Investigation of the child with

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Investigation of the child with metabolic
acidosis Martin Konrad University Childrens
Hospital, Inselspital Bern, Switzerland
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Metabolic Acidosis, Outline

• Background, Physiology
• Clinical work-up
• Renal tubular acidosis
• Example

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Metabolic Acidosis, Outline

• Background, Physiology
• Clinical work-up
• Renal tubular acidosis
• Example

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Acid
ACUTE vomiting / respiratory distress / seizures
CHRONIC growth / stones / bone density
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Acid Base balance
Children produce 2-3 meq/kg of non-volatile
acid, mostly sulfuric acid or amino
acids These hydrogen ions must be excreted
(steady state) Buffers HCO3- (extracellular
fluid) proteins, phosphate (inside cells)
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Renal excretion of acid
1. Reabsorption of filtered HCO3- 2. Secretion
of hydrogen ions, that combine either with
titratable acids or with ammonia. a) HPO42-
H ? H2PO4- b) NH3 H ? NH4
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acid disposal per day 15,000 mmol via lung as
CO2 non-volatile H consumes 100 mmol
HCO3- 70 mmol H requires secretion
into urine
Collecting duct ?-intercalated cell
Proximal tubule cell
lumen interstitium
lumen interstitium
Urine pH 4.5 - 8.5
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Mechanisms of Bicarbonate Reabsorption
UpToDate?
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Titrabable Acidity
UpToDate?
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Formation of Ammonium
UpToDate?
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Metabolic Acidosis, Outline

• Background, Physiology
• Clinical work-up
• Renal tubular acidosis
• Example

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Metabolic acidosis (low pH, low HCO3-)

• 1. Net gain of H ions (acid generation)
  - exogenous (e.g. salicylate) - endogenous
  (ketone and lactate)
• 2. Net loss of HCO3-
• - gastrointestinal tract - kidney - loss
  of HCO3- precursor (ketoacids)
• Diminished renal acid excretion - renal
  failure - distal renal tubular acidosis

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Metabolic acidosis, compensatory response
?
?
Increased ventilation begins 1st hour, completed
by 12 14 hrs.
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Alterations in primary acid base disorders
Disorder pH HCO3- PaCO2 Normal 7.40 24
meq/L 40 mmHg Metabolic acidosis decreased decrea
sed decreased Metabolic alkalosis increased incre
ased increased Respiratory acidosis decreased incr
eased increased Respiratory alkalosis increased de
creased decreased
Unfortunately, this rarely happens like this.....
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Expected alterations in metabolic acidosis
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Simple and mixed disorders (I)
Example infant with gastroenteritis pH
7.22 HCO3- 9 meq /
L PaCO2 22 mmHg
Respiratory compensation results in a 1.2 mmHg
fall in the PaCO2 for every 1 meq reduction in
the serum HCO3-. Reduction of HCO3- 15 meq /
L (24 9),the expected fall in PaCO2 18
mmHg (15 x 1.2) ? simple metabolic acidosis
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Simple and mixed disorders (II)
Example infant with gastroenteritis pH
7.22 HCO3- 9 meq /
L PaCO2 22 mmHg
The expected PaCO2 can be calculated by Winters
formula PaCO2 (1.5 x HCO3- ) 8 2 the
expected PaCO2 (1.5 x 9) 8 21.5
mmHg ? simple metabolic acidosis
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Simple and mixed disorders (III)
Example infant with gastroenteritis pH
7.22 HCO3- 9 meq /
L PaCO2 22 mmHg
PaCO2 should be approximately equal to the last
two digits of the pH. ? simple metabolic
acidosis
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Expected alterations in metabolic acidosis
It works...
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Metabolic acidosis, diagnostic tools
1. Clinical history, physical examination,labora
tory investigation (BGA, Na, Cl, K, Alb, Gluc,
Crea)
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Metabolic acidosis, infants are more vulnerable

