Acid-Base Pathophysiology Victor L. Schuster, MD Chairman

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Acid-Base Pathophysiology
Victor L. Schuster, MDChairmanDepartment of
Medicine
Albert Einstein College of Medicine Bronx, NY
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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You will also understand this poster
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
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Metabolic Acidosis The Anion Gap
? Na - (Cl- HCO3-)
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What happens after HCl addition
Na Cl-
Cl has gone up by the same amount HCO3 has gone
down
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Metabolic Acidosis The Anion Gap
? Na - (Cl- HCO3-)
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What happens after AH addition where A is a
retained anion
Na A- Cl-
A- has gone up by the same amount HCO3 has gone
down
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Metabolic Acidosis The Anion Gap
? Na - (Cl- HCO3-)
Nl Anion gap M acidosis
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Clinician short-hand you should know
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And now, its time for Calculate That Gap
140 ? 105 ? 30 Glucose 90 4.5 ? 25 ? 1.5
140 -(105 25) 10 normal
141 ? 105 ? 27 Glucose 100 4.2 ? 6 ? 1.2
141 - (105 6) 30 high
139 ? 113 ? 33 Glucose 126 3.7 ? 16 ? 1.4
139 - (113 16) 10 normal
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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Differential Dx of high-anion gap acidosis
"SLUMPED" Salicylates Lactic
acidosis Uremia Methanol intoxication Paint
sniffing (toluene) Ethylene glycol
intoxication DKA or alcoholic ketoacidosis
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Usually mixed respiratory alkalosis metabolic
acidosis (rare metab pure acidosis)
Toxic at lt 5 mEq/l, so no A- contrib to AG
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Treatment for salicylate intoxication Un-ionized
form (protonated) enters the brain and is
excreted poorly So.alkalinize (HCO3 infusion)
to maximize renal excretion (dialysis)
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Lactic acidosis
Type A increased O2 demand or decreased
O2 delivery Cardiogenic, septic, hemorrhagic
shock Acute hypoxia Carbon monoxide
poisoning Anemia
Type B Malignancies (e.g. lymphoma) Drugs
phenformin, metformin, cyanide, salicylate,
ethylene glycol, methanol, propylene glycol (IV
benzodiazepines), propofol, linezolid
(Zyvox) Hepatic failure Thiamine
deficiency HAART (stavudine, didanosine) Congenita
l enzyme deficiencies(glucose-6-phosphatase) Mitoc
hondrial encephalomyopathy, lactic acidosis, and
stroke-like symptoms (MELAS)
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Uremia is indicated by BUN, creatinine (chronicit
y by kidney size and Hct)
Methanol - presents with abdominal pain,
vomiting, headache CT BL putamen
infarcts visual disturbance (optic neuritis)
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Methanol intoxication neurological effects
Normal retina (left) optic neuritis (right)
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Anion gap may be gt 50
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Paint sniffing (huffing) (toluene) may
present as either anion gap acidosis or normal
gap acidosis Anion hippurate
Street boy in Brazil inhaling paint
thinner. Soda bottle lined with blue paint
after recreational inhalation
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Metabolism of toluene to hippurate
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Ethylene glycol - presents with CNS
disturbances, cardiovascular collapse,
respiratory failure, renal failure
Oxalate crystals (octahedral or dumbell) in
urine are diagnostic
Anion gap may be gt 50
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Oxalate crystals
back of the envelope
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Treatment for methanol ethylene glycol
intoxication
1. Ethanol infusion to compete with alcohol
dehydrogenase (dialysis) OR 2. Antizol
(fomepizole) (inhibits ADH) load, then 10 mg/kg
q12 x 4
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Diabetic ketoacidosis - Key clinical features
are generally type I DM (i.e. no insulin) a
trigger e.g. sepsis, fracture, stroke
hyperglycemia ECF vol depletion renal
insufficiency acetoacetic- and ?
hydroxybutyric- acids
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Alcoholic ketoacidosis - key clinical features
are recent stopping ingestion of ethanol,
hypoglycemia, and contracted ECF (usually due
to vomiting)
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Questions?
