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potassium secretion by the collecting duct are listed

in Table 5.

0036 In the medullary collecting duct, potassium re-

absorption occurs again. Potassium reabsorption is

accompanied by proton secretion that is mediated

via hydrogen–potassium ion (H

–K

) exchange

pumps in the luminal membrane of intercalated cells

of the medullary collecting duct. The activity of the

–K

exchange pump increases with potassium de-

pletion and decreases with potassium loading.

0037 It should be noted that the amount of potassium

excreted in the urine depends on the relative degree of

potassium secretion and reabsorption at the distal

nephron. Moreover, it is clear, therefore, that the net

potassium excretion is tightly linked to sodium re-

absorption and hydrogen ion secretion in the distal

nephron. Generally, renal regulation of sodium and

hydrogen ion balance takes priority over regulation of

potassium balance.

Response to Dietary Potassium Intake

0038 Urinary excretion of a potassium load occurs over

24–48 h. It is not surprising that other factors, which

are rapid and extremely sensitive to a change in po-

tassium intake and output, are involved to maintain

the constancy of the ratio of potassium concentration

between the ICF and ECF.

0039High dietary potassium intake triggers several pro-

tective mechanisms to increase the cellular uptake of

potassium, and to excrete the excessive potassium

load by the colon and kidneys. The increase in cellular

uptake of potassium is mediated through the release

of insulin and catecholamine (Table 4) and probably

mediated through an increase in activity of Na

–K

–

ATPase pumps in skeletal muscle as well. Hyperkale-

mia stimulates aldosterone secretion. This hormone

increases the colonic excretion of potassium directly

as well as indirectly through an increase in Na

–K

–

ATPase pump activity in the basolateral membrane of

the colon.

0040Most of the potassium load is excreted by the

kidneys. Similar to the colon, aldosterone increases

urinary potassium secretion through an increase in

–K

–ATPase pump activity, and by increasing

the potassium channels of the principal cells of the

collecting duct. In addition, a high potassium intake

inhibits sodium reabsorption, and hence water re-

absorption, at the proximal convoluted tubule and

the thick ascending limb of the loop of Henle. Conse-

quently, sodium delivery and urine flow to the distal

nephron increase. Moreover, hyperkalemia decreases

renal ammonia production, which in turn stimulates

aldosterone secretion. All these factors work directly

on the distal nephron to increase potassium secretion

(Table 5). The adapted kidney can excrete up to 20

times more potassium than the baseline.

0041Basically, the adaptation response to a low potas-

sium intake is the reverse of that to a high potassium

diet. The cellular uptake of potassium decreases by a

decrease in the number of Na

–K

–ATPase pumps in

skeletal muscle but not in other tissues like red blood

cells and cardiac muscle. This shifting of potassium

extracellularly from skeletal muscle aims to correct

an extracellular potassium deficit caused by a low

dietary intake. The colon and kidneys also conserve

potassium by decreasing the secretion and increasing

the reabsorption of potassium, respectively.

See also: Potassium: Properties and Determination;

Physiology; Renal Function and Disorders: Kidney:

Structure and Function; Sodium: Properties and

Determination; Physiology; Thirst; Water: Physiology

Further Reading

Halperin ML and Goldstein MB (1999) Fluid, Electrolyte,

and Acid–Base Physiology: A Problem-based Approach.

Philadelphia, PA: W B Saunders.

Koeppen BM and Stanton BA (2001) Renal Physiology.

St. Louis, MO: Mosby.

Kokko JP and Tannen RL (1996) Fluids and Electrolytes.

