Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 30

Acid-Base Regulation

image Regulation of hydrogen ion (H+) balance is similar in some ways to the regulation of other ions in the body. For instance, there must be a balance between the intake or production of H+ and the net removal of H+ from the body to achieve homeostasis. And, as is true for other ions, the kidneys play a key role in regulating H+ removal from the body. However, precise control of extracellular fluid H+ concentration involves much more than simple elimination of H+ by the kidneys. There are also multiple acid-base buffering mechanisms involving the blood, cells, and lungs that are essential in maintaining normal H+ concentrations in both the extracellular and intracellular fluid.

In this chapter, the various mechanisms that contribute to the regulation of H+ concentration are discussed, with special emphasis on the control of renal H+ secretion and renal reabsorption, production, and excretion of bicarbonate ions (image), one of the key components of acid-base control systems in the body fluids.

H+ Concentration Is Precisely Regulated

Precise H+ regulation is essential because the activities of almost all enzyme systems in the body are influenced by H+ concentration. Therefore, changes in H+ concentration alter virtually all cell and body functions.

Compared with other ions, the H+ concentration of the body fluids normally is kept at a low level. For example, the concentration of sodium in extracellular fluid (142 mEq/L) is about 3.5 million times as great as the normal concentration of H+, which averages only 0.00004 mEq/L. Equally important, the normal variation in H+ concentration in extracellular fluid is only about one millionth as great as the normal variation in sodium ion (Na+) concentration. Thus, the precision with which H+ is regulated emphasizes its importance to the various cell functions.

Acids and Bases—Their Definitions and Meanings

A hydrogen ion is a single free proton released from a hydrogen atom. Molecules containing hydrogen atoms that can release hydrogen ions in solutions are referred to as acids. An example is hydrochloric acid (HCl), which ionizes in water to form hydrogen ions (H+) and chloride ions (Cl). Likewise, carbonic acid (H2CO3) ionizes in water to form H+ and bicarbonate ions (image).

base is an ion or a molecule that can accept an H+. For example, image is a base because it can combine with H+ to form H2CO3. Likewise, image is a base because it can accept an H+ to form image. The proteins in the body also function as bases because some of the amino acids that make up proteins have net negative charges that readily accept H+. The protein hemoglobin in the red blood cells and proteins in the other cells of the body are among the most important of the body’s bases.

The terms base and alkali are often used synonymously. An alkali is a molecule formed by the combination of one or more of the alkaline metals—sodium, potassium, lithium, and so forth—with a highly basic ion such as a hydroxyl ion (OH). The base portion of these molecules reacts quickly with H+ to remove it from solution; they are, therefore, typical bases. For similar reasons, the term alkalosis refers to excess removal of H+ from the body fluids, in contrast to the excess addition of H+, which is referred to as acidosis.

Strong and Weak Acids and Bases

A strong acid is one that rapidly dissociates and releases especially large amounts of H+ in solution. An example is HCl. Weak acids are less likely to dissociate their ions and, therefore, release H+ with less vigor. An example is H2CO3. A strong base is one that reacts rapidly and strongly with H+ and, therefore, quickly removes these from a solution. A typical example is OH, which reacts with H+ to form water (H2O). A typical weak base is imagebecause it binds with H+ much more weakly than does OH. Most acids and bases in the extracellular fluid that are involved in normal acid-base regulation are weak acids and bases. The most important ones that we discuss in detail are H2CO3 and image base.

Normal H+ Concentration and pH of Body Fluids and Changes That Occur in Acidosis and Alkalosis

As discussed earlier, the blood H+ concentration is normally maintained within tight limits around a normal value of about 0.00004 mEq/L (40 nEq/L). Normal variations are only about 3 to 5 nEq/L, but under extreme conditions, the H+ concentration can vary from as low as 10 nEq/L to as high as 160 nEq/L without causing death.

Because H+ concentration normally is low, and because these small numbers are cumbersome, it is customary to express H+ concentration on a logarithm scale, using pH units. pH is related to the actual H+concentration by the following formula (H+ concentration [H+] is expressed in equivalents per liter):

image

For example, the normal [H+] is 40 nEq/L (0.00000004 Eq/L). Therefore, the normal pH is

image

image

From this formula, one can see that pH is inversely related to the H+ concentration; therefore, a low pH corresponds to a high H+ concentration and a high pH corresponds to a low H+ concentration.

The normal pH of arterial blood is 7.4, whereas the pH of venous blood and interstitial fluids is about 7.35 because of the extra amounts of carbon dioxide (CO2) released from the tissues to form H2CO3 in these fluids (Table 30-1). Because the normal pH of arterial blood is 7.4, a person is considered to have acidosis when the pH falls below this value and to have alkalosis when the pH rises above 7.4. The lower limit of pH at which a person can live more than a few hours is about 6.8, and the upper limit is about 8.0.

Table 30-1 pH and H+ Concentration of Body Fluids

 

H+ Concentration (mEq/L)

pH

Extracellular fluid

   

Arterial blood

4.0 × 10−5

7.40

Venous blood

4.5 × 10−5

7.35

Interstitial fluid

4.5 × 10−5

7.35

Intracellular fluid

1 × 10−3 to 4 × 10−5

6.0-7.4

Urine

3 × 10−2 to 1 × 10−5

4.5-8.0

Gastric HCl

160

0.8

Intracellular pH usually is slightly lower than plasma pH because the metabolism of the cells produces acid, especially H2CO3. Depending on the type of cells, the pH of intracellular fluid has been estimated to range between 6.0 and 7.4. Hypoxia of the tissues and poor blood flow to the tissues can cause acid accumulation and decreased intracellular pH.

The pH of urine can range from 4.5 to 8.0, depending on the acid-base status of the extracellular fluid. As discussed later, the kidneys play a major role in correcting abnormalities of extracellular fluid H+concentration by excreting acids or bases at variable rates.

An extreme example of an acidic body fluid is the HCl secreted into the stomach by the oxyntic (parietal) cells of the stomach mucosa, as discussed in Chapter 64. The H+ concentration in these cells is about 4 million times greater than the hydrogen concentration in blood, with a pH of 0.8. In the remainder of this chapter, we discuss the regulation of extracellular fluid H+ concentration.

Defending Against Changes in H+ Concentration: Buffers, Lungs, and Kidneys

Three primary systems regulate the H+ concentration in the body fluids to prevent acidosis or alkalosis: (1) the chemical acid-base buffer systems of the body fluids, which immediately combine with acid or base to prevent excessive changes in H+ concentration; (2) the respiratory center, which regulates the removal of CO2 (and, therefore, H2CO3) from the extracellular fluid; and (3) the kidneys, which can excrete either acid or alkaline urine, thereby readjusting the extracellular fluid H+ concentration toward normal during acidosis or alkalosis.

When there is a change in H+ concentration, the buffer systems of the body fluids react within seconds to minimize these changes. Buffer systems do not eliminate H+ from or add them to the body but only keep them tied up until balance can be re-established.

The second line of defense, the respiratory system, acts within a few minutes to eliminate CO2 and, therefore, H2CO3 from the body.

These first two lines of defense keep the H+ concentration from changing too much until the more slowly responding third line of defense, the kidneys, can eliminate the excess acid or base from the body. Although the kidneys are relatively slow to respond compared with the other defenses, over a period of hours to several days, they are by far the most powerful of the acid-base regulatory systems.

Buffering of H+in the Body Fluids

A buffer is any substance that can reversibly bind H+. The general form of the buffering reaction is

image

In this example, a free H+ combines with the buffer to form a weak acid (H buffer) that can either remain as an unassociated molecule or dissociate back to buffer and H+. When the H+ concentration increases, the reaction is forced to the right and more H+ binds to the buffer, as long as buffer is available. Conversely, when the H+ concentration decreases, the reaction shifts toward the left and H+ is released from the buffer. In this way, changes in H+ concentration are minimized.

The importance of the body fluid buffers can be quickly realized if one considers the low concentration of H+ in the body fluids and the relatively large amounts of acids produced by the body each day. For example, about 80 milliequivalents of H+ is either ingested or produced each day by metabolism, whereas the H+ concentration of the body fluids normally is only about 0.00004 mEq/L. Without buffering, the daily production and ingestion of acids would cause huge changes in body fluid H+ concentration.

The action of acid-base buffers can perhaps best be explained by considering the buffer system that is quantitatively the most important in the extracellular fluid—the bicarbonate buffer system.

Bicarbonate Buffer System

The bicarbonate buffer system consists of a water solution that contains two ingredients: (1) a weak acid, H2CO3, and (2) a bicarbonate salt, such as NaHCO3.

H2CO3 is formed in the body by the reaction of CO2 with H2O.

image

This reaction is slow, and exceedingly small amounts of H2CO3 are formed unless the enzyme carbonic anhydrase is present. This enzyme is especially abundant in the walls of the lung alveoli, where CO2 is released; carbonic anhydrase is also present in the epithelial cells of the renal tubules, where CO2 reacts with H2O to form H2CO3.

