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Home , Renal physiology

CHAPTER The Regulation of Fluid and Balance 2424 George A. Tanner, Ph.D.

CHAPTER OUTLINE

■ OF THE BODY ■ BALANCE ■ BALANCE ■ BALANCE ■ BALANCE ■ BALANCE ■ BALANCE ■ URINARY TRACT

KEY CONCEPTS

1. Total is distributed in two major compart- rate, II and , intrarenal ments: intracellular water and extracellular water. In an av- physical forces, natriuretic and factors such as erage young adult man, total body water, intracellular wa- atrial natriuretic peptide, and renal sympathetic nerves. ter, and extracellular water amount to 60%, 40%, and 20% Changes in these factors may account for altered Naϩ ex- of body weight, respectively. The corresponding figures for cretion in response to excess Naϩ or Naϩ depletion. Estro- an average young adult woman are 50%, 30%, and 20% of gens, , osmotic , poorly reabsorbed body weight. anions in the , and drugs also affect renal Naϩ 2. The volumes of body fluid compartments are determined . by using the indicator dilution method and this equation is: 9. The effective arterial volume (EABV) depends on the Volume ϭ Amount of indicatorϵConcentration of indicator degree of filling of the arterial system and determines the at equilibrium. perfusion of the body’s tissues. A decrease in EABV leads 3. Electrical neutrality is present in of ; to Naϩ retention by the kidneys and contributes to the de- that is, the sum of the cations is equal to the sum of the an- velopment of generalized edema in pathophysiological (both expressed in milliequivalents). conditions, such as congestive heart failure. 4. Sodium (Naϩ) is the major osmotically active solute in ex- 10. The kidneys play a major role in the control of Kϩ balance. tracellular fluid (ECF), and potassium (Kϩ) has the same Kϩ is reabsorbed by the proximal convoluted tubule and role in the intracellular fluid (ICF) compartment. Cells are the and is secreted by cortical collecting duct typically in osmotic equilibrium with their external environ- principal cells. Inadequate renal Kϩ excretion produces hy- ment. The amount of water in (and, hence, the volume of) perkalemia and excessive Kϩ excretion produces hy- cells depends on the amount of Kϩ they contain and, simi- pokalemia. larly, the amount of water in (and, hence, the volume of) 11. Calcium balance is regulated on both input and output the ECF is determined by its Naϩ content. sides. The absorption of Ca2ϩ from the small intestine is

5. is closely regulated by arginine vaso- controlled by 1,25(OH)2 vitamin D3, and the excretion of pressin (AVP), which governs renal excretion of water, and Ca2ϩ by the kidneys is controlled by parathyroid by habit and , which govern water intake. (PTH). 6. AVP is synthesized in the , released from the 12. Magnesium in the body is mostly in bone, but it is also an posterior pituitary gland, and acts on the collecting ducts important intracellular . The kidneys regulate the of the to increase their water permeability. The ma- plasma [Mg2ϩ]. jor stimuli for the release of AVP are an increase in effec- 13. Filtered phosphate usually exceeds the maximal reabsorp-

tive plasma osmolality (detected by osmoreceptors in the tive capacity of the kidney tubules for phosphate (TmPO4), anterior hypothalamus) and a decrease in blood volume and about 5 to 20% of filtered phosphate is usually ex- (detected by stretch receptors in the left atrium, carotid si- creted. Phosphate occurs mainly in the proxi- nuses, and aortic arch). mal tubules and is inhibited by PTH. Phosphate is an im- 7. The kidneys are the primary site of control of Naϩ excre- portant pH buffer in the urine. Hyperphosphatemia is a tion. Only a small percentage (usually about 1%) of the fil- significant problem in chronic renal failure. tered Naϩ is excreted in the urine, but this amount is of 14. The urinary bladder stores urine until it can be conve- critical importance in overall Naϩ balance. niently emptied. Micturition is a complex act involving 8. Multiple factors affect Naϩ excretion, including glomerular both autonomic and somatic nerves.

403 404 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

major function of the kidneys is to regulate the volume, Interstitial fluid composition, and osmolality of the body fluids. The and lymph water A (15% body fluid surrounding our body cells (the ECF) is constantly re- Intracellular water weight; 10.5 L) Plasma water newed and replenished by the circulating . (40% body weight; 28 L) (5% body The kidneys constantly process the plasma; they filter, re- weight; 3.5 L) absorb, and secrete substances and, in health, maintain the internal environment within narrow limits. In this chapter, we begin with a discussion of the fluid compartments of the body—their location, magnitude, and composition. Then we consider water, sodium, potassium, calcium, magne- sium, and phosphate balance, with special emphasis on the role of the kidneys in maintaining our fluid and electrolyte balance. Finally, we consider the role of the ureters, urinary bladder, and urethra in the transport, storage, and elimina- tion of urine. Extracellular water (20% body weight; 14 L)

FLUID COMPARTMENTS OF THE BODY Total body water (60% body weight; 42 L) Water is the major constituent of all body fluid compart- FIGURE 24.1 Water distribution in the body. This dia- ments. Total body water averages about 60% of body gram is for an average young adult man weigh- weight in young adult men and about 50% of body weight ing 70 kg. In an average young adult woman, total body water is in young adult women (Table 24.1). The percentage of 50% of body weight, intracellular water is 30% of body weight, body weight water occupies depends on the amount of adi- and extracellular water is 20% of body weight. pose tissue (fat) a person has. A lean person has a high per- centage and an obese individual a low percentage of body weight that is water because adipose tissue contains a low percentage of water (about 10%), whereas most other tis- ter is in the ICF, and one third is in the ECF (Fig. 24.1). sues have a much higher percentage of water. For example, These two fluids differ strikingly in terms of their electrolyte muscle is about 75% water. Newborns have a low percent- composition. However, their total solute concentrations age of body weight as water because of a relatively large (osmolalities) are normally equal, because of the high water ECF volume and little fat (see Table 24.1). Adult women permeability of most membranes, so that an osmotic dif- have relatively less water than men because, on average, ference between cells and ECF rapidly disappears. they have more subcutaneous fat and less muscle mass. As The ECF can be further subdivided into two major sub- people age, they tend to lose muscle and add adipose tissue; compartments, which are separated from each other by the hence, water content declines with age. endothelium of blood vessels. The blood plasma is the ECF found within the vascular system; it is the fluid portion of the blood in which blood cells and platelets are suspended. Body Water Is Distributed in The blood plasma water comprises about one fourth of the Several Fluid Compartments ECF or about 3.5 L for an average 70-kg man (see Fig. 24.1). The interstitial fluid and lymph are considered together be- Total body water can be divided into two compartments or cause they cannot be easily separated. The water of the in- spaces: intracellular fluid (ICF) and terstitial fluid and lymph comprises three fourths of the (ECF). The ICF is comprised of the fluid within the trillions ECF. The interstitial fluid directly bathes most body cells, of cells in our body. The ECF is comprised of fluid outside and the lymph is the fluid within lymphatic vessels. The of the cells. In a young adult man, two thirds of the body wa- blood plasma, interstitial fluid, and lymph are nearly iden- tical in composition, except for the higher protein concen- tration in the plasma. An additional ECF compartment (not shown in Fig. 24.1), Average Total Body Water as a Percent- TABLE 24.1 the transcellular fluid, is small but physiologically important. age of Body Weight Transcellular fluid amounts to about 1 to 3% of body weight. Age Men Both Sexes Women Transcellular fluids include cerebrospinal fluid, aqueous hu- mor of the eye, secretions of the digestive tract and associated 0–1 month 76 organs (saliva, bile, pancreatic juice), renal and 1–12 months 65 bladder urine, synovial fluid, and sweat. In these cases, the 1–10 years 62 10–16 years 59 57 fluid is separated from the blood plasma by an epithelial cell 17–39 years 61 50 layer in addition to a endothelium. The epithelial 40–59 years 55 52 layer modifies the electrolyte composition of the fluid, so that 60 years and older 52 46 transcellular fluids are not plasma ultrafiltrates (as is intersti- tial fluid and lymph); they have a distinct ionic composition. From Edelman IS, Leibman J. Anatomy of body water and electrolytes. Am J Med 1959;27:256–277. There is a constant turnover of transcellular fluids; they are continuously formed and absorbed or removed. Impaired for- CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 405 mation, abnormal loss from the body, or blockage of fluid re- Cellular water cannot be determined directly with any moval can have serious consequences. indicator. It can, however, be calculated from the differ- ence between measurements of total body water and extra- cellular water. The Indicator Dilution Method Measures Plasma water is determined by using Evans blue dye, Fluid Compartment Size which avidly binds serum albumin or radioiodinated serum The indicator dilution method can be used to determine albumin (RISA), and by collecting and analyzing a blood the size of body fluid compartments (see Chapter 14). A plasma sample. In effect, the plasma volume is measured known amount of a substance (the indicator), which should from the distribution volume of serum albumin. The as- be confined to the compartment of interest, is adminis- sumption is that serum albumin is completely confined to tered. After allowing sufficient time for uniform distribu- the vascular compartment, but this is not entirely true. In- tion of the indicator throughout the compartment, a plasma deed, serum albumin is slowly (3 to 4% per hour) lost from sample is collected. The concentration of the indicator in the blood by diffusive and convective transport through the plasma at equilibrium is measured, and the distribution capillary walls. To correct for this loss, repeated blood sam- volume is calculated from this formula ples can be collected at timed intervals, and the concentra- tion of albumin at time zero (the time at which no loss Volume ϭ Amount of indicator/ would have occurred) can be determined by extrapolation. Concentration of indicator (1) Alternatively, the plasma concentration of indicator 10 If there was loss of indicator from the fluid compart- minutes after injection can be used; this value is usually ment, the amount lost is subtracted from the amount ad- close to the extrapolated value. If plasma volume and hema- ministered. tocrit are known, total circulating blood volume can be cal- To measure total body water, heavy water (deuterium culated (see Chapter 11). oxide), tritiated water (HTO), or antipyrene (a drug that Interstitial fluid and lymph volume cannot be deter- distributes throughout all of the body water) is used as an mined directly. It can be calculated as the difference be- indicator. For example, suppose we want to measure total tween ECF and plasma volumes. body water in a 60-kg woman. We inject 30 mL of deu- terium oxide (D2O) as an isotonic saline into an arm vein. After a 2-hr equilibration period, a blood sample Body Fluids Differ in Electrolyte Composition is withdrawn, and the plasma is separated and analyzed for Body fluids contain many uncharged molecules (e.g., glu- D2O. A concentration of 0.001 mL D2O/mL plasma water cose and urea), but quantitatively speaking, electrolytes is found. Suppose during the equilibration period, urinary, (ionized substances) contribute most to the total solute respiratory, and cutaneous losses of D2O are 0.12 mL. Sub- concentration (or osmolality) of body fluids. Osmolality is stituting these values into the indicator dilution equation, of prime importance in determining the distribution of wa- we get ter between intracellular and ECF compartments. ϩ Total body water ϭ (30 Ϫ 0.12 mL D2O) ϫ The importance of ions (particularly Na ) in determin- 0.001 mL D2O/mL water ϭ ing the plasma osmolality (Posm) is exemplified by an equa- 29,880 mL or 30 L (2) tion that is of value in the clinic: ϩ Therefore, total body water as a percentage of body Posm ϭ 2 ϫ [Na ] weight equals 50% in this woman. ϩ ᎏ[]ᎏin mg/dL To measure extracellular water volume, the ideal indica- 18 [] in mg/dL tor should distribute rapidly and uniformly outside the cells ϩ ᎏᎏᎏᎏ (3) and should not enter the cell compartment. Unfortunately, 2.8 there is no such ideal indicator, so the exact volume of the If the plasma [Naϩ] is 140 mmol/L, blood glucose is 100 ECF cannot be measured. A reasonable estimate, however, mg/dL (5.6 mmol/L), and blood urea nitrogen is 10 mg/dL can be obtained using two different classes of substances: (3.6 mmol/L), the calculated osmolality is 289 mOsm/kg ϩ impermeant ions and inert sugars. ECF volume has been de- H2O. The equation indicates that Na and its accompany- Ϫ Ϫ termined from the volume of distribution of these ions: ra- ing anions (mainly Cl and HCO3 ) normally account for dioactive Naϩ, radioactive ClϪ, radioactive sulfate, thio- more than 95% of the plasma osmolality. In some special Ϫ 2– cyanate (SCN ), and thiosulfate (S2O3 ); radioactive circumstances (e.g., alcohol intoxication), plasma osmolal- 35 2– sulfate ( SO4 ) is probably the most accurate. However, ity calculated from the above equation may be much lower ions are not completely impermeant; they slowly enter the than the true, measured osmolality as a result of the presence cell compartment, so measurements tend to lead to an over- of unmeasured osmotically active solutes (e.g., ethanol). estimate of ECF volume. Measurements with inert sugars The concentrations of various electrolytes in plasma, in- (such as mannitol, sucrose, and ) tend to lead to an terstitial fluid, and ICF are summarized in Table 24.2. The underestimate of ECF volume because they are excluded ICF values are based on determinations made in skeletal from some of the extracellular water—for example, the wa- muscle cells. These cells account for about two thirds of the ter in dense connective tissue and cartilage. Special tech- cell mass in the human body. Concentrations are expressed niques are required when using these sugars because they in terms of milliequivalents per liter or per kg H2O. are rapidly filtered and excreted by the kidneys after their An equivalent contains one mole of univalent ions, and a intravenous injection. milliequivalent (mEq) is 1/1,000th of an equivalent. Equiv- 406 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