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
1. GI bicarbonate loss diarrhea villous
adenoma pancreatic, biliary, small bowel
fistulae uretero-sigmoidostomy obstructed
uretero-ileostomy
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Diarrhea Causes Loss of HCO3- And a Normal Anion
Gap Acidosis And Hypokalemia
Pancreas
Pancreas
HCO3-
HCO3-
Ileum
HCO3-
Ileum
Colon
Colon
HCO3-
K
Normal
Diarrhea
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Flooding the colon or CCD with HCO3- instead of
Cl- drives K secretion
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Pancreatic fistula or transplant loss of HCO3-
Pancreas
HCO3-
Ileum
Skin or urinary bladder
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Obstructed Uretero-ileostomy Causes a Normal
Anion Gap Acidosis
Skin
HCO3-
Ureter
Obstructed ileal loop
Ileal loop
Ileostomy bag
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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
2. Ingestions infusions ammonium
chloride hyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent)
loss proximal RTA distal RTA type IV
RTA early renal failure acetazolamide hydrated
DKA
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Daily proximal tubule HCO3- reclamation 180 L/d
x 25 mEq/L 4500 mEq/d !

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Proximal RTA (Type II)
HCO3- glucose amino acids phosphate
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Type II Renal Tubular Acidosis (Proximal RTA)
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
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Type II Renal Tubular Acidosis (RTA)
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Net acid excretion urinary NH4
urinary H2PO4- - urinary HCO3-
H
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How Diarrhea and Proximal RTA Are Alike
Glomerulus
Pancreas
Ileum
Prox tubule
CCD
Colon
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Urine pH in proximal RTA
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Fractional excretion of HCO3- in proximal RTA
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Features of Proximal Renal Tubular Acidosis
(Type II)
Diminished proximal resorption of HCO3- Plasma
HCO3- 10-15 mEq/L Urine pH depends on plasma
HCO3- GFR relative to proximal HCO3-
Tm Fractional HCO3- excretion high (15-20) at
nl plasma HCO3- Plasma K reduced, worsens
with HCO3- therapy Dose of daily HCO3- required
10-15 mEq/kg/d Non-renal rickets or osteomalacia
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Radiograph of rickets in proximal RTA
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Questions?
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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
3. Renal bicarbonate (or equivalent)
loss proximal RTA distal RTA type IV
RTA early renal failure acetazolamide hydrated
DKA
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Distal RTA
Principal cell
a IC cell
b IC cell
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Distal RTA
Principal cell
(Window air conditioner running with window open)
a IC cell
b IC cell
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Distal RTA
Principal cell
a IC cell
b IC cell
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Hypo- kalemia in distal RTA H no longer
shunts Na current so K must do so
Principal cell
a IC cell
b IC cell
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Urine pH in distal RTA
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Fractional excretion of HCO3- in distal RTA
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Features of Classic Distal Renal Tubular Acidosis
(Type I)
Diminished distal H secretion (autoimmune) or
backleak of secreted H (ampho-B) Plasma HCO3-
may be below 10 mEq/L Urine pH always gt
5.5 Fractional HCO3- lt3 at nl plasma
HCO3- Plasma K reduced Dose of daily
HCO3- required 1-2 mEq/kg/d Non-renal
nephrocalcinosis, renal stones
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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
3. Renal bicarbonate (or equivalent)
loss proximal RTA distal RTA type IV
RTA early renal failure acetazolamide hydrated
DKA
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Hyporenin- hypo aldosteronism
Principal cell
Diabetes is the main cause
a IC cell
b IC cell
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Voltage type Hyperkalemic Distal RTA
Principal cell
Obstruction Sickle Cell Triamterene Amiloride Tri
methoprim Pentamidine Pseudohypo- aldosteronism
a IC cell
b IC cell
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Lasix amiloride
Urine pH
Lasix
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Total Body K Excess Decreases Proximal Tubule
Acidification and Ammoniagenesis via
Intracellular Alkalosis
2. Total body K excess
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Features of the Hyperkalemic Distal RTAs
Aldosterone deficiency or resistance
(voltage) Plasma HCO3- usually above 15
mEq/L Urine pH depends generally lt 5.5 in
hypoaldosteronism generally gt 5.5 in voltage
defect Fractional HCO3- excretion lt3 at nl
plasma HCO3- Plasma K elevated Dose of
daily HCO3- required 1-3 mEq/kg/d Non-renal
none
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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
2. Ingestions infusions ammonium
chloride hyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent)
loss proximal RTA distal RTA type IV
RTA early renal failure acetazolamide hydrated
DKA
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Excretion of the Daily Acid Load is Decreased
in Chronic Renal Failure (CRF) or Distal Renal
Tubular Acidosis (dRTA)
TA titratable acidity phosphate
Kim et al, AJKD 1996
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Causes of a normal anion gap (A.K.A.
