PHYSIOLOGY: ACID-BASE BALANCE

Lecturer: Michael Van Haute, MD Date of Lecture: Dec. 04, 2012

Transcribed by: Aaron Abad, Io Angeles, Dana Arellano, Kayemar Aseron, Aaron Ayro

3. Input and output of acids alter bicarbonate but not

pH partial pressure of CO2.
Measure of the acidity or basicity of an aqueous 4. Excretion of CO2 and bicarbonate are independent of
solution each other
Normal range: 7.35-7.45
pKa Acids and bases obey the balance principle
A quantitative measure of the strength of an acid in a Routes for entry of acids and bases into body fluids
solution (Ka) De novo generation of acids and bases (e.g.,
Extent of which an acid (HA) dissociates into its metabolism of stored fat and glycogen)
+
conjugate base (A ) and H Activity of GI tract that adds acids and bases
+
HA A + H Processing of ingested foods (dietary
+
Ka = [A ][H ]/[HA] protein, fruits and vegetables)
log Ka = pKa Normal kidneys excrete acids and bases to exactly
The larger the pKa, the smaller the extent of match input, thus maintaining balance
dissociation
Body fluids are buffered
+
ACID compound that releases H when dissolved in water Buffered system
Strong acid o Contains weak acids and their respective
o Acid that dissociates/ionizes completely in conjugate bases in equilibrium
+
an aqueous solution o Free aqueous concentration of protons (H ) only
o Have pKas < 2 a trivial fraction
Weak acid o Prevents large changes in pH
+
o Acid that dissociates incompletely o Does not have an infinite capacity to keep [H ] at
+
o Acid conjugate base + H a constant value (buffer is consumed in the
o Have pKas in the range of 2 to 12 reaction), but blunt the change in pH and give
+
BASE compound that accepts H kidneys time to alter their excretion

ACIDOSIS a process adding acid to the blood (accumulation Input and output of acids alter bicarbonate but not PCO2
- +
+
of H /loss of HCO3 ) CO2 + H2O H2CO3 HCO3 + H

+
Adding H drives reaction to the left;
+
ALKALOSIS a process adding base to the blood removing H drives reaction to the right
+
(accumulation of HCO3 /loss of H ) Moleformole basis
+
o For every H ion added to the body, one HCO3
ACIDEMIA arterial pH < 7.35 disappears
ALKALEMIA arterial pH > 7.45 o To maintain balance, it is necessary to generate

a new HCO3 to replace the one that was lost

FUNCTIONAL PARTS OF THE NEPHRON o Generation of new HCO3 is the responsibility of
PROXIMAL TUBULE the kidney
o Achieves massive absorption of water and solute
LOOP OF HENLE Concentration of CO2 is essentially constant
o Creates the corticopapillary gradient of solute o Produced at 9 mmol/min, but is eliminated at the
and osmoles in the interstitial space (affects same rate, therefore no net addition
transport of water and ions by the distal nephron) o Regulated by the respiratory system to be ~40
DISTAL TUBULE & COLLECTING DUCTS mmHg (3545 mmHg)
o Can reabsorb 1015% of filtered salt and water Any rise or fall in PCO2 is sensed by respiratory centers of
+
(enable finetuning of systemic salt, water, K , the brainstem alter rate of ventilation
and acidbase balance)

o Collecting ducts Excretion of CO2 and HCO3 are independent of each other
Principal cells, intercalated cells If there is excess generation of CO2, the CO2 cannot be
converted to fixed acid and excreted by the kidneys
GUIDELINES FOR UNDERSTANDING ACID-BASE If there is excess input of fixed acid (resulting in a lowering

PHYSIOLOGY of HCO3 ), the body cannot convert this acid to CO2 and
1. Acids and bases obey the balance principle. excrete it through the lungs
2. Body fluids are buffered.