Philadelphia, PA: W B Saunders.

tbl0005 Table 5 Factors affecting potassium secretion by the collecting

duct

Factors Potassium secretion

Plasma potassium concentration

Urine flow rate at distal nephron

Sodium delivered to distal nephron

# (<30 mM) #

Aldosterone "

Arginine vasopressin "

Poorly absorbed anions in distal nephron "

Acidemia #

Alkalemia "

Renal ammonia production #

Glucocorticoid "

Catecholamine

adrenergic agonist #

adrenergic agonist "

Insulin #

Dietary potassium intake

High "

Low #

Potassium-sparing diuretic #

ELECTROLYTES/Water–Electrolyte Balance 2047

Acid–Base Balance

E W Kun and A W Yu, The Chinese University of Hong

Kong, Hong Kong, China

Introduction

0001 Virtually all cellular, tissue, and organ systems are

sensitive to changes in the hydrogen ion (H

) concen-

tration in the body. They function best at an extracel-

lular fluid H

concentration of 35–45 nmol l

1

(each

nmol l

1

equals 10

6

mmol l

1

). This concentration is

extremely low compared with other ions; sodium

(Na

), for example, has a 3 million times greater

concentration. Therefore, H

concentration is com-

monly expressed as pH, a negative logarithm of H

concentration. Maintenance of acid–base balance

in the body is important because H

binds avidly

to proteins and changes their shape and function.

Many essential metabolic, enzymatic, and trans-

membrane transport processes can be jeopardized

because of alterations of the protein structure and

function, resulting in severe organ dysfunction

and clinical consequences. With an increase in body

concentration, a patient may experience hypoten-

sion, depressed myocardial contractility, and sensor-

ium. With decreased body H

concentration, the

patient may develop coronary spasm, cardiac arrhy-

thmias, hyperreflexia, muscle spasm, and seizure

(Table 1).

0002 In normal conditions, H

varies little from the

normal value of approximately 40 nmol l

1

, even

though acids and bases are continually being added

to the extracellular fluid. This can be achieved by

three homeostatic mechanisms: (1) intracellular and

extracellular buffers; (2) changing partial pressure of

carbon dioxide in the blood by altering the ventilation

rate; and (3) renal H

excretion. The basic principles

of acid–base physiology and the role of the kidneys

and lungs in acid–base balance will be discussed in

this article.

General Concepts

0003 An acid is defined as a compound capable of donating

an H

, and a base is a compound that is capable

of accepting an H

. Examples of acids in the body

include H

, HCl, NH

and H



, and

examples of bases in the body are HCO



,Cl



,NH

and HPO

2

0004 Food and cellular metabolism produces more acid

than base. Base is lost in the feces daily. The net effect

is the addition of acid to the body fluids. To maintain

acid–base balance, acid must be excreted from the

body at a rate equivalent to its addition. Acidosis (a

disease process that tends to decrease the pH) results

if acid addition exceeds excretion. Conversely, alkal-

osis (a disease process that tends to increase the pH)

results if acid excretion exceeds addition. Systemic

pH can still be maintained within a normal range at

acidosis or alkalosis because of compensatory mech-

anisms, which are discussed in the section below. If

these conditions or processes are left unopposed, the

pH will increase or decrease from the normal range,

and result in acidemia (pH < 7.35) or alkalemia

(pH > 7.45). Metabolic acidosis results from a pri-

mary reduction in plasma bicarbonate concentration

and respiratory acidosis results from a primary in-

crease in CO

partial pressure (Pco

). Metabolic al-

kalosis is a result of a primary decrease in plasma

bicarbonate concentration and respiratory alkalosis

is a result of a primary decrease in Pco

. An increase

in Pco

secondary to compensation for metabolic

alkalosis is not called respiratory acidosis; a second-

ary decrease in Pco

in response to metabolic acidosis

is not called respiratory alkalosis.

Acid and Alkali Generation

0005The major constituents of the human diet are carbo-

hydrates, fats, and proteins. In normal conditions,

15 000 mmol CO

is generated from the metabolism

of carbohydrates and fats. Although not an acid, this

will combine with H

O to form H

; there-

fore, it is termed a volatile acid, reflecting the fact that

it has the potential to generate H

after hydration

with H

O. An accumulation of this endogenously

produced CO

will result in respiratory acidosis

(Table 2). Fortunately, this large quantity of CO

is eliminated by alveolar ventilation, and acid–base

balance is maintained.

