This document provides an overview of acid-base disorders and metabolic acidosis. It discusses: 1. Normal acid-base balance parameters and the basic regulation of acid-base balance by the lungs and kidneys. 2. The different types of acids in the body including volatile, fixed, organic, and toxic acids. Metabolic acidosis is often caused by organic acids like ketoacids, lactic acid, or toxic acids. 3. Diagnosis of metabolic acidosis including anion gap, serum osmolar gap, and urine anion gap measurements. Common causes of increased or decreased anion gap acidosis are described. 4. Treatment principles for metabolic acidosis including conservative b

1. A New Perspective on
Metabolic acidosis
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
H+

3. Analysis of Acid-Base Disorders

4. NORMAL ACID-BASE BALANCE
23-27 mEq/L22-26 mEq/LStandard HCO3
42-50 mmHg35-45 mmHgPaCO2
42-48 nEq/L35-45 nEq/LH+
7.32-7.387.35-7.45pH
VenousArterialParameter

6. Basic Regulation of Acid-Base Balance
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3
The lungs help control acid-base balance by blowing off or
retaining CO2. The kidneys help regulate acid-base balance by
excreting or retaining HCO3

7. Na+
NHE-3
H+ HCO3-
Na+
NBC
H2O CO2+
CA-2
Na+
K+
Na/K
ATPase
PCT: Re-absorption of HCO3-
H+HCO3-

8. H+
ATP
ase
H+
H2O
OH- CO2
HCO3-
+
Cl-
CA
CCD: H+ secretion
AE-1

9. CCD: HCO3- secretion  generation
Pendrin

10. Types of Acids in the body
 Volatile acids:
– Can leave solution and enter the atmosphere.
– H2C03 (Carbonic acid).
– Pco2 is most important factor in pH of body
tissues.
• Pco2 is a measurement of tension or partial
pressure of carbon dioxide in the blood.

11. Types of Acids in the body
 Fixed Acids:
– Acids that do not leave solution.
– Sulfuric and phosphoric acids.
( H2SO4& H3PO4)
– Catabolism of amino acids, nucleic acids, and
phospholipids.

12. Types of Acids in the body
 Organic Acids:
– Byproducts of aerobic metabolism, during
anaerobic metabolism and during starvation,
diabetes.
– Lactic acid ,
Ketones

13. Types of Acids in the body
 Toxic Acids:
– Hippuratic acid

16. Immediate response (Hb)
1~2 X all chemical ECF buffers
1 x
3x

17. Chemical buffer system
– Bicarbonate/carbonic acid
• major plasma buffer
– Phosphate: H2PO4- / HPO42-
• major urine buffer
– Ammonium: NH3 / NH4+
• also used to buffer the urine
– Proteins: important in ICF
– Hb: is the main buffer against CO2 change
~ 25%
~75%

18. Bicarbonate Buffer System
 Carbonic acid (H2CO3)
– Weak acid
 Bicarbonate ion (HCO3
-)
– Weak base
 CO2 + H20  H2CO3  H+ + HCO3
-
 Works along with lung and kidney
– These systems remove CO2 or HCO3
-
• Bicarbonate/Carbonic acid = 20:1 normally
• Alterations in the ratio changes pH
irrespective of absolute concentrations

20. Phosphate Buffer System
• Dihydrogen phosphate ion (H2PO4
-)
– Weak acid
• Monohydrogen phosphate ion (HPO4
2-)
– Weak base
• H2PO4
-  H+ + HPO4
2-
• More important in buffering kidney filtrate than in tissue
• The amount of phosphate filtered is limited and relatively
fixed, and only a fraction of the secreted H+ can be
buffered by HPO4
2-

21. Degree of phosphate buffering if 50 mmol/L of
phosphate excreted
Segment pH HPO4 H2PO4 Amount
buffered by
HPO4
Filtrate 7.4 40 10 0
Proximal
tubule
6.8 25 25 15
Final urine 4.8 0.5 49.5
39.5

22. Titratable acid excretion15 ~40

23. Ammonia Buffer System
• NH4+
– Weak acid
• NH3
– Weak base
• NH4+  H+ + NH3-
• Ammonia is produced in the proximal tubule from the
amino acid glutamine, and this reaction is enhanced by
an acid load and by hypokalemia
• Under basal conditions, ~50% of the ammonia that is
produced is excreted in urine and 50% is added to the
systemic circulation via renal veins