Page 1 of 9
USEFUL-TO-KNOW FACTS BUFFER SYSTEMS

+
Normal ECF [H ] range: 35-45 nmol/L Provide adequate defense against changes in pH
+
o At pH of 7.40, [H ] is estimated at 40 nmol/L Weak acids in equilibrium with their respective conjugate
o Each 0.01unit change in pH from 7.40 bases
+
corresponds to an inverse change of ~1 nmol/L in Acid conjugate base + H
+
+
[H ] in the 7.307.50 pH range HA H + A
+ +
o pH = log [H in mol/L] Ka = [H ][A ]
7 + 7
o Water contains 10 mol/L of H , so log 10 = 7.0 [HA]
+
(pH of water) [H ] = Ka [HA]/[A ]

Normal arterial pH is 7.357.45 pH = pKa + log[A ]/[HA]
Normal venous pH is 7.317.41 (HendersonHasselbalch equation)
We produce enough CO2 at rest each day to add ~10,000
+
mmol of H per day.
Our usual diets typically result in the formation of 50100
+
mmol of H per day.
Urine pH is usually around 7.0, but can range from 4.4 to
8.0

THE pH IS UNDER CONSTANT THREAT!

VOLATILE ACIDS
+
o CO2 + H2O H2CO3 H + HCO3
o Product of oxidation of carbohydrates, fats, and
amino acids
o Enough CO2 is produced each day to add
+
~10,000 mmol of H to body fluids
o Exercise and hypermetabolic states produces
Consider a weak acid with a pKa of 7.0
even greater amounts of CO2
NONVOLATILE or FIXED ACIDS
In 1 L of solution, A and HA are each present at 10
o Metabolism of dietary proteins
mmol/L
o GI processes
ORGANIC ACIDS HA H + A
+
o Anaerobic metabolism of carbohydrates and fats
pH = pKa + log [A ]/[HA]
pH = 7.0 + log (10/10)
Nonvolatile/Fixed Acids
pH = 7.0
Metabolism of dietary proteins
o Methionine and cysteine sulfuric acid 1 mmol of strong acid (HX) is added to the solution
o Phospholipids, nucleic acids, phosphoproteins
and phosphoglycerides phosphoric acid HX H + X
+
o Lysine, arginine, and histidine hydrochloric
acid HX H + X
+
GI processes +
(HA H + A )

+
o GI tract lined with epithelium that can secrete H , +
H + X + A HA + X


HCO3 , or a combination
pH = pKa + log[A ]/[HA]
o Pancreatic and hepatic exocrine secretions into pH = 7.0 + log (9/11)

the duodenum contain large amounts of HCO3 pH 6.9
o Vomiting, diarrhea
What if the same amount of strong acid HX (1 mmol) is
Organic Acids added to 1L of unbuffered solution such as water?
Normally further oxidized to CO2 and H2O
From anaerobic metabolism of carbohydrate and fat Recall:
Lactic acid +
pH = log [H in mol/L]
From anaerobic metabolism of 7
Water contains 10 mol/L or 0.001 mmol/L
carbohydrate
Accumulate during conditions of The unbuffered solution now contains 1.001
poor tissue perfusion + 3
mmol/L of [H ] round off to 1 mmol/L 10 mol/L
Ketone bodies
From anaerobic metabolism of pH = log 10
3
triglycerides (hydroxybutyrate pH = 3.0
and acetoacetate)
Consider a weak acid with a pKa of 7.0

In 1 L of solution, A and HA are each present at 2 mmol/L

Page 2 of 9
 o pH of tubular fluid generally becomes more
+
HA H + A acidic than ECF (thus closer to its pKa)

pH = pKa + log [A ]/[HA]
pH = 7.0 + log (2/2) Bicarbonate


+
pH = 7.0 H + HCO3 H2CO3
pKa = 3.7

-
1 mmol of strong acid (HX) is added to the solution pH = 3.7 + log [HCO3 ]/[H2CO3]
+
HX H + X H
+
+ HCO3 H2CO3 CO2 + H2O
+
pKa = 6.1
HX H + X
-
pH = 6.1 + log [HCO3 ]/[CO2]
+
(HA H + A )
-
pH = 6.1 + log [HCO3 ]/0.03 pCO2
+
H + X + A HA + X