• 1. Lower threshold for HCO3- reabsorption
• Normal serum HCO3- is lower
• Normal PCO2 is lower
• Maximum net acid excretion is limited
• Acid load is higher (50 100 )

? Limited compensation capacity
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Metabolic acidosis, diagnostic tools
1. Clinical history, physical examination,laborat
ory investigation (BGA, Na, Cl, K, Alb, Gluc,
Crea)
2. Serum anion gap - normal anion gap
metabolic acidosis - elevated anion gap
metabolic acidosis AG (meq/L) Na - (Cl -
HCO3- ) AG unmeasured anions (primarily
albumin)Children AG is elevated above 14 16
meq/LNewborns AG is elevated above 16 meq/L
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Anion Gap
normal
elevated
lactate beta-hydroxybutyrate
each 1 g/dL reduction in albumin reduces AG by
appr. 2.5 meq/L Adjusted AG observed AG (2.5
x normal Alb observed Alb) Is this
clinically relevant ?
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Prospective Study metabolic acidosis in PICU
In 134 children with metabolic acidosis, the
correction for serum albuminresulted in an
average increase of the AG by 2.7 meq/L.
Incidence of high AG (gt 18 meq/L) 28 ? 44
Only pts with HCO3- less than 22 meq/L 38
? 73
Durward et al, Arch Dis Child 2003
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Anion Gap
normal
elevated
Loss of HCO3- gastrointestinal
loss diarrhea chronic laxative abuse enteric
fistula ureterosigmoidostomy renal
loss proximal RTA Diminished H
secretion distal RTA early renal failure
Lactic acidosis hypoperfusion mitochondrial
disorders inborn errors of metabolism
corbohydrate metabolism Ketoacidosis diabetes
mellitusInborn errors of metabolism organic
acidemia Ingestions ethanol, salicylates Renal
failure Rhabdomyolysis
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Metabolic acidosis, diagnostic tools

• 1. Clinical history, physical examination,
  biochemistry
• Serum anion gap

3. Urine pHhigher than expected RTA ?Low pH,
normal anion gap diarrhea ? CAVE
hypokalemia 4. Urinary anion gap
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Anion Gap
normal
elevated
Urinary anion gap (UNa UK) - UCl
gt 10
lt - 10
Normal 0
RTArenal failure
diarrhea
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Management of acute metabolic acidosis
Cause specificmeasures
Alkali therapy forsevere acidemia pH lt 7.?
Especially inlactic acidosisketoacidosis
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Metabolic Acidosis, Outline

• Background, Physiology
• Clinical work-up
• Renal tubular acidosis
• Example

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Renal tubular acidoses Type 1
(distal) Primary (inherited) Idiopathic Im
munological disorders e.g. Sjogrens Medullary
sponge kidney Drugs Type 2
(proximal) Primary 2o to Fanconi
syndrome Myeloma Drugs/toxins Type 3
(mixed) Transient Osteopetrosis (CA2
deficiency) Type 4 (?K, distal) Parenchymal
disease Low aldosterone states Toluene
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Acid disposal per day 15,000 mmol via lung as
CO2 non-volatile H consumes 100 mmol
HCO3- overall 70 mmol H requires
secretion into urine
Collecting duct ?-intercalated cell
Proximal tubule cell
lumen interstitium
lumen interstitium
Urine pH 4.5 - 8.5
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• Proximal (Type 2) RTA
• Most often part of Fanconi syndrome (generalised
  proximal tubule dysfunction)
• (e.g.) - cystinosis
• Lowe syndrome
• Wilson's
• tyrosinaemia
• Drugs/toxins - old tetracycline
• - ifosfamide
• - lead, mercury poisoning
• Myeloma
• Also isolated - inherited
• - acetazolamide
• - (CA2 deficiency)

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Usually failure to absorb HCO3, citrate,
urate, amino acids, glucose
hypokalaemia no nephrocalcinosis Acidosis and
urine acidification limited by threshold for
HCO3- Usually milder acidosis Treatment
requires large amounts HCO3, also often K
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• Primary proximal RTA
• very rare
• short stature
• acidosis with bicarbonate wasting
• eye defects band keratopathy
• glaucoma, cataracts
• /- mental retardation
• SLC4A4 (Na bicarb co-transporter) gene defects

