Disorders of Water Homeostasis

Tomas Berl and Robert W. Schrier

Historical and Evolutionary Aspects of Renal Concentrating and Diluting Processes

In From Fish to Philosopher, Smith (1) suggested that the concentrating capacity of the mammalian kidney may have played an important role in the evolution of various biologic species, including Homo sapiens. He suggested that the earliest protovertebrates resided in a saltwater environment that had a composition similar to their own extracellular fluid (ECF); therefore, these species could ingest freely from the surrounding sea without greatly disturbing the composition of their own milieu interieur. However, when these early vertebrates migrated into freshwater streams, the evolution of a relatively water-impermeable integument was mandatory to avoid fatal dilution from their hyposmotic, freshwater environment. Thus a vascular tuft—which we now call the glomerulus—developed, enabling the fish to filter the excess fluid from their blood.

The proximal tubule, which reabsorbed isotonic fluid, evolved in response to the need for salt preservation. However, this did not allow the excretion of hypotonic urine, which is critical for the survival of organisms ingesting hypotonic fluid from their freshwater environment. This need was met by the development of the distal tubule, which could dilute tubular fluid and ultimately urine. This dilution is accomplished by reabsorption of salt without water, because the distal tubular epithelium was relatively impermeable to water. The fish then could excrete the excess solute-free water they had obtained from their freshwater environment while concomitantly conserving their body salts.

Vertebrates began to reside on dry land several million years later. The problem of salt conservation persisted in this terrestrial environment, but the excretion of large volumes of dilute fluid was no longer necessary. Rather, conservation of fluid became of primary importance in the new arid environment. The kidneys of reptiles, birds, and mammals, however, had glomeruli, which filtered large amounts of fluid and salt, even though excretion of only minute amounts of these substances was needed to maintain daily balance. In reptiles and birds, the kidneys responded to this challenge by a decrease in the number of capillary loops in their glomerular tufts. Aglomerular kidneys even evolved in some fish, such as the sea horse and pipefish, which may have been the first vertebrates to return to the sea. Tubular secretory systems evolved in these nephrons to allow elimination of nitrogenous wastes without the need for large volumes of filtered fluid. Also, a relatively insoluble nitrogenous end product, uric acid, was produced that could be excreted in supersaturated solutions with minimal water loss.

The high-pressure glomerular filters were maintained in mammals; however, the countercurrent mechanism developed for concentrating urine. Mammals, along with birds, are unique among vertebrates in possessing loops of Henle and in their ability to compensate for water deficits by elaborating urine more concentrated than blood.

Countercurrent Concentrating Mechanism

By analogy with heat exchangers, the functional significance of the loops of Henle was proposed when Kuhn and Ryffel of the physical chemistry department at the University of Basel, Switzerland, originated the concept of the countercurrent multiplier system for urine concentration in 1942 (2). The hypothesis states that a small difference in osmotic concentration (single effect, or einzeln Effekt) at any point between fluid flowing in opposite directions in two parallel tubes connected in hairpin manner can be multiplied many times along the length of the tubes. In the kidney, a small, 200 mOsm gradient results in a large osmolar concentration difference between the corticomedullary junction and the hairpin loop at the tip of the papilla. Since then, although numerous experiments have confirmed the overall operation of a countercurrent multiplier in the kidney, with the thick ascending limb of Henle as the water-impermeable site of active solute reabsorption (3), the precise mechanism that culminates in the generation of the medullary osmotic gradient is not fully understood (4).

URINARY CONCENTRATION AND DILUTION

As disturbances in the capacity of the kidney to concentrate and dilute the urine are central to the pathogenesis of disorders of water balance, we will briefly review the components of the diluting and concentrating process in the mammalian kidney. These are depicted in Figure 1-1A and B, respectively (5). It is important to emphasize that many of these processes are the same whether the final excreted urine is hypotonic or hypertonic to plasma.

The rates of glomerular filtration and proximal tubular reabsorption are important primarily in determining the rate of sodium and water delivery to the more distal portions of the nephron, where the renal concentrating and diluting mechanisms are operative. Fluid reabsorption in the proximal tubule is isosmotic; therefore, tubular fluid is neither concentrated nor diluted in the proximal portion of the nephron. Rather, after approximately 70% of glomerular filtrate is reabsorbed in the proximal tubules, the remaining 30% of fluid entering the loop of Henle is still isotonic to plasma. The reabsorption of sodium chloride is primarily driven by the Na/H 3 transporter whereas the isotonic removal of water is facilitated by the robust expression of the water channel aquaporin 1 (AQP₁), depicted in Figure 1-2. A decrease in glomerular filtration rate (GFR) or an increase in proximal tubular reabsorption, or both, may diminish the amount of fluid delivered to the distal nephron and thus limit the renal capacity to excrete water. Similarly, a diminished GFR and increased proximal tubular reabsorption may limit the delivery of sodium chloride to the ascending limb, where the tubular transport of these ions without water initiates the formation of the hypertonic medullary interstitium. With diminished delivery of sodium chloride to the ascending limb, the resultant lowering of medullary hypertonicity impairs maximal renal concentrating capacity.

Because the urine that emerges from the proximal tubule is isosmotic, the first nephron segment actually involved in urinary concentration is the descending limb of Henle’s loop. There are two types of descending limbs. The short loops originate in superficial and mid cortical glomeruli and turn in the outer medulla. The long loops originate in deep cortical and juxtamedullary glomeruli and penetrate variable distances into the inner medulla. Short and long descending limbs are anatomically distinct; the long limbs in particular display considerable interspecies variability (6). Interestingly, no correlation is apparent between a species’ maximal concentrating ability and the ratio of short and long loops. In fact, in rodents with highest urinary concentrations, the number of short loops is considerably greater than the number of long loops. Approximately 15% of nephrons possess long loops in the human kidney; the other 85% of nephrons have short loops. The descending thin limb is very water permeable as it also has, in its first portion, abundant expression of AQP₁ (7). Thus, tubular fluid is concentrated as it descends primarily, but probably not exclusively, by the extraction of water.

