Transcript RTA - The European Society for Paediatric Nephrology

Electrolytes and pH
disturbancies: clinical signs to
make a correct diagnosis and
an early treatment
Alberto Bettinelli
Departments of Pediatrics
Leopoldo Mandic Hospital, Merate (LC)
Italy
Case 1
An Albanese child…
Clinical presentation
• Male. Age: 2 years and 3 months
• Poor clinical condition with signs of dehydration
and chronic malnutrition (hypotrophia of muscles
with abdominal protrusion, hypotonia,
psychomotor retardation)
• Polypnea, 60/min
• Weight Kg. 7.610, lenght cm. 75 (< 3° percentile)
• Blood pressure 68/34 mmHg
Emergency measures
• - adequate periferal perfusion with
administration of isotonic saline (20
ml/kg/h)
• - delivery of 02
First biochemical
examinations
• venous pH 7.101
• plasma bicarbonates, 5.0
mmol/l
• pC02 16.2 mmHg
QUESTIONS ?
1) Is it a simple metabolic acidosis?
2) Is it a metabolic acidosis with
normal plasmatic anion gap?
Is it a simple metabolic
acidosis?
• Predicted metabolic and respiratory compensations
to simple primary acid-base disturbances
• (Bianchetti MG and Bettinelli A in Comprehensive
Pediatric Nephrology, Geary DF and Schaefer F Ed;
Mosby Elsevier 2008:395-432)
• Metabolic Acidosis: Primary Change  HCO3• Compensatory response:  pCO2 by 1.3∆ mm Hg 
for  1.0 mmol/L* in HCO3• ∆ range approximately ± 3 mm Hg; * from 25 mmol/L;
range approximately ± 2.0 mmol/L;  from 40 mm Hg.
First biochemical examinations
• Venous ph 7.101; plasma bicarbonates
5.0 mmol/l; pC02 16.2 mmHg
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∆bicarbonates: 25-5 = 20
∆pC02: 20 x 1.3 = 26.0
40-26.0 = 14.0 = expected pC02
The respiratory compensation is
appropriate = simple metabolic acidosis
After some hours
• Venous ph 7.150; plasma bicarbonate 8.7
mmol/l, pC02 26.9 mmHg
• Plasma Na 135, K 4.3, Cl 116 mmol/l
• Plasma anion gap:
• (Nap + Kp) – (Clp + Bicarbonate) = 14.6
• (Ref values 8-18; If you do not include K = 4-14)
• Plasma anion gap is normal: the major cause
of metabolic acidosis with normal anion gap was
excluded (gastrointestinal loss di bicarbonates)
Metabolic acidosis with normal anion gap
•
- Losses of bicarbonate HCO3-
•
- intestinal: diarrhea, surgical drainage of the intestinal tract, gastrointestinal fistulas
resulting in losses of fluid rich in HCO3-, patients whose ureters have been attached
to the intestinal tract
- urinary: carbonic anhydrase inhibitors (e.g.: acetazolamide), proximal renal tubular
acidosis (= type 2)
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- Failure to replenish HCO3- stores depleted by the daily production of
fixed acids
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- distal renal tubular acidosis (either classic, also called type 1 or type 4)
- diminished mineralocorticoid (or glucocorticoid) activity (adrenal insufficiency,
selective hypoaldosteronism, aldosterone resistance)
- administration of potassium sparing diuretics (spironolactone , eplerenone,
amiloride, triamterene)
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- Exogenous infusions
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- Amino acids like L-arginine and L-lysine (during parenteral nutrition)
- HCl or NH4Cl
- Rapid administration of normal saline (= NaCl 9 g/L) solution (= “dilutional”
metabolic acidosis)
•
Other questions
3) How is the urinary ammonium (urinary
anion gap)?
4) Can you perform some simple
investigations?
Response: question 3
3) How is the urinary ammonium (urinary anion
gap) ?
• Urinary anion gap: in non renal metabolic
acidosis urinary Cl>Na+K; this is because
urinary ammonium accompanies Cl
• In this case: Cl 23; Na 20; K 11.4 mmol/l
• Na + K – Cl = 31.4 -23 = + 8.4; a positive net
charge indicates an impaired ammonium
secretion and, therefore, impaired distal
acidification of renal tubule
Response to question 4)
4) Can you perform some simple
investigations?