hyperchloremic) metabolic acidosis
2. Ingestions infusions ammonium
chloride hyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent)
loss proximal RTA distal RTA type IV
RTA early renal failure acetazolamide hydrated
DKA
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Renal handling of acetoacetate in the dog
Self-inhibition of absorption
Schwab and Lotspeich 1954
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Renal handling of acetoacetate And b-OH butyrate
in the rat
Self-inhibition of absorption
Endogenous levels Good resorption
Elevated levels Poor resorption
Ferrier et al, 1992
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Pathophysiology of normal anion gap acidosis in
diabetic ketoacidosis
(high anion gap acidosis)
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Questions?
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
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Vomiting
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Vomiting
Na loss
Chloride loss
H loss
K loss, K intake
TG feedback
ECF volume
Plasma pH and HCO3
Sympathetic tone
Renin
pCO2
Distal chloride delivery
Local Ang II
GFR
Systemic Ang II
High HCO3 Tm
Filtered HCO3
Low filtered HCO3 load
CCD HCO3 secretion
CCD HCO3 resorption
Aldosterone
Renal HCO3 resorption
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DIFFERENTIAL DIAGNOSIS OF METABOLIC ALKALOSIS
USING URINE Cl
Normal Urine Cl-
Low Urine Cl-
Mineralocorticoidism RAS aldosteronism 11-b?OH?
DH deficiencies Bartters Gitelmans
Vomiting
NG suction
Diuretics (late)
Posthypercapnia
Cystic fibrosis
Diuretics (early)
Low Cl- intake
Severe K depletion
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Questions?
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
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The Drives to Ventilation CO2 and O2
Central chemoreceptors ventilation
Carotid aortic bodies
Minute ventilation
20
40
60
40
80
120
pCO2
pO2
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Causes of Respiratory Acidosis
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Chronically Elevated pCO2 Causes Low pHi in
Proximal Tubules which Stimulates Formation of
New HCO3- by Ammoniagenesis
Glutaminase
Glutamine NH3
Na
H
H
NH4
NH3
NH3
HCO3-
Na
NH4
NH4
Proximal tubule
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The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
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Causes of Respiratory Alkalosis
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Chronic Reduction in pCO2 Lowers HCO3- Tm
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
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EXTRA CREDIT WHAT IS THE ACID-BASE DISTURBANCE?
1. Anion gap is high (20) addition of organic
acid (footprints)
2. pH is high alkalosis must be superimposed
on Anion Gap acidosis but respiratory alkalosis
would lower HCO3- so must be metabolic alkalosis
(vomiting?)
3. But the pCO2 is too low for a normal HCO3-
respiratory alkalosis
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Survivors in Andromeda Strain
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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NH4 undergoes counter-current multiplication-1
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Counter-Current Multiplication
1. At the start all cups have 10 pennies 2. All
new incoming cups have 10 pennies
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What you will understand after todays lectures

• The derivation and use of the anion gap in
  metabolic acidosis
• The causes of high anion gap metabolic acidoses
• The causes of normal anion gap metabolic
  acidoses
• The pathophysiology of metabolic alkalosis due to
  prolonged vomiting
• The causes of respiratory acidosis
• The causes of respiratory alkalosis
• How solute transfer and solvent flow concentrate
  medullary solutes by counter-current
  multiplication

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End of Patho-Physiology Section (Acid-Base Part 2)
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