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State the normal ranges of arterial pH,

and define alkalosis and acidosis

List the potential causes of respiratory acidosis and alkalosis and metabolic

■

acidosis and alkalosis

Discuss the respiratory mechanisms that help compensate for acidosis

The respiratory and renal systems maintain the balance of

acids and bases in the body This chapter will introduce the

major concepts of the respiratory system’s contribution to

acid–base balance; Chapter 47 addresses the renal system

con-tribution to acid–base balance and includes a more detailed

discussion of the basic chemistry of acid–base physiology,

buf-fers, and the chemistry of the CO2–bicarbonate system

INTRODUCTION TO

ACID–BASE CHEMISTRY

An acid can be simply defined as a substance that can donate

a hydrogen ion (a proton) to another substance and a base as

a substance that can accept a hydrogen ion from another

sub-stance A strong acid is a substance that is completely or

almost completely dissociated into a hydrogen ion and its

cor-responding or conjugate base in dilute aqueous solution; a

weak acid is only slightly ionized in aqueous solution In

gen-eral, a strong acid has a weak conjugate base and a weak acid

has a strong conjugate base The strength of an acid or a base

should not be confused with its concentration

A buffer is a mixture of substances in aqueous solution

(usually a combination of a weak acid and its conjugate base)

that can resist changes in hydrogen ion concentration when

strong acids or bases are added; that is, the changes in gen ion concentration that occur when a strong acid or base is added to a buffer system are much smaller than those that would occur if the same amount of acid or base were added to pure water or another nonbuffer solution

hydro-The hydrogen ion activity of pure water is about 1.0 ×

10–7 mol/L By convention, solutions with hydrogen ion ties above 10–7 mol/L are considered to be acid; those with hydrogen ion activities below 10–7 are considered to be alka-line The range of hydrogen ion concentrations or activities in the body is normally from about 10–1 for gastric acid to about

activi-10–8 for the most alkaline pancreatic secretion This wide range

of hydrogen ion activities necessitates the use of the more venient pH scale The pH of a solution is the negative loga-rithm of its hydrogen ion activity With the exception of the highly concentrated gastric acid, in most instances in the body, the hydrogen ion activity is about equal to the hydrogen ion concentration

con-The pH of arterial blood is normally close to 7.40, with a normal range considered to be about 7.35–7.45 An arterial

pH (pHa) less than 7.35 is considered acidemia; a pHa greater than 7.45 is considered alkalemia The underlying condition

characterized by hydrogen ion retention or by loss of

bicar-bonate or other bases is referred to as acidosis; the underlying

condition characterized by hydrogen ion loss or retention of

base is referred to as alkalosis Under pathologic conditions,

the extremes of arterial blood pH have been noted to range as

high as 7.8 and as low as 6.9 These correspond to hydrogen

ion concentrations as seen in Table 37–1 (hydrogen ion

con-centrations are expressed as nanomoles [10–9 mol/L] for

conve-nience)

Note that the pH scale is “inverted” by the negative sign and

is also logarithmic as it is defined An increase in pH

repre-sents a decrease in hydrogen ion concentration In fact, an

increase of only 0.3 pH units indicates that the hydrogen ion

concentration was cut in half

Hydrogen ions are the most reactive cations in body fluids,

and they interact with negatively charged regions of other

molecules, such as those of body proteins Interactions of

hydrogen ions with negatively charged functional groups of

proteins can lead to marked changes in protein structural

con-formations with resulting alterations in the behavior of the

proteins An example of this was already seen in Chapter 36,

where hemoglobin was noted to combine with less oxygen at a

lower pH (the Bohr effect) Alterations in the structural

con-formations and charges of protein enzymes affect their

activi-ties, with resulting alterations in the functions of body tissues

Extreme changes in the hydrogen ion concentration of the

body can result in loss of organ system function and may be

fatal

Under normal circumstances, cellular metabolism is the

main source of acids in the body These acids are the waste

products of substances ingested as foodstuffs The greatest

source of hydrogen ions is the carbon dioxide produced as one

of the end products of the oxidation of glucose and fatty acids

during aerobic metabolism The hydration of carbon dioxide

results in the formation of carbonic acid, which then can

dis-sociate into a hydrogen ion and a bicarbonate ion, as discussed

in Chapter 36 This process is reversed in the pulmonary

capil-laries, and CO2 then diffuses through the alveolar–capillary

barrier into the alveoli, from which it is removed by alveolar

ventilation Carbonic acid is therefore said to be a volatile acid

because it can be converted into a gas and then removed from

an open system such as the body Very great amounts of bon dioxide can be removed from the lungs by alveolar venti-lation: under normal circumstances, about 15,000–25,000 mmol of carbon dioxide is removed via the lungs daily

car-A much smaller quantity of fixed or nonvolatile acids is

also normally produced during the course of the metabolism

of foodstuffs The fixed acids produced by the body include sulfuric acid, which originates from the oxidation of sulfur-containing amino acids such as cysteine; phosphoric acid from the oxidation of phospholipids and phosphoproteins; hydro-chloric acid, which is produced during the conversion of ingested ammonium chloride to urea and by other reactions;

and lactic acid from the anaerobic metabolism of glucose

Other fixed acids may be ingested accidentally or formed in abnormally large quantities by disease processes, such as the

acetoacetic and butyric acid formed during diabetic

ketoaci-dosis (see Chapter 66) About 70 mEq of fixed acids is

nor-mally removed from the body each day (about 1 mEq/kg/body weight per day); the range is 50–100 mEq A vegetarian diet may produce significantly less fixed acid and may even result

in no net production of fixed acids The removal of fixed acids

is accomplished mainly by the kidneys, as will be discussed in Chapter 47 Some may also be removed via the gastrointestinal tract Fixed acids normally represent only about 0.2% of the total body acid production

The body contains a variety of substances that can act as buffers in the physiologic pH range These include bicarbon-ate, phosphate, and proteins in the blood, the interstitial fluid, and inside cells (discussed in greater detail in Chapter 47) The

isohydric principle states that all the buffer pairs in a

homo-geneous solution are in equilibrium with the same hydrogen ion concentration For this reason, all the buffer pairs in the plasma behave similarly, so that the detailed analysis of a single buffer pair, like the bicarbonate buffer system, can reveal a great deal about the chemistry of all the plasma buffers

The main buffers of the blood are bicarbonate, phosphate, and proteins The bicarbonate buffer system consists of the buffer pair of the weak acid, carbonic acid, and its conjugate base, bicarbonate The ability of the bicarbonate system to function as a buffer of fixed acids in the body is largely due to the ability of the lungs to remove carbon dioxide from the body In a closed system, bicarbonate would not be nearly as effective

At a temperature of 37°C, about 0.03 mmol of carbon

diox-ide per mm Hg of Pco

2 will dissolve in a liter of plasma (Note that the solubility of CO2 was expressed as milliliters of CO2per 100 mL of plasma in Chapter 36.) Therefore, the carbon

dioxide dissolved in the plasma, expressed as millimoles per liter, is equal to 0.03 x Pco

2 At body temperature in the plasma, the equilibrium of the reaction is such that there is roughly 1,000 times more carbon dioxide physically dissolved in the plasma than there is in the form of carbonic acid The dis-solved carbon dioxide is in equilibrium with the carbonic acid, though, so both the dissolved carbon dioxide and the carbonic

TABLE 37–1 The pH scale.

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

acid are considered as the undissociated HA in the

Hender-son–Hasselbalch equation (see Chapter 47) for the

bicarbon-ate system:

pH = pK + log _ [HCO3]p

[CO2 + H2CO3] (1)

where [HCO3−]p stands for plasma bicarbonate concentration

The concentration of carbonic acid is negligible, so we have:

pH = pK′ + log [HCO3 ]p

_

0.03 Pco2

where pK ′ is the pK of the HCO3

−–CO2 system in blood

The pK′ of this system at physiologic pH values and at 37°C

is 6.1 Therefore, at a pHa of 7.40 and an arterial Pco

2 of 40 mm

Hg, we have:

7.40 = 6.1 + log _ [HCO3]p

Therefore, the arterial plasma bicarbonate concentration is

about 24 mmol/L (the normal range is 23–28 mmol/L) because

the logarithm of 20 is equal to 1.3

Note that the term total CO 2 refers to the dissolved carbon

dioxide (including carbonic acid) plus the carbon dioxide

is the pH–bicarbonate diagram shown in Figure 37–1

As can be seen from Figure 37–1, pH is on the abscissa of

the pH–bicarbonate diagram, and the plasma bicarbonate

concentration in millimoles per liter is on the ordinate For

each value of pH and bicarbonate ion concentration, there is a

2 is held constant, for example, at 40 mm Hg, an isobar line

can be constructed, connecting the resulting points as the pH

is varied The representative isobars shown in Figure 37–1 give

an indication of the potential alterations of acid–base status when alveolar ventilation is increased or decreased If every-thing else remains constant, hypoventilation leads to acidosis; hyperventilation leads to alkalosis

The bicarbonate buffer system is a poor buffer for carbonic

acid The presence of hemoglobin makes blood a much better

buffer The buffer value of plasma in the presence of hemoglobin

is four to five times that of plasma separated from erythrocytes Therefore, the slope of the normal in vivo buffer line shown in Figures 37–1 is mainly determined by the nonbicarbonate buf-fers present in the body The phosphate buffer system mainly consists of the buffer pair of the dihydrogen phosphate (H2PO4−) and the monohydrogen phosphate (HPO42−) anions

Although several potential buffering groups are found on

proteins, only one large group has pK in the pH range

encountered in the blood These are the imidazole groups in the histidine residues of the peptide chains The protein pres-ent in the greatest quantity in the blood is hemoglobin As already noted, deoxyhemoglobin is a weaker acid than is oxyhemoglobin Thus, as oxygen leaves hemoglobin in the tissue capillaries, the imidazole group removes hydrogen ions from the erythrocyte interior, allowing more carbon dioxide to be transported as bicarbonate This process is reversed in the lungs

The bicarbonate buffer system is the major buffer found in the interstitial fluid, including the lymph The phosphate buffer pair is also found in the interstitial fluid The volume of the interstitial compartment is much larger than that of the plasma,

so the interstitial fluid may play an important role in buffering

The extracellular portion of bone contains very large its of calcium and phosphate salts, mainly in the form of

depos-hydroxyapatite In an otherwise healthy adult, where bone

growth and resorption are in a steady state, bone salts can fer hydrogen ions in chronic acidosis Chronic buffering of hydrogen ions by the bone salts may therefore lead to demin-eralization of bone

buf-The intracellular proteins and organic phosphates of most cells can function to buffer both fixed acids and carbonic acid

Of course, buffering by the hemoglobin in erythrocytes is intracellular

ACIDOSIS AND ALKALOSIS

Acid–base disorders can be divided into four major categories: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis These primary acid–base disorders may occur singly (“simple”) or in combination (“mixed”) or may be altered by compensatory mechanisms

10 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8

pH 15

20 25 30 35

Normal buffer line

Note the hydrogen ion concentration in nanomoles per liter at the

top of the figure corresponding to the pH values on the abscissa

Points A to E correspond to different pH values and bicarbonate

concentrations all falling on the same PCO 2 isobar (Modified with

permission of the University of Chicago Press from Davenport HW: The ABC of

Acid–Base Chemistry, 6th ed 1974.)

RESPIRATORY ACIDOSIS

The arterial Pco

2 is normally maintained at or near 40 mm Hg (normal range is 35–45 mm Hg) by the mechanisms that reg-

ulate breathing Sensors exposed to the arterial blood and to

the cerebrospinal fluid provide the central controllers of

breathing with the information necessary to regulate the

arte-rial Pco

2 at or near 40 mm Hg (see Chapter 38) Any short-term

alterations (i.e., those which occur without renal

compensa-tion) in alveolar ventilation that result in an increase in

alveo-lar and therefore also in arterial Pco

2 tend to lower the pHa,

resulting in respiratory acidosis This can be appreciated by

examining the Pco

2 = 60 and 80 mm Hg isobars in Figure 37–1

The pHa at any Paco

2 depends on the bicarbonate and other

buffers present in the blood Pure changes in arterial Pco

2caused by changes in ventilation travel along the normal in

vivo buffer line (Figures 37–1 and 37–2) Pure

uncompen-sated respiratory acidosis would correspond with point C in

Figure 37–2 (at the intersection of an elevated Pco

2 isobar and the normal buffer line)

In respiratory acidosis, the ratio of bicarbonate to CO2

decreases Yet, as can be seen at point C in Figure 37–2, in

uncompensated primary (simple) respiratory acidosis, the

absolute plasma bicarbonate concentration does increase

somewhat because of the buffering of some of the hydrogen

ions liberated by the dissociation of carbonic acid by

nonbi-carbonate buffers

Any impairment of alveolar ventilation can cause

respira-tory acidosis As shown in Table 37–2, depression of the

respiratory centers in the medulla (see Chapter 38) by

anes-thetic agents, narcotics, hypoxia, central nervous system

dis-ease or trauma, or even greatly incrdis-eased PaCo

2 itself results in

hypoventilation and respiratory acidosis Interference with

the neural transmission to the respiratory muscles by disease

processes, drugs or toxins, or dysfunctions or deformities of the respiratory muscles or the chest wall can result in respi-ratory acidosis Restrictive, obstructive, and obliterative dis-eases of the lungs can also result in respiratory acidosis

respi-results in movement to a lower Pco

2 isobar along the normal fer line, as seen at point B in Figure 37–2 The decreased Paco

buf-2shifts the equilibrium of the series of reactions describing car-bon dioxide hydration and carbonic acid dissociation to the left

This results in a decreased arterial hydrogen ion concentration, increased pH, and a decreased plasma bicarbonate concentra-tion The ratio of bicarbonate to carbon dioxide increases

The causes of respiratory alkalosis include anything leading

to hyperventilation As shown in Table 37–3, hyperventilation

syndrome, a psychological dysfunction of unknown cause,

results in chronic or recurrent episodes of hyperventilation and

respiratory alkalosis Drugs, hormones (such as progesterone),

toxic substances, central nervous system diseases or disorders,

Metabolic alkalosis and respiratory acidosis

Metabolic alkalosis and respiratory alkalosis Metabolic acidosis

and respiratory acidosis

Metabolic acidosis and respiratory alkalosis

Uncompensated metabolic acidosis Uncompensated

respiratory alkalosis

Metabolic acidosis

Metabolic alkalosis Uncompensated

the University of Chicago Press from Davenport HW: The ABC of Acid–Base Chemistry,

6th ed 1974.)

TABLE 37–2 Common causes of respiratory acidosis.

Depression of the respiratory control centers Anesthetics

Sedatives Opiates Brain injury or disease Severe hypercapnia, hypoxia Neuromuscular disorders Spinal cord injury Phrenic nerve injury Poliomyelitis, Guillain–Barré syndrome, etc.

Botulism, tetanus Myasthenia gravis Administration of curarelike drugs Diseases affecting the respiratory muscles Chest wall restriction

Kyphoscoliosis Extreme obesity Lung restriction Pulmonary fibrosis Sarcoidosis Pneumothorax, pleural effusions, etc.

Pulmonary parenchymal diseases Pneumonia, etc.