TABLE 24.2 Electrolyte Composition of the Body Fluids

Plasma Electrolyte Plasma Water Interstitial Fluid Intracellular Fluida

(mEq/L) (mEq/kg H2O) (mEq/kg H2O) (mEq/kg H2O) Cations Naϩ 42 153 145 10 Kϩ 4 4.3 4 159 Ca2ϩ 55.431 Mg2ϩ 22.2240 Total 153 165 154 210 Anions ClϪ 103 111 117 3 Ϫ HCO3 25 27 28 7 Protein 17 18 — 45 Others 8 9 9 155 Total 153 165 154 210 a Skeletal muscle cells.

alents are calculated as the product of moles times valence stitial fluid than in plasma and the concentrations of dif- and represent the concentration of charged species. For fusible anions (such as ClϪ) are higher in interstitial fluid singly charged (univalent) ions, such as Naϩ, Kϩ, ClϪ, or than in plasma. Second, Ca2ϩ and Mg2ϩ are bound to some Ϫ HCO3 , 1 mmol is equal to 1 mEq. For doubly charged (di- extent (about 40% and 30%, respectively) by plasma pro- 2ϩ 2ϩ 2– valent) ions, such as Ca , Mg , or SO4 , 1 mmol is equal teins, and it is only the unbound ions that can diffuse to 2 mEq. Some electrolytes, such as proteins, are polyva- through capillary walls. Hence, the total plasma Ca2ϩ and lent, so there are several mEq/mmol. The usefulness of ex- Mg2ϩ concentrations are higher than in interstitial fluid. pressing concentrations in terms of mEq/L is based on the ICF composition (Table 24.2, Column 4) is different fact that in solutions, we have electrical neutrality; that is from ECF composition. The cells have a higher Kϩ, Mg2ϩ, and protein concentration than in the surrounding intersti- 3 cations ϭ 3 anions (4) ϩ 2ϩ Ϫ Ϫ tial fluid. The intracellular Na , Ca , Cl , and HCO3 If we know the total concentration (mEq/L) of all cations levels are lower than outside the cell. The anions in skele- in a solution and know only some of the anions, we can eas- tal muscle cells labeled “Others” are mainly organic phos- ily calculate the concentration of the remaining anions. phate compounds important in cell energy metabolism, This was done in Table 24.2 for the anions labeled “Oth- such as creatine phosphate, ATP, and ADP. As described in ers.” Plasma concentrations are listed in the first column of Chapter 2, the high intracellular [Kϩ] and low intracellular Table 24.2. Naϩ is the major cation in plasma, and ClϪ and [Naϩ] are a consequence of plasma membrane Naϩ/Kϩ- Ϫ ϩ HCO3 are the major anions. The plasma proteins (mainly ATPase activity; this extrudes Na from the cell ϩ Ϫ Ϫ serum albumin) bear net negative charges at physiological and takes up K . The low intracellular [Cl ] and [HCO3 ] pH. The electrolytes are actually dissolved in the plasma in skeletal muscle cells are primarily a consequence of the water, so the second column in Table 24.2 expresses con- inside negative membrane potential (Ϫ90 mV), which fa- centrations per kg H2O. The water content of plasma is vors the outward movement of these small, negatively usually about 93%; about 7% of plasma volume is occupied charged ions. The intracellular [Mg2ϩ] is high; most is not by solutes, mainly the plasma proteins. To convert concen- free, but is bound to cell proteins. Intracellular [Ca2ϩ] is tration in plasma to concentration in plasma water, we di- low; as discussed in Chapter 1, the cytosolic [Ca2ϩ] in rest- vided the plasma concentration by the plasma water con- ing cells is about 10Ϫ7 M (0.0002 mEq/L). Most of the cell ϩ 2ϩ tent (0.93 L H2O/L plasma). Therefore, 142 mEq Na /L Ca is sequestered in organelles, such as the sarcoplasmic plasma becomes 153 mEq/L H2O or 153 mEq/kg H2O reticulum in skeletal muscle. (since 1 L of water weighs 1 kg). Interstitial fluid (Column 3 of Table 24.2) is an ultrafil- trate of plasma. It contains all of the small electrolytes in es- Intracellular and Extracellular Fluids Are sentially the same concentration as in plasma, but little pro- Normally in Osmotic Equilibrium tein. The proteins are largely confined to the plasma Despite the different compositions of ICF and ECF, the to- because of their large molecular size. Differences in small tal solute concentration (osmolality) of these two fluid ion concentrations between plasma and interstitial fluid compartments is normally the same. ICF and ECF are in os- (compare Columns 2 and 3) occur because of the different motic equilibrium because of the high water permeability protein concentrations in these two compartments. Two of cell membranes, which does not permit an osmolality factors are involved. The first is an electrostatic effect: Be- difference to be sustained. If the osmolality changes in one cause the plasma proteins are negatively charged, they compartment, water moves to restore a new osmotic equi- cause a redistribution of small ions, so that the concentra- ϩ librium (see Chapter 2). tions of diffusible cations (such as Na ) are lower in inter- The volumes of ICF and ECF depend primarily on the CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 407 volume of water present in these compartments. But the lat- added to an original total body water volume of 42 L, the ter depends on the amount of solute present and the osmo- new total body water volume is 44 L. No solute was added, lality. This fact follows from the definition of the term con- so the new osmolality at equilibrium is (7,980 ϩ 3,990 centration: concentration ϭ amount/volume; hence, volume mOsm)/44 kg ϭ 272 mOsm/kg H2O. The volume of the ϭ amount/concentration. The main osmotically active ICF at equilibrium, calculated by solving the equation, 272 ϩ ϩ solute in cells is K ; therefore, a loss of cell K will cause mOsm/kg H2O ϫ volume ϭ 7,980 mOsm, is 29.3 L The cells to lose water and shrink (see Chapter 2). The main os- volume of the ECF at equilibrium is 14.7 L. From these cal- motically active solute in the ECF is Naϩ; therefore, a gain culations, we conclude that two thirds of the added water or loss of Naϩ from the body will cause the ECF volume to ends up in the cell compartment and one third stays in the swell or shrink, respectively. ECF. This description of events is artificial because, in real- The distribution of water between intracellular and ex- ity, the kidneys would excrete the added water over the tracellular compartments changes in a variety of circum- course of a few hours, minimizing the fall in plasma osmo- stances. Figure 24.2 provides some examples. Total body lality and cell swelling. water is divided into the two major compartments, ICF and In Figure 24.2C, 2.0 L of isotonic saline (0.9% NaCl so- ECF. The y-axis represents total solute concentration and lution) were added to the ECF. Isotonic saline is isosmotic the x-axis the volume; the area of a box (concentration to plasma or ECF and, by definition, causes no change in times volume) gives the amount of solute present in a com- cell volume. Therefore, all of the isotonic saline is retained partment. Note that the height of the boxes is always equal, in the ECF and there is no change in osmolality. since osmotic equilibrium (equal osmolalities) is achieved. Figure 24.2D shows the effect of infusing intravenously In the normal situation (shown in Figure 24.2A), two 1.0 L of a 5% NaCl solution (osmolality about 1,580 thirds (28 L for a 70-kg man) of total body water is in the mOsm/kg H2O). All the salt stays in the ECF. The cells are ICF, and one third (14 L) is in the ECF. The osmolality of exposed to a hypertonic environment, and water leaves the both fluids is 285 mOsm/kg H2O. Hence, the cell com- cells. Solutes left behind in the cells become more concen- partment contains 7,980 mOsm and the ECF contains trated as water leaves. A new equilibrium will be established, 3,990 mOsm. with the final osmolality higher than normal but equal in- In Figure 24.2B, 2.0 L of pure water were added to the side and outside the cells. The final osmolality can be calcu- ECF (e.g., by drinking water). Plasma osmolality is low- lated from the amount of solute present (7,980 ϩ 3,990 ϩ ered, and water moves into the cell compartment along the 1,580 mOsm) divided by the final volume (28 ϩ 14 ϩ 1 L); osmotic gradient. The entry of water into the cells causes it is equal to 315 mOsm/kg H2O. The final volume of the them to swell, and intracellular osmolality falls until a new ICF equals 7,980 mOsm divided by 315 mOsm/kg H2O or equilibrium (solid lines) is achieved. Since 2 L of water were 25.3 L, which is 2.7 L less than the initial volume. The final

285

O) O) 272 2 2

ICF ECF ICF ECF

Osmolality (mOsm/kg H 0 Osmolality (mOsm/kg H 0 0284204429.3 Volume (L) Volume (L)

A Normal B Add 2.0 L pure H2O

315 285 O) 2 O) 2

FIGURE 24.2 Effects of vari- ICF ECF ICF ECF ous distur- bances on the osmolalities and volumes of intracellular fluid (ICF) and extracellular fluid

Osmolality (mOsm/kg H (ECF). The dashed lines indicate Osmolality (mOsm/kg H 0 0 the normal condition; the solid 028440 25.3 43 lines, the situation after a new os- Volume (L) Volume (L) motic equilibrium has been at- C Add 2.0 L isotonic saline D Add 1.0 L 5% NaCl solution tained. (See text for details.) 408 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS volume of the ECF is 17.7 L, which is 3.7 L more than its ini- and higher metabolic rate. They are much more susceptible tial value. The addition of hypertonic saline to the ECF, to volume depletion. therefore, led to its considerable expansion mostly because of loss of water from the cell compartment. Arginine Is Critical in the Control of Renal Water Output and Plasma Osmolality WATER BALANCE Arginine vasopressin (AVP), also known as antidiuretic People normally stay in a stable water balance; that is, wa- hormone (ADH), is a nonapeptide synthesized in the body ter input and output are equal. There are three major as- of nerve cells located in the supraoptic and paraventricular pects to the control of water balance: arginine vasopressin, nuclei of the anterior hypothalamus (Fig. 24.3) (see Chap- excretion of water by the kidneys, and habit and thirst. ter 32). The hormone travels by axoplasmic flow down the hypothalamic-neurohypophyseal tract and is stored in vesi- cles in nerve terminals in the median eminence and, mostly, Water Input and Output Are Equal the posterior pituitary. When the cells are brought to threshold, they rapidly fire action potentials, Ca2ϩ enters A balance chart for water for an average 70-kg man is pre- the nerve terminals, the AVP-containing vesicles release sented in Table 24.3. The person is in a stable balance (or their contents into the interstitial fluid surrounding the steady state) because the total input and total output of wa- nerve terminals, and AVP diffuses into nearby . ter from the body are equal (2,500 mL/day). On the input The hormone is carried by the blood stream to its target tis- side, water is found in the beverages we drink and in the sue, the collecting ducts of the kidneys, where it increases foods we eat. Solid foods, which consist of animal or veg- water reabsorption (see Chapter 23). etable matter, are, like our own bodies, mostly water. Wa- ter of oxidation is produced during metabolism; for exam- Factors Affecting AVP Release. Many factors influence ple, when 1 mol of glucose is oxidized, 6 mol of water are the release of AVP, including pain, trauma, emotional produced. In a hospital setting, the input of water as a result stress, nausea, fainting, most anesthetics, nicotine, mor- of intravenous infusions would also need to be considered. phine, and angiotensin II. These conditions or agents pro- On the output side, losses of water occur via the skin, lungs, duce a decline in urine output and more concentrated urine. , and kidneys. We always lose water by Ethanol and atrial natriuretic peptide inhibit AVP release, simple evaporation from the skin and lungs; this is called in- leading to the excretion of a large volume of dilute urine. sensible water loss. The main factor controlling AVP release under ordinary Appreciable water loss from the skin, in the form of circumstances is a change in plasma osmolality. Figure 24.4 sweat, occurs at high temperatures or with heavy exercise. shows how plasma AVP concentrations vary as a function As much as 4 L of water per hour can be lost in sweat. of plasma osmolality. When plasma osmolality rises, neu- Sweat, which is a hypoosmotic fluid, contains NaCl; exces- rons called osmoreceptor cells, located in the anterior hy- sive sweating can lead to significant losses of salt. Gas- pothalamus, shrink. This stimulates the nearby neurons in trointestinal losses of water are normally small (see Table 24.3), but with diarrhea, vomiting, or drainage of gastroin- testinal secretions, massive quantities of water and elec- Paraventricular nucleus trolytes may be lost from the body. The kidneys are the sites of adjustment of water output Supraoptic nucleus from the body. Renal water excretion changes to maintain Posterior balance. If there is a water deficiency, the kidneys diminish Anterior hypothalamus hypothalamus the excretion of water and urine output falls. If there is wa- Hypothalamic neurohypophyseal ter excess, the kidneys increase water excretion and urine Optic tract chiasm flow to remove the extra water. The renal excretion of wa- Hypophyseal ter is controlled by arginine vasopressin. stalk The water needs of an infant or young child, per kg body weight, are several times higher than that of an adult. Chil- Median eminence Mammillary dren have, for their body weight, a larger body surface area body Pars tuberalis

