WATER METABOLISM

Edward P. Nord, M.D.



Objectives

-To understand the physiology of osmoregulation including the central mechanisms (osmo- and volumo-regulation), tubular countercurrent system, medullary osmolarity, and vasopressin-sensitive mechanisms of water transport leading to the generation or reabsorption of osmotically “free” water.

-To be able to distinguish pseudohyponatremia from the actual one and analyze the causes of hyponatremia.

-Learn how to calculate water excess in a hyponatremic patient.

-Understand causes and approaches to a patient with hypernatremia.

-To be able to calculate water deficit in such patients
 

FUNDAMENTAL CONCEPTS

            Total body water and water balance:           Approximately 60% of lean body mass is water: two thirds of total body water is located inside cell as intracellular fluid (ICF), and one third is extra cellular fluid (ECF). The ECF is further divided into an intravascular compartment (25%) and an interstitial compartment (75%). This, in a 70 kg man, total body water is 42 liters of which 28 liters is intracellular, and 14 liters are extra cellular: 3.5 liters of the extra cellular fluid is located in the intravascular compartment, while most of the other 10.5 liters is located in the interstitial fluid



                   

 

 

 

 

 

 

 

 

compartment. Notethat a small component of extra cellular fluid (about 1-2 liters) is founding the transcellular compartment (in joints, the peritoneal space etc.)but under certain circumstances can account for a substantial component of extra cellular fluid (e.g. peritonitis) where it is termed the “thirdspace”. Total body water distributions illustrated in Fig. 1.

            Under normal physiologic circumstances, the body is in fluid balance. Under such conditions water intake equals water output, by definition. Water intake is normally influenced by thirst and personal habit, while renal fluid losses, and insensible water loss via perspiration and loss via the pulmonary and gastrointestinal routes determine water loss. Water of metabolism contributes to the water intake column: “Average” intake is tabulated below; obviously the main determinant of balance under steady state conditions will be water intake, which can vary widely.

                        

 

 

 

            If water intake exceeds loss, total body water increases and water balance will be positive. Conversely, if loss exceeds intake, total body water decreases and water balance will be negative. Under both circumstances the two major body fluid compartments share the gain or loss of pure water proportionally so that the gain or loss of pure water does not alter the relative volumes of these two compartments.

            Osmolality:     the osmolality of a solution depends on the number of particles per kg water. The osmolality of the extra cellular fluid is accounted for by Na and its accompanying anions Cl and HCO3, and the no electrolytes glucose and urea. It can be measured by an osmometer or calculated as follows:

 

 

 


In the absence of hyperglycemia and azotemia extracellular osmolality is largely accounted for by Na and its accompanying anions and can be estimated by doubling the serum Na concentration. Other solutes can contribute to osmolality in certain situation: (a) mannitoland glycerol used as osmotic diuretic and in the treatment of cerebral edema and acute glaucoma; (b) high osmolar radiographic dyes; and (c) during acute intoxication or poisoning by ethanol, methanol and ethylene glycoly.

            Effective osmolality or tonicity:        As indicated earlier, the major extracelular solute is Na and its associated anions. The major intracellular solute is K and its associated anions. These solutes are relatively restricted to their compartments via a number of transport proteins of which Na-K-ATPase is most important. Solutes that are relatively restricted to one particular body fluid compartment are able to exert an osmotic force for water movement from other compartments. Such solutes are called osmotically effective, or simply effective solutes. Effective osmolality or tonicity is thus determined by the amount of effective solute in a particular body fluid compartment. It is important to realize that tonicity is a unit less concept that can be expressed only in reference to a physiologic system: a hypertonic solutions one that would shrink cells, while a hypotonic one would cause them to swell. In this context Na and glucose are effective extracellular solutes since they can cause movement of water out of cells (hypertonic).Mannitol, glycerol and sorbitol also behave as effective solutes.

            Some solutes, notable urea pass freely across cell membranes and do not exerta force for water movement between the two major body fluid compartments. Ethanol, methanol and ethylene glycol are also noneffective solutes. Such noneffective solutes contribute to body osmolality but not to tonicity. Importantly in the presence of the aforementioned toxins measured serum osmolality will be increased whereas calculated serum osmolality will be normal. This so called “osmolar gap” serves as an important clue for the presence of an imbibed toxin.