Pulmonary edema Airway obstruction Chronic obstructive pulmonary disease Upper airway obstruction

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

bacteremias, fever, overventilation by mechanical ventilators

(or the clinician), or ascent to high altitude may all result in

respiratory alkalosis

METABOLIC ACIDOSIS

Metabolic acidosis may be thought of as nonrespiratory

acidosis It can be caused by the ingestion, infusion, or

production of a fixed acid; decreased renal excretion of

hydrogen ions; the movement of hydrogen ions from the

intracellular to the extracellular compartment; or the

loss of bicarbonate or other bases from the extracellular

com-partment As can be seen in Figure 37–2, primary

uncom-pensated metabolic acidosis results in a downward movement

along the Pco

2 = 40 mm Hg isobar to point G, that is, a net loss

of buffer establishes a new blood–buffer line lower than and

parallel to the normal blood–buffer line Pco

2 is unchanged, hydrogen ion concentration is increased, and the ratio of

bicarbonate concentration to CO2 is decreased

As shown in Table 37–4, ingestion of methyl alcohol or

sali-cylates can cause metabolic acidosis by increasing the fixed

acids in the blood (Salicylate poisoning—for example, aspirin

overdose—causes both metabolic acidosis and later

respira-tory alkalosis.) Diarrhea can cause significant bicarbonate

losses, resulting in metabolic acidosis Renal dysfunction can

lead to an inability to excrete hydrogen ions, as well as an

inability to reabsorb bicarbonate ions, as will be discussed in

the next section True “metabolic” acidosis may be caused by

an accumulation of lactic acid in severe hypoxemia or shock

and by diabetic ketoacidosis.

METABOLIC ALKALOSIS

Metabolic, or nonrespiratory, alkalosis occurs when there is

an excessive loss of fixed acids from the body, or it may occur

as a consequence of the ingestion, infusion, or excessive renal reabsorption of bases such as bicarbonate Figure 37–2 shows that primary uncompensated metabolic alkalosis results in an upward movement along the Pco

As shown in Table 37–5, loss of gastric juice by vomiting

results in a loss of hydrogen ions and may cause metabolic alkalosis Excessive ingestion of bicarbonate or other bases (e.g., stomach antacids) or overinfusion of bicarbonate by the clinician may cause metabolic alkalosis In addition,

TABLE 37–3 Common causes of respiratory alkalosis.

Central nervous system

Pulmonary vascular diseases (pulmonary embolism)

Overventilation with mechanical ventilators

Hypoxia; high altitude

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

TABLE 37–4 Common causes of metabolic acidosis.

Ingested drugs or toxic substances Methanol

Ethanol Salicylates Ethylene glycol Ammonium chloride Loss of bicarbonate ions Diarrhea

Pancreatic fistulas Renal dysfunction Lactic acidosis Hypoxemia Anemia, carbon monoxide Shock (hypovolemic, cardiogenic, septic, etc.) Severe exercise

Acute respiratory distress syndrome (ARDS) Ketoacidosis

Diabetes mellitus Alcoholism Starvation Inability to excrete hydrogen ions Renal dysfunction

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

TABLE 37–5 Common causes of metabolic alkalosis.

Loss of hydrogen ions Vomiting

Gastric fistulas Diuretic therapy Treatment with or overproduction of steroids (aldosterone or other mineralocorticoids)

Ingestion or administration of excess bicarbonate or other bases Intravenous bicarbonate

Ingestion of bicarbonate or other bases (e.g., antacids)

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

diuretic therapy, treatment with steroids (or the

overpro-duction of endogenous steroids), and conditions leading to

severe potassium depletion may also cause metabolic

alkalosis

COMPENSATORY MECHANISMS

Uncompensated primary acid–base disturbances, such as

those indicated by points B–D and G in Figure 37–2, seldom

occur because respiratory and renal compensatory

mecha-nisms are called into play to offset these disturbances The two

main compensatory mechanisms are functions of the

respira-tory and renal systems

RESPIRATORY COMPENSATORY

MECHANISMS

The respiratory system can compensate for metabolic acidosis

or alkalosis by altering alveolar ventilation As discussed in

Chapter 33, if carbon dioxide production is constant, the

alve-olar Pco

2 is inversely proportional to the alveolar ventilation In

metabolic acidosis, the increased blood hydrogen ion

concen-tration stimulates chemoreceptors, which, in turn, increase

alveolar ventilation, thus decreasing arterial Pco

2 This causes

an increase in pHa, returning it toward normal (The

mecha-nisms by which ventilation is regulated are discussed in detail

in Chapter 38.) These events can be better understood by

look-ing at Figure 37–2 Point G represents uncompensated

meta-bolic acidosis As the respiratory compensation for the

metabolic acidosis occurs, in the form of an increase in

venti-lation, the arterial Pco

2 decreases The point representing blood pHa, Paco

2, and bicarbonate concentration would then move a short distance along the lower-than-normal buffer line (from

point G toward point H) until a new lower Paco

2 is attained

This returns the pHa toward normal; complete compensation

does not occur The respiratory compensation for metabolic

acidosis occurs almost simultaneously with the development

of the acidosis The blood pH, Pco

2, and bicarbonate tration point does not really move first from the normal

concen-(point A) to point G and then move a short distance along line

GH; instead, the compensation begins to occur as the acidosis

develops, so the point takes an intermediate pathway between

the two lines

The respiratory compensation for metabolic alkalosis is to

decrease alveolar ventilation, thus increasing Paco

2 This decreases pHa toward normal, as can be seen in Figure 37–2

Point D represents uncompensated metabolic alkalosis;

respi-ratory compensation would move the blood pHa, PaCo

2, and bicarbonate concentration point a short distance along the

new higher-than-normal blood–buffer line toward point F

Again the compensation occurs as the alkalosis develops, with

the point moving along an intermediate course

Under most circumstances, the cause of respiratory

aci-dosis or alkalosis is a dysfunction in the ventilatory control

mechanism or the breathing apparatus itself tion for acidosis or alkalosis in these conditions must there-fore come from outside the respiratory system The respiratory compensatory mechanism can operate very rapidly (within minutes) to partially correct metabolic aci-dosis or alkalosis

Compensa-RENAL COMPENSATORY MECHANISMS

The kidneys can compensate for respiratory acidosis and abolic acidosis of nonrenal origin by excreting fixed acids and

met-by retaining filtered bicarbonate They can also compensate for respiratory alkalosis or metabolic alkalosis of nonrenal ori-gin by decreasing hydrogen ion excretion and by decreasing the retention of filtered bicarbonate These mechanisms are discussed in Chapter 47 Renal compensatory mechanisms for acid–base disturbances operate much more slowly than respi-ratory compensatory mechanisms For example, the renal compensatory responses to sustained respiratory acidosis or alkalosis may take 3–6 days

The kidneys help regulate acid–base balance by altering the excretion of fixed acids and the retention of the filtered bicar-bonate; the respiratory system helps regulate body acid–base

balance by adjusting alveolar ventilation to alter alveolar Pco

2 For these reasons, the Henderson–Hasselbalch equation is in effect:

pH = Constant + Kidneys

CLINICAL INTERPRETATION

OF ARTERIAL BLOOD GASES

Samples of arterial blood are usually analyzed clinically to

determine the “arterial blood gases”: the arterial Po

2, Pco

2, and

pH The plasma bicarbonate can then be calculated from the

pH and Pco

2 by using the Henderson–Hasselbalch equation

This can be done directly, or by using a nomogram, or by graphical analysis such as the pH–bicarbonate diagram (the “Davenport plot,” after its popularizer), the pH– Pco

2 gram (the “Siggaard-Andersen”), or the composite acid–base diagram Blood gas analyzers perform these calculations automatically

dia-Table 37–6 summarizes the changes in pHa, Paco

2, and plasma bicarbonate concentration that occur in simple, mixed, and partially compensated acid–base disturbances It contains the same information shown in Figure 37–2, depicted differ-ently A thorough understanding of the patterns shown in

Table 37–6 coupled with knowledge of a patient’s Pco

2 and other clinical findings can reveal a great deal about the under-lying pathophysiologic processes in progress

A simple approach to interpreting a blood gas set is to first look at the pH to determine whether the predominant prob-lem is acidosis or alkalosis (Note that an acidemia could rep-resent more than one cause of acidosis, an acidosis with some

compensation, or even an acidosis and a separate underlying

alkalosis Similarly, an alkalemia could represent more than

one cause of alkalosis, an alkalosis with some compensation, or

even an alkalosis and a separate underlying acidosis.) After

evaluating the pH, look at the arterial Pco

2 to see if it explains

the pH For example, if the pH is low and the Pco

2 is increased, then the primary problem is respiratory acidosis If the pH is

low and the Pco

2 is near 40 mm Hg, then the primary problem

is metabolic acidosis with little or no compensation If both the

pH and the Pco

2 are low, there is metabolic acidosis with ratory compensation Then look at the bicarbonate concentra-

respi-tion to confirm your diagnosis It should be slightly increased

in uncompensated respiratory acidosis, high in partially

com-pensated respiratory acidosis, and low in metabolic acidosis

If the pH is high and the Pco

2 is low, then the primary

prob-lem is respiratory alkalosis If the pH is high and the Pco

2 is near 40 mm Hg, then the problem is uncompensated meta-

bolic alkalosis If both the pH and the Pco

2 are high, then there

is partially compensated metabolic alkalosis The bicarbonate

should be slightly decreased in respiratory alkalosis, decreased

in partially compensated respiratory alkalosis, and increased

in metabolic alkalosis

BASE EXCESS

Calculation of the base excess or base deficit may be very

useful in determining the therapeutic measures to be

admin-istered to a patient The base excess or base deficit is the ber of milliequivalents of acid or base needed to titrate 1 L of blood to pH 7.4 at 37°C if the Paco

num-2 were held constant at

40 mm Hg It is not, therefore, just the difference between the plasma bicarbonate concentration of the sample in question and the normal plasma bicarbonate concentration because respiratory adjustments also cause a change in bicarbonate

concentration: the arterial Pco

2 must be considered, although

in most cases the vertical deviation of the bicarbonate level above or below the blood–buffer line on the Davenport dia-gram at the pH of the sample is a reasonable estimate Base excess can be determined by actually titrating a sample or by using a nomogram, diagram, or calculator program Most blood gas analyzers calculate the base excess automatically The base excess is expressed in milliequivalents per liter above

or below the normal buffer-base range—it therefore has

a normal value of 0 ± 2 mEq/L A base deficit is also called a

negative base excess.

The base deficit can be used to estimate how much sodium bicarbonate (in mEq) should be given to a patient by multiply-ing the base deficit (in mEq/L) times the patient’s estimated extracellular fluid (ECF) space (in liters), which is the distri-bution space for the bicarbonate The ECF is usually estimated

to be 0.3 times the lean body mass in kilograms

ANION GAP

Calculation of the anion gap can be helpful in determining the

cause of a patient’s metabolic acidosis It is determined by tracting the sum of a patient’s plasma chloride and bicarbonate concentrations (in mEq/L) from his or her plasma sodium concentration:

sub-Anion gap =[Na+]–([C1–]+[HCO3–]) (5)

The anion gap is normally 12 ± 4 mEq/L

The sum of all of the plasma cations must equal the sum of all of the plasma anions, so the anion gap exists only because all of the plasma cations and anions are not measured when standard blood chemistry is done Sodium, chloride, and bicarbonate concentrations are almost always reported The normal anion gap is a result of the presence of more unmea-sured anions than unmeasured cations in normal blood:

[Na+]+[Unmeasured cations]=

[ C1–]+[HCO3–]+[Unmeasured anions] (6)

[Na+]–([ C1–]+[HCO3–])=

[Unmeasured anions]–[Unmeasured cations] (7)The anion gap is therefore the difference between the unmea-sured anions and the unmeasured cations

The negative charges on the plasma proteins probably make

up most of the normal anion gap, because the total charges of the other plasma cations (K+, Ca2+, Mg2+) are approximately equal to the total charges of the other anions (PO43−, SO42−, organic anions)

TABLE 37–6 Acid–base disturbances.

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed

New York: McGraw-Hill Medical, 2007.

An increased anion gap usually indicates an increased

num-ber of unmeasured anions (those other than C1– and HCO3−)

or a decreased number of unmeasured cations (K+, Ca2+, or

Mg2+), or both This is most likely to happen when the

mea-sured anions, [HCO3−] or [Cl–], are lost and replaced by

unmea-sured anions For example, the buffering by HCO3− of H+ from

ingested or metabolically produced acids produces an increased

anion gap

Thus, metabolic acidosis with an abnormally great anion

gap (i.e., greater than 16 mEq/L) would probably be caused by

lactic acidosis or ketoacidosis; ingestion of organic anions

such as salicylate, methanol, and ethylene glycol; or renal

retention of anions such as sulfate, phosphate, and urate

THE CAUSES OF HYPOXIA

Thus far, only two of the three variables referred to as the

arte-rial blood gases, the artearte-rial Pco

2, and pH have been discussed

Many abnormal conditions or diseases can cause a low arterial

Po

2 They are discussed in the following section about the

causes of tissue hypoxia in the discussion of hypoxic hypoxia.

The causes of tissue hypoxia can be classified (in some cases

rather arbitrarily) into four or five major groups (Table 37–7)

The underlying physiology of most of these types of hypoxia

has already been discussed in this or previous chapters

HYPOXIC HYPOXIA

Hypoxic hypoxia refers to conditions in which the arterial Po

2

is abnormally low Because the amount of oxygen that will

combine with hemoglobin is mainly determined by the Po

2, such conditions may lead to decreased oxygen delivery to the

tissues if reflexes or other responses cannot adequately increase

the cardiac output or hemoglobin concentration of the blood

Conditions causing low alveolar Po

2 inevitably lead to low

dis-of kyphoscoliosis or obesity, and airway obstruction Ascent to

high altitude causes alveolar hypoxia because of the reduced

total barometric pressure encountered above sea level Reduced

FIo

2(fractional concentration of inspired oxygen) has a similar effect Alveolar carbon dioxide is decreased because of the reflex increase in ventilation caused by hypoxic stimulation, as will be discussed in Chapter 71 Hypoventilation and ascent to

high altitude lead to decreased venous Po

2 and oxygen content

as oxygen is extracted from the already hypoxic arterial blood

Administration of increased oxygen concentrations in the inspired gas can alleviate the alveolar and arterial hypoxia in hypoventilation and in ascent to high altitude, but it cannot reverse the hypercapnia of hypoventilation In fact, adminis-

tration of increased FIo

2 to spontaneously breathing patients hypoventilating because of a depressed central response to car-bon dioxide (see Chapter 38) can further depress ventilation

Diffusion Impairment

Alveolar–capillary diffusion is discussed in greater detail in

Chapter 35 Conditions such as interstitial fibrosis and

inter-stitial or alveolar edema can lead to low arterial Po

2 and

con-tents with normal or elevated alveolar Po

2 High FIo

2 that

increases the alveolar Po

2 to very high levels may increase the

TABLE 37–7 A classifi cation of the causes of hypoxia.

N, normal.

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.

arterial Po

2 by increasing the partial pressure gradient for gen diffusion

oxy-Shunts

True right-to-left shunts, such as anatomic shunts and

abso-lute intrapulmonary shunts, can cause decreased arterial Po

2

with normal or even increased alveolar Po

2 Patients with

intrapulmonary shunts have low arterial Po

2, but may not have

significantly increased Pco

2 if they are able to increase their olar ventilation or if they are mechanically ventilated This is a

alve-result of the different shapes of the oxyhemoglobin dissociation

curve (see Figure 36–1) and the carbon dioxide dissociation

curve (see Figure 36–5) The carbon dioxide dissociation curve

is almost linear in the normal range of arterial Pco

2, and arterial

Pco

2 is very tightly regulated by the respiratory control system

(see Chapter 38) Carbon dioxide retained in the shunted blood

stimulates increased alveolar ventilation, and because the

car-bon dioxide dissociation curve is nearly linear, increased

venti-lation will allow more carbon dioxide to diffuse from the

nonshunted blood into well-ventilated alveoli and be exhaled

On the other hand, increasing alveolar ventilation will not get

any more oxygen into the shunted blood and, because of the

shape of the oxyhemoglobin dissociation curve, very little more

into the unshunted blood This is because the hemoglobin of

well-ventilated and perfused alveoli is nearly saturated with

oxygen, and little more will dissolve in the plasma Similarly,

arterial hypoxemia caused by true shunts is not relieved by high

FIo

2 because the shunted blood does not come into contact with

the high levels of oxygen The hemoglobin of the unshunted

blood is nearly completely saturated with oxygen at a normal

FIo

2 of 0.21, and the small additional volume of oxygen

dis-solved in the blood at high FIo

2 cannot make up for the low hemoglobin saturation of the shunted blood

VENTILATION–PERFUSION MISMATCH

Alveolar–capillary units with low ventilation–perfusion (V ˙ /Q ˙ )

ratios contribute to arterial hypoxia, as already discussed Units

with high V ˙ /Q ˙ do not by themselves lead to arterial hypoxia, of

course, but large lung areas that are underperfused are usually

associated either with overperfusion of other units or with low

cardiac outputs (see the section “Hypoperfusion Hypoxia”)

Hypoxic pulmonary vasoconstriction (discussed in Chapter

34) and local airway responses (discussed in Chapter 32)

nor-mally help minimize V ˙ / Q ˙ mismatch.