24. NH4+ excretion

25. Arterial pH and urine pH
on NH4 excretion

26. Diet acid load on NH4 excretion

27. Renal Control of Acid-Base Balance
• Acidosis
→↑ urinary HCO3- re-absorption
↑ new HCO3- production

28. HCO3 reabsorption ↑ HCO3 generation↑
AE-1
H+
K+

30. TYPES OF ACID-BASE DISTURBANCES
Depression of the central
nervous system, as evidenced
by disorientation followed by
coma
Excitability of the nervous
system; muscles may go
into a state of tetany and
convulsions

32. Regulatory mechanisms of metabolic acidosis in the bone
microenvironment
Acid-sensing ion channels (ASIC),
Transient receptor potential vanilloid channels (TRP),
G-protein-associated receptors such as OGR1,
Receptor activator of the nuclear factor κB ligand (RANKL)
V-ATPase ion pump, an enzyme that promotes acidification of the bone
surface where the resorption process will take place
In persons with chronic uremic acidosis,
bone salts contribute to buffering, and the
serum HCO3
- level usually remains > 12
mEq/L.

35. Ulcerative colitis
High intestinal fistula
Prolonged intestinal
aspiration
H

36. Unmeasured
anions:
10~16 meq/L

37. Anion Gap
– This is a calculated estimation of the
undetermined or unmeasured anions in the
blood
Anion gap(AG) = (Na) - (HCO3+Cl)
– Normal anion gap ~ 10-16 meq / L

38. Unmeasured
cations = K/Ca/Mg

39. Unmeasured anions ↑:
↑Pi ; ↑Albumin
Unmeasured cations ↓ :
↓K ; ↓Ca ; ↓Mg
AG ↑

40. Anion Gap
– This is a calculated estimation of the
undetermined or unmeasured anions in the
blood
Anion gap(AG) = (Na) - (HCO3+Cl)
– Normal anion gap ~ 10-16 meq / L
– Albumin(↓1G/dl) = AG (↓2.3-2.5 meq/L)
– If K included(↑), normal AG drops 4 meq/L(↓)

42. AG metabolic acidosis
• Ketoacidosis: DKA/SKA/AKA
(Beta-hydroxybutyrate, acetoacetate)
• Lactic acidosis
• Salicylate poisoning
• Ethelene glycol intoxication (glycolate, oxalate)
• Methanol poisoning: Formaldehyde (
Formate); Formic acid
• Renal failure
(Sulfate, phosphate, urate, and hippurate)
• Massive rhabdomyolysis (release of H + and
organic anions from damaged muscle)

43. Non AG metabolic acidosis: ↑Cl/↓HCO3
• Acid load / Total parenteral nutrition
(TPN)
• Chronic renal failure
• Carbonic anhydrase inhibitors: acetazolamide
• Renal tubular acidosis(RTA)
• Ureterosigmoidostomy/Intestinal fisula or
drainage
• Expansion
• Diarrhea

45. Plasma osmolar gap (POG)
 Posm = [2 X Na+]+ [glucose in mg/dL] /18+
[BUN in mg/dL]/2.8
 POG = the difference between the measured
value and the calculated one:
no more than 10-15 mOsm/kg
 ↑ POG:
Mannitol, radioactive contrast agents
High-AG acidosis: Methanol, ethylene
glycol, and acetone …

46. Urine anion gap (UAG)
= Na + K – Cl: ~ NH4+ (near zero in normal)
Cl-
Na+ K+
HCO3-
~ 0 meq/L
NH4 +
~ 0 meq/L

47. Urine anion gap (UAG):
negative in metabolic acidosis
Cl-
Na+ K+NH3 +
H+ =
NH4 +
Acid load

48. Positive UAG in non AG
metabolic acidosis  RTA
Cl-
Na+ K+NH3 +
H+ =
NH4 +
HCO3-

50. Simple or mixed ?
Conditions Primary event Secondary response
Metabolic acidosis
(30 minutes onset,
12-24H completion)
HCO3 ↓ 1 meq/L pCO2 ↓ 1.2 mmHg
Metabolic alkalosis
(30 minutes onset,
12-24H completion)
HCO3 ↑ 1 meq/L pCO2 ↑ 0.7 mmHg
Respiratory acidosis
Acute
Chronic > 3-5days
pCO2 ↑ 10 mmHg HCO3
↑ 1 meq/L
↑ 3.5-4 meq/L
Respiratory alkalosis
Acute
Chronic >3-5 days
pCO2 ↓ 10 mmHg HCO3
↓ 2 meq/L
↓ 4-5 meq/L