            Specific gravity:         Whereas osmolality of a solution depends on the number of particles per kg water, the specific gravity of a solution is dependent upon the weight of the particles relative to the volume it occupies. Urinary specific gravity and osmolality usually change in parallel, but discrepancies occur between the two parameters. For example, for a given molar concentration, the specific gravity of urine tends to rise less with urea than with glucose. Urinary specific gravity can be easily measured at the bedside using a hygrometer and provides rapid and useful information regarding urine concentration and/or dilution. A rough approximation between urine osmolality and specific gravity is as follows:



 

Osmolality

 

Specific gravity

300 mOsm

 

1010

650 mOsm

 

1020

1000 mOsm

 

1030

 

 

DISTRIBUTION OF TOTALBODY WATER

            Water freely permeates across cell membranes in contradistinction to the major extracellular and intracellular effective solutes (Na and K receptively), which do not. However, under steady state conditions, intracellular fluid and extracellular fluid osmolalities are equal (about 290 mOsm/kg water), so that despite the nature of the composition of the solute in each compartment, the water concentration on both sides of the cell membrane is identical. Thus total body water must distribute according to the total amount of solute that is (relatively) restricted to each body fluid compartment. This explains why under normal circumstances, the intracellular fluid contains two-thirds of total body osmotically active solute and the extracellular fluid contains the remaining one-third. Thus the relative volumes of the two major body fluid compartments are determined by their respective effective solute contents.

MECHANISMS OF WATERHANDLING BY THE KIDNEY

Figs 2, 3 and 4 should be consulted in conjunction with this section.

            Proximal tubule handling of water: Fluid that is filtered by the glomerulus and appears in Bowman’s space is osmotic with serum (300 mOsm/kg water).The proximal tubule is comprised of a “leaky” epithelium so that fluid is neither concentrated nor diluted in this nephron segment.Quantitatively,70% of filtered water is reabsorbed in the proximal tubule; it passively follows solutes that are absorbed in this segment of which Na is the most important. The remaining 30% of fluid entering the loop of Henle is still isosmotic. 

 

 

 


           



 

 

 

 

 

 

 

 

 

 

 

Loop of Henle water handling:         The descending limb of Henle’s loop is very water permeable. The high tonicity of the medulla (see below) is responsible for the abstraction of water and solutes from the tubule lumen so that the fluid entering the bend in Henle’s loop is in equilibrium with the medulla and its high tonicity(1200 mOsm/kg water).Somewhere in the hairpin bend of the loop within the renal medulla, the epithelium changes from water permeable to water impermeable and remains so throughout the thin and thick ascending limb as it reemerges into the cortex. The thick ascending limb, while water impermeable, actively transports Na outfox the tubule lumen. The consequence of this arrangement is that the tubule fluid becomes diluted and enters the distal nephron as a hypo-osmotic (100 mOsm/kg water) solution, while the interstitium acquires Na and thereby becomes hypertonic. Hence the ascending loop of Henle is the nephron segment where the tubular fluid is diluted.

            Distal tubule and collecting duct handling of water:         The distal convoluted tubule is the segment between the macula densa and the collecting ducts and in humans is water impermeable and can therefore be considered as a component of the diluting segment. Somewhere between the late distal tubule and early collecting duct tubule fluid becomes concentrated and can attain an osmolality of up to 1400 mOsm/kg water. The collecting duct is thus where the urine attains final concentration. Concentration of tubule fluid is accomplished primarily by reabsorption of water outfox the tubule lumen across a somewhat water permeable epithelium. The permeability of this epithelium is greatly enhanced by vasopressin or antidiuretic hormone (ADH), receptors for which are present only on collecting duct cells. Water reabsorption is also facilitated by the hypertonic nature of the interstitium. Thus reabsorption of the bulk of the remaining glomerular filtrate (20%) occurs in the collecting duct.

            Maintenance and generation of a hypertonic interstitium:            The hypertonic nature of the renal interstitium is an important determinant of urine concentration. The major solutes responsible for medullary tonicity are Na and urea. As indicated earlier, Na enters the interstitial compartment primarily via active transport in the loop of Henle (Fig 4).Urea is reabsorbed all along the cortical collecting duct by passive diffusion and via specific urea transport proteins both of which are responsive to ADH which results in increased movement of urea out of the tubule lumen into the interstitium (Fig 4).