Pars Central Daily Water Balance in an Average intermedia cavity TABLE 24.3 70-kg Man Pars Pars nervosa anterior Input Output FIGURE 24.3 The pituitary and hypothalamus. AVP is syn- Water in beverages 1,000 mL Skin and lungs 900 mL thesized primarily in the supraoptic nucleus and Water in food 1,200 mL Gastrointestinal 100 mL to a lesser extent in the paraventricular nuclei in the anterior hypo- Water of oxidation 300 mL tract (feces) thalamus. It is then transported down the hypothalamic neurohy- Kidneys (urine) 1,500 mL pophyseal tract and stored in vesicles in the median eminence and Total 2,500 mL Total 2,500 mL posterior pituitary, where it can be released into the blood. CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 409

Thirst volume. An increased blood volume inhibits AVP release, whereas a decreased blood volume (hypovolemia) stimu- lates AVP release. Intuitively, this makes sense, since with 12 excess volume, a low plasma AVP level would promote the excretion of water by the kidneys. With hypovolemia, a high plasma AVP level would promote conservation of wa- ter by the kidneys. The receptors for blood volume include stretch recep- tors in the left atrium of the heart and in the pulmonary 8 veins within the pericardium. More stretch results in more impulses transmitted to the brain via vagal afferents and in- hibition of AVP release. The common experiences of pro- ducing a large volume of dilute urine, a water — when lying down in bed at night, when exposed to cold 4 weather, or when immersed in a pool during the summer— Plasma AVP (pg/mL) may be related to activation of this pathway. In all of these situations, the atria are stretched by an increased central blood volume. Arterial baroreceptors in the carotid sinuses and aortic arch also reflexly change AVP release; a fall in pressure at these sites stimulates AVP release. Finally, a de- crease in renal blood flow stimulates release, which leads to increased angiotensin II production. Angiotensin II 270 280 290 300 310 stimulates AVP release by acting on the brain. Relatively large blood losses (more than 10% of blood Plasma osmolality (mOsm/kg H2O) volume) are required to increase AVP release (Fig. 24.6).

FIGURE 24.4 The relationship between plasma AVP level With a loss of 15 to 20% of blood volume, however, large and plasma osmolality in healthy people. increases in plasma AVP are observed. Plasma levels of AVP Decreases in plasma osmolality were produced by drinking water may rise to levels much higher (e.g., 50 pg/mL) than are and increases by fluid restriction. Plasma AVP levels were meas- needed to concentrate the urine maximally (e.g., 5 pg/mL). ured by radioimmunoassay. At plasma osmolalities below 280 (Compare Figures 24.5 and 24.6.) With severe hemorrhage, mOsm/kg H2O, plasma AVP is decreased to low or undetectable high circulating levels of AVP exert a significant vasocon- levels. Above this threshold, plasma AVP increases linearly with plasma osmolality. Normal plasma osmolality is about 285 to 287 strictor effect, which helps compensate by raising the . mOsm/kg H2O, so we live above the threshold for AVP release. The thirst threshold is attained at a plasma osmolality of 290 mOsm/kg H2O, so the thirst mechanism “kicks in” only when there is an appreciable water deficit. Changes in plasma AVP and consequent changes in renal water excretion are normally capable 1,400 of maintaining a normal plasma osmolality below the thirst threshold. (From Robertson GL, Aycinena P, Zerbe RL. Neuro- O) 1,200 genic disorders of osmoregulation. Am J Med 1982;72:339–353.) 2

1,000 the paraventricular and supraoptic nuclei to release AVP, 800 and plasma AVP concentration rises. The result is the for- mation of osmotically concentrated urine. Not all solutes 600 are equally effective in stimulating the osmoreceptor cells; for example, urea, which can enter these cells and, there- 400 fore, does not cause the osmotic withdrawal of water, is in- effective. Extracellular NaCl, however, is an effective stim- Urine osmolaity (mOsm/kg H 200 ulus for AVP release. When plasma osmolality falls in response to the addition of excess water, the osmoreceptor 0 cells swell, AVP release is inhibited, and plasma AVP levels 0 1 2 3 4 5 10 15 fall. In this situation, the collecting ducts express their in- Plasma AVP (pg/mL) trinsically low water permeability, less water is reabsorbed, The relationship between urine osmolality a dilute urine is excreted, and plasma osmolality can be re- FIGURE 24.5 stored to normal by elimination of the excess water. Figure and plasma AVP levels. With low plasma AVP levels, a hypoosmotic (compared to plasma) urine is ex- 24.5 shows that the entire range of urine osmolalities, from creted and, with high plasma AVP levels, a hyperosmotic urine is dilute to concentrated , is a linear function of plasma excreted. Note that maximally concentrated urine (1,200 to 1,400 AVP in healthy people. mOsm/kg H2O) is produced when the plasma AVP level is about A second important factor controlling AVP release is the 5 pg/mL. (From Robertson GL, Aycinena P, Zerbe RL. Neuro- blood volume—more precisely, the effective arterial blood genic disorders of osmoregulation. Am J Med 1982;72:339–353.) 410 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

AVP levels are low, and a large volume of dilute urine (up 50 to 20 L/day) is excreted. In nephrogenic in- 45 sipidus, the collecting ducts are partially or completely un- responsive to AVP. Urine output is increased, but the 40 plasma AVP level is usually higher than normal (secondary 35 to excessive loss of dilute fluid from the body). Nephro- 30 genic diabetes insipidus may be acquired (e.g., via drugs such as lithium) or inherited. Mutations in the collecting 25 duct AVP receptor gene or in the water channel (aqua- 20 porin-2) gene have now been identified in some families. In the syndrome of inappropriate secretion of ADH 15 (SIADH), plasma AVP levels are inappropriately high for Plasma AVP (pg/mL) 10 the existing osmolality. Plasma osmolality is low because the kidneys form concentrated urine and save water. This 5 condition is sometimes caused by a bronchogenic tumor 0 that produces AVP in an uncontrolled fashion.

0 5 10 15 20 Habit and Thirst Govern Water Intake Blood volume depletion (%) People drink water largely from habit, and this water intake FIGURE 24.6 The relationship between plasma AVP and blood volume depletion in the rat. Note normally covers an individual’s water needs. Most of the that severe hemorrhage (a loss of 20% of blood volume) causes a time, we operate below the threshold for thirst. Thirst, a striking increase in plasma AVP. In this situation, the vasocon- conscious desire to drink water, is mainly an emergency strictor effect of AVP becomes significant and counteracts the mechanism that comes into play when there is a perceived low blood pressure. (From Dunn FL, Brennan TJ, Nelson AE, water deficit. Its function is obviously to encourage water Robertson GL. The role of blood osmolality and volume in regu- intake to repair the water deficit. The thirst center is lo- lating vasopressin secretion in the rat. J Clin Invest cated in the anterior hypothalamus, close to the neurons 1973;52:3212–3219) that produce and control AVP release. This center relays impulses to the cerebral cortex, so that thirst becomes a conscious sensation. Interaction Between Stimuli Affecting AVP Release. Several factors affect the thirst sensation (Fig. 24.7). The The two stimuli, plasma osmolality and blood volume, most major stimulus is an increase in osmolality of the blood, often work synergistically to increase or decrease AVP re- which is detected by osmoreceptor cells in the hypothala- lease. For example, a great excess of water intake in a mus. These cells are distinct from those that affect AVP re- healthy person will inhibit AVP release because of both the lease. Ethanol and urea are not effective stimuli for the os- fall in plasma osmolality and increase in blood volume. In moreceptors because they readily penetrate these cells and certain important clinical circumstances, however, there is do not cause them to shrink. NaCl is an effective stimulus. a conflict between these two inputs. For example, severe An increase in plasma osmolality of 1 to 2% (i.e., about 3 to congestive heart failure is characterized by a decrease in the 6 mOsm/kg H2O) is needed to reach the thirst threshold. effective arterial blood volume, even though total blood Hypovolemia or a decrease in the effective arterial volume is greater than normal. This condition results be- blood volume stimulates thirst. Blood volume loss must be cause the heart does not pump sufficient blood into the ar- considerable for the thirst threshold to be reached; most terial system to maintain adequate tissue perfusion. The ar- blood donors do not become thirsty after donating 500 mL terial baroreceptors signal less volume, and AVP release is of blood (10% of blood volume). A larger blood loss (15 to stimulated. The patient will produce osmotically concen- 20% of blood volume), however, evokes intense thirst. A trated urine and will also be thirsty from the decreased ef- decrease in effective arterial blood volume as a result of se- fective arterial blood volume, with consequent increased vere diarrhea, vomiting, or congestive heart failure may water intake. The combination of decreased renal water ex- also provoke thirst. cretion and increased water intake leads to hypoosmolality The receptors for blood volume that stimulate thirst in- ϩ of the body fluids, which is reflected in a low plasma [Na ] clude the arterial baroreceptors in the carotid sinuses and or hyponatremia. Despite the hypoosmolality, plasma AVP aortic arch and stretch receptors in the cardiac atria and levels remain elevated and thirst persists. It appears that great veins in the thorax. The kidneys may also act as vol- maintaining an effective arterial blood volume is of over- ume receptors. When blood volume is decreased, the kid- riding importance, so osmolality may be sacrificed in this neys release renin into the circulation. This results in pro- condition. The hypoosmolality creates new problems, such duction of angiotensin II, which acts on neurons near the as the swelling of brain cells. Hyponatremia is discussed in third ventricle of the brain to stimulate thirst. Clinical Focus Box 24.1. The thirst sensation is reinforced by dryness of the mouth and throat, which is caused by a reflex decrease in se- Clinical AVP Disorders. Neurogenic diabetes insipidus cretion by salivary and buccal glands in a water-deprived (central, hypothalamic, pituitary) is a condition character- person. The gastrointestinal tract also monitors water in- ized by a deficient production or release of AVP. Plasma take. Moistening of the mouth or distension of the stomach, CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 411

CLINICAL FOCUS BOX 24.1

Hyponatremia effective arterial blood volume stimulates thirst and AVP Hyponatremia, defined as a plasma [Naϩ] Ͻ 135 mEq/L, release. Excretion of a dilute urine may also be impaired is the most common disorder of body fluid and electrolyte because of decreased delivery of fluid to diluting sites balance in hospitalized patients. Most often it reflects too along the and collecting ducts. Although Naϩ and much water, not too little Naϩ, in the plasma. Since Naϩ is water are retained by the kidneys in the edematous states, the major solute in the plasma, it is not surprising that hy- relatively more water is conserved, leading to a dilutional ponatremia is usually associated with hypoosmolality. Hy- hyponatremia. ponatremia, however, may also occur with a normal or Hyponatremia and hypoosmolality can cause a variety even elevated plasma osmolality. of symptoms, including muscle cramps, lethargy, fatigue, Drinking large quantities of water (20 L/day) rarely disorientation, headache, anorexia, nausea, agitation, hy- causes frank hyponatremia because of the large capacity pothermia, seizures, and coma. These symptoms, mainly of the kidneys to excrete dilute urine. If, however, plasma neurological, are a consequence of the swelling of brain AVP is not decreased when plasma osmolality is de- cells as plasma osmolality falls. Excessive brain swelling creased or if the ability of the kidneys to dilute the urine is may be fatal or may cause permanent damage. Treatment impaired, hyponatremia may develop even with a normal requires identifying and treating the underlying cause. If water intake. Naϩ loss is responsible for the hyponatremia, isotonic or Hyponatremia with hypoosmolality can occur in the hypertonic saline or NaCl by mouth is usually given. If the presence of a decreased, normal, or even increased total blood volume is normal or the patient is edematous, water body Naϩ. Hyponatremia and decreased body Naϩ content restriction is recommended. Hyponatremia should be cor- may be seen with increased Naϩ loss, such as with vomit- rected slowly and with constant monitoring because too ing, diarrhea, and diuretic therapy. In these instances, the rapid correction can be harmful. decrease in ECF volume stimulates thirst and AVP release. Hyponatremia in the presence of increased plasma os- More water is ingested, but the kidneys form osmotically molality is seen in hyperglycemic patients with uncon- concentrated urine and plasma hypoosmolality and hy- trolled diabetes mellitus. In this condition, the high plasma ponatremia result. Hyponatremia and a normal body Naϩ [glucose] causes the osmotic withdrawal of water from content are seen in hypothyroidism, cortisol deficiency, cells, and the extra water in the ECF space leads to hy- and the syndrome of inappropriate secretion of antidi- ponatremia. Plasma [Naϩ] falls by 1.6 mEq/L for each 100 uretic hormone (SIADH). SIADH occurs with neurological mg/dL rise in plasma glucose. disease, severe pain, certain drugs (such as hypoglycemic Hyponatremia and a normal plasma osmolality are seen agents), and with some tumors. For example, a bron- with so-called pseudohyponatremia. This occurs when chogenic tumor may secrete AVP without control by plasma lipids or proteins are greatly elevated. These mole- plasma osmolality. The result is renal conservation of wa- cules do not significantly elevate plasma osmolality. They ter. Hyponatremia and increased total body Naϩ are seen do, however, occupy a significant volume of the plasma, in edematous states, such as congestive heart failure, he- and because the Naϩ is dissolved only in the plasma water, patic cirrhosis, and nephrotic syndrome. The decrease in the [Naϩ] measured in the entire plasma is low.