53. General Principles of Treatment
 Exogenous alkali may not be required if the
acidemia is not severe (arterial pH >7.20),
the patient is asymptomatic, and the
underlying process, such as diarrhea, can be
controlled
 Bicarbonate therapy is generally not given
unless the arterial pH is
< 7.00 in Ketoacidosis
or < 7.10 in Lactic acidosis

54. Potential Acids in the body
 Organic Acids  Potential bicarbonate
– Byproducts of aerobic metabolism, during
anaerobic metabolism and during starvation,
diabetes.
– Ketones
– Lactate
– Conservative supply of HCO3-

55. Bicarbonate deficit
 Assuming that respiratory function is normal,
attainment of a pH of 7.20 usually requires raising
the serum Bicarbonate to 10 ~ 12 meq/L
 HCO3 deficit = HCO3 space x HCO3 deficit per
liter
 HCO3 space = [0.4 + (2.6 ÷ [HCO3])] x lean body
weight (LBW, Kg) = 0.55~0.7 x LBW
 Approximately 250 meq of alkali (usually as
intravenous sodium bicarbonate) can be given
over the first 4 to 8 hours

57. Positive UAG in non AG
metabolic acidosis  RTA
Cl-
Na+ K+NH3 +
H+ =
NH4 +
HCO3-

58. Renal Tubular Acidosis:RTA-1
 Any patient with non-AG metabolic acidosis and a
urine pH > 5.0
 Re-absorb HCO3
- normally
 FE of HCO3
- < 3%
 Serum HCO3
- : variable; in some cases
( < 10 mEq/L )
 Serum K+ level typically is low in patients with distal
RTA; can be high if the distal RTA is secondary to
voltage-dependent  Hyper-kalemic RTA-1

59. H+
ATP
ase
H+
H2O
OH- CO2
HCO3-
+
Cl-
CA
CCD: H+ secretion ↓ in RTA-1
H+
K+
AE-1

60. The causes of RTA-1
 Primary: Genetic or sporadic
 Drug-related: Amphotericin B, lithium, analgesics,
ifosfamide, topiramate, toluene
 Autoimmune disease: SLE, chronic active
hepatitis, Sjögren syndrome, RA, primary biliary
cirrhosis
 Other systemic diseases: Sickle cell disease,
hyperparathyroidism, light chain disease,
cryoglobulinemia, Wilson disease, Fabry disease
 Tubulointerstitial disease - Obstructive uropathy,
transplant rejection, medullary cystic kidney
disease, hypercalciuria

61. Hypokalemia in RTA-1
 Decreased net H + secretion results in more
Na + re-absorption in exchange for K
 The drop in serum HCO 3
- and, therefore, filtered
HCO 3
-, reduces the amount of Na + reabsorbed
by the Na +/H + exchanger in the proximal tubule,
leading to mild volume depletion. The associated
activation of the RAA system increases
K + secretion in the collecting duct. + secretion.
 A possible defect in K +/H + –ATPase results in
decreased H + secretion and decreased K + re-
absorption.

62. Nephrocalcinosis and
Nephrolithiasis in RTA-1
 A constant release of calcium phosphate from
bones to buffer the extracellular H +
 ↓ Re-absorption of calcium and phosphate
 hypercalciuria and hyperphosphaturia
 Relatively alkaline urine
 promotes calcium phosphate precipitation
 Metabolic acidosis and hypokalemia lead to
hypocitraturia, a risk factor for stones

63. Renal Tubular Acidosis:RTA-2
 Any non-AG metabolic acidosis with a serum
HCO3
- > 15 mEq/L (usually) + acidic urine (pH <
5.0)  the strong ability of the collecting duct to
reabsorb some HCO3
 FEHCO3
- less than 3% when their serum HCO3
- is
low. However, raising serum HCO3
- above their
lower threshold and closer to normal levels results
in significant HCO3
- wasting and an
FEHCO3exceeding 15% HCO3
- loading test
 Patients with type 2 RTA typically have
hypokalemia and increased urinary K+wasting 
Bicarbonaturia

