structure and function. Am Heart J 78:101-118, 1969 150. Kokko JP: Membrane characteristics governing salt and water transport in the loop of Henle. Fed Proc 33:24-30, 1974 151. Stephenson JL: Concentration of urine in a central core model of the renal counterflow system. Kidney Int 2:85-94, 1972 152. Stephenson JL: Concentrating engines and the kidney: I and It. Biophys J 13:512-546, 1973 153. Kokko JP, Rector FC Jr: Countercurrent multiplication system without active transport in inner medulla. Kidney Int 2: 214-223, 1972 154. Rocha AS, Koddo JP: Sodium chloride and water transport in the medullary thick ascending limb of Henle. J Clin Invest 52:612, 1973 155. Grantham JJ, Burg MB: Effect of vasopressin and cyclic AMP on permeability of isolated collecting tubules. Am J Physiol 211:255, 1966 156. Britton KE, Carson ER, Cage PE: A "bootstrap" model of the renal medulla. Postgrad Med J 52:279-284, 1976 157. Ullrich KJ, Jarausch KH: Untersuchungen zum Problem der Harn Konzentrierung und Verdunnung. Pflugers Arch Gesamte Physiol 262:537, 1956 158. Burg MB: Tubular chloride transport and the mode of action of some diuretics. Kidney Int 9:189-197, 1976 159. Pennell JP, Sanjana V, Frey NR: The effect of urea infusion on the urinary concentrating mechanism in protein depleted rats. J Clin Invest 55:399-409, 1975 160. Johnston PA, Battilana CA, Lacy FB, et al: Evidence for a concentration gradient favoring outward movement of sodium from the thin loop of Henle. J Clin Invest 59:234-240, 1977 161. Gertz KH, Schmidt-Nielsen B, Pagel D: Exchange of water, urea and salt between mammalian renal papilla and the surrounding urine (abstract). Fed Proc 25:327, 1966 162. Schiitz W, Schnermann JP: Pelvic urine composition as a determinant of inner medullary solute concentration and urine osmolality. Pfluigers Arch 334:154, 1972 163. Berliner RW, Bennett CM: Concentration of urine in the mammalian kidneys. Am J Med 42:777-789, 1967 164. Andreoli TE, Schafer JA: Mass transport across cell membranes: The effects of antidiuretic hormone on water and solute flows in epithelia, In Knobil E, Sonnenschein RR, Edelman IS (Eds): Annual Review of Physiology, Vol 38. Palo Alto CA, Annual Reviews, Inc, 1977, p 451 165. Hays RM: Antidiuretic hormone. N Engl J Med 292:659, 1976 166. Walter R, Clark WS, Mehta PK, et al: Conformational considerations of vasopressin as a guide to development of biological probes and therapeutic agents, In Andreoli TE, Grantham JJ, Rector FC Jr (Eds): Disturbances in Body Fluid Osmolality. Bethesda MD, American Physiology Society, 1977, chap 1, p 1 167. Handler JH, Orloff J: The mechanism of action of antidiuretic hormone, In Orloff J, Berliner RW (Eds): Handbook of Physiology, Sect. 8, Renal Physiology. Baltimore, Waverly Press, Inc, 1973, p 791 168. Dousa TP, Valtin H: Cellular actions of vasopressin in the mammalian kidney. Kidney Int 10:55-72, 1976 169. Kuo JF, Greengard P: Cyclic nucleotide dependent protein kinases-IV. Widespread occurrence of adenosine 3'5' monophosphate dependent protein kinase in various tissues and phyla of the animal kingdom. Proc Natl Acad Sci USA 64:1349-1355, 1969 170. Taylor A: Role of microtubules and microfilaments in the action of vasopressin, In Andreoli TE, Grantham JJ, Rector FC Jr (Eds): Disturbances in Body Fluid Osmolality. Bethesda MD, American Physiology Society, 1977, chap 5, p 97 171. Dousa TP, Barnes LD: Effects of colchicine and vinblastine cn the cellular action of vasopressin in mammaiian kidney-A possible role of microtubules. J Clin Invest 54:252-262, 1974 172. Kachadorian WA, Wade JB, Di Scala VA: Vasopressin induced structural change in toad bladder luminal membrane. Science 190:67-69, 1975 173. Kachadorian WA, Wade JB, Viterwyk CC, et al: Membrane structural and functional responses to vasopressin in toad bladder. J Membr Biol 30:381-401, 1977