for example, inhibit thirst, preventing excessive water in- the mouth and stomach in this situation limits water intake, take. For example, if a dog is deprived of water for some time preventing a dip in plasma osmolality below normal. and is then presented with water, it will commence drinking but will stop before all of the ingested water has been ab- sorbed by the small intestine. Monitoring of water intake by SODIUM BALANCE Naϩ is the most abundant cation in the ECF and, with its Ϫ Ϫ accompanying anions Cl and HCO3 , largely determines Plasma Blood the osmolality of the ECF. Because the osmolality of the osmolality volume ECF is closely regulated by AVP, the kidneys, and thirst, the amount of water in (and, hence, the volume of) the ECF Osmoreceptors Baroreceptors ϩ ++ compartment is mainly determined by its Na content. The kidneys are primarily involved in the regulation of ϩ Thirst + Renin Na balance. We consider first the renal mechanisms in- + volved in Naϩ excretion and then overall Naϩ balance. Angiotensin II

Dryness of Monitoring of The Kidneys Excrete Only a Small Percentage ϩ mouth and throat water intake of the Filtered Na Load by GI tract Table 24.4 shows the magnitude of filtration, reabsorption, and excretion of ions and water for a healthy adult man on FIGURE 24.7 Factors affecting the thirst sensation. A plus ϩ sign indicates stimulation of thirst, the minus an average American diet. The amount of Na filtered was ϩ sign indicates an inhibitory influence. calculated from the product of the plasma [Na ] and 412 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Magnitude of Daily Filtration, Reabsorption, and Excretion of Ions and Water in a Healthy Young Man TABLE 24.4 on a Typical American Diet

[Plasma] GFR Filtered Excreted Reabsorbed % (mEq/L) (L/day) (mEq/day) (mEq/day) (mEq/day) Reabsorbed Sodium 140 180 25,200 100 25,100 99.6 105 180 18,900 100 18,800 99.5 24 180 4,320 2 4318 99.9 Potassium 4 180 720 L/day 100 L/day 620 L/day 86.1 Water 0.93a 180 167 1.5 165.5 99.1

a Plasma contains about 0.93 L H2O per L.

glomerular filtration rate (GFR). The quantity of Naϩ reab- filtered Naϩ, together with the same percentage of filtered sorbed was calculated from the difference between filtered water, is reabsorbed in the proximal convoluted tubule. and excreted amounts. Note that 99.6% (25,100ϵ25,200) The loop of Henle reabsorbs about 20% of filtered Naϩ, of the filtered Naϩ was reabsorbed or, in other words, per- but only 10% of filtered water. The distal convoluted centage excretion of Naϩ was only 0.4% of the filtered load. tubule reabsorbs about 6% of filtered Naϩ (and no water), In terms of overall Naϩ balance for the body, the quantity and the collecting ducts reabsorb about 3% of the filtered of Naϩ excreted by the kidneys is of key importance be- Naϩ (and 19% of the filtered water). Only about 1% of the cause ordinarily about 95% of the Naϩ we consume is ex- filtered Naϩ (and water) is usually excreted. The distal creted by way of the kidneys. Tubular reabsorption of Naϩ nephron (distal convoluted tubule, connecting tubule, and must be finely regulated to keep us in Naϩ balance. collecting duct) has a lower capacity for Naϩ transport Figure 24.8 shows the percentage of filtered Naϩ reab- than more proximal segments and can be overwhelmed if sorbed in different parts of the nephron. Seventy percent of too much Naϩ fails to be reabsorbed in proximal segments. The distal nephron is of critical importance in determining the final excretion of Naϩ. Distal Proximal convoluted ϩ convoluted 70% tubule 6% Many Factors Affect Renal Na Excretion tubule Multiple factors affect renal Naϩ excretion; these are dis- 100% cussed below. A factor may promote Naϩ excretion either by increasing the amount of Naϩ filtered by the glomeruli or by decreasing the amount of Naϩ reabsorbed by the kid- ney tubules or, in some cases, by affecting both processes.

ϩ Glomerular Filtration Rate. Na excretion tends to Space of Collecting Bowman's change in the same direction as GFR. If GFR rises—for ex- duct capsule 20% ample, from an expanded ECF volume—the tubules reabsorb the increased filtered load less completely, and Naϩ excre- tion increases. If GFR falls—for example, as a result of blood loss—the tubules can reabsorb the reduced filtered Naϩ load more completely, and Naϩ excretion falls. These changes are 3% of obvious benefit in restoring a normal ECF volume. Small changes in GFR could potentially lead to massive changes in Naϩ excretion, if it were not for a phenomenon called glomerulotubular balance (Table 24.5). There is a balance between the amount of Naϩ filtered and the ϩ Loop of Henle amount of Na reabsorbed by the tubules, so the tubules increase the rate of Naϩ reabsorption when GFR is in- creased and decrease the rate of Naϩ reabsorption when GFR is decreased. This adjustment is a function of the prox- imal convoluted tubule and the loop of Henle, and it re- duces the impact of changes in GFR on Naϩ excretion. 1% Urine The Renin-Angiotensin-Aldosterone System. Renin is a ϩ proteolytic enzyme produced by granular cells, which are FIGURE 24.8 The percentage of the filtered load of Na reabsorbed along the nephron. About 1% of located in afferent arterioles in the kidneys (see Fig. 23.4). the filtered Naϩ is usually excreted. There are three main stimuli for renin release: CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 413

a Angiotensin II is also a potent vasoconstrictor of both TABLE 24.5 Glomerulotubular Balance resistance and capacitance vessels; increased plasma levels following hemorrhage, for example, help sustain blood Filtered Naϩ Ϫ Reabsorbed Naϩ ϩ pressure. Inhibiting angiotensin II production by giving an ϭ Excreted Na ACE inhibitor lowers blood pressure and is used in the treatment of hypertension. Period (mEq/min) (mEq/min) (mEq/min) The RAAS plays an important role in the day-to-day ϩ ϩ 1 6.00 5.95 0.05 control of Na excretion. It favors Na conservation by Increase GFR by one third the kidneys when there is a Naϩ or volume deficit in the 2 8.00 7.90 0.10 body. When there is an excess of Naϩ or volume, dimin- ϩ a Results from an experiment performed on a 10-kg dog. Note that in ished RAAS activity permits enhanced Na excretion. In response to an increase in GFR (produced by infusing a drug that di- the absence of aldosterone (e.g., in an adrenalectomized lated afferent arterioles), tubular reabsorption of Naϩ increased, so that ϩ individual) or in a person with adrenal cortical insuffi- only a modest increase in Na excretion occurred. If there had been ϩ ϩ ciency—Addison’s disease—excessive amounts of Na are no glomerulotubular balance and if tubular Na reabsorption had ϩ stayed at 5.95 mEq/min, the kidneys would have excreted 2.05 lost in the urine. Percentage reabsorption of Na may de- mEq/min in period 2. If we assume that the ECF volume in the dog is 2 crease from a normal value of about 99.6% to a value of L (20% of body weight) and if plasma [Naϩ] is 140 mEq/L, an excre- 98%. This change (1.6% of the filtered Naϩ load) may not tion rate of 2.05 mEq/min would result in excretion of the entire ECF ϩ seem like much, but if the kidneys filter 25,200 mEq/day Na (280 mEq) in a little more than 2 hours. The dog would have (see Table 24.4) and excrete an extra 0.016 ϫ 25,200 ϭ been dead long before this could happen, which underscores the im- ϩ portance of glomerulotubular balance. 403 mEq/day, this is the amount of Na in almost 3 L of ECF (assuming a [Naϩ] of 140 mEq/L). Such a loss of Naϩ would lead to a decrease in plasma and blood volume, cir- culatory collapse, and even death. 1) A decrease in pressure in the afferent arteriole, with ϩ the granular cells being sensitive to stretch and function as When there is an extra need for Na , people and many an intrarenal baroreceptor animals display a sodium appetite, an urge for salt intake, 2) Stimulation of sympathetic nerve fibers to the kid- which can be viewed as a brain mechanism, much like neys via ␤2-adrenergic receptors on the granular cells thirst, that helps compensate for a deficit. Patients with Ad- 3) A decrease in fluid delivery to the macula densa re- dison’s disease often show a well-developed sodium ap- gion of the nephron, resulting, for example, from a decrease petite, which helps keep them alive. Large doses of a potent mineralocorticoid will cause a in GFR ϩ All three of these pathways are activated and reinforce person to retain about 200 to 300 mEq Na (equivalent to each other when there is a decrease in the effective arterial about 1.4 to 2 L of ECF), and the person will “escape” from blood volume—for example, following hemorrhage, tran- the salt-retaining action of the steroid. Retention of this sudation of fluid out of the vascular system, diarrhea, severe amount of fluid is not sufficient to produce obvious edema. sweating, or a low salt intake. Conversely, an increase in The fact that the person will not continue to accumulate ϩ the effective arterial blood volume inhibits renin release. Na and water is due to the existence of numerous factors Long-term stimulation causes vascular smooth muscle cells that are called into play when ECF volume is expanded; ϩ in the afferent arteriole to differentiate into granular cells these factors promote renal Na excretion and overpower and leads to further increases in renin supply. Renin in the the salt-retaining action of aldosterone. This phenomenon blood plasma acts on a plasma ␣2-globulin produced by the is called mineralocorticoid escape. liver, called angiotensinogen (or renin substrate) and splits off the decapeptide angiotensin I (Fig. 24.9). Angiotensin I Intrarenal Physical Forces (Peritubular Capillary Starling is converted to the octapeptide angiotensin II as the blood Forces). An increase in the hydrostatic pressure or a de- courses through the lungs. This reaction is catalyzed by the crease in the colloid osmotic pressure in peritubular capil- angiotensin-converting enzyme (ACE), which is present laries (the so-called “physical” or Starling forces) results in on the surface of endothelial cells. All the components of reduced fluid uptake by the capillaries. In turn, an accumu- this system (renin, angiotensinogen, angiotensin-convert- lation of the reabsorbed fluid in the kidney interstitial ing enzyme) are present in some organs (e.g., the kidneys spaces results. The increased interstitial pressure causes a and brain), so that angiotensin II may also be formed and widening of the tight junctions between act locally. cells, and the epithelium becomes even more leaky than The renin-angiotensin-aldosterone system (RAAS) is a normal. The result is increased back-leak of salt and water salt-conserving system. Angiotensin II has several actions into the tubule lumen and an overall reduction in net reab- related to Naϩ and water balance: sorption. These changes occur, for example, if a large vol- 1) It stimulates the production and secretion of the al- ume of isotonic saline is infused intravenously. They also dosterone from the zona glomerulosa of the adrenal cortex occur if the (GFR/RPF) is lowered from (see Chapter 36). This mineralocorticoid hormone then the dilation of efferent arterioles, for example. In this case, acts on the distal nephron to increase Naϩ reabsorption. the protein concentration (or colloid osmotic pressure) in 2) Angiotensin II directly stimulates tubular Naϩ reab- efferent arteriolar blood and peritubular capillary blood is sorption. lower than normal because a smaller proportion of the 3) Angiotensin stimulates thirst and the release of AVP plasma is filtered in the glomeruli. Also, with upstream va- by the posterior pituitary. sodilation of efferent arterioles, hydrostatic pressure in the 414 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Angiotensinogen Liver