H2CO3 ionizes weakly to form small amounts of H+ and image.

image

The second component of the system, bicarbonate salt, occurs predominantly as sodium bicarbonate (NaHCO3) in the extracellular fluid. NaHCO3 ionizes almost completely to form image and Na+, as follows:

image

Now, putting the entire system together, we have the following:

image

Because of the weak dissociation of H2CO3, the H+ concentration is extremely small.

When a strong acid such as HCl is added to the bicarbonate buffer solution, the increased H+ released from the acid (HCl → H+ + Cl) is buffered by image.

image

As a result, more H2CO3 is formed, causing increased CO2 and H2O production. From these reactions, one can see that H+ from the strong acid HCl reacts with image to form the very weak acid H2CO3, which in turn forms CO2and H2O. The excess CO2 greatly stimulates respiration, which eliminates the CO2 from the extracellular fluid.

The opposite reactions take place when a strong base, such as sodium hydroxide (NaOH), is added to the bicarbonate buffer solution.

image

In this case, the OH from the NaOH combines with H2CO3 to form additional image. Thus, the weak base NaHCO3 replaces the strong base NaOH. At the same time, the concentration of H2CO3decreases (because it reacts with NaOH), causing more CO2 to combine with H2O to replace the H2CO3.

image

The net result, therefore, is a tendency for the CO2 levels in the blood to decrease, but the decreased CO2 in the blood inhibits respiration and decreases the rate of CO2 expiration. The rise in blood image that occurs is compensated for by increased renal excretion of image.

Quantitative Dynamics of the Bicarbonate Buffer System

All acids, including H2CO3, are ionized to some extent. From mass balance considerations, the concentrations of H+ and image are proportional to the concentration of H2CO3.

image

For any acid, the concentration of the acid relative to its dissociated ions is defined by the dissociation constant K′.

image

This equation indicates that in an H2CO3 solution, the amount of free H+ is equal to

image

The concentration of undissociated H2CO3 cannot be measured in solution because it rapidly dissociates into CO2 and H2O or to H+ and image. However, the CO2 dissolved in the blood is directly proportional to the amount of undissociated H2CO3. Therefore, equation 2 can be rewritten as

image

The dissociation constant (K) for equation 3 is only about image of the dissociation constant (K′) of equation 2 because the proportionality ratio between H2CO3 and CO2 is 1:400.

Equation 3 is written in terms of the total amount of CO2 dissolved in solution. However, most clinical laboratories measure the blood CO2 tension (PCO2) rather than the actual amount of CO2. Fortunately, the amount of CO2 in the blood is a linear function of PCO2 multiplied by the solubility coefficient for CO2; under physiologic conditions, the solubility coefficient for CO2 is 0.03 mmol/mm Hg at body temperature. This means that 0.03 millimole of H2CO3is present in the blood for each mm Hg PCO2 measured. Therefore, equation 3 can be rewritten as

image

Henderson-Hasselbalch Equation

As discussed earlier, it is customary to express H+ concentration in pH units rather than in actual concentrations. Recall that pH is defined as pH = −log H+.

The dissociation constant can be expressed in a similar manner.

image

Therefore, we can express the H+ concentration in equation 4 in pH units by taking the negative logarithm of that equation, which yields

image

Therefore,

image

Rather than work with a negative logarithm, we can change the sign of the logarithm and invert the numerator and denominator in the last term, using the law of logarithms to yield

image

For the bicarbonate buffer system, the pK is 6.1, and equation 7 can be written as

image

Equation 8 is the Henderson-Hasselbalch equation, and with it, one can calculate the pH of a solution if the molar concentration of image and the PCO2 are known.

From the Henderson-Hasselbalch equation, it is apparent that an increase in image concentration causes the pH to rise, shifting the acid-base balance toward alkalosis. An increase in PCO2 causes the pH to decrease, shifting the acid-base balance toward acidosis.

The Henderson-Hasselbalch equation, in addition to defining the determinants of normal pH regulation and acid-base balance in the extracellular fluid, provides insight into the physiologic control of acid and base composition of the extracellular fluid. As discussed later, the image concentration is regulated mainly by the kidneys, whereas the PCO2 in extracellular fluid is controlled by the rate of respiration. By increasing the rate of respiration, the lungs remove CO2 from the plasma, and by decreasing respiration, the lungs elevate PCO2. Normal physiologic acid-base homeostasis results from the coordinated efforts of both of these organs, the lungs and the kidneys, and acid-base disorders occur when one or both of these control mechanisms are impaired, thus altering either the image concentration or the PCO2 of extracellular fluid.

When disturbances of acid-base balance result from a primary change in extracellular fluid image concentration, they are referred to as metabolic acid-base disorders. Therefore, acidosis caused by a primary decrease in imageconcentration is termed metabolic acidosis, whereas alkalosis caused by a primary increase in image concentration is called metabolic alkalosis. Acidosis caused by an increase in PCO2 is called respiratory acidosis, whereas alkalosis caused by a decrease in PCO2 is termed respiratory alkalosis.

Bicarbonate Buffer System Titration Curve

Figure 30-1 shows the changes in pH of the extracellular fluid when the ratio of image to CO2 in extracellular fluid is altered. When the concentrations of these two components are equal, the right-hand portion of equation 8 becomes the log of 1, which is equal to 0. Therefore, when the two components of the buffer system are equal, the pH of the solution is the same as the pK (6.1) of the bicarbonate buffer system. When base is added to the system, part of the dissolved CO2 is converted into image causing an increase in the ratio of image to CO2 and increasing the pH, as is evident from the Henderson-Hasselbalch equation. When acid is added, it is buffered by image, which is then converted into dissolved CO2, decreasing the ratio of image to CO2 and decreasing the pH of the extracellular fluid.

image

Figure 30-1 Titration curve for bicarbonate buffer system showing the pH of extracellular fluid when the percentages of buffer in the form of image and CO2 (or H2CO3) are altered.

“Buffer Power” Is Determined by the Amount and Relative Concentrations of the Buffer Components

From the titration curve in Figure 30-1, several points are apparent. First, the pH of the system is the same as the pK when each of the components (image and CO2) constitutes 50 percent of the total concentration of the buffer system. Second, the buffer system is most effective in the central part of the curve, where the pH is near the pK of the system. This means that the change in pH for any given amount of acid or base added to the system is least when the pH is near the pK of the system. The buffer system is still reasonably effective for 1.0 pH unit on either side of the pK, which for the bicarbonate buffer system extends from a pH of about 5.1 to 7.1 units. Beyond these limits, the buffering power rapidly diminishes. And when all the CO2 has been converted into image or when all the image has been converted into CO2, the system has no more buffering power.

The absolute concentration of the buffers is also an important factor in determining the buffer power of a system. With low concentrations of the buffers, only a small amount of acid or base added to the solution changes the pH considerably.

Bicarbonate Buffer System Is the Most Important Extracellular Buffer

From the titration curve shown in Figure 30-1, one would not expect the bicarbonate buffer system to be powerful, for two reasons: First, the pH of the extracellular fluid is about 7.4, whereas the pK of the bicarbonate buffer system is 6.1. This means that there is about 20 times as much of the bicarbonate buffer system in the form of image as in the form of dissolved CO2. For this reason, this system operates on the portion of the buffering curve where the slope is low and the buffering power is poor. Second, the concentrations of the two elements of the bicarbonate system, CO2 and image, are not great.

Despite these characteristics, the bicarbonate buffer system is the most powerful extracellular buffer in the body. This apparent paradox is due mainly to the fact that the two elements of the buffer system, image and CO2, are regulated, respectively, by the kidneys and the lungs, as discussed later. As a result of this regulation, the pH of the extracellular fluid can be precisely controlled by the relative rate of removal and addition of image by the kidneys and the rate of removal of CO2 by the lungs.

Phosphate Buffer System

Although the phosphate buffer system is not important as an extracellular fluid buffer, it plays a major role in buffering renal tubular fluid and intracellular fluids.

The main elements of the phosphate buffer system are image and image. When a strong acid such as HCl is added to a mixture of these two substances, the hydrogen is accepted by the base image and converted to image.

image

The result of this reaction is that the strong acid, HCl, is replaced by an additional amount of a weak acid, NaH2PO4, and the decrease in pH is minimized.

When a strong base, such as NaOH, is added to the buffer system, the OH is buffered by the image to form additional amounts of image.

image

In this case, a strong base, NaOH, is traded for a weak base, NaH2PO4, causing only a slight increase in pH.

The phosphate buffer system has a pK of 6.8, which is not far from the normal pH of 7.4 in the body fluids; this allows the system to operate near its maximum buffering power. However, its concentration in the extracellular fluid is low, only about 8 percent of the concentration of the bicarbonate buffer. Therefore, the total buffering power of the phosphate system in the extracellular fluid is much less than that of the bicarbonate buffering system.

