Chapter25 Fluid, Electrolyte, and Acid-Base Balance

Body Water Content

Human beings are mostly water, ranging from about 75 percent of body mass in infants to about 50–60 percent in adults to as low as 45 percent in old age. The percent of body water changes with development, because the proportions of the body given over to each organ and to muscles, fat, bone, and other tissues change from infancy to adulthood (Figure 25.1). Your brain and kidneys have the highest proportions of water, which comprises 80–85 percent of their mass. In contrast, teeth have the lowest proportion of water, at 8–10 percent.

Fluid Compartments

Body fluids can be discussed in terms of their specific fluid compartment, a location that is largely separate from another compartment by some form of physical barrier. The intracellular fluid (ICF) compartment is the system that includes all fluid enclosed in cells by their plasma membranes. Extracellular fluid (ECF) surrounds all cells in the body. Extracellular fluid has two primary constituents: the fluid component of the blood, called plasma, and the interstitial fluid (IF) that surrounds all cells (Figure 25.2).

Composition of Body Fluids

The compositions of the two components of the ECF—plasma and IF—are more similar to each other than either is to the ICF. Blood plasma has high concentrations of sodium, chloride, bicarbonate, and protein. The IF has high concentrations of sodium, chloride, and bicarbonate but a relatively lower concentration of protein. In contrast, the ICF has elevated amounts of potassium, phosphate, magnesium, and protein. Overall, the ICF contains high concentrations of potassium and phosphate (${\text{HPO}}_4^{2-}$), whereas both plasma and the ECF contain high concentrations of sodium and chloride.

Most body fluids are neutral in charge. Thus, cations, or positively charged ions, and anions, or negatively charged ions, are balanced in fluids. Sodium (Na⁺) ions and chloride (Cl-) ions are concentrated in the ECF of the body, whereas potassium (K⁺) ions are concentrated inside cells. Although sodium and potassium can “leak” through “pores” into and out of cells, respectively, the high levels of potassium and low levels of sodium in the ICF are maintained by sodium-potassium pumps in the cell membranes. These pumps use the energy supplied by ATP to pump sodium out of the cell and potassium into the cell (Figure 25.4).

Fluid Movement Between Compartments

Hydrostatic pressure, the force exerted by a fluid against a wall, produces movement of fluid between compartments. The hydrostatic pressure of blood is the pressure exerted by blood against the walls of blood vessels by the pumping action of the heart. In capillaries, hydrostatic pressure (also known as capillary blood pressure) is higher than the opposing “colloid osmotic pressure” in blood—a “constant” pressure primarily produced by circulating albumin—at the arteriolar end of the capillary (Figure 25.5). This pressure forces plasma and nutrients out of the capillaries and into surrounding tissues. Fluid and the cellular wastes in the tissues enter the capillaries at the venule end, where the hydrostatic pressure is less than the osmotic pressure in the vessel. Filtration pressure squeezes fluid from the plasma in the blood to the IF surrounding the tissue cells. The surplus fluid in the interstitial space that is not returned directly back to the capillaries is drained from tissues by the lymphatic system and then reenters the vascular system at the subclavian veins.

Hydrostatic pressure is especially important in governing the movement of water in the nephrons of the kidneys to ensure proper filtering of the blood to form urine. As hydrostatic pressure in the kidneys increases, the amount of water leaving the capillaries also increases, and more urine filtrate is formed. If hydrostatic pressure in the kidneys drops too low, as can happen in dehydration, the functions of the kidneys will be impaired, and less nitrogenous wastes will be removed from the bloodstream. Extreme dehydration can result in kidney failure.

Fluid also moves between compartments along an osmotic gradient. Recall that an osmotic gradient is produced by the difference in concentration of all solutes on either side of a semipermeable membrane. The magnitude of the osmotic gradient is proportional to the difference between the concentration of solutes on one side of the cell membrane and that on the other side. Water will move by osmosis from the side where its concentration is high (and the concentration of solute is low) to the side of the membrane where its concentration is low (and the concentration of solute is high). In the body, water moves by osmosis from plasma to the IF (and the reverse) and from the IF to the ICF (and the reverse). Water moves constantly into and out of fluid compartments as conditions change in different parts of the body.