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1962 191. Vejjajiva A, Sitprija V, Shuangshoti S: Chronic sustained hypernatremia and hypovolemia in hypothalamic tumor-A physiologic study. Neurology 19:161-166, 1969 192. Duchen GW: Metastatic carcinoma in the pituitary gland and hypothalamus. J Pathol Bacteriol 91:347-355, 1966 193. Adams JM, Kenny JD, Rudolph AJ: Central diabetes insipidus following intraventricular hemorrhage. J Pediatr 88:292-294, 1976 194. Braverman LE, Mancini JP, McGoldrick DPM: Hereditary idiopathic diabetes insipidus-A case report with autopsy findings. Ann Intern Med 63:504-508, 1965 195. Raff SB, Greenberg H: Night sweats-A dominant symptom in diabetes insipidus. JAMA 234:1252-1253, 1975 196. Friedland GW, Axman MM, Russi MF, et al: Renal back pressure atrophy with compromised renal function due to diabetes insipidus-Case report. Radiology 98: 359-360, 1971 197. Helbock H, Krivit W, Nesbit ME: Patterns of antidiuretic fuinction in diabetes insipidus caused by histiocytosis X. J Lab Clin Med 78:194-202, 1971 198. Rogers PW, Kurtzman NA: Renal failure-Uncontrollable thirst and hyperreninemia. JAMA 225:1236-1238, 1973 199. Cutler R, Kleeman CR, Maxwell MH, et al: Physiologic studies in nephrogenic diabetes insipidus. J Clin Endocrinol 22: 827-838, 1962 200. Feigin RD, Rimoin DL, Kaufman RL: Nephrogenic diabetes insipidus in a Negro kindred. Am J Dis Child 120:64-68, 1970 201. Kaplan SA. Yuceoglu AM, Strauss J: Vasopressin-resistant diabetes insipidus. Am J Dis Child 97:308-313, 1959 202. Bode HH, Crawford JD: Nephrogenic diabetes insipidus in North America: The Hopewell hypothesis. N Engl J Med 280: 750-754, 1969 203. Robertson GL: Immunoassay of plasma vasopressin in man. Proc Natl Acad Sci 66:1298-1305, 1970 204. Beardwell CG: Radioimmunoassay of arginine vasopressin in human plasma. J Clin Endocrinol Metab 33:254-260, 1971
1970 218. Meinders AE, Touber JL, de Vries LA: Chlorpropamide insipidus. Lancet 2:544-546, 1967 219. Webster B, Bain J: Antidiuretic effect and complications of chlorpropamide therapy in diabetes insipidus. J Clin Endocrinol Metab 30:215-227, 1970 220. Berndt WO, Miller M, Kettyle WM, et al: Potentiation of the antidiuretic effect of vasopressin by chlorpropamide. Endocrinology 86:1028-1032, 1970 221. Miller M, Moses AM: Mechanism of chlorpropamide action in diabetes insipidus. J Clin Endocrinol Metab 30:488-496, 1970 222. Hagen GA, Frawley TF: Hyponatremia due to sulfonylurea compounds. J Clin Endocrinol Metab 31:570, 1970 223. Mahoney JH, Goodman DA: Hypernatremia due to hypodipsia and elevated threshold for vasopressin release-Effects of treatment with hydrochlorothiazide, chlorpropamide and tolbutamide. N Engl J Med 279:1191-1196, 1968 224. Ingelfinger JR, Hays RA: Evidence that chlorpropamide and vasopressin share a common site of action. J Clin Endocrinol Metab 29: 738-740, 1969 225. Lozada ES, Gouaux J, Franki N, et al: Studies of the mode of action of the sulfonylureas and phenylacetamides in enhancing the action of vasopressin. J Clin Endocrinol Metab 34: 704-712, 1972 226. Beck N, Kim KS, Davis BB: Effect of chlorpropamide on cyclic AMP in rat renal medulla. Endocrinology 95:771-774, 1974 227. Brooker G, Fichman M: Chlorpropamide and tolbutamide inhibition of adenosine 3'5' cyclic monophosphate phosphodiesterase. Biochem Biophys Res Commun 42:824-828, 1971 228. Bode HH, Harley BM, Crawford JD: Restorational normal drinking behavior by chlorpropamide in patients with hypodipsia and diabetes insipidus. Am J Med 51:304-313, 1971 229. Weissman PN, Shenkman L, Gregerman RI: Chlorpropamide hyponatremia-Drug-induced inappropriate antidiuretic-hormone activity. N Engl J Med 284:65-71, 1971 230. de Gennes JL, Bertrand C, Bigorie B, et al: Etudes preliminaires de l'action antidiuretique du clofibrate (ou Atromid S) dans le diabete insipide pitressosensible. Ann Endocrinol 31:300308, 1970 231. Moses AM, Howanitz J, Van Gemert M, et al: Clofibrate induced antidiuresis. J Clin Invest 52:535-542, 1973 232. Braunhofer J. Zicha L: Eroffnet Tegretal neue Therapiemo glichkeiten bei bestimmten neurologischen und endokrinen Krankheitsbildern? Med Welt 17:1875-1880, 1966 233. Rado JP: Combination of carbamazepine and chlorpropamide in the treatment of "hyporesponder" pituitary diabetes insipidus. J Clin Endocrinol Metab 38:1-7, 1974 234. Kimura T, Matsui K, Sato T, et al: Mechanism of carbamazepine (Tegretol) induced antidiuresis: Evidence for release of antidiuretic hormone and impaired excretion of a water load. J Clin Endocrinol Metab 38:356-362, 1974 235. Meinders AE, Cejka V, Robertson GL: The antidiuretic action of carbamazepine in man. Clin Sci Molec Med 47:289-299, 1974 236. Moses AM, Miller M: Drug-induced dilutional hyponatremia. N Engl J Med 291:1234-1239, 1974
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Medical Progress