Other investigations
• Renal ecography demonstrated
nephrocalcinosis
• Urinary pH; not very simple to detect with
the usual methodology
• Our urinary pH (with a plasma venous pH
between 7.101 and 7.150): 7.248-7.456
• Diagnosis of DISTAL RENAL TUBULAR
ACIDOSIS (DRTA, type 2)
Administration of bicarbonate?
• - Possible benefits: metabolic advantage of faster
glycolysis with better availability of adenosine
triphosphate in vital organs, and improved cardiac action
• - Risks: extracellular fluid volume expansion, tendency
towards hypernatremia and devolepement of
hypokalemia and hypocalcemia
• - In this case a correction was started slowly:
• Body weight x 0.5 (desired bicarbonate- current
bicarbonate): 7.6 x 0.5 (9-5) = 15.2 mmol in some hours
in normal saline
Treatment
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Glucose 5% = 1.800 ml/mq/day
NaCl = 60 mEq/mq/day
KCl = 40 mEq/day
NaHC03- = 20 mEq/day
• - Than orally: NaHC03-, 1 gr/kg/day + potassium
citrate 1 mEq/kg/die
• After 7 days: venous pH 7.310; plasma
bicarbonates 21.3 mmol/l; pC02 43.6 mmHg
Audiometry evaluation
• The first investigation (the test tones were
warble tones) was in the normal range.
• Further audiometry evaluations are
required
Molecular diagnosis
• …the molecular diagnosis was of distal renal tubular
acidosis due to an homozygous mutation in the
ATP6V1B1 gene ( homozygous L81P mutation)
• This mutation is known to be associated with
neurosensorial deafness
(Tasic V et al: Atypical presentation of DRTA in two
siblings. Pediatr Nephrol 2008; 23:1177-81)
- Laboratory investigations revealed proximal tubular
dysfunction that disappeared some months after the
beginning of the treatment
Case 2
• The child was in apparent good health up to the age of 9
months when he was admitted to the Hospital for
gastroenteritis
• In the urgency plasma Potassium was 1.7 mmol/l
• He presented a cardiac arrest followed by immediate
reanimation.
• After this episode he did not present any cardiac or
neurologic complications
• When he left the Hospital, the child was in good clinical
conditions and his plasma K was between 2.9-3.0 mmol/l
Interpretation
• The severe hypokalemia was considered
the cause of cardiac arrest (probably
associated with cardiac arrhythmias)
• Rotavirus was identified as the
pathogenetic factor of the severe
gastroenteritis
At 10 years of age
• He was admitted to the Hospital for a suspicious
of appendicitis. His plasma potassium was 2.3
mmol/l
• After surgery his plasma potassium levels
persisted at low levels (2.5 e 3.0 mmol/l )
• In this case the origin of hypokalemia was
investigated
• New hypothesis??
• It appeared as a chronic condition of
hypokalemia
How is blood pressure?
• His blood pressure was always normal: 90/60 mmHg
= in the reference range
• We can exclude hypokalemia associated with high blood
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pressure (often linked with metabolic alkalosis; total K+ body content
normal)
-  renin: primary aldosteronism (either hyperplasia or adenoma), apparent
mineralocorticoid excess (= defect in 11--hydroxysteroid-dehydrogenase),
Liddle syndrome (congenitally increased function of the collecting tubule
sodium channels), dexamethasone-responsive aldosteronism (synthesis of
aldosterone promoted not only by renin but also by adrenocorticotropin),
congenital adrenal hyperplasia (11--hydroxylase or 17--hydroxylase
deficiency), Cushing disease, exogenous mineralocorticoids, licoriceingestion (= 11--hydroxysteroid-dehydrogenase blockade)
-  or  renin: renal artery stenosis, malignant hypertension, renin
producing tumor
Hypokalemia associated with normal-low blood
pressure
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 True potassium depletion (= total K+ body content reduced)
 Extrarenal “conditions”
- Prolonged poor potassium intake, protein-energy malnutrition
- Gastrointestinal conditions: gastric (associated with alkalosis), vomiting,
nasogastric suction; small bowel ; associated with acidosis: biliary drainage,
intestinal fistula, malabsorption, diarrhea, congenital chloride diarrhea