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Acid disposal per day 15,000 mmol via lung as
CO2 non-volatile H consumes 100 mmol
HCO3- overall 70 mmol H requires
secretion into urine
Collecting duct ?-intercalated cell
Proximal tubule cell
lumen interstitium
lumen interstitium
Urine pH 4.5 - 8.5
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The ?-intercalated cell an essential collecting
duct contributor to acid-base homostasis
Urine pH 4.5 - 8.5
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Distal RTA (type 1) Lightwood, 1935 Butler et
al. 1936 Metabolic acidosis hypokalemia
nephrocalcinosis rickets
Primary autosomal dominant autosomal recessive
? deafness Secondary autoimmunity
e.g. Sjögrens drugs/toxins e.g.
amphotericin, vanadate
nephrocalcinosis other systemic
diseases pregnancy
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Clinical and biochemical features Wide spectrum
of presentation asymptomatic
? infantile failure to thrive
nephrolithiasis vomiting/dehydration
nephrocalcinosis growth failure
rickets high mortality rate
Progressive bilateral sensorineural hearing loss
in many children Treatment 1-3 mEq/Kg K per
day (e.g. K citrate) may also need
vitamin D for growth (hearing loss
irremediable)
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Diagnosis
URINE - pH ALWAYS gt 5.3 - normal glomerular
function - hypercalciuria - hypocitraturia ( 1
cit 2 HCO3 ) - low U-B (PCO2) and NH4

PLASMA - hyperchloremic metabolic acidosis
w/ normal anion gap - normal Ca and PO4 -
hypokalemia
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Biochemical diagnosis Inability to reduce
urine pH below 5.3 in the presence of
spontaneous or induced metabolic acidosis,
normal renal function Ammonium chloride
challenge Wrong and Davies 100 mg/kg water
emetic!
Fludrocortisone / frusemide test Walter et
al. 1mg 40 mg
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The ATP6 proton pump and anion exchanger AE1 work
in tandem
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Recessive dRTA proton pump failure
X
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(No Transcript)
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d2
d2
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B1 defects dRTA w/ sensorineural hearing loss a4
defects dRTA w/ milder hearing loss
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(No Transcript)
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Sensorineural hearing loss in recessive dRTA
B1 defects dRTA w/ sensorineural hearing loss a4
defects dRTA w/ milder hearing loss ?
B1 defects 37 / 40 patients with early hearing
loss (lt 10 y) a4 defects few patients with late
hearing loss (10 40 y)
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Osteopetrosis (? type 3 RTA)
Rare bone-thickening disease disruption in the
normally balanced processes of bone formation
(osteoblasts) and bone resorption (osteoclasts)
HCO-3
Cl-
Anion Exchanger
Anion Exchanger
Osteoclast
Cl-
H
HCO-3
HCO-3
Cl-
H2CO3
CA II
H
CO2
K
Cl-
ATPase
CAII
Cl-
H2O
CO2
K
ADP Pi
ATP
K
H2O CO2
Cl-
Chloride Channel
ATPase
Na
Cl-
Blood
Lumen
H
Bone
Cathepsin K
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Proximal Tubule
Collecting Duct
Cl-
H
Cl-
H
K
HCO3
HCO-3
Na
H
K
HCO-3
HCO-3 H
Na
CAII
CAII
Cl-
H2O CO2
CAIV
K
K
K
H2O CO2
Na
Na
H2O CO2
Lumen
Blood
Lumen
Blood
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Type 4 (hyperkalemic) RTA
Low renin/aldo Transient (infants)Addisonsadre
nal hyperplasia ACE inhibitors NSAIDs Critical
illness Heparin Cyclosporin Resistance to
aldosterone K sparing diuretics Trimethoprim PHA
Alkali (sodium salts) Fludrocortisone K-lowering
Rx
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Type 2 Type 1 Type 4 proximal distal hype
rkalemic HCO3 variably low may be very
low typically 15-18 K Lowish Low High Urine
pH lt 5.3 if HCO3 low gt 5.3 Usually lt
5.3 enough U-B PCO2 normal decreased decreas
edFe HCO3 gt 15 lt 5 lt 5 Tm
HCO3 decreased normal normalNC/Stones no ye
s no
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Metabolic Acidosis, Outline