In contrast to its rather insignificant role as an extracellular buffer, the phosphate buffer is especially important in the tubular fluids of the kidneys, for two reasons: (1) phosphate usually becomes greatly concentrated in the tubules, thereby increasing the buffering power of the phosphate system, and (2) the tubular fluid usually has a considerably lower pH than the extracellular fluid does, bringing the operating range of the buffer closer to the pK (6.8) of the system.

The phosphate buffer system is also important in buffering intracellular fluid because the concentration of phosphate in this fluid is many times that in the extracellular fluid. Also, the pH of intracellular fluid is lower than that of extracellular fluid and therefore is usually closer to the pK of the phosphate buffer system compared with the extracellular fluid.

Proteins Are Important Intracellular Buffers

Proteins are among the most plentiful buffers in the body because of their high concentrations, especially within the cells.

The pH of the cells, although slightly lower than in the extracellular fluid, nevertheless changes approximately in proportion to extracellular fluid pH changes. There is a slight diffusion of H+ and image through the cell membrane, although these ions require several hours to come to equilibrium with the extracellular fluid, except for rapid equilibrium that occurs in the red blood cells. CO2, however, can rapidly diffuse through all the cell membranes. This diffusion of the elements of the bicarbonate buffer system causes the pH in intracellular fluid to change when there are changes in extracellular pH. For this reason, the buffer systems within the cells help prevent changes in the pH of extracellular fluid but may take several hours to become maximally effective.

In the red blood cell, hemoglobin (Hb) is an important buffer, as follows:

image

Approximately 60 to 70 percent of the total chemical buffering of the body fluids is inside the cells, and most of this results from the intracellular proteins. However, except for the red blood cells, the slowness with which H+ and image move through the cell membranes often delays for several hours the maximum ability of the intracellular proteins to buffer extracellular acid-base abnormalities.

In addition to the high concentration of proteins in the cells, another factor that contributes to their buffering power is the fact that the pKs of many of these protein systems are fairly close to intracellular pH.

Isohydric Principle: All Buffers in a Common Solution Are in Equilibrium with the Same H+ Concentration

We have been discussing buffer systems as though they operated individually in the body fluids. However, they all work together because H+ is common to the reactions of all these systems. Therefore, whenever there is a change in H+ concentration in the extracellular fluid, the balance of all the buffer systems changes at the same time. This phenomenon is called the isohydric principle and is illustrated by the following formula:

image

K1, K2, K3 are the dissociation constants of three respective acids, HA1, HA2, HA3, and A1, A2, A3 are the concentrations of the free negative ions that constitute the bases of the three buffer systems.

The implication of this principle is that any condition that changes the balance of one of the buffer systems also changes the balance of all the others because the buffer systems actually buffer one another by shifting H+ back and forth between them.

Respiratory Regulation of Acid-Base Balance

The second line of defense against acid-base disturbances is control of extracellular fluid CO2 concentration by the lungs. An increase in ventilation eliminates CO2 from extracellular fluid, which, by mass action, reduces the H+concentration. Conversely, decreased ventilation increases CO2, thus also increasing H+ concentration in the extracellular fluid.

Pulmonary Expiration of CO2 Balances Metabolic Formation of CO2

CO2 is formed continually in the body by intracellular metabolic processes. After it is formed, it diffuses from the cells into the interstitial fluids and blood and the flowing blood transports it to the lungs, where it diffuses into the alveoli and then is transferred to the atmosphere by pulmonary ventilation. About 1.2 mol/L of dissolved CO2 normally is in the extracellular fluid, corresponding to a Pco2 of 40 mm Hg.

If the rate of metabolic formation of CO2 increases, the Pco2 of the extracellular fluid is likewise increased. Conversely, a decreased metabolic rate lowers the Pco2. If the rate of pulmonary ventilation is increased, CO2 is blown off from the lungs and the Pco2 in the extracellular fluid decreases. Therefore, changes in either pulmonary ventilation or the rate of CO2 formation by the tissues can change the extracellular fluid Pco2.

Increasing Alveolar Ventilation Decreases Extracellular Fluid H+ Concentration and Raises pH

If the metabolic formation of CO2 remains constant, the only other factor that affects Pco2 in extracellular fluid is the rate of alveolar ventilation. The higher the alveolar ventilation, the lower the Pco2; conversely, the lower the alveolar ventilation rate, the higher the Pco2. As discussed previously, when CO2 concentration increases, the H2CO3 concentration and H+ concentration also increase, thereby lowering extracellular fluid pH.

Figure 30-2 shows the approximate changes in blood pH that are caused by increasing or decreasing the rate of alveolar ventilation. Note that increasing alveolar ventilation to about twice normal raises the pH of the extracellular fluid by about 0.23. If the pH of the body fluids is 7.40 with normal alveolar ventilation, doubling the ventilation rate raises the pH to about 7.63. Conversely, a decrease in alveolar ventilation to one fourth normal reduces the pH by 0.45. That is, if the pH is 7.4 at a normal alveolar ventilation, reducing the ventilation to one fourth normal reduces the pH to 6.95. Because the alveolar ventilation rate can change markedly, from as low as 0 to as high as 15 times normal, one can easily understand how much the pH of the body fluids can be changed by the respiratory system.

image

Figure 30-2 Change in extracellular fluid pH caused by increased or decreased rate of alveolar ventilation, expressed as times normal.

Increased H+ Concentration Stimulates Alveolar Ventilation

Not only does the alveolar ventilation rate influence H+ concentration by changing the Pco2 of the body fluids, but the H+ concentration affects the rate of alveolar ventilation. Thus, Figure 30-3 shows that the alveolar ventilation rate increases four to five times normal as the pH decreases from the normal value of 7.4 to the strongly acidic value of 7.0. Conversely, when plasma pH rises above 7.4, this causes a decrease in the ventilation rate. As one can see from the graph, the change in ventilation rate per unit pH change is much greater at reduced levels of pH (corresponding to elevated H+ concentration) compared with increased levels of pH. The reason for this is that as the alveolar ventilation rate decreases, owing to an increase in pH (decreased H+ concentration), the amount of oxygen added to the blood decreases and the partial pressure of oxygen (PO2) in the blood also decreases, which stimulates the ventilation rate. Therefore, the respiratory compensation for an increase in pH is not nearly as effective as the response to a marked reduction in pH.

image

Figure 30-3 Effect of blood pH on the rate of alveolar ventilation.

Feedback Control of H+ Concentration by the Respiratory System

Because increased H+ concentration stimulates respiration, and because increased alveolar ventilation decreases the H+ concentration, the respiratory system acts as a typical negative feedback controller of H+concentration.

image

That is, whenever the H+ concentration increases above normal, the respiratory system is stimulated and alveolar ventilation increases. This decreases the PCO2 in extracellular fluid and reduces H+concentration back toward normal. Conversely, if H+ concentration falls below normal, the respiratory center becomes depressed, alveolar ventilation decreases, and H+ concentration increases back toward normal.

Efficiency of Respiratory Control of H+ Concentration

Respiratory control cannot return the H+ concentration all the way back to normal when a disturbance outside the respiratory system has altered pH. Ordinarily, the respiratory mechanism for controlling H+concentration has an effectiveness between 50 and 75 percent, corresponding to a feedback gain of 1 to 3. That is, if the pH is suddenly increased by adding acid to the extracellular fluid and pH falls from 7.4 to 7.0, the respiratory system can return the pH to a value of about 7.2 to 7.3. This response occurs within 3 to 12 minutes.

Buffering Power of the Respiratory System

Respiratory regulation of acid-base balance is a physiologic type of buffer system because it acts rapidly and keeps the H+ concentration from changing too much until the slowly responding kidneys can eliminate the imbalance. In general, the overall buffering power of the respiratory system is one to two times as great as the buffering power of all other chemical buffers in the extracellular fluid combined. That is, one to two times as much acid or base can normally be buffered by this mechanism as by the chemical buffers.

Impairment of Lung Function Can Cause Respiratory Acidosis

We have discussed thus far the role of the normal respiratory mechanism as a means of buffering changes in H+ concentration. However, abnormalities of respiration can also cause changes in H+concentration. For example, an impairment of lung function, such as severe emphysema, decreases the ability of the lungs to eliminate CO2; this causes a buildup of CO2 in the extracellular fluid and a tendency toward respiratory acidosis. Also, the ability to respond to metabolic acidosis is impaired because the compensatory reductions in PCO2 that would normally occur by means of increased ventilation are blunted. In these circumstances, the kidneys represent the sole remaining physiologic mechanism for returning pH toward normal after the initial chemical buffering in the extracellular fluid has occurred.

Renal Control of Acid-Base Balance

The kidneys control acid-base balance by excreting either acidic or basic urine. Excreting acidic urine reduces the amount of acid in extracellular fluid, whereas excreting basic urine removes base from the extracellular fluid.