Note that diffusion impairment, shunts, and V ˙ / Q ˙ mismatch

increase the alveolar–arterial Po

2 difference (see Table 35–1

and the first two columns in Table 37–7)

ANEMIC HYPOXIA

Anemic hypoxia is caused by a decrease in the amount of

func-tioning hemoglobin, which can be a result of decreased

hemo-globin or erythrocyte production, the production of abnormal

hemoglobin or red blood cells, pathologic destruction of

eryth-rocytes, or interference with the chemical combination of

oxy-gen and hemoglobin Carbon monoxide poisoning, for example,

results from the greater affinity of hemoglobin for carbon

mon-oxide than for oxygen Methemoglobinemia is a condition in

which the iron in hemoglobin has been altered from the Fe2+ to the Fe3+ form, which does not combine with oxygen

Anemic hypoxia results in a decreased oxygen content when

both alveolar and arterial Po

2 are normal Standard analysis of arterial blood gases could therefore give normal values unless

blood oxygen content is measured independently Venous Po

2and oxygen content are both decreased Administration of

high FIo

2 is not effective in greatly increasing the arterial gen content (except possibly in carbon monoxide poisoning)

oxy-HYPOPERFUSION HYPOXIA

Hypoperfusion hypoxia (sometimes called stagnant hypoxia)

results from low blood flow This can occur either locally, in a particular vascular bed, or systemically, in the case of a low car-

diac output The alveolar Po

2 and the arterial Po

2 and oxygen content may be normal, but the reduced oxygen delivery to the

tissues may result in tissue hypoxia Venous Po

2 and oxygen

con-tent are low Increasing the FIo

2 is of little value in hypoperfusion hypoxia (unless it directly increases the perfusion) because the blood flowing to the tissues is already oxygenated normally

HISTOTOXIC HYPOXIA

Histotoxic hypoxia refers to a poisoning of the cellular

machin-ery that uses oxygen to produce energy Cyanide, for example,

binds to cytochrome oxidase in the respiratory chain and

effec-tively blocks oxidative phosphorylation Alveolar Po

2 and

arte-rial Po

2 and oxygen content may be normal (or even increased, because low doses of cyanide increase ventilation by stimulat-

ing the arterial chemoreceptors) Venous Po

2 and oxygen tent are increased because oxygen is not utilized in the tissues

con-THE EFFECTS OF HYPOXIA

Hypoxia can result in reversible tissue injury or even tissue death The outcome of an hypoxic episode depends on whether the tissue hypoxia is generalized or localized, how severe the hypoxia is, the rate of development of the hypoxia (see Chapter 71), and the duration of the hypoxia Different cell types have different susceptibilities to hypoxia; unfortunately, brain cells and heart cells are the most susceptible

CLINICAL CORRELATION

A 15-year-old adolescent entered the emergency

depart-ment with dyspnea (shortness of breath), a feeling of chest

tightness, coughing, wheezing, and anxiety His nail beds

and lips were blue (cyanosis).

Ingestion, infusion, or excessive renal reabsorption of bases, or

■

loss of hydrogen ions, can cause metabolic alkalosis; the compensation for metabolic alkalosis is decreased alveolar ventilation.

Metabolic acidosis with an abnormally elevated anion gap

■

indicates an increased plasma concentration of anions other than chloride and bicarbonate or a decreased plasma concen- tration of potassium, calcium, or magnesium ions.

Tissue hypoxia can be a result of low alveolar

2 , diffusion impairment, right-to-left shunts, or ventilation–perfusion mismatch (hypoxic hypoxia), decreased functional hemoglo- bin (anemic hypoxia), low blood flow (hypoperfusion hypoxia),

or an inability of the mitochondria to use oxygen (histotoxic hypoxia).

STUDY QUESTIONS

1–4 Match each of the following sets of blood gas data to one

of the underlying problems listed below Assume the body temperature to be 37°C, and the hemoglobin concentration

= 95 mm Hg, anion gap = 25mEq/L.

He has had frequent episodes of dyspnea and wheezing

for several years, especially in the spring, and has been

diagnosed with asthma Pulmonary function tests done at

the time of his diagnosis showed lower-than-predicted

forced expiratory volume in the first second (FEV1), forced

vital capacity (FVC), FEV1/FVC, and peak expiratory flow

(PEF) Inhaling a bronchodilator improved all of these

An arterial blood gas was obtained to help determine the

severity of the episode The arterial Po

2 was 55 mm Hg, the

arterial Pco

2 was 32 mm Hg, the arterial pH was 7.52, and the

bicarbonate was 25 mEq/L, indicating hypoxemia and

uncom-pensated respiratory alkalosis.

Asthma is an episodic obstructive disease and it is

reason-able to assume that it would cause CO2 retention and

there-fore respiratory acidosis during attacks This is true in very

severe asthma attacks, but most asthma attacks result in

hypocapnia and respiratory alkalosis As the asthma attack

occurs, bronchial smooth muscle spasm and mucus secretion

obstruct the ventilation to some alveoli Although some

hypoxic pulmonary vasoconstriction may occur, it is not

suf-ficient to divert all of the mixed venous blood flow away from

these poorly ventilated alveoli This results in a right-to-left

shunt or shuntlike state (Chapter 35), which would therefore

be expected to cause the arterial Po

2 to decrease and the

arte-rial Pco

2 to increase However, the Pco

2 decreases because the

patient increases alveolar ventilation if he or she is able to

Irritant receptors in the airways are stimulated by the

mucus and by chemical mediators released during the

attack Hypoxia caused by the shunt stimulates the arterial

chemoreceptors; the patient also has the feeling of dyspnea

(many asthma attacks have an emotional component) All

of these factors cause increased breathing and therefore

increased alveolar ventilation

Increasing ventilation will get more CO2 out of the blood

perfusing ventilated alveoli (and therefore out of the body)

but it will not get much oxygen into alveoli supplied by

obstructed airways, nor will it get much more oxygen into

the blood of the unobstructed alveoli because of the shape

of the oxyhemoglobin dissociation curve Remember that

the hemoglobin is already 97.4% saturated with oxygen and

not much more will dissolve in the plasma Therefore,

dur-ing the attack the patient has hypoxemia, hypocapnia, and

respiratory alkalosis It is only when the attack is so severe

that the patient cannot do the additional work of breathing

that hypercapnia and respiratory acidosis occur

Acute treatment of asthma is aimed at dilating the airways

with a bronchodilator, such as a β 2 -adrenergic agonist, and

relieving the hypoxemia with oxygen Mechanical

ventila-tion may be used in more severe cases Chronic treatment

includes bronchodilators such as β2-adrenergic agonists;

anticholinergics, to block parasympathetically mediated

constriction and mucus production; antileuko triene drugs

and inhaled corticosteroids, to prevent inflammation; and

inhibition of mast cells to prevent them from releasing

cytokines.

spontaneous rhythm of breathing.

List the cardiopulmonary and other reflexes that influence the breathing

■

pattern

State the ability of the brain cortex to override the normal pattern of

■

inspiration and expiration temporarily

Describe the effects of alterations in body oxygen, carbon dioxide, and

■

hydrogen ion levels on the control of breathing

Describe the sensors of the respiratory system for oxygen, carbon dioxide,

RESPIRATORY CONTROL SYSTEM

Breathing is spontaneously initiated in the central nervous

system A cycle of inspiration and expiration is automatically

generated by neurons located in the brainstem Usually,

breath-ing occurs without a conscious initiation of inspiration and

expiration

This spontaneously generated cycle of inspiration and

expi-ration can be modified, altered, or even temporarily

sup-pressed by a number of mechanisms As shown in Figure 38–1,

these include reflexes arising in the lungs, the airways, and the

cardiovascular system; information from receptors in contact

with the cerebrospinal fluid; and commands from higher

cen-ters of the brain such as the hypothalamus, the cencen-ters of

speech, or other areas in the cerebral cortex The centers that

are responsible for the generation of the spontaneous rhythm

of inspiration and expiration are, therefore, able to alter their

activity to meet the increased metabolic demand on the

respi-ratory system during exercise or may even be temporarily superseded or suppressed during speech or breath holding

The respiratory control centers in the brainstem affect the automatic rhythmic control of breathing via a final common

pathway consisting of the spinal cord, the innervation of the muscles of respiration such as the phrenic nerves, and the

muscles of respiration themselves Alveolar ventilation is therefore determined by the interval between successive groups of discharges of the respiratory neurons and the inner-vation of the muscles of respiration, which determines the

respiratory rate or breathing frequency; and by the frequency

of neural discharges transmitted by individual nerve fibers to their motor units, the duration of these discharges, and the number of motor units activated during each inspiration or

expiration, which determine the depth of respiration or the

tidal volume Note that some pathways from the cerebral

cor-tex to the muscles of respiration, such as those involved in

vol-untary breathing, bypass the medullary respiratory center

described below and travel directly to the spinal α motor rons These are represented by the dashed line in Figure 38–1

neu-THE GENERATION OF

SPONTANEOUS RHYTHMICITY

The centers that initiate breathing are located in the reticular

formation of the medulla, beneath the floor of the fourth

ven-tricle This area, known as the medullary respiratory center,

consists of inspiratory neurons, that fire during inspiration to

stimulate inspiratory muscles to contract, and expiratory

neu-rons, that fire during expiration to stimulate expiratory

mus-cles to contract Because expiration is passive in normal quiet

breathing, the expiratory neurons may not discharge unless

expiration is active

There are two dense bilateral aggregations of respiratory

neurons in the medullary respiratory center known as the

dor-sal respiratory groups (DRG) and the ventral respiratory

groups (VRG) (Figure 38–2) Inspiratory and expiratory

neu-rons are anatomically intermingled to a greater or lesser extent

within these areas The dorsal respiratory groups are located

bilaterally in the nucleus of the tractus solitarius (NTS) They

consist mainly of inspiratory neurons that project primarily to

the contralateral spinal cord They serve as the principal

initia-tors of the activity of the phrenic nerves and maintain the

activity of the diaphragm Dorsal respiratory group neurons

send many collateral fibers to those in the ventral respiratory

group, but the ventral respiratory group sends only a few

col-lateral fibers to the dorsal respiratory group The NTS receives

visceral afferent fibers of the 9th cranial nerve (the

glossopha-ryngeal) and the 10th cranial nerve (the vagus) These nerves

carry information about the arterial Po

2, Pco

2, and pH from the

carotid and aortic arterial chemoreceptors (Figure 38–3)

and information concerning the systemic arterial blood sure from the carotid and aortic baroreceptors (see Chapter 29)

pres-In addition, the vagus carries information from stretch tors and other sensors in the lungs that may also exert pro-

recep-found influences on the control of breathing The effects of information from these sensors on the control of breathing will be discussed later in this chapter The location of the DRG within the NTS suggests that it may be the site of integration of various inputs that can reflexly alter the spontaneous pattern

of inspiration and expiration

The ventral respiratory groups are located bilaterally in the

retrofacial nucleus, the nucleus ambiguus, the nucleus para-ambigualis, and the nucleus retroambigualis They

consist of both inspiratory and expiratory neurons The rons in the nucleus ambiguus are primarily vagal motor neu-

neu-rons that innervate the ipsilateral laryngeal, pharyngeal, and tongue muscles involved in breathing and in maintaining

the patency of the upper airway They are both inspiratory and expiratory neurons Other neurons from the ventral respiratory groups mainly project contralaterally to innervate inspiratory muscles and the expiratory muscles The retrofa-cial nucleus, located most rostrally in the ventral respiratory groups, mainly contains expiratory neurons in a group of

cells called the Bötzinger complex Neurons in the area called the pre-Bötzinger complex have been identified as the

Influences from higher centers

Reflexes from:

Lungs Airways Cardiovascular system Muscles and joints Skin

Reflexes from:

Arterial chemoreceptors Central

chemoreceptors

Cycle of inspiration and expiration

Muscles of breathing

is automatically established in the medullary respiratory center Its output represents a final common pathway to the respiratory muscles,

except for some voluntary pathways that may go directly from higher centers to the respiratory muscles (dashed line) Reflex responses from

chemoreceptors and other sensors may modify the cycle of inspiration and expiration established by the medullary respiratory center

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

pacemakers of the respiratory rhythm—the respiratory

rhythm generator.

An area in the in the pons (the part of the brainstem just

rostral to the medulla) called the apneustic center appears to

be an integration site for afferent information that can

termi-nate inspiration The specific group of neurons that function

as the apneustic center has not been identified

A group of respiratory neurons rostral to the apneustic

cen-ter known as the pontine respiratory groups (also called the

pneumotaxic center, as in Figure 38–2) functions to

modu-late the activity of the apneustic center These cells, located in

the upper pons in the nucleus parabrachialis medialis and

the Kölliker-Fuse nucleus, probably function to “fine-tune”

the breathing pattern and smooth the transitions between

inspiration and expiration The pontine respiratory groups

may also modulate the respiratory control system response to

stimuli such as lung inflation, hypercapnia, and hypoxia

In the spinal cord axons projecting from the DRG, the VRG,

the cortex, and other supraspinal sites descend in the spinal

white matter to influence the diaphragm and the intercostal

and abdominal muscles of respiration, as already discussed

There is integration of descending influences as well as the

presence of local spinal reflexes that can affect these motor

neurons Descending axons with inspiratory activity excite phrenic and external intercostal motor neurons and also inhibit internal intercostal motor neurons by exciting spinal inhibitory interneurons They are actively inhibited during expiratory phases of the respiratory cycle

Ascending pathways in the spinal cord, carrying tion from pain, touch, and temperature receptors, as well as

informa-from proprioceptors, can also influence breathing, as will be

discussed in the next section Inspiratory and expiratory fibers appear to be separated in the spinal cord

The spontaneous rhythmicity generated in the medullary respiratory center can be completely overridden (at least tem-porarily) by influences from higher brain centers In fact, the greatest minute ventilations obtainable from healthy conscious

human subjects can be attained voluntarily, exceeding those

obtained with the stimuli of severe exercise, hypercapnia, or

hypoxia This is the underlying concept of the maximum

vol-untary ventilation (MVV) test often used to assess respiratory

function Conversely, the respiratory rhythm can be pletely suppressed for several minutes by voluntary breath

com-holding, until the chemical drive to breath (high Pco

2 and low

Po

2 and pH) overrides the voluntary suppression of breathing

at the breakpoint During speech, singing, or playing a wind

Blood gas partial pressures Arterial chemoreceptors

Pneumotaxic center Apneustic center

Spinal motor neurons

Muscles

Medulla Pons

Ventral respiratory group

(VRG)

Pre-Bötzinger complex (rhythm-generating neurons) Inspiratory

neurons

Expiratory neurons

Dorsal respiratory group

Lung stretch receptors

control centers responsible for respiratory

rhythm generation, activation of inspiratory

and expiratory neuron and muscle

activation, and monitoring lung inflation via

pulmonary stretch receptors and alveolar

ventilation via changes in arterial blood gas

partial pressures Input from the central

chemoreceptors was omitted for clarity

(Reproduced with permission from Widmaier EP, Raff H,

Strang KT: Vander’s Human Physiology, 11th ed

McGraw-Hill, 2008.)

instrument, the normal cycle of inspiration and expiration is

automatically modified by higher brain centers In certain

emotional states, chronic hyperventilation severe enough to

cause respiratory alkalosis may occur

RESPIRATORY REFLEXES

A large number of sensors located in the lungs, the

cardiovas-cular system, the muscles and tendons, and the skin and

vis-cera can elicit reflexes in the control of breathing They are

summarized in Table 38–1, which lists the stimulus, receptor,

afferent pathway, and effects for each reflex

PULMONARY STRETCH RECEPTORS

Three respiratory reflexes can be elicited by the activity of

pul-monary stretch receptors: the Hering–Breuer inflation reflex,

the Hering–Breuer deflation reflex, and the “paradoxical”

reflex.