• Background, Physiology
• Clinical work-up
• Renal tubular acidosis
• Example

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• Patient C.P., female, 29 weeks of gestation, 1250
  g
• 2nd day tachypnoe, delayed microcirculation
  metabolic acidosis
• BGA pH 7.21, HCO3 14 mmol, pCO2 31 mmHg
• Simple metabolic acidosis?
• Winters formula PaCO2 (1.5 x 14) 8 29
• Decrease HCO3 10 x 1.2 expected fall in PaCO2
  12
• Electrolytes Na 130, Cl 114Anion Gap 130
  (114 14) 2 normal AG

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• Patient C.P., female, 29 weeks of gestation, 1250
  g
• Simple metabolic acidosis with normal AG,
  hyponatremia

• No time to wait for urinary anion gap, no
  diarrhea
• suspect tubular acidosis, renal failure
• further laboratory investigations
• glucose is normal, creatinine is 63 umol/L (2nd
  day) potassium is high (29 wks)

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S-Potassium
10
mmol/L
8
6
4
2
S-Sodium
144
mmol/L
140
136
132
128
124
2
0
-2
base excess
-4
mmol/L
-6
-8
-10
0
5
10
15
20
25
30
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• Patient C.P., female, 29 weeks of gestation, 1250
  g
• Simple metabolic acidosis with normal AG,
  hyponatremia
• No time to wait for urinary anion gap, no
  diarrheasuspect tubular acidosis, renal
  failurefurther laboratory investigationsgluco
  se is normal, creatinine is 63 umol/L (2nd day)
  potassium is high (29 wks)

? hyperkalemic metabolic acidosis ! (normal AG)
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Type 4 (hyperkalemic) RTA
Low renin/aldo Transient (infants)Addisonsadre
nal hyperplasia ACE inhibitors NSAIDs Critical
illness Heparin Cyclosporin Resistance to
aldosterone K sparing diuretics Trimethoprim PHA
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Type 4 (hyperkalemic) RTA
Low renin/aldo Transient (infants)Addisonsadre
nal hyperplasia ACE inhibitors NSAIDs Critical
illness Heparin Cyclosporin Resistance to
aldosterone K sparing diuretics Trimethoprim PHA
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• Patient C.P., female, 29 weeks of gestation, 1250
  g
• adrenal hyperplasia excluded
• transient hyperkalemic RTAPseudohypoaldosteronism
  ?

• Additional information
• Polyhydramnios, otherwise uncomplicated
  pregnancymassive polyuriafollow-up?

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S-Potassium
10
mmol/L
8
6
4
2
S-Sodium
144
mmol/L
140
136
132
128
AntenatalBartterSyndrome?
124
2
0
-2
base excess
-4
mmol/L
-6
-8
-10
0
5
10
15
20
25
30
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Transient hyperkalemia in antenatal Bartter
syndrome (ROMK)
Peters et al, Am J Med 2002
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Peters et al, Am J Med 2002
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Type 4 (hyperkalemic) RTA
Low renin/aldo Transient (infants)Addisonsadre
nal hyperplasia ACE inhibitors NSAIDs Critical
illness Heparin Cyclosporin Resistance to
aldosterone K sparing diuretics Trimethoprim PHA
? Antenatal Bartter syndrome (ROMK)
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Metabolic Acidosis, Summary

• Find out the reason
• Treat the underlying cause
• Be careful with buffers

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Acknowledgements
Fiona Karet, Cambridge University