Somewhat proximal to the hairpin turn, there is a transition from the descending limb to the ascending thin limb of Henle’s loop. This segment, as well as the remainder of ascending limb, is water impermeable, As will be further discussed, the nature and particular site at which the movement of solutes (urea and NaCl) occur has not been fully defined. Active sodium transport has not been demonstrated convincingly, and this segment’s morphologic appearance with few mitochondria does not suggest active metabolic work.

The thick ascending limb of Henle’s loop appears both structurally and functionally distinct from its thin counterpart. The epithelium is remarkably uniform among species with tall, heavily interdigitating cells with large mitochondria. The observation that fluid emerges into the early distal tubule hypotonic (about 100 mOsm/kg H₂O) supports the view that active sodium chloride transport out of this water-impermeable segment provides the single effect required for the operation of the countercurrent multiplier. The primary mechanism of chloride absorption in the thick ascending limb is mediated by an electroneutral sodium, potassium, and chloride (Na⁺:K⁺:2Cl^–) cotransport (Fig. 1-2).

The distal convoluted tubule is the segment between the macula densa and collecting ducts. This is a morphologically heterogenous segment (6) that is also water impermeable and unresponsive to vasopressin. The collecting ducts are formed in the cortex by the confluence of several distal tubules. They descend through the cortex and outer medulla individually, but successively fuse together on entering the inner medulla. In humans, a terminal inner medullary collecting duct draws from as many as 7,800 nephrons. The collecting ducts possess vasopressin-sensitive adenylate cyclase in all species studied; they are virtually impermeable to water in the absence of the hormone. The vasopressin-sensitive water channel AQP₂ mediates water reabsorption in this segment of the nephron in concert with AQP₃ and AQP₄ (7,8). The collecting duct in its cortical and medullary segments is also impermeable to urea, but in response to the vasopressin-sensitive urea transporter UT 1, the inner medullary collecting duct is rendered urea permeable (9).

Kokko and Rector, as reviewed by Sands (10), have proposed a model of urinary concentration that is in concert with the anatomic features and the permeability characteristics of the various segments of the system, while limiting the active transport of solute to the thick portion of the ascending limb of Henle in the outer medulla. The components of the mechanism, as depicted in Figure 1-3A, are as follows:

To prevent urea removal from the inner medulla to the cortex, the ascending and descending vasa recta act as a countercurrent exchanger and “trap” urea in the inner medulla. The ascending vasa recta also may deposit urea into adjacent descending thin limbs of a short loop of Henle, thereby recycling it to the inner medullary collecting tubule. The descending limbs of short loops do not enter the inner medulla; thus, the addition of urea to these loops does not interfere with the removal of water from the descending thin limb in the inner medulla, a step that is so crucial to the concentrating process.

This passive model of urinary concentration has a number of attractive features, and many of its aspects have been experimentally supported (10). However the requisite difference in sodium and urea permeabilities that is needed for this model to operate passively (point 5 above) have not been met, as mathematical models that employ available permeabilities fail to generate the desired osmotic gradients. Thus, alternatives have been tested. Among these, a three-dimensional reconstruction of the components of the rat inner medulla coupled with the development of mathematical models has emerged with a variation of the previous model, designated as the solute mixing passive model, depicted in Figure 1-3B (4). This model recognizes that the water permeability of the descending limb does not extend into the inner medulla as AQP₁ is absent in the lower half of this limb of Henle’s loop. The high urea permeability and the passive exit of sodium from tubular fluid occur before the bend of the loop, equally in the descending as well as ascending thin loops rather than exclusively in the latter. Although this model predicts the generation of concentrated urine, it does not produce one that is maximally concentrated (4).

What remains widely agreed upon is that the single effect in the ascending limb of Henle, so critical to the operation of the countercurrent system and urinary concentration, also serves to dilute the urine. In the absence of vasopressin, and thus with water impermeability of the collecting ducts, the continued reabsorption of solute in the remainder of the distal nephron results in a maximally dilute urine (50 mOsm/kg). Thus, it should be apparent that impairment of sodium, chloride, and potassium cotransport in the ascending limb of the loop of Henle will limit the renal capacity both to concentrate and to dilute the urine.

Figure 1–3 (A) Schematic representation of the passive urinary concentrating mechanism. 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 sodium, chloride, and potassium cotransport renders the tubule fluid dilute and the outer medullary interstitium hyperosmotic (1). In the last part of the distal tubule and 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 (data not shown). This medullary recycling of urea, in addition to trapping of urea by countercurrent exchange in the vasa recta (data not shown), causes urea to accumulate in large quantities in the medullary interstitium (indicated by UREA), where it osmotically extracts water from the descending limb (4) and thereby concentrates sodium chloride 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. (From Jamison RL, Maffly RH. The urinary concentrating mechanism. N Engl J Med. 1976;295(19):1059, Copyright ¿ 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) (B) Illustrating the unique permeabilities and solute fluxes of current solute separation, solute mixing passive model for concentrating urine. Thick tubule border indicates AQP₁-null, water-impermeable segment of DTL as well as water-impermeable ATL and TAL. The AQP₁-null segment of the DTL is essentially impermeable to inorganic solutes and water. In this model, both the ATLs and the DTLs (including the AQP₁-null segment) are highly permeable to urea. In contrast to the original passive model, passive NaCl reabsorption without water begins with the prebend segment and is most significant around the loop bend. Also, in contrast to previous models, urea moves passively into the entire DTL and early ATL, but as this urea-rich fluid further ascends in the ATL, it reaches regions of lower interstitial urea concentration and diffuses out of the ATL again. Thus, the loops act as countercurrent exchangers for urea. (Republished with permission of American Society of Nephrology, from Dantzler W. et al Urine-concentrating mechanism in the inner medulla: function of the thin limbs of the loops of Henle. Clin J Am Soc Nephrol. 2014;9(10):1781–1789; permission conveyed through Copyright Clearance Center, Inc.)