CO2 and HCO3 concentrations can be independently

pH = pKa + log[A ]/[HA] regulated by the lungs and kidneys, respectively.
pH = 7.0 + log (1/3)
pH 6.5 Components of this buffer system can be
independently regulated by the lungs (CO2) and the
A higher concentration of the buffer appears to protect the kidneys (HCO3 )

pH better! o By regulating these components, the lungs
and kidneys also regulate the pH of the body
What makes an optimal buffer system? fluids
Having a pKa CLOSE TO PHYSIOLOGIC pH o Excess CO2 cannot be converted to fixed
(7.40) acid
Being present in a HIGH CONCENTRATION o Excess fixed acid cannot be converted to
CO2
Intracellular buffers
Hemoglobin, proteins pH of a buffer solution is determined by the ratio of
Phosphates
the concentrations of the 2 forms of the buffer (weak
Extracellular buffers
acid and its conjugate base)
Bicarbonate plasma
Phosphate tubular fluid RESPIRATORY REGULATION OF Ph
Ammonium tubular fluid
In a person with normal lungs and a fixed rate of CO 2
Albumin/plasma proteins
production, the arterial PCO2 is determined solely by,
Bone
and is inversely proportional to alveolar ventilation.
o Chemoreceptors (in medulla oblongata,
Hemoglobin and other proteins
aortic bodies, carotid bodies) respond to
Proteins contain several ionizable groups that are
arterial PCO2 alveolar ventilation
weak acids
o Chemoreceptors in carotid bodies also
Imidazole groups of histidine and Nterminal amino respond to arterial pH alveolar
groups have pKas sufficiently close to 7.4 ventilation
Hemoglobin Recall: Enough CO2 is produced each day to add
o Has concentrations 4x greater than that of +
~10,000 mmol of H to the body fluids
plasma proteins

+
H is added to venous blood when CO2 enters the
o Has 38 histidine residues, >2x as many as
capillaries from the tissues
albumin

+
This H reacts with blood buffers, primarily
o The deoxygenated form has imidazole
hemoglobin (recall: venous pH is 7.317.41, slightly
groups with somewhat higher pKas (better
+ lower than arterial pH)
able to bind H formed when CO2 enters
capillary blood from the tissues)
RENAL REGULATION OF pH

TASK 1 The kidneys regulate the amount of HCO3
Phosphate
recovered or reabsorbed from the glomerular filtrate.

+ 2
H2PO4 H + HPO4
TASK 2 The kidneys regulate HCO3 by secreting
pKa = 6.8
excess HCO3 during alkalotic conditions.
Much more effective in ICF than in ECF TASK 3 The kidneys generate HCO3 lost in

o The total concentration of phosphate in ICF buffering the various strong acids formed in the body.
>> ECF
o Intracellular pH generally is somewhat lower TASK 1 Recovery of filtered HCO3

(thus closer to its pKa) More accurately recovery rather than reabsorption
Effective in buffering the tubular fluid (distal nephron)
of HCO3 from the glomerular filtrate.
in the kidneys
Normal serum HCO3 : 24 mmol/L
o Phosphate becomes generally concentrated
Approximately 3 mmol of HCO3 are filtered by the
in the distal nephron kidneys per minute

Page 3 of 9
 +
GFR of 125 mL/min (180 L/day) Transports Na and HCO3 out of cell into

Amount of HCO3 filtered per day: 4320 mmol interstitium (3:1 ratio)
Excellent glomerulotubular balance exists for Carbonic anhydrase present both intracellularly and in
bicarbonate reabsorption (recovery) apical membrane

Distal tubule
+
H ATPase
+
Apical membrane
Generic model of H secreting cell +
Secretes H into lumen
+ +
H K ATPase
Apical membrane
+ +
Moves H into the lumen and K into the cell

Cl HCO3 exchanger
Basolateral membrane

Very similar to erythrocyte Cl HCO3
exchanger (band 3)

- +
CO2 + H2O H2CO3 HCO3 + H

Carbonic anhydrase

Plays a pivotal role in urinary acidification and HCO3
recovery
Widely distributed throughout the tissues of the body
Exists in several isoforms (cytosolic, mitochondrial,
membraneassociated)
Renal forms similar to highaffinity forms found in
erythrocytes