Inflation of the lungs of anesthetized spontaneously ing animals decreases the frequency of the inspiratory effort

breath-or causes a transient apnea (cessation of breathing) The

stimulus for this reflex is pulmonary inflation The sensors

are stretch receptors located within the smooth muscle of

large and small airways They are sometimes referred to as

slowly adapting pulmonary stretch receptors because their

activity is maintained with sustained stretches The afferent pathway consists of large myelinated fibers in the vagus, which enter the brainstem and project to the DRGs, the apneustic center, and the pontine respiratory groups The Hering–Breuer inflation reflex was originally believed to be

an important determinant of the rate and depth of tion, but recent studies have cast doubt on this conclusion because the threshold of the reflex is much higher than the normal tidal volume during eupneic breathing Tidal vol-umes of 800–1,500 mL are generally required to elicit this reflex in conscious eupneic adults The Hering–Breuer infla-tion reflex may help minimize the work of breathing by inhibiting large tidal volumes as well as prevent overdisten-tion of the alveoli It may also be important in the control of breathing in neonates Neonates have Hering–Breuer infla-tion reflex thresholds within their normal tidal volume ranges, and the reflex may be an important influence on their tidal volumes and respiratory rates

ventila-Deflation of the lungs increases the ventilatory rate This could be a result of decreased stretch receptor activity or of stimulation of other pulmonary receptors, or rapidly adapting receptors such as the irritant receptors and J receptors, which will be discussed later in this chapter The afferent pathway is the vagus, and the effect is increased minute ventilation

(hyperpnea) This reflex may be responsible for the increased

ventilation elicited when the lungs are deflated abnormally, as

in pneumothorax, or it may play a role in the periodic

sponta-neous deep breaths (sighs) that help prevent atelectasis These

sighs occur occasionally and irregularly during the course of normal, quiet, spontaneous breathing They consist of a slow deep inspiration (larger than a normal tidal volume) followed

by a slow deep expiration This response appears to be very important because patients maintained on mechanical ventila-tors must be given large tidal volumes or periodic deep breaths

or they develop diffuse atelectasis, which may lead to arterial hypoxemia

The Hering–Breuer deflation reflex may be very important

in helping to actively maintain functional residual capacities (FRCs) in infants It is very unlikely that infants’ FRCs are determined passively like those of adults because the inward recoil of their lungs is considerably greater than the outward recoil of their very compliant chest walls

After partly blocking the vagus nerves with cold tures, lung inflation causes a further inspiration instead of the apnea expected when the vagus nerves are completely func-

tempera-tional The receptors for this paradoxical reflex are located in

the lungs, but their precise location is not known Afferent information travels in the vagus; the effect is very deep inspi-rations This reflex may also be involved in the sigh response,

Heart Aortic bodies

Carotid bodies Sensory nerves Sensory nerves

Common carotid artery

Aorta

Note that the carotid bodies are close to the carotid sinuses, the

location of the major arterial baroreceptors (Reproduced with

permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology,

11th ed McGraw-Hill, 2008.)

TABLE 38–1 Respiratory refl exes.

Stimulus Reflex Name Receptor Afferent Pathway Effects

Lung inflation Hering–Breuer

inflation reflex

Stretch receptors within smooth muscle of large and small airways

Cessation of inspiratory effort, apnea,

or decreased breathing frequency;

bronchodilation Cardiovascular Increased heart rate, slight vasoconstriction Lung deflation Hering–Breuer

deflation reflex

Possibly J receptors, irritant receptors in lungs, or stretch receptors in airways

the upper airway

Pharyngeal dilator reflex

Receptors in nose, mouth, upper airways

Trigeminal, laryngeal, glossopharyngeal

Respiratory Contraction of pharyngeal dilator muscles Mechanical or

chemical irritation

of airways

airways, tracheobronchial tree

mucosa and face

Trigeminal Respiratory

Apnea Cardiovascular Decreased heart rate; vasoconstriction Pulmonary

embolism

J receptors in pulmonary vessels

Apnea or tachypnea Pulmonary vascular

congestion

J receptors in pulmonary vessels

J receptors in pulmonary vessels

Carotid bodies, aortic bodies

Glossopharyngeal, vagus

Respiratory Hyperpnea; bronchoconstriction, dilation

of upper airway Cardiovascular Decreased heart rate (direct effect), vasoconstriction

Increased systemic

arterial blood

pressure

Arterial baroreceptor reflex

Carotid sinus stretch receptors

Aortic arch stretch receptors

Glossopharyngeal, vagus

Respiratory Apnea, bronchodilation Cardiovascular Decreased heart rate, vasodilation etc.

Respiratory Provide respiratory controller with feedback about work of breathing, stimulation of proprioreceptors in joints causes hyperpnea

pathways

Respiratory Hyperpnea Cardiovascular Increased heart rate, vasoconstriction, etc.

a Discussed in Chapter 71.

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.

or it may be involved in generating the first breath of the

newborn baby; very great inspiratory efforts must be

gener-ated to inflate the fluid-filled lungs

RECEPTORS IN THE AIRWAYS

AND THE LUNGS

Negative pressure in the upper airway causes reflex

contrac-tion of the pharyngeal dilator muscles The receptors for the

pharyngeal dilator reflex appear to be located in the nose,

mouth, and upper airways; the afferent pathways appear to be

in the trigeminal, laryngeal, and glossopharyngeal nerves

This reflex may be very important in maintaining the patency

of the upper airway during strong inspiratory efforts and

dur-ing sleep

Mechanical or chemical irritation of the airways (and

pos-sibly the alveoli) can elicit a reflex cough or sneeze, or it can

cause hyperpnea, bronchoconstriction, and increased blood

pressure The receptors are located in the nasal mucosa, upper

airways, tracheobronchial tree, and possibly the alveoli

them-selves Those in the larger airways of the tracheobronchial

tree, which also respond to stretch, are sometimes referred to

as rapidly adapting pulmonary stretch receptors because

their activity decreases rapidly during a sustained stimulus

The afferent pathways are the vagus nerves for all but the

receptors located in the nasal mucosa, which send information

centrally via the trigeminal and olfactory tracts The cough

and the sneeze reflexes were discussed in Chapter 32

PULMONARY VASCULAR

RECEPTORS (J RECEPTORS)

Pulmonary embolism causes rapid shallow breathing

(tachy-pnea) or apnea; pulmonary vascular congestion also causes

tachy pnea The receptors responsible for initiating these

responses are located in the walls of the pulmonary capillaries

or in the interstitium; therefore, they are called J (for

juxtapul-monary capillary) receptors These receptors may also be

responsible for the dyspnea (a feeling of difficult or labored

breathing) encountered during the pulmonary vascular

con-gestion and edema secondary to left ventricular failure or even

the dyspnea that healthy people feel at the onset of exercise

The afferent pathway of these reflexes is slow-conducting

non-myelinated vagal fibers Other receptors that may contribute

to the sensation of dyspnea include the arterial

chemorecep-tors, stretch receptors in the heart and blood vessels, and

receptors in the respiratory muscles

OTHER CARDIOVASCULAR RECEPTORS

The arterial chemoreceptors are located bilaterally in the

carotid bodies, which are situated near the bifurcations of the

common carotid arteries, and in the aortic bodies, which are

located in the arch of the aorta as shown in Figure 38–3 They

respond to low arterial Po

2, high arterial Pco

2, and low arterial

pH (as will be discussed later in this chapter), with the carotid bodies generally capable of a greater response than the aortic bodies The afferent pathway from the carotid body is Hering’s nerve, a branch of the glossopharyngeal nerve; the afferent pathway from the aortic body is the vagus The reflex effects of stimulation of the arterial chemoreceptors are hyperpnea, bronchoconstriction, dilation of the upper airway, and

increased blood pressure The direct effect of arterial

chemore-ceptor stimulation is a decrease in heart rate; however, this is usually masked by an increase in heart rate secondary to the

increase in lung inflation The arterial baroreceptors exert a

very minor influence on the control of ventilation Low blood pressure may stimulate breathing

OTHER RECEPTORS IN MUSCLE, TENDONS, SKIN, AND VISCERA

Stimulation of receptors located in the muscles, the tendons, and the joints can increase ventilation Included are receptors

in the muscles of respiration (e.g., muscle spindles) and rib cage as well as other skeletal muscles, joints, and tendons

These receptors may play an important role in adjusting the ventilatory effort to elevated workloads and may help mini-mize the work of breathing They may also participate in initi-ating and maintaining the elevated ventilation that occurs during exercise, as will be discussed in Chapter 72 Somatic pain generally causes hyperpnea; visceral pain generally causes apnea or decreased ventilation

THE RESPONSE

TO CARBON DIOXIDE

The respiratory control system normally reacts very effectively

to alterations in the internal “chemical” environment of the

body Changes in the Pco

2, pH, and Po

2 result in alterations in alveolar ventilation designed to return these variables to their

normal values Chemoreceptors alter their activity when their

own local chemical environment changes and can therefore supply the central respiratory controller with the afferent information necessary to make the appropriate adjustments in

alveolar ventilation to change the whole-body Pco

2, pH, and

Po

2 The respiratory control system therefore functions as a

negative-feedback system as discussed in Chapter 1.

The arterial and cerebrospinal fluid partial pressures of bon dioxide are probably the most important inputs to the ventilatory control system in establishing the breath-to-breath levels of tidal volume and ventilatory frequency (Of course, changes in carbon dioxide lead to changes in hydrogen ion concentration, so the effects of these two stimuli are comple-mentary.) An increase in carbon dioxide is a very powerful stimulus to ventilation: only voluntary hyperventilation and the hyperpnea of exercise can surpass the minute ventilations

car-obtained with hypercapnia However, the arterial Pco

2 is so

precisely controlled that it changes little (<1 mm Hg) during

exercise severe enough to increase metabolic carbon dioxide

little further increase in alveolar ventilation: very high arterial

Pco

2 (>70–80 mm Hg) may directly produce respiratory

depres-sion (Very low arterial Pco

2 caused by hyperventilation may temporarily cause apnea because of decreased ventilatory

drive Metabolically produced carbon dioxide will then build

up and restore breathing.)The ventilatory response of a normal conscious person to physiologic levels of carbon dioxide is shown in Figure 38–4

Alveolar (and arterial) Pco

2 in the range of 38–50 mm Hg increase alveolar ventilation linearly The slope of the line is quite steep and varies from person to person It decreases with age

The figure also shows that hypoxia potentiates the

ventila-tory response to carbon dioxide At lower arterial Po

2 (e.g., 35 and 50 mm Hg), the response curve is shifted to the left and

the slope is steeper; that is, for any particular arterial Pco

2, the

ventilatory response is greater at a lower arterial Po

2 This may

be caused by the effects of hypoxia at the chemoreceptor itself

or at higher integrating sites; changes in the central acid–base status secondary to hypoxia may also contribute to the enhanced response

Other influences on the carbon dioxide response curve are illustrated in Figure 38–5 Sleep shifts the curve slightly to

the right The arterial Pco

2 normally increases during wave sleep, increasing as much as 5–6 mm Hg during deep sleep Because of this rightward shift in the CO2 response curve during non-REM sleep, it is possible that there is a

slow-“wakefulness” component of respiratory drive A depressed response to carbon dioxide during sleep may be involved in

central sleep apnea, a condition characterized by abnormally

long periods (1–2 minutes) between breaths during sleep This lack of central respiratory drive is a potentially dangerous con-

dition in both infants and adults (In obstructive sleep apnea,

the central respiratory controller does issue the command to breathe, but the upper airway is obstructed because the pha-ryngeal muscles do not contract properly, there is too much fat around the pharynx, or the tongue blocks the airway.) Narcot-ics and anesthetics may profoundly depress the ventilatory response to carbon dioxide Indeed, respiratory depression is

three different levels of arterial PO 2 (Modified with permission from

Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

Sleep

Awake normal Metabolic acidosis

PaCO

2 (mm Hg)

the ventilatory response to carbon dioxide (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

the most common cause of death in cases of overdose of opiate

alkaloids and their derivatives, barbiturates, and most

anes-thetics Chronic obstructive pulmonary diseases (COPD)

depress the ventilatory response to hypercapnia, in part

because of depressed ventilatory drive secondary to central

acid–base changes, and because the work of breathing may be

so great that ventilation cannot be increased normally

Meta-bolic acidosis displaces the carbon dioxide response curve to

the left, indicating that for any particular Paco

2, ventilation is increased during metabolic acidosis because of hydrogen ion

stimulation of the arterial chemoreceptors

As already discussed, the respiratory control system

consti-tutes a negative-feedback system This is exemplified by the

response to carbon dioxide Increased metabolic production of

carbon dioxide increases the carbon dioxide brought to the lung

If alveolar ventilation stayed constant, the alveolar Pco

2 would

increase, as would arterial and cerebrospinal Pco

2 This

stimu-lates alveolar ventilation by stimulating the arterial and central

chemoreceptors (described later in this chapter) Increased

alveolar ventilation decreases alveolar and arterial Pco

2, as was

discussed in Chapter 33, returning the Pco

2 to the original value

The Pco

2, pH, and Po

2 are the principal controlled variables in the respiratory control system To act as a negative-feedback

system, the respiratory controller must receive information

concerning the levels of the controlled variables from sensors

in the system The sensors are the arterial chemoreceptors

(peripheral chemoreceptors) and the central

chemorecep-tors located bilaterally near the ventrolateral surface of the

medulla in the brainstem and other sites The arterial

chemore-ceptors are exposed to arterial blood; the central

chemorecep-tors are exposed to cerebrospinal fluid The central

chemoreceptors are therefore on the brain side of the blood–

brain barrier Both the peripheral and central chemoreceptors

respond to increases in the partial pressure of carbon dioxide,

although the response may be related to the local increase in

hydrogen ion concentration that occurs with increased Pco

2; that is, the sensors may be responding to the increased carbon

dioxide concentration, the subsequent increase in hydrogen

ion concentration, or both

The arterial chemoreceptors increase their firing rate in

response to increased arterial Pco

2, decreased arterial Po

2, or decreased arterial pH The response of the receptors is both

rapid enough and sensitive enough that they can relay

infor-mation concerning breath-to-breath alterations in the

compo-sition of the arterial blood to the medullary respiratory center

The response of the arterial chemoreceptors changes nearly

linearly with the arterial Pco

2 over the range of 20–60 mm Hg

The central chemoreceptors are exposed to the

cerebrospi-nal fluid and are not in direct contact with the arterial blood

As shown in Figure 38–6, the cerebrospinal fluid is separated

from the arterial blood by the blood–brain barrier Carbon

dioxide can easily diffuse through the blood–brain barrier, but

hydrogen ions and bicarbonate ions do not Because of this,

alterations in the arterial Pco

2 are rapidly transmitted to the cerebrospinal fluid in about 60 seconds Changes in arterial

pH that are not caused by changes in Pco

2 take much longer to

influence the cerebrospinal fluid; in fact, the cerebrospinal

fluid may have changes in hydrogen ion concentration site to those seen in the blood in certain circumstances, as will

oppo-be discussed later in this chapter

The composition of the cerebrospinal fluid is considerably different from that of the blood The pH of the cerebrospinal fluid is normally about 7.32, compared with the pH of 7.40 of

arterial blood The Pco

2 of the cerebrospinal fluid is about

50 mm Hg—about 10 mm Hg higher than the normal arterial

Pco

2 of 40 mm Hg The concentration of proteins in the brospinal fluid is only in the range of 0.02-0.05 g/100 mL, whereas the concentration of proteins in the plasma normally ranges from 6.6 to 8.6 g/100 mL This does not even include the hemoglobin in the erythrocytes As a result, bicarbonate is the main buffer in the cerebrospinal fluid Arterial hypercap-nia will therefore lead to greater changes in cerebrospinal fluid hydrogen ion concentration than it does in the arterial blood

cere-The brain produces carbon dioxide as an end product of metabolism Brain carbon dioxide levels are higher than those

of the arterial blood, which explains the high Pco

2 of the brospinal fluid

cere-The central chemoreceptors respond to local increases

in hydrogen ion concentration or Pco

2, or both They do not respond to hypoxia

About 80–90% of the normal total steady-state response to increased inspired carbon dioxide concentrations comes from the central chemoreceptors; the arterial chemoreceptors contribute only 10–20% of the steady-state response However, the response comes from the arterial chemoreceptors when

rapid changes in arterial Pco

2 occur, that is, the central ceptors may be mainly responsible for establishing the resting ventilatory level but the arterial chemoreceptors are more important in short-term transient responses to carbon dioxide

chemore-Both the arterial and central chemoreceptors likely respond to

hydrogen ion concentration, not Pco

2 Of course, they are ally very closely related in the body, so it is difficult to distin-guish their effects

usu-There may be other sensors for carbon dioxide in the body that may influence the control of ventilation Chemoreceptors within the pulmonary circulation or airways have been pro-posed but have not as yet been substantiated or localized