64. Na+
NHE3
H+ HCO3-
Na+
NBC
H2O CO2+
CA-2
Na+
K+
Na/K
ATPase
PCT: Re-absorption of HCO3- in RTA-2
H+HCO3-

65. The causes of RTA-2
 Primary: Genetic or sporadic
 Inherited systemic disease - Wilson disease,
glycogen storage disease, tyrosinemia, Lowe
syndrome, cystinosis, fructose intolerance
 Related to other systemic disease - Multiple
myeloma, amyloidosis, hyperparathyroidism,
Sjögren syndrome
 Drug- and toxin-related - Carbonic anhydrase
inhibitors, ifosfamide, gentamicin, valproic acid,
lead, mercury, streptozotocin

66. Osteomalacia in RTA-2
 Any chronic acidemic state
 Proximal tubular conversion of 25(OH)-
cholecalciferol to the active 1,25(OH)2-
cholecalciferol is impaired
 Patients with more generalized defects in
proximal tubular function (as in Fanconi
syndrome) may have phosphaturia and
hypophosphatemia, which also predispose
to osteomalacia.

67. Renal Tubular Acidosis:RTA-4
 Any patient with a mild non-AG metabolic
acidosis : Diminished ammoniagenesis
 CKD stages 2-3 in most patients; Diabetes mellitus (in
approximately 50% of patients)
 Serum HCO3
- > 15 mEq/L (usually), and the
urine pH is < 5.0
 A TTKG less than 5 in the presence of
hyperkalemia indicates aldosterone deficiency or
resistance
 Hyperkalemia also reduces proximal tubular
NH4
+ production and decreases NH4
+absorption by the
thick ascending limb: ↓ the ability of the kidneys to excrete
an acid load

68. The causes of RTA-4
 Hyporeninemic hypoaldosteronism (diabetes mellitus/mild
renal impairment, chronic interstitial nephritis,
nonsteroidal anti-inflammatory drugs, beta-blockers)
 Hypoaldosteronism (high renin) - Primary adrenal defect
(isolated: congenital hypoaldosteronism; generalized:
Addison disease, adrenalectomy, AIDS), inhibition of
aldosterone secretion (heparin, ACE inhibitors, AT1
receptor blockers)
 Aldosterone resistance (drugs) - Diuretics (amiloride,
triamterene, spironolactone), calcineurin inhibitors
(cyclosporine, tacrolimus), antibiotics (trimethoprim,
pentamidine)
 Aldosterone resistance (genetic) -
Pseudohypoaldosteronism (PHA) types I and II

70. L-Lactic acidosis
 Daily L-lactate production in a healthy person is
substantial (approximately 20 mEq/kg/d), and this
is usually metabolized to pyruvate in the liver, the
kidneys, and, to a lesser degree, in the heart.
 Serum lactate > 5 mEq/L
 Type A lactic acidosis occurs in hypoxic states,
while type B occurs without associated tissue
hypoxia
 D-lactic acidosis is a form of lactic acidosis that
occurs from overproduction of D-lactate by
intestinal bacteria. It is observed in association
with intestinal bacterial overgrowth syndromes

71. L-Lactic acidosis
 Definition of acute lactic acidosis: blood lactate level ≥ 5
mEq/L, blood pH ≤ 7.35, and serum bicarbonate
concentration ≤ 20 mEq/L
 Sustained hyperlactatemia in sepsis or low-flow states
carries mortality ≥ 60%
 Sodium bicarbonate does not improve cardiac function or
reduce mortality
 In individuals predisposed to develop intracellular acidification with
bicarbonate, other buffers (such as THAM [tris-hydroxymethyl
aminomethane] or buffers containing disodium carbonate) should be
considered
 Hyperventilation to reduce carbon dioxide accumulation and infusion
of calcium to stabilize calcium concentration improve myocardial
function
 Lactate-guided therapy with the goal of normalizing blood lactate levels
(to <2 mEq/L) has shown some benefit

72. Renal failure
 CKD (GFR 20 ~ 50 mL/min): normal AG metabolic acidosis
Ammoniagenesis ↓
NH3 reabsorption and recycling↓ ; medullary
interstitial NH3 concentration ↓
Serum HCO3
- > 12 mEq/L
 GFR < 20: high AG metabolic acidosis
Accumulation of sulfates, urates and phosphates
Serum HCO3
- > 12 mEq/L, but significant loss of
bone calcium with resulting osteopenia and
osteomalacia

74. Methanol poisoning
 Methanol is metabolized by alcohol
dehydrogenase to formaldehyde and then to
formic acid
 High AG: formic acid, lactic acid, and
ketoacid
 Formaldehyde: optic nerve and CNS
toxicity
 Retinal edema, CNS depression, and
unexplained metabolic acidosis with high
anion and osmolar gaps