Medullary Blood Flow

The rate of solute delivery to the collecting duct is a known determinant of renal concentrating capacity. As depicted in Figure 1-4, in spite of maximal levels of vasopressin, urinary osmolality in normal humans progressively diminishes as solute excretion increases. At high rates of solute excretion, urinary osmolality may reach isotonicity in humans, even though supraphysiologic doses of vasopressin are infused. An increase in solute excretion even may be associated with hypotonic urine with the infusion of submaximal doses of vasopressin in patients with pituitary diabetes insipidus. At least two factors may be responsible for this effect of solute excretion on renal concentrating capacity. First, a solute diuresis generally is associated with an increase in medullary blood flow, which could lower the medullary solute concentration profile. Second, the rapid rate of tubular flow through the medullary collecting duct could shorten contact time sufficiently so that complete osmotic equilibrium of fluid would not be allowed between the collecting duct and medullary interstitium, even though vasopressin had made the collecting duct membrane maximally permeable to water.

Figure 1–4 Effect of solute excretion on renal concentration and diluting mechanisms. The submaximal response to antidiuretic hormone (ADH) may result from the presence of submaximal amounts of ADH or the diminished response of the collecting duct to maximal amounts of ADH. (Reproduced from de Wardener HE, del Greco F. Influence of solute excretion rate on production of hypotonic urine in man. Clin Sci. 14(4):715–723. © 1955, the Biochemical Society.)

Antidiuretic Hormone

The renal concentrating and diluting processes are ultimately, and most importantly, dependent on the presence or absence respectively of arginine vasopressin (AVP) to modulate the water permeability of the collecting duct. AVP, a cyclic hexapeptide (mol wt 1,099) with a tail of three amino acids, is the antidiuretic hormone (ADH) in humans (Fig. 1-5). The presence of a basic amino acid (arginine or lysine) in the middle of the intact hormone at position 8 is crucial for antidiuresis, as is the asparagine at position 5. AVP is synthesized in the supraoptic and paraventricular magnocellular nuclei in the hypothalamus. In these nuclei, a biologically inactive macromolecule is cleaved into the smaller, biologically active AVP. Both oxytocin and AVP are encoded in human chromosome 20 in close proximity to each other, depicted in Figure 1-6. The preprohormone gene is approximately 2,000 base pairs in length and comprises three exons (Fig. 1-6). AVP is encoded in the first exon following a signal peptide. Although spanning all three exons, the binding ­protein neurophysin is encoded primarily in exon B and the terminal glycoprotein in exon C. The promoter has cis-acting elements, including a glucocorticoid response element, a cyclic adenosine monophosphate (cAMP) response element, and four AP-2 binding sites (11). The precursor prohormone, called propressophysin, is cleaved by removal of the signal peptide after translation. Vasopressin, with its binding protein neurophysin II, and the glycoprotein are transported in neurosecretory granules down the axons and stored in nerve terminals in the pars nervosa. There is no known physiologic role of the neurophysins, but they neutralize the negative charge of vasopressin. The release of stored peptide hormone and its neurophysin into the systemic or hypophyseal portal circulation occurs by an exocytosis. With increased plasma osmolality, electrical impulses travel along the axons and depolarize the membrane of the terminal axonal bulbs. The membrane of the secretory granules fuses with the plasma membrane of the axonal bulbs, and the peptide contents are then extruded into the adjacent capillaries. The Brattleboro rat, a strain with an autosomal recessive defect that causes AVP deficiency, is afflicted by a single base deletion in exon B. This leads to a shift in the reading frame, with loss of the translational stop code. Although transcribed and translated in the hypothalamus, the translational product is neither transported nor processed in these mutant rats.

The regulation of AVP release from the posterior pituitary is dependent primarily on two mechanisms: osmotic and nonosmotic pathways (Fig. 1-7).

Osmotic Release of Vasopressin

The osmotic regulation of AVP is dependent on “osmoreceptor” cells in the anterior hypothalamus in proximity but separate from supraoptic nuclei. These cells, most likely by altering their cell volume, recognize changes in ECF osmolality. Cell volume is decreased most readily by substances that are restricted to the ECF, such as hypertonic saline or hypertonic mannitol, and thus enhance osmotic water movement from cells; these substances are very effective in stimulating AVP release. Since the effects of saline and mannitol are comparable, this supports the view that the response is due to changes in effective osmolality rather than to sodium per se. In contrast, urea moves readily into cells and therefore does not alter cell volume; hypertonic urea does not effectively stimulate AVP release. The effects of increased osmolality on vasopressin release are associated with measurable (twofold to fivefold) increases in vasopressin precursor messenger RNA (mRNA) in the hypothalamus. The osmoreceptor cells are very sensitive to changes in ECF osmolality. An increase of ECF osmolality by 1% stimulates AVP release, whereas water ingestion causing a 1% decrease in ECF osmolality suppresses AVP release (Fig. 1-8). A role for members of the transient receptor potential vallinoid family (TRPV 1 and 4) in osmoregulation has been suggested as knockouts of these proteins in mice become somewhat hypernatremic and display blunted vasopressin secretion in response to hypertonic stimuli as summarized by Cohen (12).