TASK 2 Secretion of HCO3
Proximal tubule
+ +
Secretion of HCO3 occurs during an alkaliload,
Na /H exchanger (NHE)
absorption of HCO3 occurs during an acidload
NHE3 in apical membrane (PCT, LoH),
In HCO3 secreting cells, HCO3 secretion by cortical
responsible for most Na+/H+ exchange in
collecting ducts depends on lumen Cl
the PCT
A Cl HCO3 exchanger is present along
NHE1, NHE4 in basolateral membrane of apical membrane
TAL
NHE8 also in brush border (function Intercalated cells
unknown) TYPE A
+
Na /HCO3 cotransporter (NBC) + +
Secrete H through apical H ATPase and
NBCn1 in basolateral membrane

Page 4 of 9

reabsorb HCO3 via basolateral Cl HCO3
exchanger
Outer medullary collecting duct
TYPE B
+ +
Extrude H through basolateral H ATPase
and secrete HCO3 into urine via apical Cl
HCO3 exchanger (pendrin)
Cortical collecting duct
NONA, NONB
+
Express both H ATPase and Cl HCO3
exchanger at the apical membrane
Specific function not known
?Transitional form of Type B cells into Type
A cells
Pendrin
Encoded in PDS/Pds gene (SLC26A4)
Disruption of gene abolishes HCO3 secretion and Cl
reabsorption alkalosis
Also found in thyroid and inner ear
Pendred syndrome deafness associated
with goiter/hypothyroidism
Low NaCl diet, angiotensin II and aldosterone
increase pendrin expression ?control vascular
volume and blood pressure
Type A intercalated cell
Type B intercalated cell
TASK 3 Generation of new HCO3
The kidneys generate HCO3 lost in buffering the
various strong acids formed in the body
+ 2- - 2- 2-
2H + SO4 + 2HCO3 SO4 + 2H2CO3 SO4 +
2CO2 + 2H2O
-
2HCO3 - lost
2CO2 removed by lungs
Organic acids (lactic acid, acetoacetic acid, b-OH
butyric acid), when they accumulate, can similarly
-
deplete the bodys store of HCO3
The net result of addition of acid (H+) to the body
reduces the amount of HCO3 on a moleformole
basis
Recall: Our usual diets typically result in the
+
formation of 50100 mmol of H per day
+
The distal nephron excretes this excess H
The kidneys must generate 50100 mmol of
new HCO3 per day to replace the HCO3
lost in titrating the strong acids produced by
the body
If we just reabsorb filtered HCO3 , nothing is
changed!
+
H ions are secreted and combined with the conjugate
base of buffers other than HCO3
Phosphate filtered buffer
Ammonia synthesized buffer
Bicarbonate buffer
Non-bicarbonate buffer
Page 5 of 9
 + -
2 amino acids (+ O2) 2 NH4 + 2 HCO3 urea or
Phosphate glutamine (+ CO2 and H2O)
Typical plasma phosphate concentration ~1 mmol/L Glutamine is released from the liver and is taken up
At GFR of 180 L/day by proximal tubule cells (from lumen and renal
Amount of phosphate filtered is ~160 interstitium)
mmol/day
75% to 90% is reabsorbed
Amount of phosphate delivered to the distal
nephron is 1240 mmol/day
This amount remains relatively
constant, even in acidotic
conditions!
2
The divalent phosphate (HPO4 ) is the conjugate
+
base, and is the form that can react with H
A titratable acid

Proximal tubule
pH is 7.4 PROXIMAL TUBULE
2 +
[HPO4 ]/[H2PO4 ] is 4:1 NH4 /NH3 secretion
+ +
Concentration is low Cytosolic NH4 competes with cytosolic H for
+ + +
At the end of the PCT, where 7590% of phosphate is exchange with luminal Na , enabling Na /NH4
already reabsorbed, only two-thirds of the filtered exchange (via NHE3)
+ + +
water is reabsorbed NH4 exchanges with K in the same fashion as H
+ + +
would with K (via H /K ATPase)
Distal tubule NH3 exits cell either by passive diffusion or transport
pH becomes more acidic compared to ECF NHE3 expression increases during metabolic
Water is reabsorbed in excess of phosphate acidosis!
By the time the minimum intratubular pH (4.4) is
2
reached, virtually all of the base (HPO4 ) has been THICK ASCENDING LIMB (Apical membrane)
+
converted to acid (H2PO4 ) NH4 reabsorption
Major contributors
+ +
Phosphate is a more effective buffer in the distal tubule! Luminal NH4 competes with K for binding
+ +
to the Na /K /Cl cotransporter (NKCC2)
+
Hypokalemia and hyperkalemia alter NH4
reabsorption
Minor contributors
+ + +
Apical K /NH4 (H ) exchange activity
+ +
K channels can contribute to luminal NH4
uptake