           

 

 

 

 

           

 

 

 

 

The countercurrent concentrating mechanisms are important for maintaining the high tonicity of the interstitium (Fig 5 and 6).In essence active Na removal from the ascending limb of Henle renders the tubule fluid hypotonic and the interstitium



 



 

 

 

 

 

 

 

 

 

 

 

 

Hypertonic relative tonew fluid entering the descending loop of Henle. The extent of which tubule fluid can be concentrated at the tip of bend in Henle’s loop is essentially a function of the length of the ascending/descending  limbs of the tubule. The ability of this anatomic arrangement to amplify a 200 mOsm gradient (i.e.300 mOsm descending limb vs. 100 mOsm ascending limb) to allow for a maximal osmolarity of 1200 mOsm at the hairpin bend with a gradient from cortex to medulla has allowed for term “countercurrent multiplier” (Fig5).The countercurrent exchanger(Fig 6), on the other hand is widespread in biology and explains how heat is preserved in the foot of the Antartic bird. By analogy, blood cursing through the vasae rectae does not dissipate the tonicity of the interstium generated by the countercurrent multiplier.

 

CELLULAR MECHANISMSOF WATER TRANSPORT

            The precise pathways whereby water crosses membranes has only recently been discovered. A family of membrane proteins has now been described, termed aquaporins. To date three members of this family have been described in mammals and are termed CHIP28, WCH-CD and MIP26 and display about 45% homology.CHIP28(channel forming integral protein) was the first known water channel molecule, is a 28 kDa protein, and within the kidney is found exclusively in the proximal tubule. WCH-CD (water channel of the collecting duct) on the other hand, is found exclusively in the collecting duct, on the lumenal surface of the tubule, and is sensitive to ADH (whereas CHIP28 is not).MIP26(major intrinsic protein of the mammalian lens) has not been detected in renal tissue. It should be noted that the CHIP28 protein is widely distributed in many tissues including lung, small intestine, and red blood cells, and therefore plays an important role in water transport in different organs.

ROLE OF VASOPRESSININ NORMAL WATER METABOLISM

            Biology of vasopressin:          Argininevasopressin (AVP) is a cyclic peptide comprised of nine amino acids and is the antidiuretic hormone (ADH) of humans. In the final analysis, renal concentrating and diluting processes are ultimately dependent on the

 




 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

actions of AVP in modulating the permeability of the collecting duct to water. AVP is synthesized in the supraoptic and paraventricular nuclei in the hypothalamus(Fig 7).Both AVP and oxytocin are encoded in human chromosome 20 in close proximity to each other. In these nuclei the biologically inactive precursor macromolecule is cleaved into smaller, biologically active AVP. AVP together with its binding protein neurophysin II, are transported in neurosecretory granules down the axon and stored in nerve terminal in the pars nervosa(posterior pituitary).Release of the stored peptide hormone and its neurophysin into the systemic and hypophyseal portal circulations occurs by a process termed exocytosis. When plasma osmolality increases, 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 axonal bulbs, and the peptide contents are then extruded into the adjacent capillaries(see Fig 7).

            Regulation of vasopressin release:   The regulation of vasopressin release from the posterior pituitary is dependent primarily on two mechanisms: (a) osmotic and (b) non-osmotic/volume.

            (A)Osmotic release of vasopressin:   Changes in serum osmolality is the major factor regulating vasopressin release. In response to an increase in serum osmolality, “osmoreceptor” cells in the anterior hypothalamus recognize changes in ECF osmolality by altering their cell volume. Substances that are restricted to the ECF, notably hypertonic saline and mannitol, result in water movement out of osmoreceptor cells, resulting in cell shrinkage which in some manner is translated into an electrical signal to release vasopressin. Urea, which readily moves into cells, does not initiate this series of events(see Fig. 8).The osmoreceptor cells activate electrical impulses which travel along the axon resulting ultimately in vasopressin release by the posterior pituitary. Concomitant to the release of vasopressin, vasopressin precursor mRNA in the hypothalamus increases two to five fold.

            The osmoreceptor cells are exceedingly sensitive to changes in ECF osmolality. Indeed, with water deprivation a 1% increase in ECF osmolality stimulates vasopressin release, while with water ingestion at 1% decrease ECF osmolality suppresses vasopressin release (see Fig 9).Some genetic variability does exist regarding individual

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


threshold and sensitivity for vasopressin release. On average, normal serum osmolality is about 280 mOsm/kg water at which time plasma vasopressin levels are barely detectable (below 1pg/ml).With small increases in osmolality to 285 or 290 mOsm/kg water vasopressin levels incrementally rise to 3-4 pg/ml. The exquisite sensitivity of this system can therefore be readily appreciated. Interestinglya similar close association

Between urine osmolality and plasma vasopressin exists as shown in Fig 10.Fromthis correlation it is also evident that when serum vasopressin has risen to 3-4 pg/ml, urine osmolality approaches maximal concentration.