The overall mechanism by which the kidneys excrete acidic or basic urine is as follows: Large numbers of image are filtered continuously into the tubules, and if they are excreted into the urine this removes base from the blood. Large numbers of H+ are also secreted into the tubular lumen by the tubular epithelial cells, thus removing acid from the blood. If more H+ is secreted than image is filtered, there will be a net loss of acid from the extracellular fluid. Conversely, if more image is filtered than H+ is secreted, there will be a net loss of base.

As discussed previously, each day the body produces about 80 mEq of nonvolatile acids, mainly from the metabolism of proteins. These acids are called nonvolatile because they are not H2CO3 and, therefore, cannot be excreted by the lungs. The primary mechanism for removal of these acids from the body is renal excretion. The kidneys must also prevent the loss of bicarbonate in the urine, a task that is quantitatively more important than the excretion of nonvolatile acids. Each day the kidneys filter about 4320 mEq of bicarbonate (180 L/day × 24 mEq/L); under normal conditions, almost all this is reabsorbed from the tubules, thereby conserving the primary buffer system of the extracellular fluid.

As discussed later, both the reabsorption of bicarbonate and the excretion of H+ are accomplished through the process of H+ secretion by the tubules. Because the image must react with a secreted H+ to form H2CO3 before it can be reabsorbed, 4320 mEq of H+ must be secreted each day just to reabsorb the filtered bicarbonate. Then an additional 80 mEq of H+ must be secreted to rid the body of the nonvolatile acids produced each day, for a total of 4400 mEq of H+ secreted into the tubular fluid each day.

When there is a reduction in the extracellular fluid H+ concentration (alkalosis), the kidneys fail to reabsorb all the filtered image, thereby increasing the excretion of image. Because image normally buffers H+ in the extracellular fluid, this loss of image is the same as adding an H+ to the extracellular fluid. Therefore, in alkalosis, the removal of image raises the extracellular fluid H+ concentration back toward normal.

In acidosis, the kidneys do not excrete image into the urine but reabsorb all the filtered image and produce new image, which is added back to the extracellular fluid. This reduces the extracellular fluid H+ concentration back toward normal.

Thus, the kidneys regulate extracellular fluid H+ concentration through three fundamental mechanisms: (1) secretion of H+, (2) reabsorption of filtered imageand (3) production of new image. All these processes are accomplished through the same basic mechanism, as discussed in the next few sections.

Secretion of H+ and Reabsorption of image by the Renal Tubules

Hydrogen ion secretion and image reabsorption occur in virtually all parts of the tubules except the descending and ascending thin limbs of the loop of Henle. Figure 30-4 summarizes image reabsorption along the tubule. Keep in mind that for each image reabsorbed, a H+ must be secreted.

image

Figure 30-4 Reabsorption of bicarbonate in different segments of the renal tubule. The percentages of the filtered load of image absorbed by the various tubular segments are shown, as well as the number of milliequivalents reabsorbed per day under normal conditions.

About 80 to 90 percent of the bicarbonate reabsorption (and H+ secretion) occurs in the proximal tubule, so only a small amount of image flows into the distal tubules and collecting ducts. In the thick ascending loop of Henle, another 10 percent of the filtered image is reabsorbed, and the remainder of the reabsorption takes place in the distal tubule and collecting duct. As discussed previously, the mechanism by which image is reabsorbed also involves tubular secretion of H+, but different tubular segments accomplish this task differently.

H+ is Secreted by Secondary Active Transport in the Early Tubular Segments

The epithelial cells of the proximal tubule, the thick segment of the ascending loop of Henle, and the early distal tubule all secrete H+ into the tubular fluid by sodium-hydrogen counter-transport, as shown in Figure 30-5. This secondary active secretion of H+ is coupled with the transport of Na+ into the cell at the luminal membrane by the sodium-hydrogen exchanger protein, and the energy for H+ secretion against a concentration gradient is derived from the sodium gradient favoring Na+ movement into the cell. This gradient is established by the sodium-potassium adenosine triphosphatase (ATPase) pump in the basolateral membrane. About 95 percent of the bicarbonate is reabsorbed in this manner, requiring about 4000 mEq of H+ to be secreted each day by the tubules. This mechanism, however, does not establish a very high H+ concentration in the tubular fluid; the tubular fluid becomes very acidic only in the collecting tubules and collecting ducts.

image

Figure 30-5 Cellular mechanisms for (1) active secretion of H+ into the renal tubule; (2) tubular reabsorption of image by combination with H+ to form carbonic acid, which dissociates to form carbon dioxide and water; and (3) sodium ion reabsorption in exchange for H+ secreted. This pattern of H+ secretion occurs in the proximal tubule, the thick ascending segment of the loop of Henle, and the early distal tubule.

Figure 30-5 shows how the process of H+ secretion achieves image reabsorption. The secretory process begins when CO2 either diffuses into the tubular cells or is formed by metabolism in the tubular epithelial cells. CO2, under the influence of the enzyme carbonic anhydrase, combines with H2O to form H2CO3, which dissociates into image and H+. The H+ is secreted from the cell into the tubular lumen by sodium-hydrogen counter-transport. That is, when Na+ moves from the lumen of the tubule to the interior of the cell, it first combines with a carrier protein in the luminal border of the cell membrane; at the same time, an H+ in the interior of the cells combines with the carrier protein. The Na+ moves into the cell down a concentration gradient that has been established by the sodium-potassium ATPase pump in the basolateral membrane. The gradient for Na+ movement into the cell then provides the energy for moving H+ in the opposite direction from the interior of the cell to the tubular lumen.

The image generated in the cell (when H+ dissociates from H2CO3) then moves downhill across the basolateral membrane into the renal interstitial fluid and the peritubular capillary blood. The net result is that for every H+secreted into the tubular lumen, an image enters the blood.

Filtered image is Reabsorbed by Interaction with H+ in the Tubules

Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells; therefore, image that is filtered by the glomerulus cannot be directly reabsorbed. Instead, image is reabsorbed by a special process in which it first combines with H+ to form H2CO3, which eventually becomes CO2 and H2O, as shown in Figure 30-5.

This reabsorption of image is initiated by a reaction in the tubules between image filtered at the glomerulus and H+ secreted by the tubular cells. The H2CO3 formed then dissociates into CO2 and H2O. The CO2 can move easily across the tubular membrane; therefore, it instantly diffuses into the tubular cell, where it recombines with H2O, under the influence of carbonic anhydrase, to generate a new H2CO3molecule. This H2CO3 in turn dissociates to form image and H+; the image then diffuses through the basolateral membrane into the interstitial fluid and is taken up into the peritubular capillary blood. The transport of HCO3 across the basolateral membrane is facilitated by two mechanisms: (1) image co-transport in the proximal tubules and (2) image exchange in the late segments of the proximal tubule, the thick ascending loop of Henle, and in the collecting tubules and ducts.

Thus, each time an H+is formed in the tubular epithelial cells, an image is also formed and released back into the blood. The net effect of these reactions is “reabsorption” of image from the tubules, although the image that actually enters the extracellular fluid is not the same as that filtered into the tubules. The reabsorption of filtered image does not result in net secretion of H+ because the secreted H+ combines with the filtered image and is therefore not excreted.

image is “Titrated” Against H+ in the Tubules

Under normal conditions, the rate of tubular H+ secretion is about 4400 mEq/day, and the rate of filtration by image is about 4320 mEq/day. Thus, the quantities of these two ions entering the tubules are almost equal, and they combine with each other to form CO2 and H2O. Therefore, it is said that image and H+ normally “titrate” each other in the tubules.

The titration process is not quite exact because there is usually a slight excess of H+ in the tubules to be excreted in the urine. This excess H+ (about 80 mEq/day) rids the body of nonvolatile acids produced by metabolism. As discussed later, most of this H+ is not excreted as free H+ but rather in combination with other urinary buffers, especially phosphate and ammonia.

When there is an excess of image over H+ in the urine, as occurs in metabolic alkalosis, the excess image cannot be reabsorbed; therefore, the excess image is left in the tubules and eventually excreted into the urine, which helps correct the metabolic alkalosis.

In acidosis, there is excess H+ relative to image causing complete reabsorption of the image; the excess H+ passes into the urine. The excess H+ is buffered in the tubules by phosphate and ammonia and eventually excreted as salts. Thus, the basic mechanism by which the kidneys correct either acidosis or alkalosis is incomplete titration of H+ against image, leaving one or the other to pass into the urine and be removed from the extracellular fluid.

Primary Active Secretion of H+ in the Intercalated Cells of Late Distal and Collecting Tubules

Beginning in the late distal tubules and continuing through the remainder of the tubular system, the tubular epithelium secretes H+ by primary active transport. The characteristics of this transport are different from those discussed for the proximal tubule, loop of Henle, and early distal tubule.