Renin

Kidney Angiotensin I Decreased effective arterial blood volume

Converting enzyme Lungs

Angiotensin II

Normal effective arterial Thirst blood volume Blood vessels Adrenal Brain cortex

H2O Vasoconstriction Aldosterone AVP intake

Blood pressure

Sodium H2O reabsorption reabsorption

FIGURE 24.9 Components of the renin-angiotensin-aldos- hemorrhage) and results in compensatory changes that help re- terone system. This system is activated by a store arterial blood pressure and blood volume to normal. decrease in the effective arterial blood volume (e.g., following

peritubular capillaries is increased, leading to a pressure na- cGMP. ANP directly inhibits aldosterone secretion by the triuresis and pressure diuresis. The term natriuresis means adrenal cortex; it also indirectly inhibits aldosterone secre- an increase in Naϩ excretion. tion by diminishing renal renin release. ANP is a vasodila- tor and, therefore, lowers blood pressure. Some evidence Natriuretic Hormones and Factors. Atrial natriuretic suggests that ANP inhibits AVP secretion. The actions of peptide (ANP) is a 28 polypeptide synthesized ANP are, in many respects, just the opposite of those of the and stored in myocytes of the cardiac atria (Fig. 24.10). It RAAS; ANP promotes salt and water loss by the kidneys is released upon stretch of the atria—for example, follow- and lowers blood pressure. ing volume expansion. This hormone has several actions Several other natriuretic hormones and factors have been that increase Naϩ excretion. ANP acts on the kidneys to in- described. Urodilatin (kidney natriuretic peptide) is a 32- crease glomerular blood flow and filtration rate and inhibits amino acid polypeptide derived from the same prohormone Naϩ reabsorption by the inner medullary collecting ducts. as ANP. It is synthesized primarily by intercalated cells in The second messenger for ANP in the collecting duct is the cortical collecting duct and secreted into the tubule lu- CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 415

tory drugs (NSAIDs), such as aspirin, may lead to a fall in ϩ Atrial renal blood flow and to Na retention. stretch Volume expansion Renal Sympathetic Nerves. The stimulation of renal sympathetic nerves reduces renal Naϩ excretion in at least Heart three ways: 1) It produces a decline in GFR and renal blood flow, ϩ + leading to a decreased filtered Na load and peritubular capillary hydrostatic pressure, both of which favor dimin- Atrial natriuretic ϩ peptide ished Na excretion. 2) It has a direct stimulatory effect on Naϩ reabsorp- tion by the renal tubules. 3) It causes renin release, which results in increased plasma angiotensin II and aldosterone levels, both of which Blood ϩ vessels increase tubular Na reabsorption. Adrenal Kidney Activation of the sympathetic nervous system occurs in cortex several stressful circumstances (such as hemorrhage) in which the conservation of salt and water by the kidneys is of clear benefit. Vasodilation Aldosterone Natriuresis ϩ Diuresis Estrogens. Estrogens decrease Na excretion, probably ϩ Angiotensin II Renin by the direct stimulation of tubular Na reabsorption. Most women tend to retain salt and water during pregnancy, FIGURE 24.10 Atrial natriuretic peptide and its actions. which may be partially related to the high plasma estrogen ANP release from the cardiac atria is stimulated levels during this time. by blood volume expansion, which stretches the atria. ANP pro- duces effects that bring blood volume back toward normal, such ϩ Glucocorticoids. Glucocorticoids, such as cortisol (see as increased Na excretion. Chapter 34), increase tubular Naϩ reabsorption and also cause an increase in GFR, which may mask the tubular ef- ϩ men, inhibiting Naϩ reabsorption by inner medullary col- fect. Usually a decrease in Na excretion is seen. lecting ducts via cGMP. There is also a brain natriuretic peptide. Guanylin and uroguanylin are polypeptide hor- Osmotic Diuretics. Osmotic diuretics are solutes that are excreted in the urine and increase urinary excretion of Naϩ mones produced by the small intestine in response to salt in- ϩ gestion. Like ANP and urodilatin, they activate guanylyl cy- and K salts and water. Examples are urea, glucose (when clase and produce cGMP as a second messenger, as their the reabsorptive capacity of the tubules for glucose has names suggest. Adrenomedullin is a polypeptide produced been exceeded), and mannitol (a six-carbon sugar alcohol used in the clinic to promote Naϩ excretion or cell shrink- by the adrenal medulla; its physiological significance is still ϩ not certain. Endoxin is an endogenous digitalis-like sub- age). Osmotic diuretics decrease the reabsorption of Na stance produced by the adrenal gland. It inhibits Naϩ/Kϩ- in the proximal tubule. This response results from the de- ϩ velopment of a Naϩ concentration gradient (lumen [Naϩ] ATPase activity and, therefore, inhibits Na transport by ϩ the kidney tubules. Bradykinin is produced locally in the Ͻ plasma Na ]) across the proximal tubular epithelium in kidneys and inhibits Naϩ reabsorption. the presence of a high concentration of unreabsorbed ϩ solute in the tubule lumen. When this occurs, there is sig- E2 and I2 (prostacyclin) increase Na ϩ excretion by the kidneys. These locally produced hor- nificant back-leak of Na into the tubule lumen, down the mones are formed from arachidonic acid, which is liberated concentration gradient. This back-leak results in decreased net Naϩ reabsorption. Because the proximal tubule is where from phospholipids in cell membranes by the enzyme ϩ phospholipase A2. Further processing is mediated by a cy- most of the filtered Na is normally reabsorbed, osmotic diuretics, by interfering with this process, can potentially clooxygenase (COX) enzyme that has two isoforms, COX- ϩ 1 and COX-2. In most tissues, COX-1 is constitutively ex- cause the excretion of large amounts of Na . Osmotic di- uretics may also increase Naϩ excretion by inhibiting distal pressed, while COX-2 is generally induced by ϩ inflammation. In the kidney, COX-1 and COX-2 are both Na reabsorption (similar to the proximal inhibition) and constitutively expressed in cortex and medulla. In the cor- by increasing medullary blood flow. tex, COX-2 may be involved in macula densa-mediated renin release. COX-1 and COX-2 are present in high Poorly Reabsorbed Anions. Poorly reabsorbed anions amounts in the , where the main role of the result in increased Naϩ excretion. Solutions are electrically prostaglandins is to inhibit Naϩ reabsorption. Because the neutral; whenever there are more anions in the urine, there prostaglandins (PGE2, PGI2) are vasodilators, the inhibi- must also be more cations. If there is increased excretion of tion of Naϩ reabsorption occurs via direct effects on the phosphate, ketone body acids (as occurs in uncontrolled di- Ϫ 2– ϩ tubules and collecting ducts and via hemodynamic effects abetes mellitus), HCO3 , or SO4 , more Na is also ex- (see Chapter 23). Inhibition of the formation of creted. To some extent, the Naϩ in the urine can be re- ϩ ϩ ϩ prostaglandins with common nonsteroidal anti-inflamma- placed by other cations, such as K , NH4 , and H . 416 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Diuretic Drugs. Most of the diuretic drugs used today are Regulated variable ϩ specific Na transport inhibitors. For example, the loop di- Extracellular fluid volume uretic drugs (furosemide, bumetanide) inhibit the Na-K- or EABV 2Cl cotransporter in the thick ascending limb, the thiazide diuretics inhibit the Na-Cl cotransporter in the distal con- + ϩ voluted tubule, and amiloride blocks the epithelial Na Renal Sensor + channel in the collecting ducts (see Chapter 23). Spirono- Na Cardiovascular ϩ lactone promotes Na excretion by competitively inhibit- excretion stretch receptors, kidneys ing the binding of aldosterone to the mineralocorticoid re- + ceptor. The diuretic drugs are really natriuretic drugs; they produce an increased urine output (diuresis) because water Effector + ϩ reabsorption is diminished whenever Na reabsorption is Kidneys decreased. Diuretics are commonly prescribed for treating 1. GFR hypertension and edema. 2. Aldosterone 3. Intrarenal physical forces 4. Natriuretic hormones and factors 5. Sympathetic nerve activity The Kidneys Play a Dominant Role in Regulating Na1 Balance FIGURE 24.12 The regulation of ECF volume or effective Figure 24.11 summarizes Naϩ balance throughout the arterial blood volume (EABV) by a nega- ϩ tive-feedback control system. Arterial baroreceptors and the body. Dietary intake of Na varies and, in a typical Amer- kidneys sense the degree of fullness of the arterial system. The ican diet, amounts to about 100 to 300 mEq/day, mostly in ϩ ϩ kidneys are the effectors, and they change Na excretion to re- the form of NaCl. Ingested Na is mainly absorbed in the store EABV to normal. small intestine and is added to the ECF, where it is the ma- jor determinant of the osmolality and the amount of water in (or volume of) this fluid compartment. About 50% of the In a healthy individual, one can think of the ECF volume body’s Naϩ is in the ECF, about 40% in bone, and about as the regulated variable in a negative-feedback control sys- 10% within cells. tem (Fig. 24.12). The kidneys are the effectors, and they Losses of Naϩ occur via the skin, gastrointestinal tract, change Naϩ excretion in an appropriate manner. An in- and kidneys. Skin losses are usually small, but can be con- crease in ECF volume promotes renal Naϩ loss, which re- siderable with sweating, burns, or hemorrhage. Likewise, stores a normal volume. A decrease in ECF volume leads to gastrointestinal losses are usually small, but they can be decreased renal Naϩ excretion, and this Naϩ retention large and serious with vomiting, diarrhea, or iatrogenic suc- (with continued dietary Naϩ intake) leads to the restora- tion or drainage of gastrointestinal secretions. The kidneys tion of a normal ECF volume. Closer examination of this are ordinarily the major routes of Naϩ loss from the body, concept, particularly when considering pathophysiological excreting about 95% of the ingested Naϩ in a healthy per- states, however, suggests that it is of limited usefulness. A son. Thus, the kidneys play a dominant role in the control more considered view suggests that the effective arterial of Naϩ balance. The kidneys can adjust Naϩ excretion over blood volume (EABV) is actually the regulated variable. In a wide range, reducing it to low levels when there is a Naϩ a healthy individual, ECF volume and EABV usually change deficit and excreting more Naϩ when there is Naϩ excess together in the same direction. In an abnormal condition in the body. Adjustments in Naϩ excretion occur by en- such as congestive heart failure, however, EABV is low gaging many of the factors previously discussed. when the ECF volume is abnormally increased. In this con- dition, there is a potent stimulus for renal Naϩ retention that clearly cannot be the ECF volume. When EABV is diminished, the degree of fullness of the arterial system is less than normal and tissue blood flow is Ingested Na+ inadequate. Arterial baroreceptors in the carotid sinuses 100 300 mEq/day and aortic arch sense the decreased arterial stretch. This Input will produce reflex activation of sympathetic nerve fibers to the kidneys, with consequently decreased GFR and renal blood flow and increased renin release. These changes fa- Bone Na+ Extracellular Intracellular ϩ + vor renal Na retention. Reduced EABV is also “sensed” in 1,800 mEq fluid Na fluid Na+ 2,000 mEq 400 mEq the kidneys in three ways: 1) A low pressure at the level of the afferent arteriole stimulates renin release via the intrarenal baroreceptor Output mechanism. 2) Decreases in renal perfusion pressure lead to a re- Skin Gastrointestinal losses Kidneys ϩ (sweat, burns, (diarrhea, vomiting) duced GFR and, hence, diminished Na excretion. hemorrhage) 3) Decreases in renal perfusion pressure will also re- duce peritubular capillary hydrostatic pressure, increas- ϩ ϩ ϩ FIGURE 24.11 Na balance. Most of the Na consumed in ing the uptake of reabsorbed fluid and diminishing Na our diets is excreted by the kidneys. excretion. CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 417