0006However, nonvolatile acids (mostly sulfuric acid)

are primarily generated from the metabolism of pro-

teins. For example, oxidation of the sulfur-containing

amino acids cysteine and methionine yields sulfuric

acid (H

), whereas metabolism of lysine, argin-

ine, and histidine generates hydrochloric acid (HCl).

tbl0001Table 1 Clinical manifestations of an acid–base imbalance

Increased acidity (pH < 7.20) Increasedalkalinity (pH > 7. 5 5)

Hypotension Perioral and extremity paresthesias

Depressed myocardial

contractility

Muscle spasms

Hyperreflexia

Mental confusion Seizures

Coronary spasm

Cardiac arrhythmias

2048 ELECTROLYTES/Acid–Base Balance

Part of this nonvolatile acid is neutralized by the

bicarbonate (HCO



) generated through metabolism

of the amino acids, such as aspartate and glutamate,

and certain organic anions, such as citrate. The net

amount of nonvolatile acid produced depends on diet-

ary intake. Ingestion of a meal with a large amount of

meat will result in more acid production, whereas a

vegetarian meal can result in less acid generation. In

general, approximately 1 mmol kg

1

body weight of

nonvolatile acid is added to the body each day (50–

100 mmol day

1

for adults) on a typical diet. The

nonvolatile acids are buffered initially, followed by

renal excretion of the H

0007 In abnormal clinical conditions, e.g., diabetes mel-

litus and hypoxia, whereby carbohydrates and fats

are incompletely metabolized to CO

and H

other nonvolatile acids are produced (Table 2). In

diabetes mellitus, when insulin levels are abnormally

low, fatty acids are oxidized to yield energy. This

leads to the production of acetone and two ketoacids

(b-hydroxybutyric and acetoacetic acid). During hyp-

oxia, oxygen delivery to cells is inadequate, glucose is

metabolized anaerobically to pyruvate and then to

lactate and an H

(one per lactate). Therefore,

normal individuals performing vigorous exercise, pa-

tients with reduced cardiac output (heart failure), and

those with hypotension (shock) usually have higher

lactic acid levels. The acid produced will combine

with HCO



and lower the plasma HCO



concentra-

tion producing metabolic acidosis:

þ HCO



! H

0008 With an increased production of acid, the kidneys

may increase excretion of H

and maintain the

acid–base balance. However, in the presence of renal

diseases (renal failure or renal tubular acidosis),

endogenous acid production or ingestion of acid-

producing substances, e.g., aspirin (salicylic acid),

methanol, and ethylene glycol, may exceed the cap-

acity of the buffer system and renal excretion of H

This will result in metabolic acidosis (Table 2).

0009The loss of HCO



from the body is also equivalent

to the addition of acid and produces metabolic

acidosis. This is commonly associated with gastro-

intestinal or renal loss of bicarbonate (Table 2).

0010Whereas the stomach is an acid-secreting organ,

the gastrointestinal tract distal to the stomach is

bicarbonate-secreting. The small bowel has a daily

secretory volume of 600–700 ml and this may be

markedly increased if the small bowel is diseased.

The biliary system secretes about 1 l of fluid per day

containing an HCO



concentration of 60 mmol l

1

whereas the pancreas secretes 2 l day

1

with an

HCO



concentration reaching 120 mmol l

1

. Most

of the secretions are reabsorbed, but with diarrhea

and external drainage of pancreatic, biliary, or small-

bowel juice (external fistulae), the loss of HCO



-rich

fluid results (Table 2).

0011As mentioned above, alkali can also be produced

by the metabolism of certain amino acids but it is

neutralized by the larger amount of dietary acid pro-

duced. A net alkali excess can only occur when there

is exogenous alkali ingestion, primary increase in

ventilation with lowering of Pco

(respiratory alkal-

osis), and excessive H

loss from the stomach or

kidneys (metabolic alkalosis). Milk-alkali syndrome

is seen in patients with gastric distress who consume

large amounts of milk and antacids containing cal-

cium carbonate and sodium bicarbonate. Suppression

of parathyroid hormone secretion caused by hyper-

calcemia from absorbed calcium contributes to

failure to excrete the alkali load. Chronically, nephro-

calcinosis and renal failure develop, which further

reduces the excretion of the absorbed alkali, causing

metabolic alkalosis (Table 3).