75. Ethylene glycol poisoning
 Ethylene glycol is converted by alcohol
dehydrogenase first to glycoaldehyde and then to
glycolic and glyoxylic acids. Glyoxylic acid then is degraded
to several compounds, including oxalic acid, which is toxic, and glycine,
which is relatively innocuous
 High AG: accumulation of these acids + mild lactic
acidosis
 CNS symptoms ( slurred speech, confusion, stupor or coma) ,
myocardial depression, and renal failure with flank
pain
 Oxalate crystals in the urine; elevated osmolar gap

76. Toluene Toxicity –Renal
 Renal tubular acidosis (RTA)
 Hypokalemia
 Hypophosphatemia
 Hyperchloremia
 Azotemia
 Sterile pyuria
 Hematuria
 Proteinuria

77. Toluene Toxicity -CNS
 Acute intoxication from inhalation is characterized
by rapid onset of CNS symptoms:
euphoria, hallucinations, delusions, tinnitus,
dizziness, confusion, headache, vertigo, seizures,
ataxia, stupor, and coma.
 Chronic CNS sequelae:
neuropsychosis, cerebral and cerebellar
degeneration with ataxia, seizures,
choreoathetosis, optic and peripheral neuropathies,
decreased cognitive ability, anosmia, optic
atrophy, blindness, tinnitus, and hearing loss

78. Toluene Toxicity -CP
 Toluene has direct negative effects on
cardiac automaticity and conduction and
can sensitize the myocardium to circulating
catecholamines.
 "Sudden sniffing death" secondary to
cardiac arrhythmias has been reported.
 Pulmonary effects include bronchospasm,
asphyxia, acute lung injury (ALI), and
aspiration pneumonitis.

79. Toluene Toxicity -GI
 GI symptoms from inhalation and ingestion:
abdominal pain, nausea, vomiting, and
hematemesis.
 Hepatotoxicity: ascites, jaundice, hepatomegaly,
and liver failure.
 A rare form of hepatitis: hepatic
reticuloendothelial failure (HREF)
 Hepatitis secondary to toluene toxicity, not just
infectious causes, should be considered in the
differential diagnosis in the younger population

80. Mechanisms AG↑ Normal AG
Acid production ↑ Lactic acidosis
Ketoacidosis
Methanol intoxication
Ethylene glycol
Diethylene glycol
Propylene glycol
Aspirin
Pyroglutamic acid(5 oxo proline)
Toluene
Toluene ( if preserved renal
function/excretion of Na and K
hippurate in urine later)
Loss of HCO3
or its precursors
Diarrhea (tube drainage)
Other intestinal losses
T2RTA
CA inhibitors
Ureteral diversion(ileal loop)
Post-treatment of ketoacidosis
Renal acid secretion↓ CKD-5 (GFR <20) CKD (GFR 20~50)
T1RTA
T4RTA(hypoaldosteronism)

82. RhCG in urinary ammonium excretion
RhCG
RhCG
NH3
H-ATPase
AE1
H/K ATPase
CO2+H2OHCO3
HCl
K
H
NH3
CA
C (cortical) CD
Lithium

83. Model of collecting duct ammonia secretion

84. NH4+ excretion
Glutamine synthase (GS)
HCO- transporter:
NBC e1
GS: NH4
+ + glutamate + ATP -> glutamine + H+ + ADP + Pi.
PDG: glutamate dehydrogenase
PEPCK

85. RhCG in urinary ammonium excretion
RhCG
RhCG
NH3
H-ATPase
AE1
H/K ATPase
CO2+H2OHCO3
HCl
K
H
NH3
NaK ATPaseK(NH4)
CA
Inner medullay
CD
Lithium
NaKCC
K
(NH4)

87. Metabolic acidosis
Issues Traditional views New aspects
Definition PHCO3↓ HCO3 content if ECFV↓
Look for new Anions by P anion gap Adjusted when P albumin
(adjusted by P albumin is low) is high if ECFV is low
= Na-Cl-HCO3 in plasma Detect new anions in urine
(UAG=Na+K+NH4-Cl)
Detect NH4(urine) UAG = Na+K-Cl Uosm gap(UOG): best indirect
Urine pH indicator for NH4
Compare fall in PHCO3 Expect 1:1 Calculate HCO3 content in
with rise in P anion gap ECFV to estimate deficit
Examine effectiveness of Rely only on PaCO2 Use capillary PCO2 in
HCO3 buffer system skeletal muscle
(reflected by brachial venous PCO2)