A close correlation between AVP and plasma osmolality has been demonstrated in subjects with various states of hydration, although there are considerable genetically determined individual variations in both the threshold and sensitivity (Fig 1-8). In humans, the osmotic threshold for vasopressin release is between 280 and 290 mOsm/kg. The system is so efficient that plasma osmolality usually does not vary more than 1% to 2 %, despite great variations in water intake. There is also a close correlation between AVP and urinary osmolality, allowing for the maintenance of tonicity of body fluids.

Vasopressin release can occur in the absence of changes in plasma osmolality (5). Although a number of such nonosmotic stimuli exist, physical pain, emotional stress, and a decrement in blood pressure or volume are the most prominent ones. A 7% to 10% decrement in either blood pressure or blood volume causes the prompt release of vasopressin (Fig. 1-7). Because the integrity of the circulatory volume takes precedence over mechanisms that maintain tonicity, activation of these nonosmotic pathways overrides any decline in the osmotic stimulus that otherwise would suppress the hormone’s release. This process accounts for the pathogenesis of hyponatremia in various pathophysiologic states, including cirrhosis, heart failure, and several endocrine disorders.

There is considerable evidence for the existence of baroreceptor sensors in the low-pressure (venous) areas of the circulation, particularly in the atria. Atrial distention causes a decrease in plasma AVP levels, and a water dieresis; this reflex is mediated by the vagus nerve. Alternatively, arterial baroreceptors in the aorta and carotid sensors send impulses through the vagus and glossopharyngeal nerves to the nucleus tractus solitarii of the medulla. Unloading of these arterial baroreceptors decreases tonic inhibition and leads to the nonosmotic release of vasopressin. Denervation of these arterial baroreceptors has been shown to abolish the nonosmotic release of AVP.

It is possible that angiotensin II is a mediator of AVP release in these states because many of the pathophysiologic states associated with nonosmotic AVP release are characterized by enhanced plasma renin activity and therefore increased angiotensin II levels. The experimental results in this regard are however conflicting. Activation of the sympathetic nervous system seemed be involved in the nonosmotic stimulation of AVP. In this regard, the supraoptic nuclei are heavily innervated by noradrenergic neurons. Other pathways that could stimulate the nonosmotic secretion of AVP have been proposed; for example, the antidiuresis associated with nausea and pain has been ascribed to an emetic and to a cerebral pain center, respectively. A role for baroreceptor pathways however has not been convincingly excluded even in these settings. Other biogenic amines, polypeptides, and even cytokines have been implicated as modulators of AVP release in addition to catecholamines.

Cellular Action of Vasopressin

Once released from the posterior pituitary, vasopressin exerts its biologic action on water excretion by binding to V₂ receptors in the basolateral membrane of the collecting duct (Fig. 1-9) (13). The receptors to which vasopressin binds have been cloned. The V₁ receptor on blood vessels and elsewhere is a 394 amino acid protein with seven transmembrane domains (14). The 370 amino acid V₂ receptor, which is present only in the kidney and has a similar configuration, has been cloned for both rats (15) and humans (16). Although the V₁ receptor messenger is plentiful in the glomerulus, it is also detected in the collecting duct, where the V₂ message is predominant.

Binding of AVP to its V₂ receptor increases adenylate cyclase activity resulting in the generation of cyclic adenosine 3′,5′-monophosphate (cAMP) from adenosine triphosphate. The V₂ receptor is coupled to the catalytic unit of adenylate cyclase by the stimulatory guanine nucleotide binding regulatory protein, Gs. This is a heterotrimeric protein whose α subunit binds and hydrolyzes guanosine triphosphate. The heightened cAMP formation activates protein kinase A (PKA), which in turn phosphorylates serines and threonines. The activation of PKA brings about the phosphorylation of the water channel AQP₂ at serine 256 in intracellular vesicles, and thereby increases the trafficking of the water channel to the luminal membrane (17). This sequence of events results in a marked increase in the water permeability of the luminal membrane and thereby the collecting tubule. AQP₂ is a member of an increasingly large family of water channels whose archetypal member, AQP₁, cloned by Agre and coworkers (18) is, as mentioned previously, abundant in the proximal tubule and the proximal half of the descending limb of Henle. In contrast, AQP₂ is limited to the vasopressin-sensitive principal cell of the collecting duct, and particularly to the cytoplasm and luminal membrane. Vasopressin also is involved in the long-term regulation of the expression of AQP₂ (19). AQP₃ and AQP₄ are widely distributed, including the collecting duct principal cell, where they are localized at the basolateral membrane. In this basolateral membrane, they serve as conduits for water exit from the cell. Other AQP₆ to AQP₈ also are expressed in the kidney. AQP₆ is present in intercalated cells, AQP₇ in the S₃ segment of the proximal tubules, AQP₈ in proximal tubules and collecting ducts, and AQP₁₁ in the proximal tubule (19). The physiologic roles of these water channels in the kidney are not clear. The cytoskeleton also plays an important role in the trafficking of the AQP₂ water channel to the luminal membrane, a process involving both exocytic insertion associated with AVP stimulation and endocytic retrieval associated with suppression of AVP action.

Quantitation of Renal Water Excretion

This relationship is depicted further in Figure 1-10.