THICK ASCENDING LIMB (Basolateral membrane)

+
NH4 reabsorption
+ +
Na /H exchanger (NHE4)
+ +
Can also function as Na /NH4 exchanger
Expression also increased during metabolic
acidosis
+
HCO3 enters cell via Na /HCO3 cotransporter
+
(NBCn1) and buffers intracellular H derived from
+
NH4
Ammonia
+ + Bicarbonate shuttle
NH4 NH3 + H +
Accumulation of NH4 in the interstitium
pKa = 9.3 +
+ [NH4 ] progressively increasing toward the
At pH of 7.4, [NH3]/[NH4 ] ratio is ~1:100
+ papilla
A highly effective buffer for secreted H
Analogous to the osmotic gradient of urea
NH3 is synthesized from glutamine (PCT,
Ammonia gets secreted into the thin
DCT), and is secreted into the tubular fluid
+ descending limb, and subsequently
NH4 can masquerade as other ions (some
protonated in the lumen (ammonium
transporters and some channels are not
recycling)
completely selective for the ions they usually
move)
DISTAL TUBULE (Apical Membrane)
+
NH4 /NH3 secretion
Ammoniagenesis
Secretion by collecting ducts accounts for majority of
Protein metabolism in the liver
urinary ammonia content

Page 6 of 9
 +
Secretion involves parallel NH3 and H transport Readily exchangeable
+
H transport via Present in bone water (hydration
+ + +
H ATPase and H /K ATPase shell around each hydroxyapatite
NH3 transport initially thought to be crystal)
diffusive Becomes a major buffering system in chronic
+
Parallel NH3 and H transport metabolic acidosis
+
H transport via
+ + +
H ATPase and H /K ATPase Ionic exchange
NH3 transport RhC glycoprotein (RhCG) Acute metabolic acidosis
+ + +
Expressed in intercalated cells Uptake of H in exchange for Na and K
(except nonA and nonB) and Dissolution of bone crystals
nonintercalated cells throughout the Chronic metabolic acidosis
DCT Uremic acidosis, renal tubular
Gene deletion resulted in acidosis
decreased NH3 permeability Two processes:
Metabolic acidosis increases Direct physicochemical breakdown
+
expression in medullary collecting H is taken up in exchange
++
ducts for Ca
Osteoclastic resorption of bone
DISTAL TUBULE (Basolateral Membrane) Release of calcium
RhCG carbonate
(RhBG controversial) Associated with significant
+ +
Na /K ATPase loss of bone mineral
+ + +
NH4 competes with K at the K binding
+ +
site, enabling Na NH4 exchange ACID-BASE DISORDERS
+
Increasing interstitial NH4 /NH3 Changes in the normal value of extracellular pH that may
concentrations increase their affinity for result when:
receptors binding site (cortex > medulla) o Renal or respiratory function is abnormal
o An acid or base load overwhelms excretory
Titratable acids capacity
Several weak acids that act as buffers are filtered at Primary respiratory disorder abnormal PCO2
the glomerulus (major of which is phosphate) o Respiratory acidosis
NaOH is added to urine until pH is 7.4 (same pH as o Respiratory alkalosis

the glomerular filtrate and plasma) Primary metabolic disorder abnormal HCO3
o Metabolic acidosis
o Metabolic alkalosis

Acute or chronic
Simple or mixed
Compensatory mechanisms
o Defense mechanisms that function to reduce the
effects of a particular disorder on the pH
o Do NOT restore the pH back to normal (partial
Number of mmol of NaOH required to raise pH to 7.4 = compensation)
Number of H+ added to tubular fluid that combined with Correction of the underlying cause of
phosphate and organic buffers the disorder restores pH back to normal
o Organs used in compensation: lungs or kidneys
Net acid excretion
+
= titratable acid + NH4 urinary HCO3 RESPIRATORY ACIDOSIS
Obstructive lung diseases
Bone as Buffer CNS depression
Bone matrix Neuromuscular disorders
Organic component collagen, ground Structural disorders of the thorax
substance proteins
Inorganic component hydroxyapatite Acute Respiratory Acidosis
crystals Recall: If there is excess generation of CO2, the CO2
Bone is a major CO2 reservoir in the body cannot be converted to fixed acid and excreted by the
2
Carbonate (CO3 ) kidneys
In hydroxyapatite crystals Cellular buffering
Release requires dissolution (a Elevation in PCO2 levels leads to an
slow process) increase in H2CO3 levels in plasma
Bicarbonate H2CO3 can only be buffered by intracellular