The mechanism for primary active H+ secretion is shown in Figure 30-6. It occurs at the luminal membrane of the tubular cell, where H+ is transported directly by a specific protein, a hydrogen-transporting ATPase. The energy required for pumping the H+ is derived from the breakdown of ATP to adenosine diphosphate.

image

Figure 30-6 Primary active secretion of H+ through the luminal membrane of the intercalated epithelial cells of the late distal and collecting tubules. Note that one image is absorbed for each H+ secreted, and a chloride ion is passively secreted along with the H+.

Primary active secretion of H+ occurs in special types of cells called the intercalated cells of the late distal tubule and in the collecting tubules. Hydrogen ion secretion in these cells is accomplished in two steps: (1) the dissolved CO2in this cell combines with H2O to form H2CO3, and (2) the H2CO3 then dissociates into image, which is reabsorbed into the blood, plus H+, which is secreted into the tubule by means of the hydrogen-ATPase mechanism. For each H+ secreted, an image is reabsorbed, similar to the process in the proximal tubules. The main difference is that H+ moves across the luminal membrane by an active H+ pump instead of by counter-transport, as occurs in the early parts of the nephron.

Although the secretion of H+ in the late distal tubule and collecting tubules accounts for only about 5 percent of the total H+ secreted, this mechanism is important in forming maximally acidic urine. In the proximal tubules, H+concentration can be increased only about threefold to fourfold and the tubular fluid pH can be reduced to only about 6.7, although large amounts of H+ are secreted by this nephron segment. However, H+ concentration can be increased as much as 900-fold in the collecting tubules. This decreases the pH of the tubular fluid to about 4.5, which is the lower limit of pH that can be achieved in normal kidneys.

Combination of Excess H+ with Phosphate and Ammonia Buffers in the Tubule Generates “New” image

When H+ is secreted in excess of the image filtered into the tubular fluid, only a small part of the excess H+ can be excreted in the ionic form (H+) in the urine. The reason for this is that the minimal urine pH is about 4.5, corresponding to an H+ concentration of 10−4.5 mEq/L, or 0.03 mEq/L. Thus, for each liter of urine formed, a maximum of only about 0.03 mEq of free H+ can be excreted. To excrete the 80 mEq of nonvolatile acid formed by metabolism each day, about 2667 liters of urine would have to be excreted if the H+ remained free in solution.

The excretion of large amounts of H+ (on occasion as much as 500 mEq/day) in the urine is accomplished primarily by combining the H+ with buffers in the tubular fluid. The most important buffers are phosphate buffer and ammonia buffer. Other weak buffer systems, such as urate and citrate, are much less important.

When H+ is titrated in the tubular fluid with image, this leads to reabsorption of one image for each H+ secreted, as discussed earlier. But when there is excess H+ in the urine, it combines with buffers other than image, and this leads to generation of new image that can also enter the blood. Thus, when there is excess H+ in the extracellular fluid, the kidneys not only reabsorb all the filtered image but also generate new image, thereby helping to replenish the image lost from the extracellular fluid in acidosis. In the next two sections, we discuss the mechanisms by which phosphate and ammonia buffers contribute to the generation of new image.

Phosphate Buffer System Carries Excess H+ into the Urine and Generates New image

The phosphate buffer system is composed of image and image. Both become concentrated in the tubular fluid because water is normally reabsorbed to a greater extent than phosphate by the renal tubules. Therefore, although phosphate is not an important extracellular fluid buffer, it is much more effective as a buffer in the tubular fluid.

Another factor that makes phosphate important as a tubular buffer is the fact that the pK of this system is about 6.8. Under normal conditions, the urine is slightly acidic, and the urine pH is near the pK of the phosphate buffer system. Therefore, in the tubules, the phosphate buffer system normally functions near its most effective range of pH.

Figure 30-7 shows the sequence of events by which H+ is excreted in combination with phosphate buffer and the mechanism by which new image is added to the blood. The process of H+ secretion into the tubules is the same as described earlier. As long as there is excess image in the tubular fluid, most of the secreted H+ combines with image. However, once all the image has been reabsorbed and is no longer available to combine with H+, any excess H+ can combine with image and other tubular buffers. After the H+ combines with image to form image, it can be excreted as a sodium salt (NaH2PO4), carrying with it the excess H+.

image

Figure 30-7 Buffering of secreted H+ by filtered phosphate (NaHPO4). Note that a new image is returned to the blood for each NaHPO4 that reacts with a secreted H+.

There is one important difference in this sequence of H+ excretion from that discussed previously. In this case, the image that is generated in the tubular cell and enters the peritubular blood represents a net gain of image by the blood, rather than merely a replacement of filtered imageTherefore, whenever an H+secreted into the tubular lumen combines with a buffer other than imagethe net effect is addition of a new image to the blood. This demonstrates one of the mechanisms by which the kidneys are able to replenish the extracellular fluid stores of image.

Under normal conditions, much of the filtered phosphate is reabsorbed, and only about 30 to 40 mEq/day are available for buffering H+. Therefore, much of the buffering of excess H+ in the tubular fluid in acidosis occurs through the ammonia buffer system.

Excretion of Excess H+ and Generation of New image- by the Ammonia Buffer System

A second buffer system in the tubular fluid that is even more important quantitatively than the phosphate buffer system is composed of ammonia (NH3) and the ammonium ion (image). Ammonium ion is synthesized from glutamine, which comes mainly from the metabolism of amino acids in the liver. The glutamine delivered to the kidneys is transported into the epithelial cells of the proximal tubules, thick ascending limb of the loop of Henle, and distal tubules (Figure 30-8). Once inside the cell, each molecule of glutamine is metabolized in a series of reactions to ultimately form two image and two image. The image is secreted into the tubular lumen by a counter-transport mechanism in exchange for sodium, which is reabsorbed. The image is transported across the basolateral membrane, along with the reabsorbed Na+, into the interstitial fluid and is taken up by the peritubular capillaries. Thus, for each molecule of glutamine metabolized in the proximal tubules, two image are secreted into the urine and two image are reabsorbed into the blood. The image generated by this process constitutes new bicarbonate.

image

Figure 30-8 Production and secretion of ammonium ion (image) by proximal tubular cells. Glutamine is metabolized in the cell, yielding image and bicarbonate. The image is secreted into the lumen by a sodium-imageexchanger. For each glutamine molecule metabolized, two image are produced and secreted and two image are returned to the blood.

In the collecting tubules, the addition of image to the tubular fluids occurs through a different mechanism (Figure 30-9). Here, H+ is secreted by the tubular membrane into the lumen, where it combines with NH3 to form image, which is then excreted. The collecting ducts are permeable to NH3, which can easily diffuse into the tubular lumen. However, the luminal membrane of this part of the tubules is much less permeable to image; therefore, once the H+ has reacted with NH3 to form image, the image is trapped in the tubular lumen and eliminated in the urine. For each image excreted, a new image is generated and added to the blood.

image

Figure 30-9 Buffering of hydrogen ion secretion by ammonia (NH3) in the collecting tubules. Ammonia diffuses into the tubular lumen, where it reacts with secreted H+ to form image, which is then excreted. For each imageexcreted, a new image is formed in the tubular cells and returned to the blood.

Chronic Acidosis Increases image Excretion

One of the most important features of the renal ammonium-ammonia buffer system is that it is subject to physiologic control. An increase in extracellular fluid H+ concentration stimulates renal glutamine metabolism and, therefore, increases the formation of image and new image to be used in H+ buffering; a decrease in H+ concentration has the opposite effect.

Under normal conditions, the amount of H+ eliminated by the ammonia buffer system accounts for about 50 percent of the acid excreted and 50 percent of the new image generated by the kidneys. However, with chronic acidosis,the rate of image excretion can increase to as much as 500 mEq/day. Therefore, with chronic acidosis, the dominant mechanism by which acid is eliminated is excretion of image. This also provides the most important mechanism for generating new bicarbonate during chronic acidosis.

Quantifying Renal Acid-Base Excretion

Based on the principles discussed earlier, we can quantify the kidneys’ net excretion of acid or net addition or elimination of image from the blood as follows.

Bicarbonate excretion is calculated as the urine flow rate multiplied by urinary image concentration. This number indicates how rapidly the kidneys are removing image from the blood (which is the same as adding an H+ to the blood). In alkalosis, the loss of image helps return the plasma pH toward normal.

The amount of new image contributed to the blood at any given time is equal to the amount of H+ secreted that ends up in the tubular lumen with nonbicarbonate urinary buffers. As discussed previously, the primary sources of nonbicarbonate urinary buffers are image and phosphate. Therefore, the amount of image added to the blood (and H+ excreted by image) is calculated by measuring image excretion (urine flow rate multiplied by urinary image concentration).

The rest of the nonbicarbonate, non-image buffer excreted in the urine is measured by determining a value known as titratable acid. The amount of titratable acid in the urine is measured by titrating the urine with a strong base, such as NaOH, to a pH of 7.4, the pH of normal plasma, and the pH of the glomerular filtrate. This titration reverses the events that occurred in the tubular lumen when the tubular fluid was titrated by secreted H+. Therefore, the number of milliequivalents of NaOH required to return the urinary pH to 7.4 equals the number of milliequivalents of H+ added to the tubular fluid that combined with phosphate and other organic buffers. The titratable acid measurement does not include H+ in association with image because the pK of the ammonia-ammonium reaction is 9.2, and titration with NaOH to a pH of 7.4 does not remove the H+ from image.