The excretion of hypertonic urine has the net effect of returning solute-free water to the organism and thereby dilutes body fluids. In contrast, the excretion of hypotonic urine has the net effect of ridding the organism of solute-free water and thus concentrating body fluids. Urine osmolality alone does not give the volume of water added to or removed from the organism; the calculation of C_H2O or T^c_H2O better allows the quantitation of water balance.

A limitation of the equation is that it fails to predict clinically important alterations in tonicity and serum sodium concentration because it factors in urea. Urea is an important component of urine osmolality, but does not establish transcellular osmotic gradients because it readily crosses cell membranes. Consequently, urea influences neither the serum sodium concentration nor the release of vasopressin, and its inclusion in urine osmolality does not predict changes in serum sodium. This is better reflected if specifically electrolyte-free water clearance (C_H2O[e]) is measured. In this formulation, the serum osmolality is replaced by serum sodium and urine osmolality by U_Na + U_K.

Therefore:

Thus, only 1,500 mL of solute-free water is returned to body fluids during this maximal antidiuresis. In contrast, with the same daily solute load of 600 mOsm, a minimal urine osmolality of 60 mOsm/kg H₂O, and a daily urine volume of 10 L, the renal capacity to excrete C_H2O is much greater than the capacity to return solute-free water (T^c_H2O) to the body. More specifically,

The renal concentrating mechanism represents the first defense against water depletion and hyperosmolality. A perturbation in any component of the concentrating mechanism, shown in Figure 1-1B, culminates in an inability to maximally concentrate urine. Renal concentrating defects ensue when there is impairment in the generation of medullary hypertonicity either as a consequence of decreased delivery of solutes to the loop (diminished GFR) or inability to reabsorb NaCl in the loop of Henle (loop diuretics). Likewise, failure to render the collecting duct permeable to water because vasopressin is absent or the tubule is unresponsive to vasopressin also results in a renal concentrating defect. Thirst becomes a very effective mechanism for preventing further increases in serum sodium when renal concentration is impaired (20,21). The plasma osmolality threshold for thirst appears to be approximately 10 mOsm/kg H₂O above that of vasopressin release (Fig. 1-8). In fact, thirst is so effective that even patients with complete diabetes insipidus avoid hypernatremia by fluid intake in excess of 10 L/day. Therefore, hypernatremia supervenes only when hypotonic fluid losses occur in combination with a disturbance in water intake (22). This is most commonly seen in the aged (with an alteration in level of consciousness), the very young (with inadequate access to water), or a rare subject (with a primary disturbance in thirst).

Hypernatremia can develop with either low, normal, or, more rarely, high total body sodium, as shown in Figure 1-11 (23).

HYPERNATREMIA IN PATIENTS WITH LOW TOTAL BODY SODIUM

Patients who sustain losses of both sodium and water, but with a relatively greater loss of water, are classified as having hypernatremia with low total body sodium. Such patients exhibit the signs of hypovolemia such as orthostatic hypotension, tachycardia, flat neck veins, poor skin turgor, and dry mucous membranes. The causes that underlie the hypovolemic state are similar to those that cause hypovolemic hyponatremia. The effect on serum sodium is determined by the failure to ingest water (hypernatremia) or excessive free water intake (hyponatremia). Extrarenal loss of hypotonic fluid can occur either through the skin because of profuse sweating in a hot and/or humid environment or, more frequently, from the gastrointestinal tract in the form of diarrhea. Lactulose-induced diarrhea leading to hypernatremia appears to be common, although primarily recognized in children. Urine osmolality is high (usually >800 mOsm/kg H₂O) and urinary sodium concentration is low (<10 mEq/L) because the renal water and sodium conserving mechanisms operate normally in these patients. Hypotonic losses also can occur by the renal route during a loop diuretic–induced hypotonic diuresis or an osmotic diuresis with either mannitol, glucose, or as is not uncommon, urea in the setting of excessive protein supplementation. Elderly patients with partial urinary tract obstruction can excrete large volumes of hypotonic urine. The urine with such obstruction is hypotonic or isotonic, and the urinary sodium concentration is greater than 20 mEq/L. As glucose and mannitol enhance osmotic water movement from the intracellular fluid to the ECF compartment, these patients may have a normal or even low serum sodium concentration in spite of serum hypertonicity.

HYPERNATREMIA IN PATIENTS WITH NORMAL TOTAL BODY SODIUM

Failure to normally synthesize or secrete vasopressin limits maximal urinary concentration and causes varying degrees of polyuria and polydipsia, depending on the severity of the disease. The causes of central diabetes insipidus are listed in Table 1-1.

In a survey of 79 children and young adults, the disease was idiopathic in 52%, with a significant number having tumors and Langerhans cell histiocytosis. Most had magnetic resonance imaging (MRI) findings and some had thickening of the pituitary stalk that may reflect lymphocytic infiltration as part of an autoimmune process. The probability of also developing anterior pituitary hormone deficiency was 80% in the group that had tumors, compared to 50% in subjects with idiopathic diabetes insipidus (24,25). The disease may rarely be inherited. Families with an autosomal dominant inheritance pattern have been described (26). Mutations in the coding region of the gene in all three exons have been described affecting one allele. These mutations are in the signal protein and neurophysin. Most are missense mutations, but other mutations have been described as well (26).What is peculiar about this inherited form of central diabetes insipidus is that the onset of symptoms is delayed for several months after birth and sometimes even longer. It appears that the mutant hormone forms complexes with the native hormone and the accumulation of these complexes in the endoplasmic reticulum causes progressive loss of vasopressin-producing neurons (27). There is also a rare inherited autosomal recessive form of central diabetes insipidus that occurs in association with diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome). The syndrome appears to result from mutations in region PC 16 of chromosome 4, which codes for a protein expressed in various tissues (28).