The Buffering System

0012One of the major ways in which large changes in H

concentration are prevented is by buffering. A ‘buffer’

tbl0002 Table 2 Generation of acid

Volatile acid ^ respiratory acidosis

production (cellular metabolism)

Nonvolatile acids ^ metabolic acidosis

Dietary protein and phospholipid metabolism (sulfuric acid,

phosphoric acid)

Diabetes mellitus (b-hydroxybutyric acid and acetoacetic acid)

Hypoxia (lactic acid)

Decreased tissue perfusion, e.g., vigorous exercise, heart

failure, shock

Decreased renal H

excretion (e.g., renal failure, renal tubular

acidosis)

Loss of HCO



Gastrointestinal losses in stool, e.g., diarrhea, external fistulae

Urinary losses of HCO



, e.g., proximal renal tubular acidosis,

drug (acetazolamide)

tbl0003Table 3 Generation of alkali

Volatile alkali ^ respiratory alkalosis

removal (hyperventilation)

Nonvolatile alkali ^ metabolic alkalosis

Loss of acid

Gastrointestinal losses in gastric fluid, e.g., vomiting, gastric

suction

Urinary losses of H

: diuretics, licorice excess,

hyperaldosteronism, Bartter’s syndrome, Cushing’s syndrome

Exogenous alkali loads

Milk-alkali syndrome

Sodium bicarbonate ingestion

ELECTROLYTES/Acid–Base Balance 2049

is a pair of substances that can donate or accept an

to moderate changes in H

concentration or pH.

This is the most immediate mechanism of defense

against changes in physiological pH. The major

buffers in the body are H

-HCO



(pK

6.1),



-HPO

2

(pK

6.8), and H-protein



. The dis-

sociation constant (pK

) and pH determine whether a

buffer pair will bind or release the H

in the solution.

When the pH is 1.0 unit below the pK

will bind

to the buffer pair, whereas at 1.0 unit above the pK

will release.

0013 Bicarbonate/carbon dioxide is the most important

extracellular buffer in the body. This buffer system

can be described by the following reactions:

Carbonic anhydrase

$ CO

þ H

O $ H

$ H

þ HCO



ðgaseousÞðaqueousÞ

40 mmHg ð5:3kPaÞ 1:2 mmol l

1

24 mmol l

1

ð1Þ

The hydration/dehydration of CO

is the rate-

limiting step and is enhanced by the enzyme carbonic

anhydrase (CA). When H

is formed, it is ionized

to H

and HCO



virtually instantaneously. The rela-

tionship of pH, HCO



,andPco

is described by the

Henderson–Hasselbalch equation:

pH ¼ pK

þ logf½HCO



½0: 03  PCO

g

where pK

¼ 6.1, HCO



is in mmol l

1

,andPco

in mmHg.

0014 When nonvolatile acid is added to the body fluids,

the reaction of eqn (1) is driven to the left. HCO



consumed during the buffering and plasma HCO



concentration is reduced. In contrast, when acid is

removed from the body, the reaction is driven to the

right. More HCO



is produced from the dissociation

of H

(carbonic acid) and HCO



concentration

increases. With a normal plasma HCO



concentra-

tion of 24 mmol l

1

and an extracellular fluid volume

of 14 l, this HCO



buffer system can potentially

buffer 340 mmol acid. However, for optimal function

of this system, regeneration and maintenance of

normal HCO



concentration by the lungs and

kidneys are required.

0015 In addition, the bones can release buffer com-

pounds such as NaHCO

, K HCO

, CaCO

and Ca

HPO

into extracellular fluid when stimulated by a

decrease in the plasma HCO



concentration. It has

been estimated that as much as 40% of the buffering

of acute acid load takes place in the bones. The role of

bone buffers is even greater in chronic acidosis, such

as that seen in chronic renal failure. One of the con-

sequences is that acid loading directly increases Ca

2þ

release from the bones and urinary Ca

2þ

excretion,

promoting stone formation. An inappropriately high-

protein diet may increase acid load (a normal diet

produces about 70 mmol acid per day) and promote

calcium stone formation. In patients with end-stage

renal disease, a disorder associated with progressive

acid retention caused by impaired urinary acid excre-

tion, there is a gradual reduction in bone calcium

stores.