THE RESPONSE TO HYDROGEN IONS

Ventilation increases nearly linearly with changes in hydrogen ion concentration over the range of 20–60 nEq/L (nmol/L), as shown in Figure 38–7 A metabolic acidosis of nonbrain origin results in hyperpnea coming entirely from the peripheral chemoreceptors Hydrogen ions cross the blood–brain barrier too slowly to affect the central chemoreceptors initially Aci-dotic stimulation of the peripheral chemoreceptors increases

alveolar ventilation, and the arterial Pco

2 decreases Because

the cerebrospinal fluid Pco

2 is in a sort of dynamic equilibrium

with the arterial Pco

2, carbon dioxide diffuses out of the

cere-brospinal fluid and the pH of the cerecere-brospinal fluid increases,

thus decreasing stimulation of the central chemoreceptor If the situation lasts a long time (hours to days), the bicarbonate concentration of the cerebrospinal fluid decreases slowly, returning the pH of the cerebrospinal fluid toward the normal 7.32 The mechanism by which this occurs is not completely agreed on It may represent the slow diffusion of bicarbonate ions across the blood–brain barrier, active transport of bicar-bonate ions out of the cerebrospinal fluid, or decreased forma-tion of bicarbonate ions by carbonic anhydrase as the cerebrospinal fluid is formed

Similar mechanisms must alter the bicarbonate tion in the cerebrospinal fluid in the chronic respiratory aci-dosis of chronic obstructive lung disease because the pH of the cerebrospinal fluid is nearly normal In this case, the cere-brospinal fluid concentration of bicarbonate increases nearly proportionately to its increased concentration of carbon dioxide

concentra-BRAIN TISSUE

Blood-brain bar rier

Blood-brain bar

rier Metabolic

CO2production

H 

H 

Central Chemoreceptor

HCO 3

HCO 3

Dilates Dilates

CSF:

pH  7.32

PCO

2  50 mm Hg Little protein

Arterial blood:

pH  7.40

PCO

2  40 mm Hg Protein Buffers

Smooth muscle Smooth muscle

bicarbonate (HCO 3 ) ions in the arterial blood and cerebrospinal fluid (CSF) CO2 crosses the blood–brain barrier easily; H + and HCO3 do not

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

hydrogen ion concentration (Modified with permission from Levitzky MG:

Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

THE RESPONSE TO HYPOXIA

The ventilatory response to hypoxia arises solely from the

periph-eral chemoreceptors The carotid bodies are much more

impor-tant in this response than are the aortic bodies In the absence of

the peripheral chemoreceptors, the effect of increasing degrees of

hypoxia is a progressive direct depression of the central

respira-tory controller Therefore, when the peripheral chemoreceptors

are intact, their excitatory influence on the central respiratory

controller must offset the direct depressant effect of hypoxia

The response of the respiratory system to hypoxia is shown

in Figure 38–8 The figure shows that at a normal arterial Pco

2

of about 38–40 mm Hg, there is very little increase in

ventila-tion until the arterial Po

2 decreases below about 50–60 mm Hg

The response to hypoxia is potentiated at higher arterial Pco

2.Experiments have shown that the respiratory response to

hypoxia is related to the change in Po

2 rather than the change

in oxygen content Hypoxia alone, by stimulating alveolar

ventilation, causes a decrease in arterial Pco

2, which may lead

to respiratory alkalosis This will be discussed in Chapter 71

Th e respiratory control system functions as a negative-feedback

■

system; arterial Po2, Pco2, and pH and cerebrospinal fl uid Pco2

and pH are the regulated variables.

Th e increases in alveolar ventilation in response to increases

■

in arterial Pco2 and hydrogen ion concentrations are nearly linear within their normal ranges; the increase in alveolar

ventilation in response to decreases in arterial Po2 is small

near the normal range and very large when the Po

2 falls below 50–60 mm Hg.

The arterial chemoreceptors rapidly respond to changes in

different levels of arterial PCO

2 (Modified with permission from Levitzky MG:

Pulmonary Physiology, 7th ed New York: McGraw-Hill Medical, 2007.)

CLINICAL CORRELATION

A 14-year-old girl forgot her prescription drug on a

week-end sleepover party at her friweek-end’s house She arrives in the

emergency department lethargic, confused, and

disori-ented She has vomited twice and says she is thirsty and her stomach hurts The symptoms developed gradually over-night Her heart rate is 110/min, her blood pressure is 95/75 mm Hg, and her respiratory rate is 22/min with obvious large tidal volumes Her blood glucose is very

high at 450 mg/dL, her arterial Po

2 is slightly increased at

105 mm Hg, her arterial Pco

2 is 20 mm Hg (normal range 35–45 mm Hg), and her arterial pH is 7.15 (normal range 7.35–7.45) Her bicarbonate concentration is 15 mEq/L (normal range 22–26 mEq/L) and her anion gap is 22 mEq/L (normal range 8–16 mEq/L)

The patient has type 1 diabetes mellitus; she is in

dia-betic ketoacidosis (see Chapter 66) The drug she did not

bring with her is insulin; as a result, her blood glucose

concentration is very high and she is producing ketone bodies (see Chapter 66) Nausea, vomiting, abdominal

pain, and confusion are common symptoms and signs of diabetes mellitus, as will be discussed in Sections 7 and 9

Hydrogen ions from the ketone bodies, which are acids, have been buffered by bicarbonate and have been exhaled

as carbon dioxide, explaining the low bicarbonate tration and the elevated anion gap (see Chapter 37) The

concen-hydrogen ions are stimulating her arterial tors causing her to hyperventilate, as shown by her low

chemorecep-arterial Pco

2 Her central chemoreceptors are not

contrib-uting to the hyperventilation because the hydrogen ions

do not cross her blood–brain barrier and therefore cannot stimulate them (Figure 38–6); it is likely that her central chemoreceptors have decreased activity because as she

hyperventilates her cerebrospinal fluid Pco

2 decreases and her cerebrospinal fluid pH increases Her acid–base disor-

der can be described as a primary metabolic acidosis, with increased anion gap, with a secondary respiratory

alkalosis.

STUDY QUESTIONS

1 The ventral respiratory groups

A) are located in the nucleus of the tractus solitarius.

B) include the pacemaker for breathing.

C) consist solely of inspiratory neurons.

D) consist solely of expiratory neurons.

E) all of the above.

2 Which of the following conditions would be expected to

stimulate the central chemoreceptors?

A) mild anemia

B) severe exercise

C) hypoxia due to ascent to high altitude D) acute airway obstruction

E) all of the above

3 Stimulation of which of the following receptors should result in decreased ventilation?

A) aortic chemoreceptors B) carotid chemoreceptors C) central chemoreceptors D) Hering–Breuer infl ation (stretch) receptors E) all of the above

4 Which of the following would be expected to increase the ventilatory response to carbon dioxide, shifting the CO2response curve to the left?

A) barbiturates

C) slow-wave sleep D) deep anesthesia E) all of the above

function of the granular cells.

List the individual tubular segments in order; state the segments that

■

comprise the proximal tubule, Henle’s loop, and the collecting duct system;

define principal cells and intercalated cells

Define the basic renal processes: glomerular filtration, tubular reabsorption,

■

and tubular secretion

Define renal metabolism of a substance and give examples

■

Renal Functions, Basic

Processes, and Anatomy

FUNCTIONS

The kidneys perform a number of essential functions that go

far beyond their well-known role of eliminating waste This

chapter describes these functions and presents an overview of

how the kidneys perform them Ensuing chapters develop

more detail of the mechanisms involved

FUNCTION 1: REGULATION OF WATER AND ELECTROLYTE BALANCE

The balance concept states that our bodies are in balance for

any substance when the inputs and outputs of that substance are matched (see Figure 1–4) The kidneys vary the output of water and an array of electrolytes and other substances in close pace with their input, thereby keeping the body content of those sub-stances nearly constant, that is, in balance As an example, our input of water is enormously variable and is only sometimes

driven in response to body needs We drink water when thirsty,

but we also drink water because it is a component of beverages

that we consume for reasons other than hydration In addition,

solid food often contains large amounts of water The kidneys

respond by varying the output of water in the urine, thereby

maintaining balance for water (i.e., constant total body water

content) Similarly, electrolytes such as sodium, potassium, and

magnesium are components of foods and generally present far

in excess of body needs As with water, the kidneys excrete

elec-trolytes at a highly variable rate that, in the aggregate, matches

input One of the amazing feats of the kidneys is their ability to

regulate each of these minerals independently (i.e., we can be

on a sodium, low-potassium diet or low-sodium,

high-potassium diet, and the kidneys adjust excretion of each of these

substances appropriately) The reader should be aware that

being in balance does not by itself imply a normal state or good

health A person may have an excess or deficit of a substance, yet

still be in balance so long as output matches input This is often

the case in chronic disorders of renal function or metabolism

FUNCTION 2: REGULATION OF

ACID–BASE BALANCE

Acids and bases enter the body fluids via ingestion and from

metabolic processes The body has to excrete acids and bases

to maintain balance, and it also has to regulate the

concentra-tion of free hydrogen ions (pH) within a limited range The

kidneys accomplish both tasks by a combination of

elimina-tion and synthesis These interrelated tasks are among the

most complicated aspects of renal function and will be explored

thoroughly in Chapter 47

FUNCTION 3: EXCRETION OF

METABOLIC WASTE AND BIOACTIVE

SUBSTANCES

Our bodies continuously form the end products of metabolic

processes that for the most part serve no function and are

harmful at high concentrations; thus, they must be excreted at

the same rate they are produced These include urea (from

protein), uric acid (from nucleic acids), creatinine (from

mus-cle creatine), and the end products of hemoglobin breakdown

(which give urine much of its color) In addition, the kidneys

participate with the liver in removing drugs, hormones, and

foreign substances Clinicians have to be mindful of how fast

drugs are excreted in order to prescribe a dose that achieves

the appropriate body levels

FUNCTION 4: REGULATION OF

ARTERIAL BLOOD PRESSURE

Although most people appreciate that the kidneys excrete waste

substances such as urea (hence the name urine) and salts, few

realize the kidneys’ crucial role in controlling blood pressure (BP) BP ultimately depends on blood volume, and the kidneys’

maintenance of sodium and water balance achieves regulation of blood volume Thus, through volume control, the kidneys par-ticipate in BP control They also participate in direct regulation

of BP via the generation of vasoactive substances that regulate smooth muscle in the peripheral vasculature

FUNCTION 5: REGULATION OF RED BLOOD CELL PRODUCTION

Erythropoietin is a peptide hormone that is involved in the

con-trol of erythrocyte (red blood cell) production by the bone row Its major source is the kidneys, although the liver also secretes small amounts The renal cells that secrete it are a particular group

mar-of cells in the interstitium The stimulus for its secretion is a reduction in the partial pressure of oxygen in the kidneys, as occurs, for example, in anemia, arterial hypoxia (see Chapter 71), and inadequate renal blood flow Erythropoietin stimulates the bone marrow to increase its production of erythrocytes Renal disease may result in diminished erythropoietin secretion, and the ensuing decrease in bone marrow activity is one important causal factor of the anemia of chronic renal disease

FUNCTION 6: REGULATION OF VITAMIN D PRODUCTION

When we think of vitamin D, we often think of sunlight or

additives to milk In vivo vitamin D synthesis involves a series of biochemical transformations, the last of which

occurs in the kidneys The active form of vitamin D

(1,25-dihydroxyvitamin D) is actually made in the kidneys,

and its rate of synthesis is regulated by hormones that control calcium and phosphate balance that will be discussed in detail in Chapter 64

FUNCTION 7: GLUCONEOGENESIS

Our central nervous system is an obligate user of blood glucose regardless of whether we have just eaten sugary doughnuts or gone without food for a week Whenever the intake of carbo-hydrate is stopped for much more than half a day, our body

begins to synthesize new glucose (the process of esis) from noncarbohydrate sources (amino acids from protein

gluconeogen-and glycerol from triglycerides) Most gluconeogenesis occurs

in the liver (see Chapters 66 and 69), but a substantial fraction occurs in the kidneys, particularly during a prolonged fast

OVERVIEW OF RENAL PROCESSES

Most of what the kidneys do to perform these various functions

is, at least conceptually, fairly straightforward Of the able volume of plasma entering the kidneys each minute, they

consider-transfer (by filtration) about one fifth of it, minus the larger

pro-teins, into the renal tubules and then selectively reabsorb varying

fractions of the filtered substances back into the blood, leaving

the unreabsorbed portions to be excreted In some cases

addi-tional amounts are added by secretion or synthesis In essence,

the renal tubules operate like assembly lines; they accept the fluid

coming into them, perform some segment-specific modification

of the fluid, and send it on to the next segment

ANATOMY OF THE KIDNEYS

AND URINARY SYSTEM

The kidneys lie just under the rib cage on each side of the

ver-tebral column, behind the peritoneal cavity and in front of the

major back muscles (Figure 39–1) Each of the two kidneys is

a bean-shaped structure about the size of a fist, with the

rounded, outer convex surface of each kidney facing the side

of the body, and the indented surface, called the hilum, facing

the spine Each hilum is penetrated by blood vessels, nerves,

and a ureter, which carries urine out of the kidney to the

blad-der Each ureter is formed from funnel-like structures called

major calyces, which, in turn, are formed from minor calyces

(Figure 39–2) The minor calyces fit over underlying

cone-shaped renal tissue called pyramids The tip of each pyramid

is called a papilla and projects into a minor calyx The calyces

act as collecting cups for the urine formed by the renal tissue

in the pyramids The pyramids are arranged radially around

the hilum, with the papillae pointing toward the hilum and the

broad bases of the pyramids facing the outside, top, and

bot-tom of the kidney The pyramids constitute the medulla of the kidney Overlying the medullary tissue is a cortex, and cover-

ing the cortical tissue on the very external surface of the ney is a thin connective tissue capsule

kid-The working tissue mass of both the cortex and medulla is constructed almost entirely of tubules (nephrons and collect-ing tubules) and blood vessels (mostly capillaries and capil-larylike vessels) In the cortex, tubules and blood vessels are intertwined randomly, something like a plateful of spaghetti

In the medulla, they are arranged in parallel arrays like dles of sticks In both cases, blood vessels and tubules are always close to each other Between the tubules and blood ves-

bun-sels lies the interstitium, which comprises less than 10% of the

renal volume The interstitium contains a small amount of fluid and scattered interstitial cells (fibroblasts and others) that synthesize an extracellular matrix of collagen, proteogly-cans, and glycoproteins

It is important to realize that the cortex and medulla have very different properties both structurally and functionally On close examination, we see that (1) the cortex has a highly gran-ular appearance, absent in the medulla, and (2) each medullary pyramid is divisible into an outer zone (adjacent to the cortex) and an inner zone, which includes the papilla All these distinc-tions reflect the different arrangement of the various tubules and blood vessels in the different regions of the kidney

THE NEPHRON

Each kidney contains approximately 1 million nephrons, one

of which is shown diagrammatically in Figure 39–3 Each nephron begins with a spherical filtering component, called

the renal corpuscle, followed by a long tubule leading out of it

that continues until it merges with the tubules of other

nephrons to form collecting ducts, which are themselves long

Kidney

Ureter

Bladder

Urethra Diaphragm

location of the kidneys below the diaphragm and well above the

bladder, which is connected to the kidneys via the ureters

(Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human

Physiology, 11th ed McGraw-Hill, 2008.)

(Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical

Physiology New York: McGraw-Hill, 2009.)

tubes Collecting ducts eventually merge with others in the

renal papilla to form a ureter that conveys urine to the bladder

(Figure 39–3)

THE RENAL CORPUSCLE

The renal corpuscle is a hollow sphere (Bowman’s capsule)

filled with a compact tuft of interconnected capillary loops,

the glomerulus (plural glomeruli) (Figure 39–4a) Blood

enters the capillaries inside Bowman’s capsule through an

afferent arteriole that penetrates the surface of the capsule at

one side, called the vascular pole Blood then leaves the

capil-laries through a nearby efferent arteriole on the same side

The space within Bowman’s capsule not occupied by the

glom-erulus is called the urinary space or Bowman’s space, and it is

into this space that fluid filters from the glomerular capillaries

before flowing into the first portion of the tubule, located

opposite the vascular pole

The structure and properties of the filtration barrier that

separates plasma in the glomerular capillaries from fluid in

urinary space are crucial for renal function and will be

described thoroughly in the next chapter For now, we note

simply that the functional significance of the filtration barrier

is that it permits the filtration of large volumes of fluid from

the capillaries into Bowman’s space, but restricts filtration of

large plasma proteins such as albumin

Another cell type—the mesangial cell—is found in close

association with the capillary loops of the glomerulus

Glomerular mesangial cells act as phagocytes and remove

trapped material from the basement membrane They also

contain large numbers of myofilaments and can contract in

response to a variety of stimuli in a manner similar to

vascu-lar smooth muscle cells The role of such contraction in

influencing filtration by the renal corpuscles is discussed in

Chapters 40 and 45

THE TUBULE

Throughout its course, the tubule, which begins at and leads out

of Bowman’s capsule, is made up of a single layer of epithelial cells resting on a basement membrane and connected by tight junctions that physically link the cells together (like the plastic form that holds a six pack of soft drinks together) Table 39–1 lists the names and sequence of the various tubular segments, as illustrated in Figure 39–5 Physiologists and anatomists have traditionally grouped two or more contiguous tubular segments for purposes of reference, but the terminologies have varied considerably Table 39–1 also gives the combination terms used

to the cortical surface of the kidney

The next segment is the descending thin limb of the loop

of Henle (or simply the descending thin limb) The

descend-ing thin limbs of different nephrons penetrate into the medulla

to varying depths, and then abruptly reverse at a hairpin turn and begin an ascending portion of the loop of Henle parallel to the descending portion In long loops (depicted on the left side of Figure 39–5) the epithelium of the first portion of the ascending limb remains thin, although different functionally from that of the descending limb This segment is called the

ascending thin limb of Henle’s loop, or simply the ascending thin limb (see Figure 39–5) Further up the ascending portion

the epithelium thickens, and this next segment is called the

thick ascending limb of Henle’s loop, or simply the thick ascending limb In short loops (depicted on the right side of

Figure 39–5) there is no ascending thin portion, and the thick ascending portion begins right at the hairpin loop The thick ascending limb rises back into the cortex to the very same Bowman’s capsule from which the tubule originated Here it passes directly between the afferent and efferent arterioles at

Cortical collecting duct Thick

ascending limb Thin

descending

limb

Thin ascending limb

Proximal

tubule

Bowman’s capsule

Afferent arteriole Macula

densa

Distal tubule

Medullary collecting duct

permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology New York:

McGraw-Hill, 2009.)

TABLE 39–1 Terminology for the tubular segments.

Sequence of Segments

Combination Terms Used in Text

Proximal convoluted tubule Proximal straight tubule

Proximal tubule

Descending thin limb of Henle’s loop Ascending thin limb of Henle’s loop Thick ascending limb of Henle’s loop (contains macula densa near end)

Henle’s loop

Distal convoluted tubule Connecting tubule Cortical collecting duct Outer medullary collecting duct Inner medullary collecting duct (last portion

is papillary duct)

Collecting duct system

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,

7th ed New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub Division, 2009.

Basement membrane

Movement

of filtrate

Fenestra Capillary lume

Endothelium n

Foot processes Capsular space

Filtration slits

Cell processes Podocyte (visceral layer

of Bowman's capsule) Cell body

Glomerular capillary (cut)

Afferent arteriole

Efferent arteriole

Proximal tubule

Visceral layer (podocyte) Parietal layer

Capillary

Renal corpuscle

Bowman's capsule Glomerular capillary (covered by visceral layer)

Filtration slits

Fenestrae

Juxtaglomerular

apparatus

Juxtaglomerular cells

Macula densa

Distal tubule

(c)

(b) (a)

Substances in the blood are filtered through capillary fenestrae between endothelial cells (single layer) The filtrate then passes across the basement membrane and through slit pores between the foot processes (also called pedicels) and enters the capsular space From here, the filtrate is transported to the lumen

of the proximal convoluted tubule.

Podocytes of Bowman’s capsule surround the capillaries Filtration slits between the podocytes allow fluid to pass into Bowman’s capsule The glomerulus is composed of capillary endothelium that is fenestrated

Surrounding the endothelial cells is

a basement membrane.

Blood flows into the glomerulus through the afferent arterioles and leaves the glomerulus through the efferent arterioles The proximal tubule exits Bowman’s capsule.

a.

b.

c.

c) Transmission EM of the filtration barrier (Reproduced with permission from Daniel Friend from William Bloom and Don Fawcett, Textbook of Histology, 10th ed

W.B Saunders Co 1975.)

the point where they enter and exit the renal corpuscle at its

vascular pole (see Figure 39–4a) The cells in the thick

ascend-ing limb closest to Bowman’s capsule (between the afferent

and efferent arterioles) are a group of specialized cells known

as the macula densa (see Figure 39–6) The macula densa

marks the end of the thick ascending limb and the beginning

of the distal convoluted tubule This is followed by the

con-necting tubule, which leads to the cortical collecting tubule,

the first portion of which is called the initial collecting tubule

From Bowman’s capsule to the proximal tubule, loop of Henle, distal tubule, and initial collecting tubules, each of the

1 million nephrons in each kidney is completely separate from the others However, connecting tubules from several nephrons merge to form cortical collecting tubules, and a number of ini-

Peritubular capillaries

Efferent arteriole Afferent arteriole

Distal convoluted tubule

Proximal convoluted tubule

M e d u l l a

Cortical collecting duct

Renal corpuscle

Bowman’s capsule Glomerulus Macula densa

Corticomedullary junction

Descending limb Thick segment of ascending limb

Thin segment of ascending limb

juxtamedullary nephron with its renal corpuscle located just above the corticomedullary border (left side of figure) and a cortical nephron with

its renal corpuscle higher in the cortex (right side of figure) Cortical nephrons have efferent arterioles that give rise to peritubular capillaries, and

they have short loops of Henle In contrast, juxtamedullary nephrons have efferent arterioles that descend into the medulla to form vasa recta,

and they have long loops of Henle. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed McGraw-Hill, 2008.)

tial collecting tubules then join end to end or side to side to

form larger cortical collecting ducts All the cortical collecting

ducts then run downward to enter the medulla and become

outer medullary collecting ducts, and then inner medullary

collecting ducts The latter merge to form several hundred large

ducts, the last portions of which are called papillary collecting

ducts, each of which empties into a calyx of the renal pelvis

Each renal calyx is continuous with the ureter, which empties

into the urinary bladder, where urine is temporarily stored and

from which it is intermittently eliminated The urine is not

altered after it enters a calyx From this point on, the remainder

of the urinary system serves only to maintain the composition

of the tubular fluid established by the kidney

Up to the distal convoluted tubule, the epithelial cells

form-ing the wall of a nephron in any given segment are

homoge-neous and distinct for that segment For example, the thick

ascending limb contains only thick ascending limb cells

How-ever, beginning in the second half of the distal convoluted

tubule, two cell types are found intermingled in most of the

remaining segments One type constitutes the majority of cells

in the particular segment, is considered specific for that

seg-ment, and is named accordingly: distal convoluted tubule cells,

connecting tubule cells, and collecting duct cells, the last

known more commonly as principal cells Interspersed among

the segment-specific cells in each of these three segments are

individual cells of the second type, called intercalated cells

The last portion of the medullary collecting duct contains ther principal cells nor intercalated cells but is composed

nei-entirely of a distinct cell type called the inner medullary lecting duct cells.

col-THE JUXTAGLOMERULAR APPARATUS

Reference was made earlier to the macula densa, a portion of the late thick ascending limb at the point where this segment comes between the afferent and efferent arterioles at the vascular pole of the renal corpuscle from which the tubule arose This entire area is

known as the juxtaglomerular apparatus (JG) (see Figure 39–6),

which, as will be described later, plays a very important signaling

function (Do not confuse the term JG with juxtamedullary nephron, meaning a nephron with a glomerulus located close to

the cortical–medullary border.) Each JG apparatus is made up of

the following three cell types: (1) granular cells (called

juxtaglom-erular cells in Figure 39–6), which are differentiated smooth

mus-cle cells in the walls of the afferent arterioles; (2) extraglomerular mesangial cells; and (3) macula densa cells, which are specialized

thick ascending limb epithelial cells

The granular cells are named because they contain secretory vesicles that appear granular in light micrographs These granules

contain the hormone renin (pronounced REE-nin) As we will

describe in Chapter 45, renin is a crucial substance for control of renal function and systemic BP The extraglomerular mesangial cells are morphologically similar to and continuous with the glomerular mesangial cells, but lie outside Bowman’s capsule The macula densa cells are detectors of the composition of the fluid within the nephron at the very end of the thick ascending limb

and contribute to the control of glomerular filtration rate (GFR—see below) and to the control of renin secretion.

BASIC RENAL PROCESSES

The working structures of the kidney are the nephrons and collecting tubules into which the nephrons drain Figure 39–7 illustrates the meaning of several keywords that we use to describe how the kidneys function It is essential that any stu-dent of the kidney grasp their meaning

Filtration is the process by which water and solutes in the

blood leave the vascular system through the filtration barrier and enter Bowman’s space (a space that is topologically out-

side the body) Secretion is the process of moving substances

into the tubular lumen from the cytosol of epithelial cells that form the walls of the nephron Secreted substances may originate by synthesis within the epithelial cells or, more often, by crossing the epithelial layer from the surrounding

renal interstitium Reabsorption is the process of moving

substances from the lumen across the epithelial layer into the surrounding interstitium In most cases, reabsorbed sub-stances then move into surrounding blood vessels, so that

Sympathetic nerve fiber Podocytes

Juxtaglomerular cells

Afferent arteriole Efferent arteriole

Smooth muscle cells

Mesangial cells

apparatus It is made up of (1) juxtaglomerular cells (granular cells),

which are specialized smooth muscle cells surrounding the afferent

arteriole, (2) extraglomerular mesangial cells, and (3) cells of the macula

densa, which are part of the tubule The close proximity of these

components to each other permits chemical mediators released from

one cell to easily diffuse to other components Note that sympathetic

nerve fibers innervate the granular cells (Reproduced with permission from

Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed McGraw-Hill, 2008.)

the term reabsorption implies a two-step process of removal

from the lumen followed by movement into the blood

Excre-tion means exit of the substance from the body (i.e., the

sub-stance is present in the final urine produced by the kidneys)

Synthesis means that a substance is constructed from

molec-ular precursors, and catabolism means the substance is

bro-ken down into smaller component molecules The renal

handling of any substance consists of some combination of

these processes

GLOMERULAR FILTRATION

Urine formation begins with glomerular filtration, the bulk

flow of fluid from the glomerular capillaries into Bowman’s

capsule The glomerular filtrate (i.e., the fluid within

Bow-man’s capsule) is very much like blood plasma, but contains

very little total protein because the large plasma proteins such

as albumin and the globulins are virtually excluded from

mov-ing through the filtration barrier Smaller proteins, such as

many of the peptide hormones, are present in the filtrate, but

their mass in total is miniscule compared with the mass of

large plasma proteins in the blood The filtrate contains most

inorganic ions and low-molecular-weight organic solutes in

virtually the same concentrations as in the plasma Substances

that are present in the filtrate at the same concentration as

found in the plasma are said to be freely filtered (Note that

freely filtered does not mean all filtered It just means that the

amount filtered is in exact proportion to the fraction of plasma

volume that is filtered.) Many low-molecular-weight

compo-nents of blood are freely filtered Among the most common

substances included in the freely filtered category are the ions

sodium, potassium, chloride, and bicarbonate; the uncharged

organics glucose and urea; amino acids; and peptides such as insulin and antidiuretic hormone (ADH)

The volume of filtrate formed per unit time is known as the

glomerular filtration rate (GFR) In a healthy young adult

male, the GFR is an incredible 180 L per day (125 mL/min)!