Head trauma, hypophysectomy, and neoplasms, either primary or metastatic (mainly from lung and breast tumors), constitute most of the other causes. Other etiologic factors include encephalitis, sarcoidosis, eosinophilic granuloma, and histiocytosis. Finally, central diabetes insipidus has been described following development of cerebral edema in 11 postoperative hyponatremic women (29).

Clinical Features

Polyuria and polydipsia are the hallmarks of central diabetes insipidus and must be considered in the differential diagnosis of any patient who presents with such symptoms. As illustrated in Figure 1-10, polyuria can occur from a solute diuresis, in which case C_osm is increased and the urine osmolality is greater than 300 mOsm/kg. A diagnosis of central (vasopressin-deficient) diabetes insipidus should be considered when polyuria is caused by an increase in C_H2O and urine osmolality is less than 150 mOsm/kg. Urine flow can range between 3 and 15 L/day, depending on the severity of the disease. The disorder frequently has an abrupt onset and occurs with equal frequency in both sexes. Although the time of onset is extremely variable, it is rare in infancy and is most frequent in the 10- to 20-year age group. Patients with central diabetes insipidus often have a predilection for cold water. Nocturia frequently is marked because there is little diurnal variation in the polyuria. Bladder capacity may be increased in untreated patients, however; consequently, nocturia may not be a prominent symptom. Nevertheless, nocturia is frequent generally, and sleep deprivation commonly leads to fatigue and irritability. Patients with central diabetes insipidus do not develop hypernatremia if the thirst mechanism is intact and water is available; thus, they have no symptoms except for the inconvenience associated with marked polyuria and polydipsia. However, severe and even life-threatening hypernatremia can supervene with concomitant hypodipsia, no access to water, or an illness that precludes adequate water intake.

The differential diagnosis between central diabetes insipidus and primary polydipsia may be very difficult. Plasma vasopressin levels are diminished in both circumstances. This is caused by impaired synthesis or secretion of vasopressin in central diabetes insipidus. Thus, these patients have polydipsia secondary to impaired renal water conservation in the absence of AVP. In contrast, the patient with primary polydipsia ingests large amounts of fluids, which physiologically suppress endogenous AVP release, resulting in the urinary excretion of the large volume of ingested water. Thus, the patient with central diabetes insipidus has polydipsia because of polyuria, whereas the individual with primary polydipsia has polyuria because of polydipsia. Abnormalities in the hypothalamic-pituitary region can be seen in a majority of patients with central diabetes insipidus with the use of the computed tomography scan. MRI may improve the sensitivity further. Normally, on T1-weighted images, the posterior pituitary produces a bright signal that is indistinguishable from fatty tissue, but this signal is lost in patients with central diabetes insipidus (30).

The patient’s history can be helpful in making the differential diagnosis. Whereas the patient with central diabetes insipidus has an abrupt onset of polyuria and polydipsia, the patient with primary polydipsia has a more vague history of the onset of these symptoms. The latter patients also may have a history of considerable variation in water intake and urine output on an hour-to-hour or day-to-day basis, whereas the patient with central diabetes insipidus has a very consistent need for water intake. Large variations in water intake, in the patient whose intakes and outputs are measured, therefore are a clue to the diagnosis of compulsive water drinking. Nocturia is more severe and frequent in subjects with central diabetes insipidus. Finally, the previously noted preference for ice water usually is not described by subjects with primary polydipsia. These patients also may have a history of psychiatric disorders and not infrequently are women during menopause. A plasma osmolality below 270 mOsm/kg H₂O strongly suggests primary polydipsia because of the modest positive fluid balance, whereas the patient with central diabetes insipidus is generally in modest negative fluid balance. Thus, a sodium greater than 143 mm/L or plasma osmolality above 295 mOsm/kg H₂O essentially excludes primary polydipsia and suggests central diabetes insipidus. Although the differentiation between central and dipsogenic diabetes insipidus in their classic forms may pose no difficulties, the correct diagnosis is frequently difficult to make when the defect in vasopressin release is partial. A fluid deprivation test may provide the most reliable information regarding the assessment of these polyuric disorders (Fig. 1-12). Fluid deprivation must be instituted with careful monitoring of body weight and vital signs, because the patient with central diabetes insipidus may rapidly develop a severe negative fluid balance. The test is stopped when body weight decreases by more than 3%, the patient develops orthostatic blood pressure changes when the serum sodium is greater than 145 mmol/L, or the urine osmolality reaches a plateau in three consecutive hourly collections. This period of fluid deprivation is followed by the injection of 5 units of aqueous vasopressin or 1 μg of DDAVP subcutaneously. Normal subjects require 16 to 18 hours to achieve a mean maximum urine osmolality of approximately 1,000 to 1,200 mOsm/kg and the administration of vasopressin causes no further increase in their urine osmolality. This suggests that the dehydration test has maximally stimulated endogenous vasopressin release. One might surmise, therefore, that fluid deprivation readily discriminates between those with a normal neurohypophyseal system, such as those with primary polydipsia, and the patient with central diabetes insipidus. As illustrated in Figure 1-12, this is not always the case. Observations of normal subjects who have drunk large daily volumes of water, however, have demonstrated a blunted response to vasopressin (31). A decrease in medullary tonicity occurs as a result of an increase in medullary blood flow and is associated with the diminution in renal concentrating capacity. For this reason, patients with primary polydipsia may demonstrate submaximal concentrating ability after fluid deprivation, but their urine osmolality still generally exceeds 300 mOsm/kg. There is however, no further increase with exogenous vasopressin because endogenous vasopressin secretion is maximal with fluid deprivation. This serves to differentiate such patients from those with central diabetes insipidus, whose urine osmolality substantially increases (>10%) following the administration of vasopressin (Fig. 1-12). The recognition of patients who have only a partial defect in AVP secretion is of particular importance. Urine osmolalities in these patients and those with primary polydipsia may be similar after fluid deprivation, but only the patient with partial diabetes insipidus will respond further to exogenous vasopressin. If exogenous vasopressin increases urine osmolality by more than 10% after fluid deprivation, a defect in AVP release is probably present. Only patients with complete diabetes insipidus may demonstrate overt clinical symptoms of polyuria and polydipsia, whereas patients with partial central diabetes insipidus may remain asymptomatic. The measurement of urinary AQPs has been suggested to differentiate various forms of diabetes insipidus (32), and more specifically to differentiate psychogenic polydipsia for central diabetes insipidus (33). Urinary AQP₂ was decreased in subjects with central deficiency AVP, but not in those with psychogenic polydipsia. The clinical applicability of this test is limited at this time.