- Acid-base balance unpredictable: bowel cleansing agents, laxatives, clay
ingestion, potassium binding resin ingestion
- Sweating, full thickness burns
 Renal “conditions”
- Interstitial nephritis, post-obstructive diuresis, recovery from acute renal failure
- With metabolic acidosis: renal tubular acidosis (type I or II), carbonic
anhydrase inhibitors (e.g.: acetazolamide), amphotericin B, outdated
tetracyclines
- With metabolic alkalosis:
- Inherited conditions: Bartter syndromes, Gitelman syndrome, and
related syndromes
- Acquired conditions: normotensive primary aldosteronism, loop and thiazide
diuretics, high dose antibiotics (penicillin, naficillin, ampicillin, carbenicillin)
Main investigations
• The child was in good clinical conditions; his growth was
between the 30-50° percentile
• Main biochemical data:
• - plasma K, 2.5-2.9 mmol/l ↓; FeK 39-45% ↑
• - plasma bicarbonates 28-35 mmol/l ↑
• - plasma Na, 140-141 mmol/l; FeNa 1.4-1.8% ↑
• - plasma Cl, 94-99 mmol/l; FeCl 2.5-2.7 ↑
• - plasma Mg 0.5-0.6 mmol/l ↓; FeMg 4.7-5.4% ↑
• - urinary calcium/creatinine 0.001 mg/mg ↓ ↓
• - plasma renin activity, 11-15 ng/ml /h (ref. < 5) ↑
• - plasma aldosterone, 75-143 pg/ml (ref. 50-300)
Main probable diagnosis
• GITELMAN SYNDROME:
- hypokalemia with increased FeK and
increased FeCl
• - metabolic alkalosis
• - hypomagnesemia
• - hypocalciuria
• - hyper-reninemia associated with normal
blood pressure
• - usually diagnosis during schoolife and
young adults
• - some patients with growth failure
Differential diagnosis
• BARTTER SYNDROME TYPE III:
- hypokalemia with increased FeK and increased
FeCl
• - metabolic alkalosis
• - NORMO-MAGNESIEMIA (sometimes
hypomagnesemia, 39% of cases*)
• - VARIABLE CALCIURIA (sometimes hypocalciuria
8% of cases*)
• - hyper-reninemia associated with normal blood
pressure
• - usually diagnosis during early childhood
• - half of the patients with growth failure
*Konrad M et al; J Am Soc Nephrol 2000; 11:1449-59
Thiazide test
(Colussi G, Bettinelli A, 2007)
• A wash out period of at least 7 days was
allowed between withdrawal of any therapy
and thiazide test; however, oral KCl and Mg
salts, if already in use, were maintained and
stopped the day before the test
• Thiazide test: after un overnight fast, the
patients were invited to drink tap water (10
ml/kg b.w.) to facilitate spontaneous voiding
Hydrochlorothiazide (HCT)
1 mg/kg b.w.
- 60 - 30
Mean of the two
urinary values
0
30
60
90
120
150
Maximum urinary value obtained after HCT
Plasma Na, K, Cl and
creatinine
180
DFECl
• maximal excretion of FECl at any
time after HTC administration
• minus the mean of the two basal
FECl
DFECl: 0.60%
∆ Fractional Chloride Excretion, %
20
10
5
2
1
0.5
0.2
Bartter
Control Gitelman Syndrome
Subjects Adults Children Syndrome
Molecular evaluation
• The child presented two heterozigous
mutations on the gene SLC12 A3
• Therapy consisted of oral KCl
supplementation
• QTc was 0.44”
• No other cardiac complication was
reported
Mutations in the SLC12A3 gene
found in the Italian population
1
2
R3
4
5
6
7
8
9
10
11
12
COOH
NH2
Mutations demonstrated in patients subjected to HCT test
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Severe syncope and sudden death in
children with inborn salt-losing
hypokalaemic tuulopathies. Cortesi C,
Bettinelli A, Bianchetti M.; Nephrol Dial
Transplant 2005; 20: 1981-3
- 249 children were evaluated with inborn saltlosing hypokalaemic tubulopathies
- 19 European paediatric kidney disease
specialists
- Four patients died suddendly and 3 had severe
syncope
- These episodes occurred in the context of
severe chronic hypokalemia (< 2.5 mmol/l) or
were precipitated by acute diseases, which
exacerbated hypokalemia (< 2.0 mmol/l)
Chronic treatment
• - KCl supplementation
• - Antialdosteronic drugs (Spironolactone,
amiloride)
Final message
• In patients with inborn salt-losing
tubulopathies, diarrhoea or vomiting may
cause severe, hazardous hypokalemia (<
2.0 mmol/l)
• A prompt electrolyte and fluid repair is of
paramount importance