Contrast this value with the net filtration of fluid across all the other capillaries in the body: approximately 4 L per day The implications of this huge GFR are extremely important When

we recall that the average total volume of plasma in humans is approximately 3 L, it follows that the entire plasma volume is filtered by the kidneys some 60 times a day The opportunity

to filter such huge volumes of plasma enables the kidneys to excrete large quantities of waste products and to regulate the constituents of the internal environment very precisely One of the general consequences of healthy aging as well as many kid-ney diseases is a reduction in the GFR

TUBULAR REABSORPTION AND TUBULAR SECRETION

The volume and composition of the final urine are quite ferent from those of the glomerular filtrate Clearly, almost all the filtered volume must be reabsorbed; otherwise, with a filtration rate of 180 L per day, we would urinate ourselves into dehydration very quickly As the filtrate flows from Bow-man’s capsule through the various portions of the tubule, its composition is altered, mostly by removing material (tubular reabsorption) but also by adding material (tubular secretion)

dif-As described earlier, the tubule is, at all points, intimately associated with the vasculature, a relationship that permits rapid transfer of materials between the capillary plasma and the lumen of the tubule via the interstitial space

Most of the tubular transport consists of reabsorption rather than tubular secretion An idea of the magnitude and impor-tance of tubular reabsorption can be gained from Table 39–2, which summarizes data for a few plasma components that undergo reabsorption The values in Table 39–2 are typical for

a healthy person on an average diet There are at least three important generalizations to be drawn from this table:

1 Because of the huge GFR, the quantities filtered per day are enormous, generally larger than the amounts of the substances in the body For example, the body contains about 40 L of water, but the volume of water filtered each day may be as large as 180 L

2 Reabsorption of waste products, such as urea, is partial, so that large fractions of their filtered amounts are excreted

in the urine

3 Reabsorption of most “useful” plasma components (e.g., water, electrolytes, and glucose) is either complete (e.g., glucose) or nearly so (e.g., water and most elec-trolytes), so that little, if any, of the filtered amounts are excreted in the urine

For each plasma substance, a particular combination of tration, reabsorption, and secretion applies The relative pro-

fil-Artery

Afferent arteriole

Glomerular capillary

Efferent arteriole

Bowman’s

space

Tubule

Peritubular capillary Vein Urinary

excretion 3

2 1

1 Glomerular filtration

2 Tubular secretion

3 Tubular reabsorption

glomerular filtration, tubular secretion, and tubular

reabsorption—and the association between the tubule and

vasculature in the cortex (Reproduced with permission from Widmaier EP,

Raff H, Strang KT: Vander’s Human Physiology, 11th ed McGraw-Hill, 2008.)

portions of these processes then determine the amount excreted

A critical point is that the rates of these processes are subject to

physiological control By triggering changes in the rates of

filtration, reabsorption, or secretion when the body content of

a substance goes above or below normal, these mechanisms

regulate excretion to keep the body in balance For example,

consider what happens when a person drinks a large quantity of

water: Within 1–2 hours, all the excess water has been excreted

in the urine, partly as the result of an increase in GFR but

mainly as the result of decreased tubular reabsorption of water

The body is kept in balance for water by increasing excretion

By keeping the body in balance, the kidneys serve to maintain

body water concentration within very narrow limits

METABOLISM BY THE TUBULES

Although renal physiologists traditionally list glomerular

filtration, tubular reabsorption, and tubular secretion as the

three basic renal processes, we cannot overlook metabolism by

the tubular cells The tubular cells extract organic nutrients

from the glomerular filtrate or peritubular capillaries and

metabolize them as dictated by the cells’ own nutrient

require-ments In so doing, the renal cells are behaving no differently

from any other cells in the body In addition, there are other

metabolic transformations performed by the kidney that are

directed toward altering the composition of the urine and

plasma The most important of these are gluconeogenesis,

and the synthesis of ammonium from glutamine and the

pro-duction of bicarbonate, both described in Chapter 47

REGULATION OF RENAL FUNCTION

By far the most complex feature of renal physiology is

regula-tion of renal processes, details of which will be presented in

later chapters Neural signals, hormonal signals, and

intrare-nal chemical messengers combine to regulate the processes

described above in a manner to help the kidneys meet the

needs of the body Neural signals originate in the sympathetic

celiac plexus (see Chapter 19) These sympathetic neural

sig-nals exert major control over renal blood flow, glomerular

fil-tration, and the release of vasoactive substances that affect

both the kidneys and the peripheral vasculature Hormonal

signals originate in the adrenal gland, pituitary gland, and

heart The adrenal cortex secretes the steroid hormones terone and cortisol, and the adrenal medulla secretes the cat- echolamines epinephrine and norepinephrine All of these

aldos-hormones, but mainly aldosterone, are regulators of sodium and potassium excretion by the kidneys The posterior pitu-

itary gland secretes the hormone arginine vasopressin (AVP, also called antidiuretic hormone [ADH]) ADH is a major

regulator of water excretion, and, via its influence on the renal vasculature and possibly collecting duct principal cells, prob-ably sodium excretion as well The heart secretes hormones—

natriuretic peptides—that increase sodium excretion by the

kidneys The least understood aspect of regulation lies in the

realm of intrarenal chemical messengers (i.e., messengers that

originate in one part of the kidney and act in another part) It

is clear that an array of substances (e.g., nitric oxide, gic agonists, superoxide, eicosanoids) influence basic renal processes, but, for the most part, the specific roles of these substances are not well understood

puriner-OVERVIEW OF REGIONAL FUNCTION

We conclude this chapter with a broad overview of the tasks performed by the individual nephron segments Later, we examine renal function substance by substance and see how tasks performed in the various regions combine to produce an overall result that is useful for the body

The glomerulus is the site of filtration—about 180 L per day

of volume and proportional amounts of solutes that are freely filtered, which is the case for most solutes (large plasma pro-teins are an exception) The glomerulus is where the greatest

mass of excreted substances enters the nephron The proximal tubule (convoluted and straight portions) reabsorbs about

two thirds of the filtered water, sodium, and chloride The

proximal convoluted tubule reabsorbs all of the useful organic

molecules that the body conserves (e.g., glucose, amino acids)

It reabsorbs significant fractions, but by no means all, of many important ions, such as potassium, phosphate, calcium, and bicarbonate It is the site of secretion of a number of organic substances that are either metabolic waste products (e.g., uric acid, creatinine) or drugs (e.g., penicillin) that clinicians must administer appropriately to make up for renal excretion

The loop of Henle contains different segments that perform different functions, but the key functions occur in the thick ascending limb As a whole, the loop of Henle reabsorbs about

TABLE 39–2 Average values for several substances handled by fi ltration and reabsorption.

Substance Amount Filtered Per Day Amount Excreted Reabsorbed (%)

20% of the filtered sodium and chloride and 10% of the

fil-tered water A crucial consequence of these different

propor-tions is that, by reabsorbing relatively more salt than water, the

luminal fluid becomes diluted relative to normal plasma and

the surrounding interstitium During periods when the

kid-neys excrete dilute final urine, the role of the loop of Henle in

diluting the luminal fluid is crucial

The end of the loop of Henle contains cells of the macula

densa, which sense the sodium and chloride content of the

lumen and generate signals that influence other aspects of

renal function, specifically the renin–angiotensin system

(discussed in Chapter 45) The distal tubule and connecting

tubule together reabsorb some additional salt and water,

per-haps 5% of each The cortical collecting tubule is where

sev-eral (6–10) connecting tubules join to form a single tubule

Cells of the cortical collecting tubule are strongly responsive to

and are regulated by the hormones aldosterone and ADH

Aldosterone enhances sodium reabsorption and potassium

secretion by this segment, and ADH enhances water

reabsorp-tion The degree to which these processes are stimulated or

not stimulated plays a major role in regulating the amount of

solutes and water present in the final urine With large amounts

of ADH present, most of the water remaining in the lumen is

reabsorbed, leading to concentrated, low-volume urine With

little ADH present, most of the water passes on to the final

urine, producing dilute, high-volume urine

The medullary collecting tubule continues the functions

of the cortical collecting tubule in salt and water

reabsorp-tion In addition, it plays a major role in regulating urea

reab-sorption and in acid–base balance (secretion of protons or

bicarbonate)

CHAPTER SUMMARY

The role of the kidneys in the body includes many functions

■

that go well beyond simple excretion of waste.

A major function of the kidneys is to regulate the excretion of

■

substances at a rate that, on average, exactly balances their input into the body, and thereby maintains appropriate body content of many substances.

Another major function of the kidneys is to regulate blood

and closely associated blood vessels.

Each functional renal unit is composed of a filtering

A 57-year-old woman with type 2 diabetes mellitus has

managed her condition quite well via dietary control and

has been in good health otherwise Lately, however, she

has been feeling increasingly fatigued and so schedules a

checkup with her primary care physician (PCP) No

remarkable physical signs are noted, except that her BP is

increased at 137/92 mm Hg Analysis of her blood shows

a slightly increased fasting blood glucose of 117 mg/dL

and a low normal hematocrit of 36% Her PCP reminds

her to be extra careful about diet in terms of salt and sugar,

and suggests supplemental iron to maintain her

hemoglo-bin She schedules another checkup in 6 months

The fatigue worsens over the next 6 months, and she

suf-fers a bone fracture after a seemingly minor fall At the

6-month checkup her fasting blood glucose is 121 mg/dL,

and hematocrit is decreased to 29% BP is 135/95 mm Hg

Her PCP orders additional blood tests and a bone density

scan out of concern for possible loss of bone mineral

(osteoporosis) New blood test results reveal elevated levels

of several waste substances, indicative of a decreased GFR

The evidence strongly points to chronic renal failure, and she is referred to a nephrologist for evaluation and treatment

Chronic renal failure that has reached the point of significant

renal dysfunction is called end-stage renal disease (ESRD) It

is the consequence of major loss of functional tissue mass (nephrons and interstitial tissue) One of the common causes

of ESRD is diabetes mellitus Chronic hyperglycemia causes

the formation of glycosylated proteins that deposit in the glomerular filtration apparatus This interferes with filtration function and leads to pathology of glomerular cells Hyper-tension can be both a cause and an effect of ESRD The two normal kidneys have a considerable reserve capacity Patients can do perfectly well with just one kidney, and ESRD may progress to a considerable degree before symptoms appear

When enough nephrons are lost, function declines, although some functions are preserved better than others; thus, symp-toms do not develop uniformly Another problem in ESRD is decreased production of erythropoietin, resulting in decreased

red blood cell production and a low hematocrit The anemia

and possible accumulations of toxic substances due to the low GFR may account for the fatigue A more complex problem

in ESRD involves phosphorus, calcium, and bone As renal function is lost, the ability to excrete phosphate declines and plasma phosphate rises, in turn leading to excessive loss of calcium The body does not replace the loss, in part because

of decreased renal production of 1,25-dihydroxyvitamin D

Treatment for ESRD includes the possibility of dialysis to make up for lost excretory function, renal transplant, and var-ious dietary controls, including adding phosphate binders to the diet to prevent accumulation of phosphate in the blood

STUDY QUESTIONS

1 Renal corpuscles are located

A) along the corticomedullary border.

B) throughout the cortex.

C) throughout the cortex and outer medulla.

D) throughout the whole kidney.

2 Relative to the number of glomeruli, how many loops of Henle

and collecting ducts are present?

A) same number of loops of Henle; same number of collecting ducts

B) fewer loops of Henle; fewer collecting ducts C) same number of loops of Henle; fewer collecting ducts D) same number of loops of Henle; more collecting ducts

3 In which of the following lists are all the named substances

synthesized in the kidneys and released into the blood?

A) insulin, renin, and glucose B) red blood cells, active vitamin D, and albumin C) renin, 1,25-dihydroxyvitamin D, and erythropoietin D) glucose, urea, and erythropoietin

4 The macula densa is a group of cells located in the wall of

A) Bowman’s capsule.

B) the afferent arteriole.

C) the end of the thick ascending limb.

D) the glomerular capillaries.

5 The volume of the ultrafiltrate of plasma entering the tubules by glomerular filtration in 1 day is typically

A) about three times the renal volume.

B) about the same as the volume filtered by all the capillaries in the rest of the body.

C) about equal to the circulating plasma volume.

D) greater than the total body fluid volume.

6 A substance known to be freely filtered has a certain concentration in the afferent arteriole What can we predict about its concentration in the efferent arteriole?

A) almost zero B) close to the value in the afferent arteriole C) about 20% lower than the value in the afferent arteriole D) we cannot predict without knowing what happens in the tubules

O B J E C T I V E S

409

Define renal blood flow, renal plasma flow, glomerular filtration rate, and

■

filtration fraction, and give normal values

State the formula relating flow, pressure, and resistance in an organ

■

Identify the successive vessels through which blood flows after leaving

■

the renal artery

Describe the relative resistances of the afferent arterioles and efferent

■

arterioles

Describe the effects of changes in afferent and efferent arteriolar resistances

■

on renal blood flow

Describe the three layers of the glomerular filtration barrier, and define

■

podocyte, foot process, and slit diaphragm

Describe how molecular size and electrical charge determine filterability

in qualitative terms, why the net filtration pressure is positive

State the reason glomerular filtration rate is so large relative to filtration

■

across other capillaries in the body

Describe how arterial pressure, afferent arteriolar resistance, and efferent

■

arteriolar resistance influence glomerular capillary pressure

Describe how changes in renal plasma flow influence average glomerular

■

capillary oncotic pressure

Define autoregulation of renal blood flow and glomerular filtration rate

■

40

RENAL BLOOD FLOW

Renal blood flow (RBF) is huge relative to the mass of the

kidneys—about 1 L/min, or 20% of the resting cardiac output

Considering that the volume of each kidney is less than 150

cm3, this means that each kidney is perfused with over three

times its total volume every minute All of this blood is

deliv-ered to the cortex A small fraction of the cortical blood flow is

then directed to the medulla Blood enters each kidney at the

hilum via a renal artery After several divisions into smaller

arteries, blood reaches arcuate arteries that course across the

tops of the pyramids between the medulla and cortex From

these, cortical radial arteries project upward toward the ney surface and give off a series of afferent arterioles, each of

kid-which leads to a glomerulus within Bowman’s capsule (see

Figure 39–5) These arteries and glomeruli are found only in

the cortex, never in the medulla In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another

set of arterioles, the efferent arterioles The efferent arterioles

soon subdivide into a second set of capillaries These are the

peritubular capillaries, which are profusely distributed

throughout the cortex The peritubular capillaries then rejoin

to form the veins by which blood ultimately leaves the kidney

Renal Blood Flow and

Glomerular Filtration

Douglas C Eaton and John P Pooler

Blood flow to the medulla is far less than cortical blood flow,

perhaps 0.1 L/min, and derives from the efferent arterioles of

glomeruli situated just above the corticomedullary border

(jux-tamedullary glomeruli) These efferent arterioles do not branch

into peritubular capillaries, but rather descend downward into

the outer medulla, where they divide many times to form

bun-dles of parallel vessels called vasa recta (Latin recta for “straight”

and vasa for “vessels”) These bundles of vasa recta penetrate

deep into the medulla (see Figure 40–1) Vasa recta on the

out-side of the vascular bundles “peel off ” and give rise to

inter-bundle plexi of capillaries that surround Henle’s loops and the

collecting ducts in the outer medulla Only the center-most vasa

recta supply capillaries in the inner medulla; thus, little blood

flows into the papilla The capillaries from the inner medulla

re-form into ascending vasa recta that run in close association

with the descending vasa recta within the vascular bundles The

structural and functional properties of the vasa recta are rather

complex, and will be elucidated further in Chapter 44

The significance of the quantitative differences between

cor-tical and medullary blood flow is the following: the high blood

flow in the cortical peritubular capillaries maintains the

inter-stitial environment of the cortical renal tubules very close in

composition to that of blood plasma throughout the body In

contrast, the low blood flow in the medulla permits an

intersti-tial environment that is quite different from blood plasma As

described in Chapter 44, the interstitial environment in the

medulla plays a crucial role in regulating water excretion

FLOW, RESISTANCE, AND BLOOD

PRESSURE IN THE KIDNEYS

Blood flow in the kidneys obeys the basic hemodynamic

prin-ciples described in Chapter 22 The basic equation for blood

flow through any organ is as follows:

Q = ΔP _

where Q is organ blood flow, ΔP the mean pressure in the artery

supplying the organ minus mean pressure in the vein draining

that organ, and R the total vascular resistance in that organ The

high RBF is accounted for by low total renal vascular resistance

The resistance is low because there are so many pathways in

parallel, that is, so many glomeruli and their associated vessels

The resistances of the afferent and efferent arterioles are

about equal in most circumstances and account for most of the

total renal vascular resistance Resistances in arteries

preced-ing afferent arterioles (i.e., cortical radial arteries) and in the

capillaries play some role also, but we concentrate on the

arte-rioles because arteriolar resistances are variable and are the

sites of regulation A change in the afferent arteriole or efferent

arteriole resistance produces the same effect on RBF because

these vessels are in series When the two resistances both

change in the same direction (the most common state of

affairs), their effects on RBF are additive When they change in

different directions—one resistance increasing and the other

decreasing—the changes offset each other

Vascular pressures (i.e., hydrostatic or hydraulic pressures) are much higher in the glomerular capillaries than in the

just above the corticomedullary border, parallel to the surface, and give rise to cortical radial (interlobular) arteries radiating toward the surface Afferent arterioles originate from the cortical radial arteries at

an angle that varies with cortical location Blood is supplied to the peritubular capillaries of the cortex from the efferent flow out of superficial glomeruli It is supplied to the medulla from the efferent flow out of juxtamedullary glomeruli Efferent arterioles of juxtamedullary glomeruli give rise to bundles of descending vasa recta

in the outer stripe of the outer medulla In the inner stripe of the outer medulla, descending vasa recta and ascending vasa recta returning from the inner medulla run side by side in the vascular bundles, allowing exchange of solutes and water as described in Chapter 44

Descending vasa recta from the bundle periphery supply the interbundle capillary plexus of the inner stripe, whereas those in the center supply blood to the capillaries of the inner medulla Contractile pericytes in the walls of the descending vasa recta regulate flow DVR, descending vasa recta; AVR, ascending vasa recta (Modified with permission from Pallone TL, Zhang Z, Rhinehart K: Physiology of the renal medullary

microcirculation Am J Physiol Renal Physiol 2003;284(2):F253–F266.)