For example, if you are sweating, you will lose water through your skin. Sweating depletes your tissues of water and increases the solute concentration in those tissues. As this happens, water diffuses from your blood into sweat glands and surrounding skin tissues that have become dehydrated because of the osmotic gradient. Additionally, as water leaves the blood, it is replaced by the water in other tissues throughout your body that are not dehydrated. If this continues, dehydration spreads throughout the body. When a dehydrated person drinks water and rehydrates, the water is redistributed by the same gradient, but in the opposite direction, replenishing water in all of the tissues.

Solute Movement Between Compartments

The movement of some solutes between compartments is active, which consumes energy and is an active transport process, whereas the movement of other solutes is passive, which does not require energy. Active transport allows cells to move a specific substance against its concentration gradient through a membrane protein, requiring energy in the form of ATP.

For example, the sodium-potassium pump employs active transport to pump sodium out of cells and potassium into cells, with both substances moving against their concentration gradients.

Passive transport of a molecule or ion depends on its ability to pass through the membrane as well as the existence of a concentration gradient that allows the molecules to diffuse from an area of higher concentration to an area of lower concentration. Some molecules, like gases, lipids, and water itself (which also utilizes water channels in the membrane called aquaporins), slip fairly easily through the cell membrane; others, including polar molecules like glucose, amino acids, and ions, do not. Some of these molecules enter and leave cells using facilitated transport, whereby the molecules move down a concentration gradient through specific protein channels in the membrane.

This process does not require energy.

For example, glucose is transferred into cells by glucose transporters that use facilitated transport (Figure 25.6).

Regulation of Water Intake

Plasma osmolality is the ratio of solutes to water found in blood plasma. A person’s plasma osmolality value reflects the state of hydration. A healthy body maintains plasma osmolality within a narrow range by employing several mechanisms that regulate both water intake and output.

Drinking water is considered voluntary. So how is water intake regulated by the body? Consider someone who is experiencing dehydration, a net loss of water that results in insufficient water in blood and other tissues. The water that leaves the body as exhaled air, sweat, or urine is ultimately extracted from blood plasma. As the blood becomes more concentrated, the thirst response—a sequence of physiological processes—is triggered (Figure 25.7). Osmoreceptors are sensory receptors in the thirst centre in the hypothalamus that monitor the concentration of solutes (osmolality) in the blood. If blood osmolality increases above its ideal value, the hypothalamus transmits signals that result in a conscious awareness of thirst. The person should (and normally does) respond by drinking water. The hypothalamus of a dehydrated person also releases antidiuretic hormone (ADH) through the posterior pituitary gland. ADH signals the kidneys to recover water from urine, effectively diluting the blood plasma. To conserve water, the hypothalamus of a dehydrated person also sends signals via the sympathetic nervous system to the salivary glands in the mouth. The signals result in a decrease in watery, serous output (and an increase in stickier, thicker mucus output). These changes in secretions result in a “dry mouth” and the sensation of thirst.

Decreased blood volume resulting from water loss has two additional effects. First, baroreceptors, blood-pressure receptors in the arch of the aorta and the carotid arteries in the neck, detect a decrease in blood pressure that results from decreased blood volume. The heart is ultimately signalled to increase its rate and/or strength of contractions to compensate for the lowered blood pressure.

Second, the kidneys have a renin-angiotensin hormonal system that increases the production of the active form of the hormone angiotensin II, which helps stimulate thirst but also stimulates the release of the hormone aldosterone from the adrenal glands. Aldosterone increases the reabsorption of sodium in the distal tubules of the nephrons in the kidneys, and water follows this reabsorbed sodium back into the blood.

If adequate fluids are not consumed, dehydration results, and a person’s body contains too little water to function correctly. A person who repeatedly vomits or who has diarrhea may become dehydrated, and infants, because their body mass is so low, can become dangerously dehydrated very quickly. Endurance athletes such as distance runners often become dehydrated during long races. Dehydration can be a medical emergency, and a dehydrated person may lose consciousness, become comatose, or die if their body is not rehydrated quickly.