The Clinical Physiology of Water Metabolism

Physiologic Anatomy The nephrons of a mammalian kidney arise

DECEMBER 1979 * 131

THE WESTERN JOURNAL OF MEDICINE

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

Solute and Water Reabsorption in the Nephron

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

Impermeablet Very permeable Very permeable active chloride pump

Impermeablet Moderately permeable Impermeable

collecting duct, or both)

Permeable with AVP

Medullary collecting duct ......... Permeable with AVP

Impermeable except at collecting-duct junctions in inner medulla

DECEMBER 1979 * 131 * 6

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

before and after an infusion of urea to protein-

Two recent studies from Jamison's labora-

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

THE WESTERN JOURNAL OF MEDICINE

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

VASOPRESSIN 0.5 U/day (--)

COLCHICINE 0.1 mg/day_ (---)

3 4 5 6 Days Figure 26.-Response of urine osmolality to vasopres1

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

.-E'lS . h\'So ,v,'n,g .:x #: s *.:v, Bv sM . ..: -' ..

DECEMBER 1979 * 131

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

6 8 10 12 Excreted solute, mOsm/min

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

Concept of Free Water Clearance

liter; specific gravity, 1.037)

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

1.5 ml per minute= Cosm

V-CoSm=CH2O 0.3-1.5= -1.2 ml per minute

In recent years, the generation of a positive

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

Solute Excretion Rate The effect of the rate of solute excretion, or

DECEMBER 1979 * 131

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

Pathologic Factors Altering Maximal Concentrating Capacity

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

DECEMBER 1979 * 131 * 6

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART II

DECEMBER 1979 * 131

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

Subjects Hospitalized Onormals"

Diabetes insipidus, nephrogenic

NORMAL ADH RELEASE

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

V ml./nnI5, I 125 -1 ATTAINABLE 4

0 mOsm /Kg. 30 295

THE WESTERN JOURNAL OF MEDICINE

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11

CLINICAL PHYSIOLOGY OF WATER METABOLISM-PART 11