0016Plasma phosphate and protein also act as extra-

cellular buffers but they are less important quantita-

tively (plasma phosphate concentration is 1 mmol l

1

versus 24 mmol l

1

HCO



þ HPO

2

$ H



ð2Þ

þ protein



$ H-protein ð3Þ

However, intracellularly, phosphate and protein

are important buffers besides HCO



. In metabolic

acidosis, about 43% of buffering occurs in the extra-

cellular fluid and 57% of buffering is mediated by

intracellular buffering. Whereas extracellular H

buffered immediately, buffering by intracellular

buffers takes about 2–4 h. This is the time required

for H

to diffuse into interstitial spaces and enter

cells, which occurs more slowly.

Respiratory Control of Acid–Base Balance

0017Alveolar ventilation provides oxygen for oxidative

metabolism and eliminates the CO

produced by

these metabolic processes in order to maintain Pco

at about 5.3 kPa (40 mmHg). Approximately 15 000

mmol CO

is produced daily and eliminated by the

lungs. The stimulation to ventilation is located in the

chemoreceptors in the brainstem respiratory center

(medulla oblongata) and to a lesser extent in the ca-

rotid bodies located near the bifurcation of the carotid

arteries. The chemoreceptors are sensitive to changes

in the cerebral interstitial pH. With increased CO

the blood, cerebral interstitial pH will decrease and

result in the stimulation of ventilation that will return

Pco

to normal. In contrast, interstitial pH will in-

crease with decreased plasma CO

, resulting in venti-

lation inhibition (Figure 1).

0018Alveolar ventilation is also affected by metabolic

acid–base imbalance. Acidemia caused by metabolic

acidosis can increase minute ventilation from the

normal of approximately 5 l min

1

to greater than

30 l min

1

as the arterial pH decreases from 7.40 to

7.00. The central chemoreceptors are relatively insu-

lated by the blood–brain barrier and only CO

, but

not HCO



, rapidly crosses the blood–brain barrier.

Hence, the effect on cerebral interstitial pH is slower,

and a full ventilation response to nonvolatile acid or a

2050 ELECTROLYTES/Acid–Base Balance

decrease in plasma HCO



may only be achieved in

12–24 h. The Pco

will decrease by 0.16 kPa for

every mmol l

1

reduction of HCO



concentration.

Conversely, ventilation decreases with metabolic al-

kalosis with a consequent increase in Pco

(0.08 kPa

per every mmol l

1

increase in HCO



), lowering the

pH towards normal.

0019 An acid–base imbalance can also be initiated by a

change in carbon dioxide tension of body fluids. A

primary increase in Pco

(primary hypercapnia),

Pco

> 6.0 kPa, results in respiratory acidosis. This

needs to be distinguished from the secondary hyper-

capnia that results from the correction of metabolic

alkalosis. Hypercapnia (respiratory acidosis) could

develop from increased CO

production, decreased

excretion, or both (Table 4).

0020 The administration of large carbohydrate loads

(greater than 2000 kcal day

1

) and parenteral nutri-

tion to critically ill patients may increase CO

pro-

duction. This is rarely the sole cause of hypercapnia.

Increased CO

decreases cerebral interstitial pH,

resulting in an increment in respiratory drive, and

the overproduction of CO

is usually matched by

increased excretion and the generation of respiratory

acidosis is prevented. Patients with a marked limita-

tion in respiratory reserve (e.g., chronic obstructive

lung disease) and those receiving constant mechanical

ventilation may not be able to match the CO

pro-

duction with its removal, resulting in respiratory

acidosis (Table 4). Therefore, it is recommended

that patients with chronic obstructive airway disease

avoid a high-carbohydrate diet to avert further

retention of CO

0021 However, excessive alveolar ventilation relative to

the prevailing carbon dioxide production results in

primary hypocapnia and respiratory alkalosis. This is

usually attributed to hyperventilation as a result of

increased ventilatory drive, hypoxia, and maladjusted

mechanical ventilators (Table 5).

0022The body responds to hypercapnia and hypocapnia

in two phases (acute and chronic). The acute phase

takes about 5–10 min to complete. If hyper/hypocap-

nia persists (chronic phase), adaptation requires a few

days to complete.