Regulation of Water Output

Water loss from the body occurs predominantly through the renal system. A person produces an average of 1.5 L of urine per day. Although the volume of urine varies in response to hydration levels, there is a minimum volume of urine production required for proper bodily functions. The kidney excretes 100 to 1,200 milliosmoles of solutes per day to rid the body of a variety of excess salts and other water-soluble chemical wastes, most notably creatinine, urea, and uric acid. Failure to produce the minimum volume of urine means that metabolic wastes cannot be effectively removed from the body, a situation that can impair organ function. The minimum level of urine production necessary to maintain normal function is about 0.47 L per day.

The kidneys also must make adjustments in the event of ingestion of too much fluid. Diuresis, which is the production of urine in excess of normal levels, begins about 30 minutes after drinking a large quantity of fluid. Diuresis reaches a peak after about 1 hour, and normal urine production is reestablished after about 3 hours.

Role of ADH

Antidiuretic hormone (ADH), also known as vasopressin, controls the amount of water reabsorbed from the collecting ducts and tubules in the kidney. This hormone is produced in the hypothalamus and is delivered to the posterior pituitary for storage and release (Figure 25.8). When the osmoreceptors in the hypothalamus detect an increase in the concentration of blood plasma, the hypothalamus signals the release of ADH from the posterior pituitary into the blood.

ADH has two major effects. It constricts the arterioles in the peripheral circulation, which reduces the flow of blood to the extremities and thereby increases the blood supply to the core of the body. ADH also causes the epithelial cells that line the renal collecting tubules to move water channel proteins, called aquaporins, from the interior of the cells to the apical surface, where these proteins are inserted into the cell membrane (Figure 25.9). The result is an increase in the water permeability of these cells and, thus, a large increase in water passage from the urine through the walls of the collecting tubules, leading to more reabsorption of water into the bloodstream. When the blood plasma becomes less concentrated and the level of ADH decreases, aquaporins are removed from collecting tubule cell membranes, and the passage of water out of urine and into the blood decreases.

A diuretic is a compound that increases urine output and therefore decreases water conservation by the body. Diuretics are used to treat hypertension, congestive heart failure, and fluid retention associated with menstruation. Alcohol acts as a diuretic by inhibiting the release of ADH.

Roles of Electrolytes

These six ions aid in nerve excitability, endocrine secretion, membrane permeability, buffering of body fluids, and controlling the movement of fluids between compartments. These ions enter the body through the digestive tract. More than 90 percent of the calcium and phosphate that enters the body is incorporated into bones and teeth, with bone serving as a mineral reserve for these ions. In the event that calcium and phosphate are needed for other functions, bone tissue can be broken down to supply the blood and other tissues with these minerals. Phosphate is a normal constituent of nucleic acids; hence, blood levels of phosphate will increase whenever nucleic acids are broken down.

Excretion of ions occurs mainly through the kidneys, with lesser amounts lost in sweat and in feces. Excessive sweating may cause a significant loss, especially of sodium and chloride. Severe vomiting or diarrhea will cause a loss of chloride and bicarbonate ions. Adjustments in respiratory and renal functions allow the body to regulate the levels of these ions in the ECF.

Regulation of Sodium and Potassium

Sodium is reabsorbed from the renal filtrate, and potassium is excreted into the filtrate in the renal collecting tubule. The control of this exchange is governed principally by two hormones—aldosterone and angiotensin II.

Regulation of Calcium and Phosphate

Calcium and phosphate are both regulated through the actions of three hormones: parathyroid hormone (PTH), dihydroxyvitamin D (calcitriol), and calcitonin. All three are released or synthesized in response to the blood levels of calcium.

PTH is released from the parathyroid gland in response to a decrease in the concentration of blood calcium. The hormone activates osteoclasts to break down bone matrix and release inorganic calcium-phosphate salts. PTH also increases the gastrointestinal absorption of dietary calcium by converting vitamin D into dihydroxyvitamin D (calcitriol), an active form of vitamin D that intestinal epithelial cells require to absorb calcium.

PTH raises blood calcium levels by inhibiting the loss of calcium through the kidneys. PTH also increases the loss of phosphate through the kidneys.

Calcitonin is released from the thyroid gland in response to elevated blood levels of calcium. The hormone increases the activity of osteoblasts, which removes calcium from the blood and incorporates calcium into the bony matrix.