When kidney perfusion is threatened, the kidneys re- The distribution of Kϩ across plasma membranes—that tain salt and water, a response that tends to improve their is, the ratio of intracellular to extracellular Kϩ concentra- perfusion. tions—is the major determinant of the resting membrane po- In several important diseases, including heart and liver tential of cells and, hence, their excitability (see Chapter 3). and some kidney diseases, abnormal renal retention of Naϩ Disturbances of Kϩ balance often produce altered excitabil- contributes to the development of generalized edema, a ity of nerves and muscles. Low plasma [Kϩ] leads to mem- widespread accumulation of salt and water in the interstitial brane hyperpolarization and reduced excitability; muscle spaces of the body. The condition is often not clinically ev- weakness is a common symptom. Excessive plasma Kϩ levels ident until a person has accumulated more than 2.5 to 3 L lead to membrane depolarization and increased excitability. of ECF in the interstitial space. Expansion of the interstitial High plasma Kϩ levels cause cardiac arrhythmias and, even- space has two components: (1) an altered balance of Star- tually, ventricular fibrillation, usually a lethal event. ling forces exerted across capillaries, and (2) the retention Kϩ balance is linked to acid-base balance in complex of extra salt and water by the kidneys. Total plasma volume ways (see Chapter 25). Kϩ depletion, for example, can lead is only about 3.5 L; if edema fluid were derived solely from to metabolic alkalosis, and Kϩ excess to . the plasma, hemoconcentration and circulatory shock A primary disturbance in acid-base balance can also lead to would ensue. Conservation of salt and water by the kidneys abnormal Kϩ balance. is clearly an important part of the development of general- Kϩ affects the activity of involved in carbohy- ized edema. drate metabolism and electron transport. Kϩ is needed for Patients with congestive heart failure may accumulate tissue growth and repair. Tissue breakdown or increased many liters of edema fluid, which is easily detected as protein catabolism result in a loss of Kϩ from cells. weight gain (since 1 L of fluid weighs 1 kg). Because of the effect of gravity, the ankles become swollen and pitting ϩ edema develops. As a result of heart failure, venous pressure Most of the Body’s K Is in Cells is elevated, causing fluid to leak out of the capillaries be- Total body content of Kϩ in a healthy, young adult, 70-kg cause of their elevated hydrostatic pressure. Inadequate man is about 3,700 mEq. About 2% of this, about 60 mEq, pumping of blood by the heart leads to a decrease in EABV, is in the functional ECF (blood plasma, interstitial fluid, and so the kidneys retain salt and water. Alterations in many of lymph); this number was calculated by multiplying the the factors discussed above—decreased GFR, increased plasma [Kϩ] of 4 mEq/L times the ECF volume (20% of RAAS activity, changes in intrarenal physical forces, and body weight or 14 L). About 8% of the body’s Kϩ is in increased sympathetic nervous system activity—contribute bone, dense connective tissue, and cartilage, and another to the renal salt and water retention. To minimize the ac- 1% is in transcellular fluids. Ninety percent of the body’s cumulation of edema fluid, patients are often placed on a ϩ ϩ K is in the cell compartment. reduced Na intake and given diuretic drugs. A normal plasma [Kϩ] is 3.5 to 5.0 mEq/L. By definition, Hypertension may often be a result of a disturbance in plasma [Kϩ] below 3.5 mEq/L is hypokalemia and plasma NaCl (salt) balance. Excessive dietary intake of NaCl or in- [Kϩ] above 5.0 mEq/L is . The [Kϩ] in skele- adequate renal excretion of salt tends to increase intravas- tal muscle cells is about 150 mEq/L cell water. Skeletal mus- cular volume; this change translates into an increase in cle cells constitute the largest fraction of the cell mass in blood pressure. A reduced salt intake, ACE inhibitors, di- the human body and contain about two thirds of the body’s uretic drugs, or drugs that more directly affect the cardio- ϩ ϩ 2ϩ ␤ K . One can easily appreciate that abnormal leakage of K vascular system (e.g., Ca channel blockers or -adrener- from muscle cells, for example, as a result of trauma, may gic blockers) are useful therapies in controlling lead to dangerous hyperkalemia. hypertension in many people. A variety of factors influence the distribution of Kϩ be- tween cells and ECF (Fig. 24.13): 1) A key factor is the Naϩ/Kϩ-ATPase, which pumps POTASSIUM BALANCE Kϩ into cells. If this enzyme is inhibited—as a result of in- ϩ adequate tissue oxygen supply or digitalis overdose, for ex- Potassium (K ) is the most abundant ion in the ICF com- ample—hyperkalemia may result. partment. It has many important effects in the body, and its 2) A decrease in ECF pH (an increase in ECF [Hϩ]) tends plasma concentration is closely regulated. The kidneys play ϩ ϩ to produce a rise in ECF [K ]. This results from an exchange a dominant role in regulating K balance. of extracellular Hϩ for intracellular Kϩ. When a mineral acid such as HCl is added to the ECF, a fall in blood pH of 0.1 ϩ Kϩ Influences Cell Volume, Excitability, unit leads to about a 0.6 mEq/L rise in plasma [K ]. When an Acid-Base Balance, and Metabolism organic acid (which can penetrate plasma membranes) is added, the rise in plasma Kϩ for a given fall in blood pH is As the major osmotically active solute in cells, the amount considerably less. The fact that blood pH influences plasma of cellular Kϩ is the major determinant of the amount of [Kϩ] is sometimes used in the emergency treatment of hy- water in (and, therefore, the volume of) the ICF compart- perkalemia; intravenous infusion of a NaHCO3 solution ment, in the same way that extracellular Naϩ is a major de- (which makes the blood more alkaline) will cause Hϩ to terminant of ECF volume. When cells lose Kϩ (and accom- move out of cells and Kϩ, in exchange, to move into cells. panying anions), they also lose water and shrink; the 3) promotes the uptake of Kϩ by skeletal mus- converse is also true. cle and liver cells. This effect appears to be a result of stim- 418 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

+ + Shift K to Shift K Ingested K+ outside of cells into cells 100 mEq/day Body cell ECF pH, ECF pH, Input digitalis, K+ insulin, O lack, epinephrine Bone, dense 2 ATP hyperosmolality, connective tissue, hemolysis, cartilage K+ ADP + Pi Extracellular Intracellular infection, 300 mEq fluid K+ fluid K+ ischemia, Na+ 60 mEq Transcellular 3,300 mEq trauma + + fluid K K + - 40 mEq H + HCO3 CO2 + H2O H+ K+ Output + Urinary K K+ in feces ϩ excretion 10 mEq/day FIGURE 24.13 Factors influencing the distribution of K 90 mEq/day between intracellular and extracellular fluids. ϩ ϩ FIGURE 24.14 K balance for a healthy adult. Most K in the body is in the cell compartment. Renal Kϩ ex- ulation of plasma membrane Naϩ/Kϩ-ATPase pumps. In- cretion is normally adjusted to keep a person in balance. sulin (administered with glucose) is also used in the emer- gency treatment of hyperkalemia. 4) Epinephrine increases Kϩ uptake by cells, an effect ␤ mediated by 2-receptors. quate renal excretion is often compounded by tissue 5) Hyperosmolality (e.g., a result of hyperglycemia) ϩ trauma, infection, and acidosis, all of which raise plasma tends to raise plasma [K ]; hyperosmolality causes cells to [Kϩ]. In chronic renal failure, hyperkalemia usually does shrink and raises intracellular [Kϩ], which then favors out- ϩ not develop until GFR falls below 15 to 20 mL/min because ward of K into the ECF. of the remarkable ability of the kidney collecting ducts to 6) Tissue trauma, infection, ischemia, hemolysis, or se- adapt and increase Kϩ secretion. vere exercise release Kϩ from cells and can cause significant ϩ ϩ Excessive loss of K by the kidneys leads to hy- hyperkalemia. An artifactual increase in plasma [K ], pokalemia. The major cause of renal Kϩ wasting is iatro- pseudohyperkalemia, results if blood has been mishandled ϩ genic, an unwanted side effect of diuretic drug therapy. and red cells have been injured and allowed to leak K . Hyperaldosteronism causes excessive Kϩ excretion. In un- The plasma [Kϩ] is sometimes taken as an approximate ϩ ϩ controlled diabetes mellitus, K loss is increased because of guide to total body K stores. For example, if a condition the osmotic diuresis caused by glucosuria and an elevated is known to produce an excessive loss of Kϩ (such as taking ϩ rate of fluid flow in the cortical collecting ducts. Several a diuretic drug), a decrease in plasma [K ] of 1 mEq/L may rare inherited defects in tubular transport, including Bart- correspond to a loss of 200 to 300 mEq Kϩ. Clearly, how- ϩ ter, Gitelman, and Liddle syndromes also lead to excessive ever, many factors affect the distribution of K between renal Kϩ excretion and hypokalemia (see Table 23.3). cells and ECF; in many circumstances, the plasma [Kϩ] is ϩ not a good index of the amount of K in the body. Changes in Diet and Kϩ Excretion. As was discussed in Chapter 23, Kϩ is filtered, reabsorbed, and secreted in the ϩ The Kidneys Normally Maintain Kϩ Balance kidneys. Most of the filtered K is reabsorbed in the prox- imal convoluted tubule (70%) and the loop of Henle Figure 24.14 depicts Kϩ balance for a healthy adult man. (25%), and the majority of Kϩ excreted in the urine is usu- Most of the food we eat contains Kϩ. Kϩ intake (50 to 150 ally the result of secretion by cortical collecting duct prin- mEq/day) and absorption by the small intestine are unreg- cipal cells. The percentage of filtered Kϩ excreted in the ulated. On the output side, gastrointestinal losses are nor- urine is typically about 15% (Fig. 24.15). With prolonged mally small, but they can be large, especially with diarrhea. Kϩ depletion, the kidneys may excrete only 1% of the fil- Diarrheal fluid may contain as much as 80 mEq Kϩ/L. Kϩ tered load. However, excessive Kϩ intake may result in the loss in sweat is clinically unimportant. Normally, 90% of excretion of an amount of Kϩ that exceeds the amount fil- the ingested Kϩ is excreted by the kidneys. The kidneys are tered; in this case, there is greatly increased Kϩ secretion the major sites of control of Kϩ balance; they increase Kϩ by cortical collecting ducts. excretion when there is too much Kϩ in the body and con- When the dietary intake of Kϩ is changed, renal excre- serve Kϩ when there is too little. tion changes in the same direction. An important site for this adaptive change is the cortical collecting duct. Figure ϩ ϩ Abnormal Renal Kϩ Excretion. The major cause of K 24.16 shows the response to an increase in dietary K in- imbalances is abnormal renal Kϩ excretion. The kidneys take. Two pathways are involved. First, an elevated plasma may excrete too little Kϩ; if the dietary intake of Kϩ con- [Kϩ] leads to increased Kϩ uptake by the basolateral tinues, hyperkalemia can result. For example, in Addison’s plasma membrane Naϩ/Kϩ-ATPase in collecting duct prin- disease, a low plasma aldosterone level leads to deficient cipal cells, resulting in increased intracellular [Kϩ], Kϩ se- Kϩ excretion. Inadequate renal Kϩ excretion also occurs cretion and Kϩ excretion. Second, elevated plasma [Kϩ] with acute renal failure; the hyperkalemia caused by inade- has a direct effect (i.e., not mediated by renin and an- CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 419

Distal Increased K+ intake Proximal convoluted convoluted tubule tubule Plasma [K+] 100% 30% 5 20%

+ Aldosterone secretion Uptake of K by collecting duct principal cells Space of Plasma aldosterone Bowman's 4 150% capsule

Luminal membrane permeability to Na+ and K+ and in basolateral membrane Na+/K+-ATPase activity in collecting duct principal cells Collecting duct Increased K+ secretion

Increased K+ excretion Loop of Henle ϩ ϩ FIGURE 24.16 Effect of increased dietary K intake on K excretion. Kϩ directly stimulates aldosterone secretion and leads to an increase in cell [Kϩ] in collecting duct principal cells. Both of these lead to enhanced secretion and, hence, excretion, of Kϩ.

1 150% Urine (usually about 15%) rate in the cortical collecting ducts, which diminishes Kϩ The percentage of the filtered load of Kϩ FIGURE 24.15 secretion and counterbalances the stimulatory effect of al- remaining in tubular fluid as it flows down the ϩ ϩ dosterone. Consequently, K excretion is unaltered. nephron. K is usually secreted in the cortical collecting duct. ϩ With Kϩ loading, this secretion is so vigorous that the amount of Another puzzling question is: Why is it that K ex- Kϩ excreted may actually exceed the filtered load. With Kϩ de- cretion does not increase during water diuresis? In Chap- pletion, Kϩ is reabsorbed by the collecting ducts. ter 23, we mentioned that an increase in fluid flow through the cortical collecting ducts increases Kϩ secre- tion. AVP, in addition to its effects on water permeabil- ity, stimulates Kϩ secretion by increasing the activity of giotensin) on the adrenal cortex to stimulate the synthesis luminal membrane Kϩ channels in cortical collecting and release of aldosterone. Aldosterone acts on collecting ϩ duct principal cells. Since plasma AVP levels are low dur- duct principal cells to (1) increase the Na permeability of ing water diuresis, this will reduce Kϩ secretion, oppos- the luminal plasma membrane, (2) increase the number and activity of basolateral plasma membrane Naϩ/Kϩ-ATPase pumps, (3) increase the luminal plasma membrane Kϩ per- meability, and (4) increase cell metabolism. All of these Na+ deprivation changes result in increased Kϩ secretion. In cases of decreased dietary Kϩ intake or Kϩ depletion, the activity of the luminal plasma membrane Hϩ/Kϩ-AT- ␣ Aldosterone secretion GFR and proximal Pase found in -intercalated cells is increased. This pro- Na+ reabsorption motes Kϩ reabsorption by the collecting ducts. The col- lecting ducts can greatly diminish Kϩ excretion, but it takes ϩ a couple of weeks for K loss to reach minimal levels. Plasma aldosterone Fluid delivery to cortical collecting ducts Counterbalancing Influences on Kϩ Excretion. Consid- ϩ ering that aldosterone stimulates both Na reabsorption K+ secretion K+ secretion and Kϩ secretion, why is it that Naϩ deprivation, a stimu- lus that raises plasma aldosterone levels, does not lead to ϩ enhanced K excretion? The explanation is related to the Unchanged K+ excretion fact that Naϩ deprivation tends to lower GFR and increase ϩ proximal Na reabsorption (Fig. 24.17). This response Why Naϩ depletion does not lead to enhanced ϩ FIGURE 24.17 leads to a fall in Na delivery and a decreased fluid flow Kϩ excretion. 420 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