The above described water deprivation test followed by exogenous AVP administration is useful in the differential diagnosis of polyuric disorders in 95% of cases; it is time consuming and requires considerable patient cooperation. Occasionally, the diagnosis of central diabetes insipidus needs to be made more promptly or in acutely ill subjects. An examination of the relationship between plasma osmolality (excluding glucose and urea) and urine osmolality can be helpful. The finding of a low urine osmolality as plasma tonicity rises during a brief period of water withdrawal suggests the diagnosis of central diabetes insipidus.

Patients with central diabetes insipidus do not develop hypernatremia if the thirst mechanism is intact and water is available; thus, they have no symptoms except for the inconvenience associated with marked polyuria and polydipsia. Nonetheless, studies in acute care settings have clearly shown that patients who present with (34) or acquire (35) hypernatremia have a higher risk for mortality.

Both AVP replacement and pharmacologic agents are available for the treatment of central diabetes insipidus (Table 1-2). In acute settings, such as after hypophysectomy, the aqueous vasopressin (Pitressin) preparation is preferable. Its short duration of action allows for more careful monitoring and decreases the likelihood of complications such as water intoxication.

A modification of the natural vasopressin molecule to form desmopressin acetate (DDAVP) has resulted in a compound with prolonged antidiuretic activity (6–24 hours) and virtual elimination of V₁ vasopressor receptor activity (antidiuretic to pressor ratio of approximately 2,000:1) as compared with the natural hormone AVP (duration of action of 2–4 hours and antidiuretic to pressor ratio of approximately 1:1). Substitution of D-arginine for L-arginine at position 8 resulted in a peptide DAVP with diminished vasopressor activity, and deamination of the homocysteine at position 1 gave rise to a second peptide, with enhanced antidiuretic pressor activity and prolonged duration of action. Desmopressin acetate is administered intranasally in a dosage ranging from 10 to 20 μg every 8 to 12 hours. The drug has eliminated the need for previously employed long-acting vasopressin in oil. There are considerable individual variations in the required dosage, but most patients require twice-daily administration for good control of polyuria. Desmopressin acetate also can be administered intravenously or subcutaneously during periods of respiratory illness or surgery.in doses between 1 and 4 g. It is active orally in large doses also (between 50 and 800 μg) (34).

Large doses of DDAVP may cause transient headaches, nausea, and a slight increase in blood pressure; these symptoms disappear if the dosage is reduced. Nasal congestion, mild abdominal cramps, and vulval pain have occurred rarely. These patients need careful monitoring of water intake and serum sodium to avoid development of hyponatremia. In fact, there are increasing reports of cases of hyponatremia in patients on these agents, particularly when used for other indications such as von Willebrand disease (35) and enuresis (36).

Intranasal DDAVP currently is the treatment of choice for partial or complete central diabetes insipidus. However, alternatives to hormone replacement may be helpful at times. With dilute urine of fixed low osmolality, the urine volume is determined by the solute load requiring excretion. A reduction in salt and protein in the diet therefore will reduce the major urinary solutes and thus the volume of urine necessary to accommodate their excretion. Moreover, a number of pharmacologic agents with antidiuretic properties are used; the hypoglycemic agent chlorpropamide (Diabinese) is the most commonly employed. Its antidiuretic effects are manifested only if some vasopressin is present; therefore, it is useful only in partial diabetes insipidus. A trial of 250 mg every day or twice a day may be offered to patients with partial central diabetes insipidus and at least 7 days allowed for an effect to occur. The anticonvulsant carbamazepine (Tegretol) has caused antidiuresis in subjects with central diabetes insipidus. A combination of chlorpropamide and carbamazepine has been found to provide an effect that could be synergistic. Clofibrate also has been used to treat partial central diabetes insipidus. At present, however, none of these approaches can be recommended over intranasal DDAVP.

Congenital Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus is a rare hereditary disorder in which the renal tubule is insensitive to vasopressin (37). The disease has been described in various patterns, including the X-linked form, and autosomal recessive and even an autosomal dominant form. The most common variety is the X-linked whose complete form manifests itself in males with females expressing variable degrees of polyuria and polydipsia. In 85% of patients, the disease is a consequence of mutations on the V₂ receptor, resulting in a loss of function (38). More than 180 mutations of the V₂ receptor in chromosome region Xq28 have been identified (39). Half are missense mutations but other types of mutations occur as well. A significant number of the mutant receptors have defective intracellular trafficking (37). The autosomal recessive form of congenital nephrogenic diabetes insipidus is to a mutation in the AQP₂ water channel and accounts for approximately 15% of disease (40). At least 30 disease-causing mutations have been identified, most of them of the missense type. As was the case with the V₂ receptor mutant, misrouting of the AQP₂ mutant protein has been described in this setting (41). Mutations at the carboxy terminal of AQP₂ can cause a rare autosomal dominant form of congenital nephrogenic diabetes insipidus (42). A modest concentrating defect is present also in humans deficient in the AQP₁ water channel (43). Finally, knockout mice lacking AQP₃ and/or AQP₄ also fail to maximally concentrate their urine (44).