Page 7 of 9
 buffers (primarily hemoglobin and proteins) Represents the concentration of all
- -
H2CO3 + Hb HHb + HCO3 unmeasured anions in plasma
Negativelycharged plasma
Chronic Respiratory Acidosis proteins (10%)
Kidneys compensate Anions from organic acids produced
+
NH4 production and excretion are increased during pathologic states
+ - -
Rise in PCO2 and drop in extracellular pH AG = [Na ] [Cl ] [HCO3 ] (normal: 3 11)
+
stimulate renal tubular H secretion all Anion gap metabolic acidosis

filtered HCO3 recovered HCO3 is lost, and is replaced by anions from
+
Increased amounts of secreted H are left organic acids
over for the formation of titratable acid Nonanion gap metabolic acidosis

This process begins 26 hours after onset, and takes HCO3 is lost, and is replaced by Cl
35 days to complete
Lactic acidosis
RESPIRATORY ALKALOSIS Diabetic ketoacidosis
Hyperventilation Kidney failure (uremic acidosis)
High altitude Certain medications (aspirin, isoniazid, iron)
Certain medications Diarrhea
Pregnancy Carbonic anhydrase inhibitors
Recovery from metabolic acidosis Renal tubular acidosis
Severe anemia Lungs compensate
Drop in arterial pH stimulates both central
Acute Respiratory Alkalosis and peripheral chemoreceptors controlling
Buffering by intracellular buffers respiration
+
After 10 minutes following onset, H (from More an increase in TV than an increase in
hemoglobin, proteins, phosphates all RR
intracellular) move into the extracellular fluid If acidemia is severe, minute ventilation

and combine with HCO3 to form H2CO3 reaches a maximum of 30 L/min (normal: 4
Intracellular buffering does not offer adequate 6 L/min) Kussmaul respiration
protection against respiratory alkalosis
Metabolic Alkalosis
Chronic Respiratory Alkalosis Exogenous base (antacids)
Kidneys compensate Vomiting
Drop in PCO2 and rise in extracellular pH Volume depletion
+
reduce tubular H secretion Aldosterone excess

HCO3 secretion is stimulated Chloride depletion (diuretics)
No titratable acid in the urine (urine is Potassium depletion
alkaline in these conditions) Usually associated with some degree of renal
+
NH4 production and excretion is inhibited impairment (kidneys have a vast capacity in excreting
This process begins 26 hours after onset, and takes excess alkali)
23 days to complete Lungs compensate (hypoventilation)

METABOLIC ACIDBASE DISORDERS

Possible causes
Increased input of acid by Acid load is too great for
ingestion, infusion, or production kidneys to excrete

Decreased renal production (or Renal failure

-
excretion) of HCO3
Normal acid input not excreted)
-
Direct loss of HCO3 from the Diarrhea
body

Result: lower concentration of HCO3 and lower

plasma pH
Compensation: respiratory (hyper or
hypoventilation)

Metabolic acidosis
Anion gap

Page 8 of 9
Compensatory response
Organ
Initial ultimately
Compen
Primary chemic responsible Mechanism of
satory
disorder al for compensation
response
change compensato
ry response

Metaboli
c HCO3- pCO2 Lungs Hyperventilation
acidosis

Metaboli
c HCO3- pCO2 Lungs Hypoventilation
alkalosis

Acute: cell
buffering
Respirat Chronic:
ory pCO2 HCO3- Kidneys generation of
acidosis new HCO3-,
excretion of
NH4+

Acute: cell
buffering
Respirat Chronic:
ory pCO2 HCO3- Kidneys absorption of
alkalosis HCO3-,
excretion of
NH4+

Page 9 of 9