ing the effects of increased flow, with the result that Kϩ Distal excretion hardly changes. Proximal convoluted convoluted tubule tubule 100% 40% CALCIUM BALANCE 10% The kidneys play an important role in the maintenance of Ca2ϩ balance. Ca2ϩ intake is about 1,000 mg/day and mainly comes from dairy products in the diet. About 300 mg/day are absorbed by the small intestine, a process con- 2ϩ Space of 5% trolled by 1,25(OH)2 vitamin D3. About 150 mg Ca /day Bowman's are secreted into the gastrointestinal tract (via saliva, gastric capsule juice, pancreatic juice, bile, and intestinal secretions), so that net absorption is only about 150 mg/day. Fecal Ca2ϩ excretion is about 850 mg/day and urinary excretion about 150 mg/day. 2ϩ A normal plasma [Ca ] is about 10 mg/dL, which is Collecting equal to 2.5 mmol/L (since the atomic weight of calcium is duct 40) or 5 mEq/L. About 40% of plasma Ca2ϩ is bound to plasma proteins (mainly serum albumin), 10% is bound to small diffusible anions (such as citrate, bicarbonate, phos- phate, and sulfate) and 50% is free or ionized. It is the ion- Loop of Henle ized Ca2ϩ in the blood that is physiologically important and closely regulated (see Chapter 36). Most of the Ca2ϩ in the body is in bone (99%), which constantly turns over. In a healthy adult, the rate of release of Ca2ϩ from old bone exactly matches the rate of deposition of Ca2ϩ in newly formed bone (500 mg/day). Ca2ϩ that is not bound to plasma proteins (i.e., 60% of 0.5 2% Urine the plasma Ca2ϩ) is freely filterable in the glomeruli. About 2ϩ 2ϩ 60% of the filtered Ca is reabsorbed in the proximal con- FIGURE 24.18 The percentage of the filtered load of Ca voluted tubule (Fig. 24.18). Two thirds is reabsorbed via a remaining in tubular fluid as it flows down the paracellular route in response to and the small nephron. The kidneys filter about 10,800 mg/day (0.6 ϫ 100 lumen positive potential (ϩ3 mV) found in the late proxi- mg/L ϫ 180 L/day) and excrete only about 0.5 to 2% of the fil- tered load, that is, about 50 to 200 mg/day. Thiazides increase mal convoluted tubule. One third is reabsorbed via a tran- 2ϩ 2ϩ Ca reabsorption by the distal convoluted tubule, and PTH in- scellular route that includes Ca channels in the apical 2ϩ 2ϩ ϩ creases Ca reabsorption by the connecting tubule and cortical plasma membrane and a primary Ca -ATPase or 3 Na /1 collecting duct. Ca2ϩ exchanger in the basolateral plasma membrane. About 30% of filtered Ca2ϩ is reabsorbed along the loop of 2ϩ Henle. Most of the Ca reabsorbed in the thick ascending is usually excreted. (Chapter 34 discusses Ca2ϩ balance and limb is by through the tight junctions, its control by several hormones in more detail.) propelled by the lumen positive potential. Reabsorption continues along the distal convoluted tubule. Reabsorption here is increased by thiazide diuretics, ϩ MAGNESIUM BALANCE which may be prescribed in cases of excessive Ca2 in the urine, hypercalciuria, and kidney stone disease (see Clini- An adult body contains about 2,000 mEq of Mg2ϩ, of which cal Focus Box 24.2). Thiazides inhibit the luminal mem- about 60% is present in bone, about 39% in cells, and about brane Na-Cl cotransporter in distal convoluted tubule cells, 1% in the ECF. Mg2ϩ is the second most abundant cation in which leads to a fall in intracellular [Naϩ]. This, in turn, cells, after Kϩ (see Table 24.2). The bulk of intracellular promotes Naϩ-Ca2ϩ exchange and increased basolateral Mg2ϩ is not free, but is bound to a variety of organic com- extrusion of Ca2ϩ and increased Ca2ϩ reabsorption. pounds, such as ATP. Mg2ϩ is present in the plasma at a con- The late distal tubule (connecting tubule and initial part centration of about 1 mmol/L (2 mEq/L). About 20% of of the cortical collecting duct) is an important site of control plasma Mg2ϩ is bound to plasma proteins, 20% is complexed of Ca2ϩ excretion because this is where parathyroid hor- with various anions, and 60% is free or ionized. mone (PTH) increases Ca2ϩ reabsorption. Ca2ϩ diffuses into About 25% of the Mg2ϩ filtered by the glomeruli is re- the cells, primarily through an epithelial Ca2ϩ channel absorbed in the proximal convoluted tubule (Fig. 24.19); (ECaC) in the apical membrane, is transported through the this is a lower percentage than for Naϩ, Kϩ, Ca2ϩ, or wa- cytoplasm by a 1,25(OH)2 vitamin D3-dependent calcium- ter. The proximal tubule epithelium is rather impermeable binding protein, called calbindin, and is extruded by a to Mg2ϩ under normal conditions, so there is little passive Naϩ/Ca2ϩ exchange or Ca2ϩ-ATPase in the basolateral Mg2ϩ reabsorption. The major site of Mg2ϩ reabsorption is plasma membrane. Only about 0.5 to 2% of the filtered Ca2ϩ the loop of Henle (mainly the thick ascending limb), which CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 421

CLINICAL FOCUS BOX 24.2

Kidney Stone Disease (Nephrolithiasis) down the urinary tract and spontaneously eliminated. Mi- A kidney stone is a hard mass that forms in the urinary croscopic and chemical examination of the eliminated tract. At least 1% of Americans develop kidney stones at stones is used to determine the nature of the stone and some time during their lives. Nephrolithiasis or kidney help guide treatment. Sometimes a change in diet is rec- stone disease occurs more commonly in men than in ommended to reduce the amount of potential stone-form- women and usually strikes men between the ages of 30 ing material (e.g., Ca2ϩ, oxalate, or uric acid) in the urine. and 60. A stone lodged in the ureter will cause bleeding Thiazide diuretics are useful in reducing Ca2ϩ excretion if and intense pain. Kidney stone disease causes consider- excessive urinary Ca2ϩ excretion (hypercalciuria) is the able suffering and loss of time from work, and it may lead problem. Potassium citrate is useful in treating most stone to kidney damage. Once a stone forms in a person, stone disease because citrate complexes Ca2ϩ in the urine and formation often recurs. inhibits the crystallization of Ca2ϩ salts. It also makes the Ϫ Stones form when poorly soluble substances in the urine more alkaline (since citrate is oxidized to HCO3 in urine precipitate out of solution, causing crystals to form, the body). This is helpful in reducing the risk of uric acid aggregate, and grow. Most kidney stones (75 to 85%) are stones because urates (favored in an alkaline urine) are made up of insoluble Ca2ϩ salts of oxalate and phosphate. more soluble than uric acid (the form favored in an acidic There may be excessive amounts of Ca2ϩ or oxalate in the urine). Administering an inhibitor of uric acid synthesis, urine as a result of diet, a genetic defect, or unknown such as allopurinol, can help reduce the amount of uric causes. Stones may also form from precipitated ammo- acid in the urine. nium magnesium phosphate (struvite), uric acid, and cys- If the stone is not passed, several options are available. tine. Struvite stones (10 to 15% of all stones) are the result Surgery to remove the stone can be done, but extracor- of infection with bacteria, usually Proteus species. Uric poreal shock wave lithotripsy is more common, using acid stones (5 to 8% of all stones) may form in patients with a device called a lithotriptor. The patient is placed in a excessive uric acid production and excretion, as occurs in tub of water, and the stone is localized by X-ray imaging. some patients with gout. Defective tubular reabsorption of Shock waves are generated in the water by high-voltage cystine (in patients with cystinuria) leads to cystine stone electric discharges and are focused on the stone through (1% of stones). The rather insoluble amino acid cystine the body wall. The shock waves fragment the stone so that was first isolated from a urinary bladder stone by Wollas- it can be passed down the urinary tract and eliminated. As ton in 1810, hence, its name. Because low some renal injury is produced by this procedure, it may raises the concentration of all poorly soluble substances in not be entirely innocuous. Other procedures include pass- the urine, favoring precipitation, a key to prevention of kid- ing a tube with an ultrasound transducer through the skin ney stones is to drink plenty of water and maintain a high into the renal pelvis; stone fragments can be removed di- urine output day and night. rectly. A ureteroscope with a laser can also be used to Fortunately, most stones are small enough to be passed break up stones.

2ϩ Ϫ reabsorbs about 65% of filtered Mg . Reabsorption here is H2PO4 . Phosphate plays a variety of roles in the body: It mainly passive and occurs through the tight junctions, is an important constituent of bone; it plays a critical role in driven by the lumen positive potential. Recent studies have cell metabolism, structure, and regulation (as organic phos- identified a tight junction protein that is a channel that fa- phates); and it is a pH buffer. cilitates Mg2ϩ movement. Changes in Mg2ϩ excretion re- Phosphate is mainly unbound in the plasma and freely sult mainly from changes in loop transport. More distal filtered by the glomeruli. About 60 to 70% of filtered phos- portions of the nephron reabsorb only a small fraction of phate is actively reabsorbed in the proximal convoluted filtered Mg2ϩ and, under normal circumstances, appear to tubule and another 15% is reabsorbed by the proximal play a minor role in controlling Mg2ϩ excretion. straight tubule via a Naϩ-phosphate cotransporter in the An abnormally low plasma [Mg2ϩ] is characterized by luminal plasma membrane (Fig. 24.20). The remaining por- neuromuscular and CNS hyperirritability. Abnormally high tions of the nephron and collecting ducts reabsorb little, if plasma Mg2ϩ levels have a sedative effect and may cause car- any, phosphate. The proximal tubule is the major site of diac arrest. Dietary intake of Mg2ϩ is usually 20 to 50 phosphate reabsorption. Only about 5 to 20% of filtered mEq/day; two thirds is excreted in the feces, and one third is phosphate is usually excreted. Phosphate in the urine is an excreted in the urine. The kidneys are mainly responsible for important pH buffer and contributes to titratable acid ex- regulating the plasma [Mg2ϩ]. Excess amounts of Mg2ϩ are cretion (see Chapter 25). Phosphate reabsorption is Tm- rapidly excreted by the kidneys. In Mg2ϩ-deficient states, limited (see Chapter 23), and the amounts of phosphate fil- Mg2ϩ virtually disappears from the urine. tered usually exceed the maximum reabsorptive capacity of the tubules for phosphate. This is different from the situa- tion for glucose, in which normally less glucose is filtered PHOSPHATE BALANCE than can be reabsorbed. If more phosphate is ingested and absorbed by the intestine, plasma [phosphate] rises, more A normal plasma concentration of inorganic phosphate is phosphate is filtered, and the filtered load exceeds the Tm about 1 mmol/L. At a normal blood pH of 7.4, 80% of the more than usual and the extra phosphate is excreted. Thus, 2– phosphate is present as HPO4 and 20% is present as the kidneys participate in regulating the plasma phosphate 422 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS

Distal Distal Proximal convoluted Proximal convoluted convoluted tubule convoluted tubule tubule tubule 100% 100% 75% 30 40% 12%

5 20%

Space of 10% Space of Bowman's Bowman's capsule capsule

Collecting Collecting duct duct

Loop of Henle Loop of Henle

10% 5 20% Urine Urine

2ϩ FIGURE 24.19 The percentage of the filtered load of Mg FIGURE 24.20 The percentage of the filtered load of phos- remaining in tubular fluid as it flows down the phate remaining in tubular fluid as it flows nephron. The loop of Henle, specifically the thick ascending down the nephron. The proximal tubule is the major site of limb, is the major site of reabsorption of filtered Mg2ϩ. phosphate reabsorption, and downstream nephron segments reab- sorb little, if any, phosphate.

by an “overflow” type mechanism. When there is an excess a complex with Ca2ϩ. Second, hyperphosphatemia de- of phosphate in the body, they automatically increase creases production of 1,25(OH)2 vitamin D3 in the kidneys phosphate excretion. In cases of phosphate depletion, the by inhibiting the 1␣-hydroxylase enzyme that forms this kidneys filter less phosphate and the tubules reabsorb a hormone. With decreased plasma levels of 1,25(OH)2 vita- 2ϩ larger percentage of the filtered phosphate. min D3, there is less Ca absorption by the small intestine Phosphate reabsorption in the proximal tubule is con- and a tendency for hypocalcemia. trolled by a variety of factors. PTH is of particular im- Low plasma ionized [Ca2ϩ] stimulates hyperplasia of the portance; it decreases the phosphate Tm, increasing parathyroid glands and increased secretion of PTH. High phosphate excretion. plasma [phosphate] also stimulates PTH secretion directly. Patients with chronic renal disease often develop an el- PTH then inhibits phosphate reabsorption by the proximal evated plasma [phosphate] or hyperphosphatemia, de- tubules, promotes phosphate excretion, and helps return pending on the severity of the disease. When GFR falls, plasma [phosphate] back to normal. Elevated PTH levels, the filtered phosphate load is diminished, and the tubules however, also cause mobilization of Ca2ϩ and phosphate reabsorb phosphate more completely. Phosphate excre- from bone. Increased bone reabsorption results, and the tion is inadequate in the face of continued intake of phos- bone minerals are replaced with fibrous tissue that renders phate in the diet. Hyperphosphatemia is dangerous be- the bone more susceptible to fracture. cause of the precipitation of calcium phosphate in soft Patients with advanced chronic renal failure are often ad- tissue. For example, when calcium phosphate precipitates vised to restrict phosphate intake and consume substances in the walls of blood vessels, blood flow will be impaired. (such as Ca2ϩ salts) that bind phosphate in the intestines, so as Hyperphosphatemia can lead to myocardial failure and to avoid the many problems caused by hyperphosphatemia. pulmonary insufficiency. Administration of synthetic 1,25(OH)2 vitamin D3 may com- When plasma [phosphate] rises, the plasma ionized pensate for deficient renal production of this hormone. This [Ca2ϩ] tends to fall, for two reasons. First, phosphate forms hormone opposes hypocalcemia and inhibits PTH synthesis CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 423 and secretion. Parathyroidectomy is sometimes necessary in Micturition Involves Autonomic patients with advanced chronic renal failure. and Somatic Nerves Micturition (), the periodic emptying of the blad- der, is a complex act involving both autonomic and somatic URINARY TRACT nerve pathways and several reflexes that can be either in- The kidneys form urine all of the time. The urine is trans- hibited or facilitated by higher centers in the brain. The ba- ported by the ureters to the urinary bladder. The bladder is sic reflexes occur at the level of the sacral spinal cord and specialized to fill with urine at a low pressure and to empty are modified by centers in the midbrain and cerebral cor- its contents when appropriate. Contractions of the bladder tex. Distension of the bladder is sensed by stretch receptors and its sphincters are controlled by the nervous system. in the bladder wall; these induce reflex contraction of the detrusor and relaxation of the internal and external sphinc- ters. This reflex is released by removing inhibitory influ- The Ureters Convey Urine to the Bladder ences from the cerebral cortex. Fluid flow through the ure- The ureters are muscular tubes that propel the urine from thra reflexively causes further contraction of the detrusor the pelvis of each kidney to the urinary bladder. Peristaltic and relaxation of the external sphincter. Increased movements originate in the region of the calyces, which parasympathetic nerve activity stimulates contraction of contain specialized smooth muscle cells that generate the detrusor and relaxation of the internal sphincter. Sym- spontaneous pacemaker potentials. These pacemaker po- pathetic innervation is not essential for micturition. During tentials trigger action potentials and contractions in the micturition, the perineal and levator ani muscles relax, muscular regions of the renal pelvis that propagate distally shortening the urethra and decreasing urethral resistance. to the ureter. Peristaltic waves sweep down the ureters at a Descent of the diaphragm and contraction of abdominal frequency of one every 10 seconds to one every 2 to 3 min- muscles raises intra-abdominal pressure, and aids in the ex- utes. The ureters enter the base of the bladder obliquely, pulsion of urine from the bladder. forming a valvular flap that passively prevents the reflux of Micturition is fortunately under voluntary control in urine during contractions of the bladder. The ureters are in- healthy adults. In the young child, however, it is purely re- nervated by sympathetic and parasympathetic nerve fibers. Sensory fibers mediate the intense pain that is felt when a stone distends or blocks a ureter. Descending aorta L1 Inferior vena cava