Thus, the net acid excretion by the kidneys can be assessed as

image

The reason we subtract image excretion is that the loss of image is the same as the addition of H+ to the blood. To maintain acid-base balance, the net acid excretion must equal the nonvolatile acid production in the body. In acidosis, the net acid excretion increases markedly, especially because of increased image excretion, thereby removing acid from the blood. The net acid excretion also equals the rate of net image addition to the blood. Therefore, in acidosis, there is a net addition of image back to the blood as more image and urinary titratable acid are excreted.

In alkalosis, titratable acid and image excretion drop to 0, whereas image excretion increases. Therefore, in alkalosis, there is a negative net acid secretion. This means that there is a net loss of image from the blood (which is the same as adding H+ to the blood) and that no new image is generated by the kidneys.

Regulation of Renal Tubular H+ Secretion

As discussed earlier, H+ secretion by the tubular epithelium is necessary for both image reabsorption and generation of new image associated with titratable acid formation. Therefore, the rate of H+secretion must be carefully regulated if the kidneys are to effectively perform their functions in acid-base homeostasis. Under normal conditions, the kidney tubules must secrete at least enough H+ to reabsorb almost all the image that is filtered, and there must be enough H+ left over to be excreted as titratable acid or image to rid the body of the nonvolatile acids produced each day from metabolism.

In alkalosis, tubular secretion of H+ is reduced to a level that is too low to achieve complete image reabsorption, enabling the kidneys to increase image excretion. In this condition, titratable acid and ammonia are not excreted because there is no excess H+ available to combine with nonbicarbonate buffers; therefore, there is no new image added to the urine in alkalosis. During acidosis, the tubular H+secretion is increased sufficiently to reabsorb all the filtered image with enough H+ left over to excrete large amounts of image and titratable acid, thereby contributing large amounts of new image to the total body extracellular fluid. The most important stimuli for increasing H+secretion by the tubules in acidosis are (1) an increase in PCO2 of the extracellular fluid in respiratory acidosis and (2) an increase in H+ concentration of the extracellular fluid (decreased pH) respiratory or metabolic acidosis.

The tubular cells respond directly to an increase in PCO2 of the blood, as occurs in respiratory acidosis, with an increase in the rate of H+ secretion as follows: The increased PCO2 raises the PCO2 of the tubular cells, causing increased formation of H+ in the tubular cells, which in turn stimulates the secretion of H+. The second factor that stimulates H+ secretion is an increase in extracellular fluid H+concentration (decreased pH).

A special factor that can increase H+ secretion under some pathophysiologic conditions is excessive aldosterone secretion. Aldosterone stimulates the secretion of H+ by the intercalated cells of the collecting duct. Therefore, excessive secretion of aldosterone, as occurs in Conn’s syndrome, can increase secretion of H+ into the tubular fluid and, consequently, increase the amount of image added back to the blood. This usually causes alkalosis in patients with excessive aldosterone secretion.

The tubular cells usually respond to a decrease in H+ concentration (alkalosis) by reducing H+ secretion. The decreased H+ secretion results from decreased extracellular PCO2, as occurs in respiratory alkalosis, or from a decrease in H+ concentration per se, as occurs in both respiratory and metabolic alkalosis.

Table 30-2 summarizes the major factors that influence H+ secretion and image reabsorption. Some of these are not directly related to the regulation of acid-base balance. For example, H+ secretion is coupled to Na+ reabsorption by the Na+-H+ exchanger in the proximal tubule and thick ascending loop of Henle. Therefore, factors that stimulate Na+ reabsorption, such as decreased extracellular fluid volume, may also secondarily increase H+ secretion.

Table 30-2 Factors That Increase or Decrease H+ Secretion and image Reabsorption by the Renal Tubules

Increase H+ Secretion and image Reabsorption

Decrease H+ Secretion and image Reabsorption

↑PCO2

↓ PCO2

↑ H+, ↓ image

↓ H+, ↑ image

↓ Extracellular fluid volume

↑ Extracellular fluid volume

↑ Angiotensin II

↓ Angiotensin II

↑ Aldosterone

↓ Aldosterone

Hypokalemia

Hyperkalemia

Extracellular fluid volume depletion stimulates sodium reabsorption by the renal tubules and increases H+ secretion and image reabsorption through multiple mechanisms, including (1) increased angiotensin II levels, which directly stimulate the activity of the Na+-H+ exchanger in the renal tubules, and (2) increased aldosterone levels, which stimulate H+ secretion by the intercalated cells of the cortical collecting tubules. Therefore, extracellular fluid volume depletion tends to cause alkalosis due to excess H+ secretion and image reabsorption.

Changes in plasma potassium concentration can also influence H+ secretion, with hypokalemia stimulating and hyperkalemia inhibiting H+ secretion in the proximal tubule. A decreased plasma potassium concentration tends to increase the H+ concentration in the renal tubular cells. This, in turn, stimulates H+ secretion and image reabsorption and leads to alkalosis. Hyperkalemia decreases H+ secretion and image reabsorption and tends to cause acidosis.

Renal Correction of Acidosis—Increased Excretion of H+ and Addition of image- to the Extracellular Fluid

Now that we have described the mechanisms by which the kidneys secrete H+ and reabsorb image, we can explain how the kidneys readjust the pH of the extracellular fluid when it becomes abnormal.

Referring to equation 8, the Henderson-Hasselbalch equation, we can see that acidosis occurs when the ratio of image to CO2 in the extracellular fluid decreases, thereby decreasing pH. If this ratio decreases because of a fall in image, the acidosis is referred to as metabolic acidosis. If the pH falls because of an increase in PCO2, the acidosis is referred to as respiratory acidosis.

Acidosis Decreases the Ratio of image-/H+ in Renal Tubular Fluid

Both respiratory and metabolic acidosis cause a decrease in the ratio of image to H+ in the renal tubular fluid. As a result, there is excess H+ in the renal tubules, causing complete reabsorption of image and still leaving additional H+ available to combine with the urinary buffers image and image. Thus, in acidosis, the kidneys reabsorb all the filtered image and contribute new image through the formation of image and titratable acid.

In metabolic acidosis, an excess of H+ over image occurs in the tubular fluid primarily because of decreased filtration of image. This decreased filtration of image is caused mainly by a decrease in the extracellular fluid concentration of image.

In respiratory acidosis, the excess H+ in the tubular fluid is due mainly to the rise in extracellular fluid PCO2, which stimulates H+ secretion.

As discussed previously, with chronic acidosis, regardless of whether it is respiratory or metabolic, there is an increase in the production of image, which further contributes to the excretion of H+ and the addition of new image to the extracellular fluid. With severe chronic acidosis, as much as 500 mEq/day of H+ can be excreted in the urine, mainly in the form of image; this, in turn, contributes up to 500 mEq/day of new image that is added to the blood.

Thus, with chronic acidosis, the increased secretion of H+ by the tubules helps eliminate excess H+ from the body and increases the quantity of image in the extracellular fluid. This increases the image part of the bicarbonate buffer system, which, in accordance with the Henderson-Hasselbalch equation, helps raise the extracellular pH and corrects the acidosis. If the acidosis is metabolically mediated, additional compensation by the lungs causes a reduction in PCO2, also helping to correct the acidosis.

Table 30-3 summarizes the characteristics associated with respiratory and metabolic acidosis, as well as respiratory and metabolic alkalosis, which are discussed in the next section. Note that in respiratory acidosis, there is a reduction in pH, an increase in extracellular fluid H+ concentration, and an increase in PCO2, which is the initial cause of the acidosis. The compensatory response is an increase in plasma imagecaused by the addition of new image to the extracellular fluid by the kidneys. The rise in image helps offset the increase in PCO2, thereby returning the plasma pH toward normal.

Table 30-3 Characteristics of Primary Acid-Base Disturbances

image

In metabolic acidosis, there is also a decrease in pH and a rise in extracellular fluid H+ concentration. However, in this case, the primary abnormality is a decrease in plasma imageThe primary compensations include increased ventilation rate, which reduces PCO2, and renal compensation, which, by adding new image to the extracellular fluid, helps minimize the initial fall in extracellular image concentration.

Renal Correction of Alkalosis—Decreased Tubular Secretion of H+ and Increased Excretion of image

The compensatory responses to alkalosis are basically opposite to those that occur in acidosis. In alkalosis, the ratio of image to CO2 in the extracellular fluid increases, causing a rise in pH (a decrease in H+ concentration), as is evident from the Henderson-Hasselbalch equation.