Buffer Systems in the Body

The buffer systems in the human body are extremely efficient, and different systems work at different rates. It takes only seconds for the chemical buffers in the blood to make adjustments to pH. The respiratory tract can adjust the blood pH upward in minutes by exhaling CO₂ from the body. The renal system can also adjust blood pH through the excretion of hydrogen ions (H⁺) and the conservation of bicarbonate, but this process takes hours to days to have an effect.

The buffer systems functioning in blood plasma include plasma proteins, phosphate, and bicarbonate—carbonic acid buffers. The kidneys help control acid-base balance by excreting hydrogen ions and generating bicarbonate that helps maintain blood plasma pH within a normal range. Protein buffer systems work predominantly inside cells.

Respiratory Regulation of Acid-Base Balance

The respiratory system contributes to the balance of acids and bases in the body by regulating the blood levels of carbonic acid (Figure 25.12). CO₂ in the blood readily reacts with water to form carbonic acid, and the levels of CO₂ and carbonic acid in the blood are in equilibrium. When the CO₂ level in the blood rises (as it does when you hold your breath), the excess CO₂ reacts with water to form additional carbonic acid, lowering blood pH. Increasing the rate and/or depth of respiration (which you might feel the “urge” to do after holding your breath) allows you to exhale more CO₂. The loss of CO₂ from the body reduces blood levels of carbonic acid and thereby adjusts the pH upward, toward normal levels. As you might have surmised, this process also works in the opposite direction.

Excessive deep and rapid breathing (as in hyperventilation) rids the blood of CO₂ and reduces the level of carbonic acid, making the blood too alkaline. This brief alkalosis can be remedied by rebreathing air that has been exhaled into a paper bag. Rebreathing exhaled air will rapidly bring blood pH down toward normal.

The chemical reactions that regulate the levels of CO₂ and carbonic acid occur in the lungs when blood travels through the lung’s pulmonary capillaries. Minor adjustments in breathing are usually sufficient to adjust the pH of the blood by changing how much CO₂ is exhaled. In fact, doubling the respiratory rate for less than 1 minute, removing “extra” CO₂, would increase the blood pH by 0.2. This situation is common if you are exercising strenuously over a period of time. To keep up the necessary energy production, you would produce excess CO₂ (and lactic acid if exercising beyond your aerobic threshold). In order to balance the increased acid production, the respiration rate goes up to remove the CO₂. This helps keep you from developing acidosis.

The body regulates the respiratory rate by the use of chemoreceptors, which primarily use CO₂ as a signal. Peripheral blood sensors are found in the walls of the aorta and carotid arteries. These sensors signal the brain to provide immediate adjustments to the respiratory rate if CO₂ levels rise or fall. Yet other sensors are found in the brain itself. Changes in the pH of CSF affect the respiratory centre in the medulla oblongata, which can directly modulate breathing rate to bring the pH back into the normal range.

Hypercapnia, or abnormally elevated blood levels of CO₂, occurs in any situation that impairs respiratory functions, including pneumonia and congestive heart failure. Reduced breathing (hypoventilation) due to drugs such as morphine, barbiturates, or ethanol (or even just holding one’s breath) can also result in hypercapnia. Hypocapnia, or abnormally low blood levels of CO₂, occurs with any cause of hyperventilation that drives off the CO₂, such as salicylate toxicity, elevated room temperatures, fever, or hysteria.

Renal Regulation of Acid-Base Balance

The renal regulation of the body’s acid-base balance addresses the metabolic component of the buffering system.

Whereas the respiratory system (together with breathing centres in the brain) controls the blood levels of carbonic acid by controlling the exhalation of CO₂, the renal system controls the blood levels of bicarbonate. A decrease of blood bicarbonate can result from the inhibition of carbonic anhydrase by certain diuretics or from excessive bicarbonate loss due to diarrhea. Blood bicarbonate levels are also typically lower in people who have Addison’s disease (chronic adrenal insufficiency), in which aldosterone levels are reduced, and in people who have renal damage, such as chronic nephritis. Finally, low bicarbonate blood levels can result from elevated levels of ketones (common in unmanaged diabetes mellitus), which bind bicarbonate in the filtrate and prevent its conservation.