The Bladder Stores Urine Until It Can Be L2 Sympathetic trunk Conveniently Emptied L3 The urinary bladder is a distensible hollow vessel contain- ing smooth muscle in its wall (Fig. 24.21). The muscle is called the detrusor (from Latin for “that which pushes down”). The neck of the bladder, the involuntary internal sphincter, also contains smooth muscle. The bladder body and neck are innervated by parasympathetic pelvic nerves and sympathetic hypogastric nerves. The external sphinc- S2 ter, the compressor urethrae, is composed of skeletal mus- Right ureter S3 cle and innervated by somatic nerve fibers that travel in the Hypogastric S4 pudendal nerves. Pelvic, hypogastric, and pudendal nerves nerve Pelvic nerve contain both motor and sensory fibers. Bladder The bladder has two functions: to serve as a distensible reservoir for urine and to empty its contents at appropriate Pudendal nerve intervals. When the bladder fills, it adjusts its tone to its ca- Internal (involuntary) pacity, so that minimal increases in bladder pressure occur. sphincter The external sphincter is kept closed by discharges along External (voluntary) Urethra the pudendal nerves. The first sensation of bladder filling is sphincter experienced at a volume of 100 to 150 mL in an adult, and the first desire to void is elicited when the bladder contains FIGURE 24.21 The innervation of the urinary bladder. The about 150 to 250 mL of urine. A person becomes uncom- parasympathetic pelvic nerves arise from spinal fortably aware of a full bladder when the volume is 350 to cord segments S2 to S4 and supply motor fibers to the bladder 400 mL; at this volume, hydrostatic pressure in the bladder musculature and internal (involuntary) sphincter. Sympathetic is about 10 cm H O. With further volume increases, blad- motor fibers supply the bladder via the hypogastric nerves, which 2 arise from lumbar segments of the spinal cord. The pudendal der pressure rises steeply, partly as a result of reflex con- nerves supply somatic motor innervation to the external (volun- tractions of the detrusor. An increase in volume to 700 mL tary) sphincter. Sensory afferents (dashed lines) from the bladder creates pain and often loss of control. The sensations of travel mainly in the pelvic nerves but also to some extent in the bladder filling, of conscious desire to void, and painful dis- hypogastric nerves. (Modified from Anderson JE. Grant’s Atlas of tension are mediated by afferents in the pelvic nerves. Anatomy. 8th Ed. Baltimore: Williams & Wilkins, 1983.) 424 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS flex and occurs whenever the bladder is sufficiently dis- the upper urethra commonly occurs in older men and is a tended. At about 2 /2 years of age, it begins to come under result of enlargement of the surrounding prostate gland. 1 cortical control and, in most children, complete control is This condition is called benign prostatic hyperplasia, and achieved by age 3. Damage to the nerves that supply the it results in decreased urine stream, overdistension of the bladder and its sphincters can produce abnormalities of bladder as a result of incomplete emptying, and increased micturition and incontinence. An increased resistance of urgency and frequency of urination.

REVIEW QUESTIONS

DIRECTIONS: Each of the numbered 6.The nephron segment that reabsorbs 12.A 60-year-old woman is always thirsty items of incomplete statements in this the largest percentage of filtered Mg2ϩ and wakes up several times during the section is followed by answers or is the night to empty her bladder. Plasma completions of the statement. Select the (A) Proximal convoluted tubule osmolality is 295 mOsm/kg H2O ONE lettered answer or completion that is (B) Thick ascending limb (normal range, 281 to 297 mOsm/kg BEST in each case. (C) Distal convoluted tubule H2O), urine osmolality is 100 (D) Cortical collecting duct mOsm/kg H2O, and plasma AVP levels 1.Which of the following body fluid (E) Medullary collecting duct are higher than normal. The urine is volumes cannot be directly determined 7.Which of the following causes negative for glucose. The most likely with a single indicator? decreased renin release by the kidneys? diagnosis is (A) Extracellular fluid volume (A) Decreased fluid and solute delivery (A) Diabetes mellitus (B) Intracellular fluid volume to the macula densa (B) Diuretic drug abuse (C) Plasma volume (B) Hemorrhage (C) Nephrogenic diabetes insipidus (D) Total body water (C) Intravenous infusion of isotonic (D) Neurogenic diabetes insipidus 2.Which of the following results in saline (E) Primary polydipsia thirst? (D) Narrowing (stenosis) of the renal 13.The volume of the extracellular fluid is (A) Cardiac failure artery most closely related to the amount of (B) Decreased plasma levels of (E) Stimulation of renal sympathetic which solute in this compartment? Ϫ angiotensin II nerves (A) HCO3 (C) Distension of the cardiac atria 8.Which of the following may cause (B) Glucose (D) Distension of the stomach hyperkalemia? (C) Kϩ (E) Hypotonic volume expansion (A) Epinephrine injection (D) Serum albumin 3.Arginine vasopressin (AVP) is (B) Hyperaldosteronism (E) Naϩ synthesized in the (C) Insulin administration 14.A homeless man was found comatose, (A) Adrenal cortex (D) Intravenous infusion of a NaHCO3 lying in the doorway of a downtown (B) Anterior hypothalamus solution department store at night. His plasma (C) Anterior pituitary (E) Skeletal muscle injury osmolality was 370 mOsm/kg H2O (D) Collecting ducts of the kidneys 9. (PTH) (normal, 281 to 297 mOsm/kg H2O), (E) Posterior pituitary (A) Decreases tubular reabsorption of plasma [Naϩ] was 140 mEq/L (normal, 4.A 60-kg woman is given 10 Ca2ϩ 136 to 145 mEq/L), plasma [glucose] microcuries (␮CI) (370 kilobecquerels) (B) Decreases tubular reabsorption of 100 mg/dL (normal fasting level, 70 to of radioiodinated serum albumin phosphate 110 mg/dL), and BUN 15 mg/dL (RISA) intravenously. Ten minutes (C) Inhibits bone resorption. (normal, 7 to 18 mg/dL). His most later, a venous blood sample is (D) Secretion is decreased in patients likely problem is collected, and the plasma RISA activity with chronic renal failure (A) Alcohol intoxication is 4 ␮CI/L. Her ratio is (E) Secretion is stimulated by a rise in (B) Dehydration 0.40. What is her blood volume? plasma ionized Ca2ϩ (C) Diabetes insipidus (A) 417 mL 10.Aldosterone acts on cortical collecting (D) Diabetes mellitus (B) 625 mL ducts to (E) Renal failure (C) 2.5 L (A) Decrease Kϩ secretion 15.A hypertensive patient is given an (D) 4.17 L (B) Decrease Naϩ reabsorption angiotensin-converting enzyme (ACE) (E) 6.25 L (C) Decrease water permeability inhibitor. Which of the following 5.Which of the following leads to (D) Increase Kϩ secretion changes would be expected? decreased Naϩ reabsorption by the (E) Increase water permeability (A) Plasma aldosterone level will rise kidneys? 11.In response to an increase in GFR, the (B) Plasma angiotensin I level will rise (A) An increase in central blood proximal tubule and the loop of Henle (C) Plasma angiotensin II level will rise volume demonstrate an increase in the rate of (D) Plasma bradykinin level will fall (B) An increase in colloid osmotic Naϩ reabsorption. This phenomenon is (E) Plasma renin level will fall pressure in the peritubular capillaries called 16.If a person consumes a high-Kϩ diet, (C) An increase in GFR (A) Autoregulation the majority of Kϩ excreted in the (D) An increase in plasma aldosterone (B) Glomerulotubular balance urine is derived from level (C) Mineralocorticoid escape (A) Glomerular filtrate (E) An increase in renal sympathetic (D) Saturation of tubular transport (B) Kϩ that is not reabsorbed in the nerve activity (E) Tubuloglomerular feedback proximal tubule (continued) CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 425

(C) Kϩ secreted in the loop of Henle isotonic saline (0.9% NaCl) results in course for teaching renal physiology. (D) Kϩ secreted by the cortical increased Adv Physiol Education collecting duct (A) Intracellular fluid volume 1998;20:S114–S245. (E) Kϩ secreted by the inner (B) Plasma aldosterone level Giebisch G. Renal potassium transport: medullary-collecting duct (C) Plasma arginine vasopressin (AVP) Mechanisms and regulation. Am J 17.Which of the following set of values concentration Physiol 1998;274:F817–F833. would lead you to suspect that a (D) Plasma atrial natriuretic peptide Hoenderop JGJ, Willems PHGM, Bindels person has syndrome of inappropriate (ANP) concentration RJM. Toward a comprehensive molecu- secretion of ADH (SIADH)? (E) Plasma volume, but no change in lar model of active calcium reabsorp- Plasma Urine other body fluid compartments tion. Am J Physiol Osmolality Plasma Osmolality 20.The kidneys of a person with congestive 2000;278:F352–F360. (mOsm/ [Naϩ] (mOsm/ heart failure avidly retain Naϩ. The best Koeppen BM, Stanton BA. Renal Physiol- kg H2O) (mEq/L) kg H2O) explanation for this is that the ogy. 3rd Ed. St. Louis: Mosby-Year (A) 300 145 100 (A) Effective arterial blood volume is Book, 2001. (B) 270 130 50 decreased Kumar R. New concepts concerning the (C) 285 140 600 (B) Extracellular fluid volume is regulation of renal phosphate excre- (D) 270 130 450 decreased tion. News Physiol Sci (E) 285 140 1,200 (C) Extracellular fluid volume is 1997;12:211–214. 18.A dehydrated hospitalized patient increased Quamme GA. Renal magnesium handling: with uncontrolled diabetes mellitus (D) Total blood volume is decreased New insights in understanding old has a plasma [Kϩ] of 4.5 mEq/L (E) Total blood volume is increased problems. Kidney Int (normal, 3.5 to 5.0 mEq/L), a plasma 1997;52:1180–1195. [glucose] of 500 mg/dL, and an SUGGESTED READING Rose BD. Clinical Physiology of Acid-Base arterial blood pH of 7.00 (normal, Adrogue HJ, Madias NE. Hypernatremia. and Electrolyte Disorders. 4th Ed. New 7.35 to 7.45). These data suggest that N Engl J Med 2000;342:1493–1499. York:McGraw-Hill, 1994. the patient has Adrogue HJ, Madias NE. Hyponatremia. Valtin H, Schafer JA. Renal Function. 3rd (A) A decreased total body store of Kϩ N Engl J Med 2000;342:1581–1589. Ed. Boston: Little, Brown, 1995. (B) A normal total body store of Kϩ Braunwald E. Edema. In: Fauci AS, et al., Vander AJ. Renal Physiology. 5th Ed. New (C) An increased total body store of Kϩ eds. Harrison’s Principles of Internal York: McGraw-Hill, 1995. (D) Hypokalemia Medicine, 14th Ed. New York: Mc- Weiner ID, Wingo CS. Hyperkalemia: A (E) Hyperkalemia Graw-Hill, 1998;210–214. potential silent killer. J Am Soc 19.Intravenous infusion of 2.0 L of Brooks VL, Vander AJ, eds. Refresher Nephrol 1998;9:1535–1543.