Alkalosis Increases the Ratio of image/H+ in Renal Tubular Fluid

Regardless of whether the alkalosis is caused by metabolic or respiratory abnormalities, there is still an increase in the ratio of image to H+ in the renal tubular fluid. The net effect of this is an excess of image that cannot be reabsorbed from the tubules and is, therefore, excreted in the urine. Thus, in alkalosis, image is removed from the extracellular fluid by renal excretion, which has the same effect as adding an H+ to the extracellular fluid. This helps return the H+ concentration and pH back toward normal.

Table 30-3 shows the overall characteristics of respiratory and metabolic alkalosis. In respiratory alkalosis, there is an increase in extracellular fluid pH and a decrease in H+ concentration. The cause of the alkalosis is a decrease in plasma PCO2, caused by hyperventilation. The reduction in PCO2 then leads to a decrease in the rate of H+ secretion by the renal tubules. The decrease in H+ secretion reduces the amount of H+ in the renal tubular fluid. Consequently, there is not enough H+ to react with all the image that is filtered. Therefore, the image that cannot react with H+ is not reabsorbed and is excreted in the urine. This results in a decrease in plasma imageconcentration and correction of the alkalosis. Therefore, the compensatory response to a primary reduction in PCO2 in respiratory alkalosis is a reduction in plasma image concentration, caused by increased renal excretion of image.

In metabolic alkalosis, there is also an increase in plasma pH and a decrease in H+ concentration. The cause of metabolic alkalosis, however, is a rise in the extracellular fluid image concentration. This is partly compensated for by a reduction in the respiration rate, which increases PCO2 and helps return the extracellular fluid pH toward normal. In addition, the increase in image concentration in the extracellular fluid leads to an increase in the filtered load of image, which in turn causes an excess of image over H+ secreted in the renal tubular fluid. The excess image in the tubular fluid fails to be reabsorbed because there is no H+ to react with, and it is excreted in the urine. In metabolic alkalosis, the primary compensations are decreased ventilation, which raises PCO2, and increased renal image excretion, which helps compensate for the initial rise in extracellular fluid image concentration.

Clinical Causes of Acid-Base Disorders

Respiratory Acidosis Results from Decreased Ventilation and Increased Pco2

From the previous discussion, it is obvious that any factor that decreases the rate of pulmonary ventilation also increases the PCO2 of extracellular fluid. This causes an increase in H2CO3 and H+concentration, thus resulting in acidosis. Because the acidosis is caused by an abnormality in respiration, it is called respiratory acidosis.

Respiratory acidosis can occur from pathological conditions that damage the respiratory centers or that decrease the ability of the lungs to eliminate CO2. For example, damage to the respiratory center in the medulla oblongata can lead to respiratory acidosis. Also, obstruction of the passageways of the respiratory tract, pneumonia, emphysema, or decreased pulmonary membrane surface area, as well as any factor that interferes with the exchange of gases between the blood and the alveolar air, can cause respiratory acidosis.

In respiratory acidosis, the compensatory responses available are (1) the buffers of the body fluids and (2) the kidneys, which require several days to compensate for the disorder.

Respiratory Alkalosis Results from Increased Ventilation and Decreased Pco2

Respiratory alkalosis is caused by excessive ventilation by the lungs. Rarely does this occur because of physical pathological conditions. However, a psychoneurosis can occasionally increase breathing to the extent that a person becomes alkalotic.

A physiologic type of respiratory alkalosis occurs when a person ascends to high altitude. The low oxygen content of the air stimulates respiration, which causes loss of CO2 and development of mild respiratory alkalosis. Again, the major means for compensation are the chemical buffers of the body fluids and the ability of the kidneys to increase image excretion.

Metabolic Acidosis Results from Decreased Extracellular Fluid image Concentration

The term metabolic acidosis refers to all other types of acidosis besides those caused by excess CO2 in the body fluids. Metabolic acidosis can result from several general causes: (1) failure of the kidneys to excrete metabolic acids normally formed in the body, (2) formation of excess quantities of metabolic acids in the body, (3) addition of metabolic acids to the body by ingestion or infusion of acids, and (4) loss of base from the body fluids, which has the same effect as adding an acid to the body fluids. Some specific conditions that cause metabolic acidosis are the following.

Renal Tubular Acidosis

This type of acidosis results from a defect in renal secretion of H+ or in reabsorption of image, or both. These disorders are generally of two types: (1) impairment of renal tubular image reabsorption, causing loss of image in the urine, or (2) inability of the renal tubular H+ secretory mechanism to establish normal acidic urine, causing the excretion of alkaline urine. In these cases, inadequate amounts of titratable acid and image are excreted, so there is net accumulation of acid in the body fluids. Some causes of renal tubular acidosis include chronic renal failure, insufficient aldosterone secretion (Addison’s disease), and several hereditary and acquired disorders that impair tubular function, such as Fanconi’s syndrome (see Chapter 31).

Diarrhea

Severe diarrhea is probably the most frequent cause of metabolic acidosis. The cause of this acidosis is the loss of large amounts of sodium bicarbonate into the feces. The gastrointestinal secretions normally contain large amounts of bicarbonate, and diarrhea results in the loss of image from the body, which has the same effect as losing large amounts of bicarbonate in the urine. This form of metabolic acidosis can be particularly serious and can cause death, especially in young children.

Vomiting of Intestinal Contents

Vomiting of gastric contents alone would cause loss of acid and a tendency toward alkalosis because the stomach secretions are highly acidic. However, vomiting large amounts from deeper in the gastrointestinal tract, which sometimes occurs, causes loss of bicarbonate and results in metabolic acidosis in the same way that diarrhea causes acidosis.

Diabetes Mellitus

Diabetes mellitus is caused by lack of insulin secretion by the pancreas (type I diabetes) or by insufficient insulin secretion to compensate for decreased sensitivity to the effects of insulin (type II diabetes). In the absence of sufficient insulin, the normal use of glucose for metabolism is prevented. Instead, some of the fats are split into acetoacetic acid, and this is metabolized by the tissues for energy in place of glucose. With severe diabetes mellitus, blood acetoacetic acid levels can rise very high, causing severe metabolic acidosis. In an attempt to compensate for this acidosis, large amounts of acid are excreted in the urine, sometimes as much as 500 mmol/day.

Ingestion of Acids

Rarely are large amounts of acids ingested in normal foods. However, severe metabolic acidosis occasionally results from the ingestion of certain acidic poisons. Some of these include acetylsalicylics (aspirin) and methyl alcohol (which forms formic acid when it is metabolized).

Chronic Renal Failure

When kidney function declines markedly, there is a buildup of the anions of weak acids in the body fluids that are not being excreted by the kidneys. In addition, the decreased glomerular filtration rate reduces the excretion of phosphates and image, which reduces the amount of image added back to the body fluids. Thus, chronic renal failure can be associated with severe metabolic acidosis.

Metabolic Alkalosis Results from Increased Extracellular Fluid image Concentration

When there is excess retention of image or loss of H+ from the body, this causes metabolic alkalosis. Metabolic alkalosis is not nearly as common as metabolic acidosis, but some of the causes of metabolic alkalosis are as follows.

Administration of Diuretics (Except the Carbonic Anhydrase Inhibitors)

All diuretics cause increased flow of fluid along the tubules, usually increasing flow in the distal and collecting tubules. This leads to increased reabsorption of Na+ from these parts of the nephrons. Because the sodium reabsorption here is coupled with H+ secretion, the enhanced sodium reabsorption also leads to an increase in H+ secretion and an increase in bicarbonate reabsorption. These changes lead to the development of alkalosis, characterized by increased extracellular fluid bicarbonate concentration.

Excess Aldosterone

When large amounts of aldosterone are secreted by the adrenal glands, a mild metabolic alkalosis develops. As discussed previously, aldosterone promotes extensive reabsorption of Na+ from the distal and collecting tubules and at the same time stimulates the secretion of H+ by the intercalated cells of the collecting tubules. This increased secretion of H+ leads to its increased excretion by the kidneys and, therefore, metabolic alkalosis.

Vomiting of Gastric Contents

Vomiting of the gastric contents alone, without vomiting of the lower gastrointestinal contents, causes loss of the HCl secreted by the stomach mucosa. The net result is a loss of acid from the extracellular fluid and development of metabolic alkalosis. This type of alkalosis occurs especially in neonates who have pyloric obstruction caused by hypertrophied pyloric sphincter muscles.

Ingestion of Alkaline Drugs

A common cause of metabolic alkalosis is ingestion of alkaline drugs, such as sodium bicarbonate, for the treatment of gastritis or peptic ulcer.

Treatment of Acidosis or Alkalosis

The best treatment for acidosis or alkalosis is to correct the condition that caused the abnormality. This is often difficult, especially in chronic diseases that cause impaired lung function or kidney failure. In these circumstances, various agents can be used to neutralize the excess acid or base in the extracellular fluid.