0023In acute hypercapnia, CO

diffuses into the cells,

forming carbonic acid which is buffered by intracel-

lular buffers (such as phosphate or hemoglobulin),

resulting in an increase of plasma bicarbonate con-

centration (Figure 2). On average, plasma bicarbon-

ate concentration increases by 0.8 mmol l

1

for each

kPa acute increase in Pco

. Mild increases of Na

and K

are also observed in addition to the increment

in plasma bicarbonate concentration.

tbl0004Table 4 Causes of primary respiratory acidosis

Increased CO

production

High-carbohydrate diet with constant mechanical ventilation

insufflation during endoscopic procedures

Decreased CO

removal

Pulmonary disease

Asthma

Chronic obstruction airway disease

Pulmonary fibrosis

Mechanical ventilatory defect

Pneumothorax

Hemothorax/hydrothorax

Adult respiratory distress syndrome

Muscular or neuromuscular diseases (e.g., Guillain–Barre

syndrome, amyotrophic lateral sclerosis, multiple sclerosis)

Defect in respiratory drive

Brainstem infarct

Sleep apnea

Drugs (opiates and sedatives)

Other

Cardiac arrest

Shock

Severe pulmonary edema

Massive pulmonary embolus

Increase Decrease

IncreaseDecrease

Ventilation

Chemoreceptor

CSF

interstitial

Metabolic or respiratory

acidosis

Metabolic or respiratory

alkalosis

fig0001 Figure 1 Respiratory control of acid–base balance. CSF, cere-

brospinal fluid.

tbl0005Table 5 Causes of primary respiratory alkalosis

Increased central nervous system respiratory drive

Anxiety

Brain infarction, trauma

Sepsis and fever

Drugs (salicylate, nicotine, doxapram)

Tissue hypoxia

Severe anemia

High altitude

Cyanotic heart disease

Pneumonia

Iatrogenic

Increased mechanical ventilation

ELECTROLYTES/Acid–Base Balance 2051

0024 If hypercapnia persists, an adaptive increment in

plasma bicarbonate concentration is markedly ampli-

fied as a result of increasing renal acid excretion,

generating new bicarbonate that is returned to the

blood. Plasma bicarbonate increases by 3.0 mmol l

1

with each kPa chronic increase in Pco

. The renal

response usually takes 1–2 days to develop fully.

0025 In contrast, adaptation to hypocapnia is associated

with an immediate decrement in plasma bicarbonate

of 1.5 mmol l

1

for each kPa acute decrease in Pco

With persisting hypocapnia, renal adaptation re-

quires 3–4 days to complete. This results in a larger

decrement in plasma bicarbonate (3.8 mmol l

1

for

each kPa of chronic decrease in Pco

). The relative

changes of Pco

, HCO



, and pH in various acid–base

disorders are summarized in Table 6.

Renal Control of Acid–Base Balance

0026 Despite the efficacy of respiratory and buffering

systems in maintaining the acid–base balance, the

ventilation rate is limited, and the body buffers even-

tually deplete if the dietary acid load (50–100 mmol

) is not excreted in the urine. The kidneys have the

important role of regulating the systemic bicarbonate

concentration and defending against acid–base im-

balance. The kidneys make appropriate adjustments

in the secretion of HCO



and H

. The renal response

requires several days to complete. There are two com-

ponents in this regulatory process: (1) reabsorption of

filtered HCO



, and (2) generation of bicarbonate by

net H

excretion.

Reabsorption of Filtered Bicarbonate

0027The glomeruli filter about 4300 mmol bicarbonate

per day. About 80% of the filtered bicarbonate is

reabsorbed in the proximal tubules, whereas the re-

mainder is reabsorbed in the distal segments. CA has

a central role in reabsorption of HCO



. The filtered

HCO



generates carbonic acid (H

) by combin-

ing with the excreted H

. CA, located in the brush

border of the proximal tubular cells, rapidly dissoci-

ates H

into water and CO

.CO

then diffuses

into the tubular cells where it combines with the OH



from H

O, forming HCO



and H

is excreted by

-H

antiporters and the HCO



leaves the cells

and enters the peritubular capillary blood by Na

–3

HCO



cotransporter in the basolateral membrane.