Bicarbonate ions, HCO₃−, found in the filtrate, are essential to the bicarbonate buffer system, yet the cells of the tubule are not permeable to bicarbonate ions. The steps involved in supplying bicarbonate ions to the system are summarized as follows:

• • Step 1: Sodium ions are reabsorbed from the filtrate in exchange for H⁺ by an antiport mechanism in the apical membranes of cells lining the renal tubule.
• • Step 2: The cells produce bicarbonate ions that can be shunted to peritubular capillaries.
• • Step 3: When CO₂ is available, the reaction is driven to the formation of carbonic acid, which dissociates to form a bicarbonate ion and a hydrogen ion.
• • Step 4: The bicarbonate ion passes into the peritubular capillaries and returns to the blood. The hydrogen ion is secreted into the filtrate, where it can become part of new water molecules and be reabsorbed as such, or removed in the urine.

It is also possible that salts in the filtrate, such as sulfates, phosphates, or ammonia, will capture hydrogen ions. If this occurs, the hydrogen ions will not be available to combine with bicarbonate ions and produce CO₂. In such cases, bicarbonate ions are not conserved from the filtrate to the blood, which will also contribute to a pH imbalance and acidosis.

The hydrogen ions also compete with potassium to exchange with sodium in the renal tubules. If more potassium is present than normal, potassium, rather than the hydrogen ions, will be exchanged, and increased potassium enters the filtrate. When this occurs, fewer hydrogen ions in the filtrate participate in the conversion of bicarbonate into CO₂ and less bicarbonate is conserved. If there is less potassium, more hydrogen ions enter the filtrate to be exchanged with sodium and more bicarbonate is conserved.

Chloride ions are important in neutralizing positive ion charges in the body. If chloride is lost, the body uses bicarbonate ions in place of the lost chloride ions. Thus, lost chloride results in an increased reabsorption of bicarbonate by the renal system.

Metabolic Acidosis: Primary Bicarbonate Deficiency

Metabolic acidosis occurs when the blood is too acidic (pH below 7.35) due to too little bicarbonate, a condition called primary bicarbonate deficiency. At the normal pH of 7.40, the ratio of bicarbonate to carbonic acid buffer is 20:1. If a person’s blood pH drops below 7.35, then the person is in metabolic acidosis. The most common cause of metabolic acidosis is the presence of organic acids or excessive ketone bodies in the blood. Table 25.1 lists some other causes of metabolic acidosis.

* Acid metabolites from ingested chemical.

The first three of the nine causes of metabolic acidosis listed are medical (or unusual physiological) conditions.

Strenuous exercise can cause temporary metabolic acidosis due to the production of lactic acid. The last five causes result from the ingestion of specific substances. The active form of aspirin is its metabolite, sulfosalicylic acid. An overdose of aspirin causes acidosis due to the acidity of this metabolite. Metabolic acidosis can also result from uremia, which is the retention of urea and uric acid. Metabolic acidosis can also arise from diabetic ketoacidosis, wherein an excess of ketone bodies is present in the blood. Other causes of metabolic acidosis are a decrease in the excretion of hydrogen ions, which inhibits the conservation of bicarbonate ions, and excessive loss of bicarbonate ions through the gastrointestinal tract due to diarrhea.

Metabolic Alkalosis: Primary Bicarbonate Excess

Metabolic alkalosis is the opposite of metabolic acidosis. It occurs when the blood is too alkaline (pH above 7.45) due to too much bicarbonate (called primary bicarbonate excess).

A transient excess of bicarbonate in the blood can follow ingestion of excessive amounts of bicarbonate, citrate, or antacids for conditions such as stomach acid reflux—known as heartburn. Cushing’s disease, which is the chronic hypersecretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary gland, can cause chronic metabolic alkalosis. The oversecretion of ACTH results in elevated aldosterone levels and an increased loss of potassium by urinary excretion. Other causes of metabolic alkalosis include the loss of hydrochloric acid from the stomach through vomiting, potassium depletion due to the use of diuretics for hypertension, and the excessive use of laxatives.

Respiratory Acidosis: Primary Carbonic Acid/CO₂ Excess

Respiratory acidosis occurs when the blood is overly acidic due to an excess of carbonic acid, resulting from too much CO₂ in the blood. Respiratory acidosis can result from anything that interferes with respiration, such as pneumonia, emphysema, or congestive heart failure.