To neutralize excess acid, large amounts of sodium bicarbonate can be ingested by mouth. The sodium bicarbonate is absorbed from the gastrointestinal tract into the blood and increases the image portion of the bicarbonate buffer system, thereby increasing pH toward normal. Sodium bicarbonate can also be infused intravenously, but because of the potentially dangerous physiologic effects of such treatment, other substances are often used instead, such as sodium lactate and sodium gluconate. The lactate and gluconate portions of the molecules are metabolized in the body, leaving the sodium in the extracellular fluid in the form of sodium bicarbonate and thereby increasing the pH of the fluid toward normal.

For the treatment of alkalosis, ammonium chloride can be administered by mouth. When the ammonium chloride is absorbed into the blood, the ammonia portion is converted by the liver into urea. This reaction liberates HCl, which immediately reacts with the buffers of the body fluids to shift the H+ concentration in the acidic direction. Ammonium chloride occasionally is infused intravenously, but image is highly toxic and this procedure can be dangerous. Another substance used occasionally is lysine monohydrochloride.

Clinical Measurements and Analysis of Acid-Base Disorders

Appropriate therapy of acid-base disorders requires proper diagnosis. The simple acid-base disorders described previously can be diagnosed by analyzing three measurements from an arterial blood sample: pH, plasma imageconcentration, and PCO2.

The diagnosis of simple acid-base disorders involves several steps, as shown in Figure 30-10. By examining the pH, one can determine whether the disorder is acidosis or alkalosis. A pH less than 7.4 indicates acidosis, whereas a pH greater than 7.4 indicates alkalosis.

image

Figure 30-10 Analysis of simple acid-base disorders. If the compensatory responses are markedly different from those shown at the bottom of the figure, one should suspect a mixed acid-base disorder.

The second step is to examine the plasma PCO2 and image concentration. The normal value for PCO2 is about 40 mm Hg, and for image, it is 24 mEq/L. If the disorder has been characterized as acidosis and the plasma PCO2 is increased, there must be a respiratory component to the acidosis. After renal compensation, the plasma image concentration in respiratory acidosis would tend to increase above normal. Therefore, the expected values for a simple respiratory acidosis would be reduced plasma pH, increased PCO2, and increased plasma image concentration after partial renal compensation.

For metabolic acidosis, there would also be a decrease in plasma pH. However, with metabolic acidosis, the primary abnormality is a decrease in plasma image concentration. Therefore, if a low pH is associated with a low image concentration, there must be a metabolic component to the acidosis. In simple metabolic acidosis, the PCO2 is reduced because of partial respiratory compensation, in contrast to respiratory acidosis, in which PCO2 is increased. Therefore, in simple metabolic acidosis, one would expect to find a low pH, a low plasma image concentration, and a reduction in PCO2 after partial respiratory compensation.

The procedures for categorizing the types of alkalosis involve the same basic steps. First, alkalosis implies that there is an increase in plasma pH. If the increase in pH is associated with decreased PCO2, there must be a respiratory component to the alkalosis. If the rise in pH is associated with increased image, there must be a metabolic component to the alkalosis. Therefore, in simple respiratory alkalosis, one would expect to find increased pH, decreased PCO2, and decreased image concentration in the plasma. In simple metabolic alkalosis, one would expect to find increased pH, increased plasma imageand increased PCO2.

Complex Acid-Base Disorders and Use of the Acid-Base Nomogram for Diagnosis

In some instances, acid-base disorders are not accompanied by appropriate compensatory responses. When this occurs, the abnormality is referred to as a mixed acid-base disorder. This means that there are two or more underlying causes for the acid-base disturbance. For example, a patient with low pH would be categorized as acidotic. If the disorder was metabolically mediated, this would also be accompanied by a low plasma image concentration and, after appropriate respiratory compensation, a low PCO2. However, if the low plasma pH and low image concentration are associated with elevated PCO2, one would suspect a respiratory component to the acidosis, as well as a metabolic component. Therefore, this disorder would be categorized as a mixed acidosis. This could occur, for example, in a patient with acute image loss from the gastrointestinal tract because of diarrhea (metabolic acidosis) who also has emphysema (respiratory acidosis).

A convenient way to diagnose acid-base disorders is to use an acid-base nomogram, as shown in Figure 30-11. This diagram can be used to determine the type of acidosis or alkalosis, as well as its severity. In this acid-base diagram, pH, image concentration, and PCO2 values intersect according to the Henderson-Hasselbalch equation. The central open circle shows normal values and the deviations that can still be considered within the normal range. The shaded areas of the diagram show the 95 percent confidence limits for the normal compensations to simple metabolic and respiratory disorders.

image

Figure 30-11 Acid-base nomogram showing arterial blood pH, arterial plasma image, and PCO2 values. The central open circle shows the approximate limits for acid-base status in normal people. The shaded areas in the nomogram show the approximate limits for the normal compensations caused by simple metabolic and respiratory disorders. For values lying outside the shaded areas, one should suspect a mixed acid-base disorder.

(Adapted from Cogan MG, Rector FC Jr: Acid-Base Disorders in the Kidney, 3rd ed. Philadelphia: WB Saunders, 1986.)

When using this diagram, one must assume that sufficient time has elapsed for a full compensatory response, which is 6 to 12 hours for the ventilatory compensations in primary metabolic disorders and 3 to 5 days for the metabolic compensations in primary respiratory disorders. If a value is within the shaded area, this suggests that there is a simple acid-base disturbance. Conversely, if the values for pH, bicarbonate, or PCO2 lie outside the shaded area, this suggests that there may be a mixed acid-base disorder.

It is important to recognize that an acid-base value within the shaded area does not always mean that there is a simple acid-base disorder. With this reservation in mind, the acid-base diagrams can be used as a quick means of determining the specific type and severity of an acid-base disorder.

For example, assume that the arterial plasma from a patient yields the following values: pH 7.30, plasma image concentration 12.0 mEq/L, and plasma PCO2 25 mm Hg. With these values, one can look at the diagram and find that this represents a simple metabolic acidosis, with appropriate respiratory compensation that reduces the PCO2 from its normal value of 40 mm Hg to 25 mm Hg.

A second example would be a patient with the following values: pH 7.15, plasma image concentration 7 mEq/L, and plasma PCO2 50 mm Hg. In this example, the patient is acidotic, and there appears to be a metabolic component because the plasma image concentration is lower than the normal value of 24 mEq/L. However, the respiratory compensation that would normally reduce PCO2 is absent and PCO2 is slightly increased above the normal value of 40 mm Hg. This is consistent with a mixed acid-base disturbance consisting of metabolic acidosis, as well as a respiratory component.

The acid-base diagram serves as a quick way to assess the type and severity of disorders that may be contributing to abnormal pH, PCO2, and plasma bicarbonate concentrations. In a clinical setting, the patient’s history and other physical findings also provide important clues concerning causes and treatment of the acid-base disorders.

Use of Anion Gap to Diagnose Acid-Base Disorders

The concentrations of anions and cations in plasma must be equal to maintain electrical neutrality. Therefore, there is no real “anion gap” in the plasma. However, only certain cations and anions are routinely measured in the clinical laboratory. The cation normally measured is Na+, and the anions are usually Cl and image. The “anion gap” (which is only a diagnostic concept) is the difference between unmeasured anions and unmeasured cations and is estimated as

image

The anion gap will increase if unmeasured anions rise or if unmeasured cations fall. The most important unmeasured cations include calcium, magnesium, and potassium, and the major unmeasured anions are albumin, phosphate, sulfate, and other organic anions. Usually the unmeasured anions exceed the unmeasured cations, and the anion gap ranges between 8 and 16 mEq/L.

The plasma anion gap is used mainly in diagnosing different causes of metabolic acidosis. In metabolic acidosis, the plasma image is reduced. If the plasma sodium concentration is unchanged, the concentration of anions (either Cl or an unmeasured anion) must increase to maintain electroneutrality. If plasma Cl increases in proportion to the fall in plasma image, the anion gap will remain normal. This is often referred to as hyperchloremic metabolic acidosis.

If the decrease in plasma image is not accompanied by increased Cl, there must be increased levels of unmeasured anions and therefore an increase in the calculated anion gap. Metabolic acidosis caused by excess nonvolatile acids (besides HCl), such as lactic acid or ketoacids, is associated with an increased plasma anion gap because the fall in image is not matched by an equal increase in Cl. Some examples of metabolic acidosis associated with a normal or increased anion gap are shown in Table 30-4. By calculating the anion gap, one can narrow some of the potential causes of metabolic acidosis.

Table 30-4 Metabolic Acidosis Associated with Normal or Increased Plasma Anion Gap

Increased Anion Gap (Normochloremia)

Normal Anion Gap (Hyperchloremia)

Diabetes mellitus (ketoacidosis)

Lactic acidosis

Chronic renal failure

Aspirin (acetylsalicylic acid) poisoning

Methanol poisoning

Ethylene glycol poisoning

Starvation

Diarrhea Renal tubular acidosis

Carbonic anhydrase inhibitors

Addison’s disease

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