The tubular fluid pH decreases from 7.40 in the

filtrate to about 6.70 by the end of the proximal

convoluted tubule (Figure 3).

Renal Tubular H

Excretion

0028The above process reclaims the filtered bicarbonate

but does not participate in the excretion of the dietary

acid load. The H

requires combination with buffers

or the formation of ammonium for excretion. Weak

acids (titratable acids) filtered from the glomeruli,

mostly monobasic phosphate (HPO

2

), act as import-

ant buffers in the tubular fluid (Figure 3). This can

account for the excretion of 10–40 mmol H

per day.

Buffering by phosphate and, to a lesser extent, other

buffers such as urate and creatinine is called titratable

acidity. In the presence of an acid load, the amount

of titratable acidity cannot be easily increased.

tbl0006 Table 6 Changes of pH, PCO

(kPa) and HCO



(mmol l

1

) in simple acid–base

Disorder pH P

HCO



Expectedchanges

Metabolic acidosis ## # DP

¼ 0.16  D [HCO



]

Metabolic alkalosis "" " DP

¼ 0.08  D [HCO



]

Respiratory acidosis #" "

Acute D [HCO



] ¼ 0.8  DPCO

Chronic D [HCO



] ¼ 3.0  DPCO

Respiratory alkalosis "# #

Acute D [HCO



] ¼ 1.5  DPCO

Chronic D [HCO



] ¼ 3.8  DPCO

Intracellular Extracellular

Buf

−

HBuf

HCO

−

HCO

−

fig0002 Figure 2 Intracellular buffering response to respiratory acid-

osis. Buf



, buffer.

2052 ELECTROLYTES/Acid–Base Balance

Ammonium excretion constitutes the major adaptive

response to an acid load.

Ammonium Excretion

0029 The excretion of H

as ammonium (NH

)isanim-

portant step in acid–base regulation because the rate

of NH

production and excretion can be regulated in

response to the physiological needs. NH

excretion in

the urine represents acid excretion and generation of

new bicarbonate by the kidneys.

þ NH

$ NH

The normal rate of NH

excretion in the urine is

about 30–40 mmol day

1

. It can be increased to

> 300 mmol day

1

after a maximum acid load.

0030 NH

production in the kidneys takes place pre-

dominantly in the proximal tubules. Glutamine

(primarily from the liver) is the major precursor of

ammonia in the kidneys. Glutamine is metabolized in

the kidneys to glutamate and NH

Glutamine ! 2NH

þ glutamate



2NH

þ -ketoglutarate

2

The metabolism of a-ketoglutarate generates two

HCO



that are returned to the systemic circulation.

0031 In the proximal tubules, NH

is secreted into the

tubular lumen by Na

-H

antiporter with NH

sub-

stituting the H

, and the HCO



enters the blood

(Figure 4a). Some secreted NH

is reabsorbed in the

ascending limbs of loops of Henle into the medullary

interstitium where it exists as both NH

and NH

.In

the collecting tubules, lipid-soluble ammonia (NH

)

passively diffuses into the lumen and combines with

secreted H

to form NH

(Figure 4b). Cationic NH

is lipid-insoluble and excreted in the urine because

back-diffusion into the cells cannot occur.

Regulation of Renal Bicarbonate Reabsorption and

Acid Excretion

0032A variety of factors, such as intracellular pH, effective

circulating volume, changes in plasma potassium

concentration, as well as several hormones, may

affect bicarbonate reabsorption and acid secretion,

leading to alkalosis or acidosis (Table 7).

0033Decreases in intracellular pH, as a result of meta-

bolic acidosis (increased H

) or respiratory acidosis

(increased Pco

), will increase the availability of

for excretion. At increased acid load or meta-

bolic acidosis, plasma bicarbonate concentration is

decreased. A greater concentration gradient allows

HCO



to diffuse out of the tubular cells. A decrease

in intracellular HCO



will lower intracellular pH

and provide a signal to increase HCO



reabsorption

and H

secretion. In respiratory acidosis or alkal-

osis, changes in intracellular pH are mediated by

the diffusion of lipid-soluble CO

into or out of

the cells.