Interlobular artery

Arcuate artery Efferent

arteriole

Vascular bundle

Interbundle plexus

H2O NaCl Urea

Inner stripe Outer stripe

peritubular capillaries As blood flows through any vascular

resistance, the pressure progressively decreases Pressure at the

beginning of a given afferent arteriole is close to mean systemic

arterial pressure (about 100 mm Hg) and decreases to about 60

mm Hg at the point where it feeds a glomerulus Because there

are so many glomerular capillaries in parallel, pressure decreases

very little during flow through those capillaries; thus,

glomeru-lar capilglomeru-lary pressure remains close to 60 mm Hg Then

pres-sure decreases again during flow through an efferent arteriole,

to about 20 mm Hg at the point where it feeds a peritubular

capillary (see Figure 40–2) The high glomerular pressure of

about 60 mm Hg is necessary to drive glomerular filtration,

whereas the low peritubular capillary pressure of 20 mm Hg is

equally necessary to permit the reabsorption of fluid

GLOMERULAR FILTRATION

FORMATION OF GLOMERULAR

FILTRATE

The glomerular filtrate contains most inorganic ions and

low-molecular-weight organic solutes in virtually the same

concen-trations as in the plasma It also contains small plasma peptides

and a very limited amount of albumin (see Chapter 43) Filtered

fluid must pass through a three-layered glomerular filtration

barrier The first layer, the endothelial cells of the capillaries, is

perforated by many large fenestrae (“windows”), like a slice of

Swiss cheese, which occupy about 10% of the endothelial surface

area They are freely permeable to everything in the blood except

cells and platelets The middle layer, the capillary basement

membrane, is a gel-like acellular meshwork of glycoproteins and

proteoglycans, with a structure like a kitchen sponge The third

layer consists of epithelial cells (podocytes) that surround the

capillaries and rest on the basement membrane The podocytes have an unusual octopuslike structure Small “fingers,” called

pedicels (or foot processes), extend from each arm of the

podo-cyte and are embedded in the basement membrane (see ure 39–4c) Pedicels from a given podocyte interdigitate with the pedicels from adjacent podocytes Spaces between adjacent pedicels constitute the path through which the filtrate, once it has passed through the endothelial cells and basement mem-brane, travels to enter Bowman’s space The foot processes are coated by a thick layer of extracellular material, which partially

Fig-occludes the slits Extremely thin processes called slit phragms bridge the slits between the pedicels Slit diaphragms

dia-are widened versions of the tight junctions and adhering tions that link all contiguous epithelial cells together and are like miniature ladders The pedicels form the sides of the ladder, and the slit diaphragms are the rungs

junc-Both the slit diaphragms and basement membrane are posed of an array of proteins, and while the basement mem-brane may contribute to selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein (mainly albumin) Some protein- wasting diseases are associated with abnormal slit diaphragm structure Selectivity of the barrier to filtered solute is based on both

com-molecular size and electrical charge Let us look first at size.

The filtration barrier of the renal corpuscle provides no drance to the movement of molecules with molecular weights less than 7,000 d (i.e., solutes this small are all freely filtered) This includes all small ions, glucose, urea, amino acids, and many hormones The filtration barrier almost totally excludes plasma albumin (molecular weight of approximately 66,000 d) (We are, for simplicity, using molecular weight as our reference for size; in reality, it is molecular radius and shape that is criti-cal.) The hindrance to plasma albumin is not 100%, however, so the glomerular filtrate does contain extremely small quantities

hin-Renal ar

ter y

Aff erent ar

ter iole

Glomer

ular capillar y

Eff erent ar

ter iole

itub ular capillar y

Intr arenal v

ein

Renal v ein

Sites of largest vascular resistance

0 25 50 75 100

through the renal vascular network The largest drops occur in the

sites of largest resistance—the afferent and efferent arterioles The location of the glomerular capillaries, between the sites of high resistance, results in their having a much higher pressure than the peritubular capillaries (Reproduced with permission from Kibble J, Halsey CR:

The Big Picture, Medical Physiology New York: McGraw-Hill, 2009.)

of albumin, on the order of 10 mg/L or less This is only about

0.02% of the concentration of albumin in plasma and is the

rea-son for the use of the phrase “nearly protein-free” earlier Some

small substances are partly or mostly bound to large plasma

proteins and are thus not free to be filtered, even though the

unbound fractions can easily move through the filtration

bar-rier This includes hydrophobic hormones of the steroid and

thyroid classes and about 40% of the calcium in the blood

For molecules with a molecular weight ranging from 7,000

to 70,000 d, the amount filtered becomes progressively smaller

as the molecule becomes larger (Figure 40–3) Thus, many

normally occurring small- and medium-sized plasma

pep-tides and proteins are actually filtered to a significant degree

Moreover, when certain small proteins not normally present

in the plasma appear because of disease (e.g., hemoglobin

released from damaged erythrocytes or myoglobin released from damaged muscles), considerable filtration of these may occur as well

Electrical charge is the second variable determining ability of macromolecules For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules This is because the surfaces of all the com-ponents of the filtration barrier (the cell coats of the endothe-lium, the basement membrane, and the cell coats of the podocytes) contain fixed polyanions, which repel negatively charged macromolecules during filtration Because almost all plasma proteins bear net negative charges, this electrical repulsion plays a very important restrictive role, enhancing that of purely size hindrance In other words, if either albumin

filter-or the filtration barrier were not charged, even albumin would

be filtered to a considerable degree (see Figure 40–3) Certain diseases that cause glomerular capillaries to become “leaky”

to protein do so by eliminating negative charges in the membranes

It must be emphasized that the negative charges in the tion membranes act as a hindrance only to macromolecules, not to mineral anions or low-molecular-weight organic anions

filtra-Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered

DIRECT DETERMINANTS OF GFR

Variation in glomerular filtration rate (GFR) is a crucial

determinant of renal function because, everything else being equal, a higher GFR means greater excretion of salt and water

Regulation of the GFR is straightforward in terms of physical principles but very complex functionally because there are many regulated variables The rate of filtration in all capillaries, including the glomeruli, is determined by the hydraulic perme-

ability of the capillaries, their surface area, and the net tion pressure (NFP) acting across them, given as follows:

filtra-Rate of filtration = Hydraulic permeability × Surface area × NFP (2)Because it is difficult to estimate the area of a capillary bed,

a parameter called the filtration coefficient (K f) is used to denote the product of the hydraulic permeability and the area

The NFP is the algebraic sum of the hydrostatic pressures

and the osmotic pressures resulting from protein—the oncotic,

or colloid osmotic pressures—on the two sides of the

capil-lary wall There are four pressures to consider: two hydrostatic

pressures and two oncotic pressures These are the Starling forces that were described earlier in Chapter 26 Applying this

same principle to the glomerular capillaries, we have:

NPF = (PGC – PBC) – (πGC – πBC) (3)

where PGC is glomerular capillary hydraulic pressure, πBC the

oncotic pressure of fluid in Bowman’s capsule, PBC the

hydraulic pressure in Bowman’s capsule, and πGC the oncotic

Hemoglobin (68,000) Albumin (~ 69,000)

increases, filterability declines, so that proteins with a molecular

weight above 70,000 d are hardly filtered at all B) For any given

molecular size, negatively charged molecules are restricted far more

than neutral molecules, while positively charged molecules are

restricted less (Reproduced with permission from Kibble J, Halsey CR: The Big

Picture, Medical Physiology New York: McGraw-Hill, 2009.)

pressure in glomerular capillary plasma, shown

schemati-cally in Figure 40–4, along with typical average values

Because there is normally little total protein in Bowman’s

capsule, πBC may be taken as zero and not considered in our

analysis Accordingly, the overall equation for GFR becomes:

GFR = Kf (PGC – PBC – πGC) (4)

Figure 40–5 shows that the hydraulic pressure changes only

slightly along the glomeruli This is because there are so many

glomeruli in parallel, and collectively they provide only a small

resistance to flow, but the oncotic pressure in the glomerular

capillaries does change substantially along the length of the

glomeruli Water moves out of the vascular space and leaves

protein behind, thereby increasing protein concentration and,

hence, the oncotic pressure of the unfiltered plasma remaining

in the glomerular capillaries Mainly because of this large

increase in oncotic pressure, the NFP decreases from the

beginning of the glomerular capillaries to the end The NFP

when averaged over the whole length of the glomerulus is

about 16 mm Hg This average NFP is higher than that found

in most nonrenal capillary beds Taken together with a very

high value for Kf, it accounts for the enormous filtration of 180

L of fluid per day (compared with 3 L per day or so in all other

capillary beds combined)

The GFR is not fixed but shows marked fluctuations in

differ-ing physiological states and in disease To grasp this situation, it

is essential to see how a change in any one factor affects GFR

under the assumption that all other factors are held constant

Table 40–1 presents a summary of these factors It provides,

in essence, a checklist to review when trying to understand how diseases or vasoactive chemical messengers and drugs change GFR It should be noted that the major cause of decreased GFR in renal disease is not a change in these param-eters within individual nephrons, but rather simply a decrease

in the number of functioning nephrons, which reduces Kf

Kf

Changes in Kf are caused most often by glomerular disease, but also by normal physiological control The details are still not completely clear, but chemical messengers released within the kidneys cause contraction of glomerular mesangial cells Such contraction may restrict flow through some of the capil-lary loops, effectively reducing the area available for filtration,

Kf, and, hence GFR

PGC

Hydrostatic pressure in the glomerular capillaries (PGC) is influenced by many factors We can help depict the situation by using the analogy of a leaking garden hose If pressure in the pipes feeding the hose changes, the pressure in the hose and, hence, the rate of leak will be altered Resistances in the hose also affect the leak If we kink the hose upstream from the leak, pressure at the region of leak decreases and less water leaks out

However, if we kink the hose beyond the leak, this increases

pressure at the region of leak and increases the leak rate

PGC

Glomerular capillary

PBS

π GC

Bowman’s space

Forces

60

15 29 16

mmHg Favoring filtration*:

Glomerular capillary blood pressure (PGC)

Opposing filtration:

Fluid pressure in Bowman’s space (PBS)

Osmotic force due to protein in plasma ( π GC )

Net glomerular filtration pressure = PGC – PBS – πGC

described in the text (Reproduced with permission from Widmaier EP, Raff H,

Strang KT: Vander’s Human Physiology, 11th ed McGraw-Hill, 2008.)

PGC

NFP 60

the length of the glomerular capillaries Note that the oncotic

pressure within the capillaries (πGC) rises due to loss of water and that the net filtration pressure (shaded region) decreases as a result (Modified

with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology, 7th ed

New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub Division, 2009.)

These same principles apply to PGC and GFR First, a change in

renal arterial pressure causes a change in PGC in the same

direc-tion If resistances remain constant, PGC rises and falls as renal

artery pressure rises and falls This is a crucial point because a

major influence on renal function is arterial blood pressure

Second, changes in the resistance of the afferent and efferent

arterioles have opposite effects on PGC An increase in afferent

arteriolar resistance, which is upstream from the glomerulus,

is like kinking the hose above the leak (it decreases PGC),

whereas an increase in efferent arteriolar resistance is

down-stream from the glomerulus and is like kinking the hose

beyond the leak (it increases PGC) Of course, dilation of the

afferent arteriole raises PGC, and hence GFR, while dilation of

the efferent arteriole lower PGC and GFR It should also be clear

that when the afferent and efferent arteriolar resistances both

change in the same direction (i.e., they both increase or

decrease), they exert opposing effects on PGC

The real significance for this is that the kidney can

regu-late PGC and, hence, GFR independently of RBF The effects of

changes in arteriolar resistances are summarized in

Figure 40–6

PBC

Changes in this variable are usually of very minor importance

However, obstruction anywhere along the tubule or in the nal portions of the urinary system (e.g., the ureter) increases the tubular pressure everywhere proximal to the occlusion, all the way back to Bowman’s capsule The result is to decrease GFR

exter-πGC

Oncotic pressure in the plasma at the very beginning of the erular capillaries is, of course, simply the oncotic pressure of sys-temic arterial plasma Accordingly, a decrease in arterial plasma protein concentration, as occurs, for example, in liver disease, decreases arterial oncotic pressure and tends to increase GFR, whereas increased arterial oncotic pressure tends to reduce GFR

glom-However, recall that πGC is the same as arterial oncotic sure only at the very beginning of the glomerular capillaries;

pres-πGC then progressively increases along the glomerular ies as protein-free fluid filters out of the capillary, concentrat-ing the protein left behind This means that NFP and, hence, filtration progressively decrease along the capillary length

capillar-Accordingly, anything that causes a steeper increase in πGC

tends to lower average NFP and hence GFR

Such a steep increase in oncotic pressure occurs when RBF is very low Since blood is composed of cells and plasma, low RBF

means that renal plasma flow (RPF) is also low When RPF is

low, any given rate of filtration removes a larger fraction of the plasma, leaving a smaller volume of plasma behind in the glom-

eruli to contain all the plasma protein This causes the πGC to reach a final value at the end of the glomerular capillaries that is

higher than normal This increases the average πGC along the capillaries and lowers average NFP and, hence, GFR Conversely,

a high RPF, all other factors remaining constant, causes πGC to increase less steeply and reach a final value at the end of the cap-illaries that is less than normal, which will increase the GFR

These concepts can be expressed as a filtration fraction: the

ratio GFR/RPF, which is normally about 20% The increase in

πGC along the glomerular capillaries is directly proportional to the filtration fraction (i.e., the greater the percentage of vol-

ume filtered from the plasma, the greater the increase in πGC)

Therefore, if you know that filtration fraction has changed, you can be certain that there has also been a proportional

change in πGC and that this has played a role in altering GFR

FILTERED LOAD

A term we use in other chapters is filtered load It is the amount

of substance that is filtered per unit time For freely filtered stances, the filtered load is just the product of GFR and plasma concentration Consider sodium Its normal plasma concentra-tion is 140 mEq/L, or 0.14 mEq/mL A normal GFR in healthy young adult males is 125 mL/min, so the filtered load of sodium

sub-is 0.14 mEq/mL × 125 mL/min = 17.5 mEq/min We can do the same calculation for any other substance, being careful in each case to be aware of the unit of measure in which concentration

is expressed The filtered load is what is presented to the rest of

TABLE 40–1 Summary of direct GFR determinants

and factors that infl uence them.

Direct Determinants

of GFR:

GFR = Kf (P GC − P BC − π GC)

Major Factors that Tend

to Increase the Magnitude

of the Direct Determinant

(because of relaxation of glomerular mesangial cells) Result: ↑ GFR

2 ↓ Afferent arteriolar resistance (afferent dilation)

3 ↑ Efferent arteriolar resistance (efferent constriction) Result: ↑ GFR

PBC 1 ↑ Intratubular pressure because

of obstruction of tubule or extrarenal urinary system Result: ↓ GFR

pressure (sets πGC at beginning

of glomerular capillaries)

2 ↓ Renal plasma flow (causes

increased rise of πGC along glomerular capillaries) Result: ↓ GFR

GFR, glomerular filtration rate; Kf, filtration coefficient; PGC, glomerular capillary

hydraulic pressure; PBC, Bowman’s capsule hydraulic pressure; πGC, glomerular

capillary oncotic pressure A reversal of all arrows in the table will cause

a decrease in the magnitudes of Kf, PGC, PBC, and πGC.

Reproduced with permission from Eaton DC, Pooler JP: Vander’s Renal Physiology,

7th ed New York, NY: Lange Medical Books/McGraw-Hill, Medical Pub Division, 2009.)