 

            (B)Non-osmotic release of vasopressin: AVP release can also occur in the absence of changes in plasma osmolality. There are a large number of non-osmotic stimuli to AVP release of which physical pain, emotional stress, hypoxia, volume depletion (isotonic), cardiac failure, liver disease and adrenal insufficiency are the most notable. The common denominator appears to be changes in autonomic neural tone. Afferentvagal and glossopharyngeal pathways from the left atrium (low pressure)and carotid sinus (high pressure) baroreceptor modulate this non-osmotic regulation of AVP.

 

 



 

 

 

 

 

 

 

 

 

 

 

 

 


Importantly, the non-osmotic mechanisms are less sensitive stimuli for AVP release than are the osmotic stimuli, since a 1 % change in blood osmolality vs. a 5-10% change in blood volume will evoke a comparable release of AVP. It is also a higher gain system since quantitatively larger amounts of AVP are released by this mechanism.



RENAL WATER AND SOLUTEEXCRETION

            In the final analysis, the kidney is the major determinant of total body water balance. It is able to conserve water during periods of deprivation and to excrete water when fluid intake is excessive. In parallel, the kidney also plays a central role in the maintenance of solute balance since excretion of the major body solutes (Na, K and their anions and urea) is determined by the kidney. It is this balance between solute and water intake on the one hand, and solute and water excretion on the other, that determines the osmolality of the different body compartments. Its is also important to understand that HYPONATREMIA AND HYPERNATREMIAARE PROBLEMS OF WATER METABOLISM AND THAT AVP IS THE MAJOR DETERMINANTOF WATER BALANCE. On the other hand, aldosterone is the major determinant of Na balance and hyponatremia and hypernatremia are      NOTPROBLEMS OF SODIUM BALANCE.

            Under steady state conditions the daily solute excretion must equal the daily solute load. The excretion of urinary solute obligates the excretion of a certain amount of water, the magnitude of which is dependent on both the solute load and renal concentrating ability. This concept is illustrated in Fig 12 below, and is based on the knowledge that the usual range of solute excretion ranges from 600-900 mOsm/day.



 

 

 

 

 

 

 

 

 

 

 

 

Consider:          1.Giventhat maximal renal concentrating ability is 1200 mOsm/kg H20, and average solute excretion is 600 mOsm/day, the obligatory water loss for such an individual will be 600/1200 or 0.5 liters/day.

                        2.Ifthe maximal concentration ability of an individual is pathologically reduced to 300 mOsm/kg H2O the same solute excretion load of 600 mOsm/day will be excreted in 600/300 or 2 liters/day.

                        3.Ifthe individual were totally unable to concentrate the urine i.e. above75 mOsm/kg H2O, the same solute

load of 600 mOsm/day would be excreted in 600/75 or 8 liters/day.


Thus, even at a fixed solute excretion rate, obligatory renal water losses are NOT CONSTANT, rather they are determined by renal concentrating ability. Alternatively, with normal concentrating ability, urine volume will be determined by fluid intake independent of the fixed solute load.

            The ability of the kidney to vary water excretion is best illustrated by considering the normal responses to water ingestion and deprivation. Under water deprivation conditions urine concentration progressively reaches 1200mOsm/kg H2O (maximal) with a concomitant decrease in urine volume. Continued water deprivation beyond this point is not associated with a further increase in urine osmolality or with a further decrease in urine volume. At this point, the only water excreted in the urine is that obligated by the excretion of solute. There is no “free water” excretion. Conversely, in response to water ingestion, urine concentration progressively decreases to 50-75 mOsm/kg H2O (minimal) with a concomitant increase in volume. Water excretion under these circumstances is not obligated by the solute load and is excreted purely for the purpose of maintaining normal ECF tonicity. This component of urine excretion is termed “free water” excretion since it is a necessary mechanism for removing from the body excess water UNRELATED to the solute load.

            Finally, it is important to realize that during the transition from water diuresis to antidiuresis, small changes PLASMA osmolality are translated into huge changes in URINE osmolality and volume, and this is particularly true for dilute urine. For example a ~5% increase in plasma osmolality from 280 to 295 mOsm/dg H2Ois associated with a change in urine osmolality from 50 to 1200 mOsm/kgH2O, which represents a 20 fold decrease in urine volume.