Respiratory Alkalosis: Primary Carbonic Acid/CO₂ Deficiency

Respiratory alkalosis occurs when the blood is overly alkaline due to a deficiency in carbonic acid and CO₂ levels in the blood. This condition usually occurs when too much CO₂ is exhaled from the lungs, as occurs in hyperventilation, which is breathing that is deeper or more frequent than normal. An elevated respiratory rate leading to hyperventilation can be due to extreme emotional upset or fear, fever, infections, hypoxia, or abnormally high levels of catecholamines, such as epinephrine and norepinephrine. Surprisingly, aspirin overdose—salicylate toxicity—can result in respiratory alkalosis as the body tries to compensate for initial acidosis.

Compensation Mechanisms

Various compensatory mechanisms exist to maintain blood pH within a narrow range, including buffers, respiration, and renal mechanisms. Although compensatory mechanisms usually work very well, when one of these mechanisms is not working properly (like in kidney failure or respiratory disease), they have their limits. If the pH and bicarbonate to carbonic acid ratio are changed too drastically, the body may not be able to compensate. Moreover, extreme changes in pH can denature proteins. Extensive damage to proteins in this way can result in disruption of normal metabolic processes, serious tissue damage, and ultimately death.

25.1 Body Fluids and Fluid Compartments

Your body is mostly water. Body fluids are aqueous solutions with differing concentrations of materials called solutes. An appropriate balance of water and solute concentrations must be maintained to ensure cellular functions. If the cytosol becomes too concentrated due to water loss, cell functions deteriorate. If the cytosol becomes too dilute due to water intake by cells, cell membranes can be damaged, and the cell can burst. Hydrostatic pressure is the force exerted by a fluid against a wall and causes movement of fluid between compartments. Fluid can also move between compartments along an osmotic gradient.

Active transport processes require ATP to move some solutes against their concentration gradients between compartments. Passive transport of a molecule or ion depends on its ability to pass easily through the membrane as well as the existence of a high to low concentration gradient.

25.2 Water Balance

Homeostasis requires that water intake and output be balanced. Most water intake comes through the digestive tract via liquids and food, but roughly 10 percent of water available to the body is generated at the end of aerobic respiration during cellular metabolism. Urine produced by the kidneys accounts for the largest amount of water leaving the body. The kidneys can adjust the concentration of the urine to reflect the body’s water needs, conserving water if the body is dehydrated or making urine more dilute to expel excess water when necessary. ADH is a hormone that helps the body retain water by increasing water reabsorption by the kidneys.

25.3 Electrolyte Balance

Electrolytes serve various purposes, such as helping conduct electrical impulses along cell membranes in neurons and muscles, stabilizing enzyme structures, and releasing hormones from endocrine glands. The ions in plasma also contribute to the osmotic balance that controls the movement of water between cells and their environment. Imbalances of these ions can result in various problems in the body, and their concentrations are tightly regulated. Aldosterone and angiotensin II control the exchange of sodium and potassium between the renal filtrate and the renal collecting tubule. Calcium and phosphate are regulated by PTH, calcitriol, and calcitonin.

25.4 Acid-Base Balance

A variety of buffering systems exist in the body that helps maintain the pH of the blood and other fluids within a narrow range—between pH 7.35 and 7.45. A buffer is a substance that prevents a radical change in fluid pH by absorbing excess hydrogen or hydroxyl ions. Most commonly, the substance that absorbs the ion is either a weak acid, which takes up a hydroxyl ion (OH-), or a weak base, which takes up a hydrogen ion (H⁺). Several substances serve as buffers in the body, including cell and plasma proteins, hemoglobin, phosphates, bicarbonate ions, and carbonic acid. The bicarbonate buffer is the primary buffering system of the IF surrounding the cells in tissues throughout the body. The respiratory and renal systems also play major roles in acid-base homeostasis by removing CO₂ and hydrogen ions, respectively, from the body.

25.5 Disorders of Acid-Base Balance

Acidosis and alkalosis describe conditions in which a person’s blood is, respectively, too acidic (pH below 7.35) and too alkaline (pH above 7.45). Each of these conditions can be caused either by metabolic problems related to bicarbonate levels or by respiratory problems related to carbonic acid and CO₂ levels.

Several compensatory mechanisms allow the body to maintain a normal pH.