Clinical Manifestations

Distinct phenotype differences among the various genotypes have not been completely described. The most complete clinical description is available for the X-linked form. Although the disease is most probably inborn, the diagnosis of this form of congenital nephrogenic diabetes insipidus is usually not made until the infant presents with hypoosmolar urine in the face of severe dehydration, hypernatremia, vomiting, and fever. Unlike some of the females, who have partial responsiveness to vasopressin, males with the full-blown complete form of this disorder do not elaborate hypertonic urine even in the face of severe dehydration. The impaired growth and occasional mental retardation that occur in these cases, if not treated with adequate fluids, are most likely the result of repeated episodes of dehydration and hypernatremia rather than being integral components of the disease. Hydronephrosis is common in these patients perhaps because of voluntary retention of large volumes of urine with subsequent vesicoureteral reflux.

Limitation of oral solute intake (low-sodium diet) also may lead to a decrease in urine flow in patients with nephrogenic diabetes insipidus. Thiazide diuretics, which inhibit sodium reabsorption in the cortical diluting segment of the nephron, have met with some success in the management of these patients. The ability of thiazides to diminish sodium reabsorption in this water-impermeable portion of the nephron would by itself decrease C_H2O but not urine flow. It seems most likely that the decrease in urine flow is secondary to the sodium loss and ECF volume contraction. ECF volume depletion in turn decreases GFR and increases proximal tubular sodium and water reabsorption. These secondary effects of the diuretic agent then decrease urine flow. The ECF volume contraction can be maintained with a low sodium intake after discontinuance of the diuretic, so that the therapy still remains effective. The addition of amiloride to hydrochlorothiazide may provide added benefit. Nonsteroidal antiinflammatory drugs have been found to be effective, and in this regard, tolmetin appears to be particularly well tolerated in children. It should be noted that none of these modalities results in the elaboration of hypertonic urine. Even an increase in urine osmolality from 50 to 200 mOsm/kg H₂O is very important, however, because it significantly reduces obligatory urine loss from 10 to 12 L/day to a tolerable 3 to 4 L/day. Such a change in urine flow also minimizes the dilatation of the urinary tract. An intriguing new approach involves the use of cell-permeable vasopressin antagonists as chaperones that facilitate the folding of the mutant protein retained in the endoplasmic reticulum and increase the expression of the cell surface (45). In one study of subjects with nephrogenic diabetes insipidus, this approach resulted in a decrease in urine flow from 12 to 8 L with a modest increase in urinary osmolality (46).

Acquired Nephrogenic Diabetes Insipidus

The acquired form of nephrogenic diabetes insipidus is much more common than the congenital form of the disease, but it is rarely severe. In fact, although maximal concentrating ability is impaired in this disorder, the ability to elaborate hypertonic urine usually is preserved. Nocturia, polyuria, and polydipsia may occur in this acquired form of nephrogenic diabetes insipidus, but the urine volumes generally are less (<3–4 L/day) than those observed with complete central diabetes insipidus, psychogenic water drinking, or congenital nephrogenic central diabetes insipidus. The more common causes of acquired nephrogenic diabetes insipidus are listed in Table 1-3.

Chronic Renal Disease

A defect in renal concentrating capacity is a consistent accompaniment of most forms of advanced renal failure. Thus, chronic renal disease constitutes a form of acquired nephrogenic diabetes insipidus. Advanced renal insufficiency of any cause can cause a vasopressin resistance associated with hypotonic urine (47).

In some forms of kidney disease, listed in Table 1-3, vasopressin unresponsiveness can occur at a stage when GFR is not markedly diminished. The occurrence of a profound diuresis in association with a concentrating defect in glomerular diseases of the kidney is rare, and in general, a close correlation exists between GFR and maximal urine osmolality.

The causes of the defect in renal concentrating capacity associated with chronic renal failure are probably multiple (48). These include: (a) a disruption of inner medullary structures or local alterations in medullary blood flow as is seen in tubulointerstitial diseases, sickle cell disease, and analgesic nephropathy; (b) an impairment in sodium chloride transport out of the thick ascending limb of Henle’s loop, a process that limits maximal interstitial tonicity; and (c) an increase in solute excretion in the remaining few functioning nephrons, an adaptive response to the need to excrete the same solute load as the normal kidney. Solute diuresis in normal humans may cause isotonic urine in the presence of maximal amounts of vasopressin. However, none of these pathogenic mechanisms alone can explain the observation that vasopressin-resistant hypotonic urine may be found in patients with advanced renal failure (47). If the assumption is made that even in the absence of a countercurrent system the tonicity of the renal medulla is never less than that of plasma, a failure of complete osmotic equilibration between the collecting duct and medullary interstitium must occur to explain vasopressin-resistant hypotonic urine. One possibility is that the response to AVP of the collecting duct membranes in the damaged kidney is submaximal as a result of selective downregulation of the V₂ receptor (49). In a model of 5/6 nephrectomy-induced renal failure, a decrease in collecting duct AQP₂ and AQP₃ expression was reported (50). A similar decrement in AQP₂ has been described in obstructive uropathy and during recovery from acute tubular necrosis (Fig. 1-13).

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