0034The effective volume status can influence bicarbon-

ate reabsorption. Decreases in the effective circu-

lating volume increase bicarbonate reabsorption,

whereas increases in the effective circulating volume

Proximal

tubular cell

Tubular

lumen

Capillary

blood

3HCO

+ H

3HCO

−

+ HCO

−

+ HPO

2−

−

fig0003 Figure 3 Bicarbonate reabsorption and acid excretion in the proximal tubule. CA, carbonic anhydrase.

ELECTROLYTES/Acid–Base Balance 2053

inhibit proximal bicarbonate reabsorption. This is

clinically important in patients with volume-depleted

metabolic alkalosis. The inability to excrete excess

HCO



prevents resolution of metabolic alkalosis. In

this situation, Na

reabsorption (together with

HCO



) prevents further volume depletion at the

expense of systemic pH.

0035The plasma potassium concentration varies in-

versely with both HCO



reabsorption and H

excre-

tion. With potassium loss, hypokalemia causes a

transcellular shift of potassium out of the cells

(which contain approximately 98% of total body

potassium). To maintain electroneutrality, Na

and

move into the cells. Intracellular acidosis results,

stimulating HCO



reabsorption and H

excretion.

0036Several hormones also influence bicarbonate re-

absorption and H

excretion. Angiotensin II stimu-

lates bicarbonate reabsorption in the early proximal

tubules by increasing the activity of both the Na

-H

antiporters and the basolateral Na

-3HCO



co-

transporters. Aldosterone, however, acts on distal

nephrons and promotes H

excretion in the collecting

tubules.

0037The parathyroid hormone inhibits proximal HCO



reabsorption by inhibiting Na

-H

antiporters in lu-

minal membranes and Na

-3HCO



cotransporters in

basolateral membranes. The physiological import-

ance is unknown because the extra HCO



delivered

out of the proximal tubules is mostly reabsorbed in

the distal tubules. However, patients with primary

hyperparathyroidism and hypercalcemia tend to

have metabolic acidosis.

Summary

0038In summary, the pH of body fluids is maintained

within a narrow limit by the coordinated function of

the buffers, lungs, and the kidneys. Volatile and non-

volatile acids together with other acids and alkali

ingested must be excreted to maintain acid–base

2NH

2HCO

Glutamine

α-Ketoglutarate

2−

Capillary

blood

Proximal

tubular cell

Tubular

lumen

−

2HCO

−

2NH

(a)

Medullary

interstitium

Collecting

tubular cell

Tubular

lumen

HCO

(Blood)

−

(b)

fig0004 Figure 4 Acid excretion as ammonium in (a) the proximal

tubule; (b) the collecting tubule. CA, carbonic anhydrase.

tbl0007Table 7 Factors affecting renal HCO



reabsorption and/or H

excretion

Increase Decrease

Metabolic acidosis Respiratory alkalosis

Metabolic alkalosis with volume

depletion

Volume expansion

Hyperkalemia

Respiratory acidosis Parathyroid hormone

Volume depletion

Hypokalemia

Angiotensin II

Aldosterone

tbl0008Table 8 Sequential event in response to an acid or alkali load

Duration

Extracellular HCO



buffering Immediate

Respiratory response by changing P

Minutes to hours

Intracellular and bone buffering 2–4 h

Adjustment in renal HCO



reabsorption

and H

excretion

24 h to few days

2054 ELECTROLYTES/Acid–Base Balance

balance. The sequential responses to acid or alkali

load are depicted in Table 8. The kidney is the ultim-

ate organ to control acid–base balance by adjusting

the amount of H

excretion. With kidney failure,

acid–base balance cannot be maintained despite the

presence of other intact buffering systems.

See also: Acids: Properties and Determination; Natural

Acids and Acidulants; Amino Acids: Metabolism;

Diabetes Mellitus: Secondary Complications; Glucose:

Function and Metabolism; pH – Principles and

Measurement; Phosphorus: Physiology; Renal

Function and Disorders: Kidney: Structure and Function