Electrolytes and pH disturbancies: clinical signs to make a correct diagnosis and

an early treatment

Alberto BettinelliDepartments 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

• ∆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)

• - Failure to replenish HCO3- stores depleted by the daily production of fixed acids

• - 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)• - Exogenous infusions• - 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

• 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 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, licorice-ingestion (= 11--hydroxysteroid-dehydrogenase blockade)

• - or renin: renal artery stenosis, malignant hypertension, renin producing tumor

Hypokalemia associated with normal-low blood pressure

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

- 60 - 30 0 30 60 12090 150 180

Plasma Na, K, Cl and creatinine

Hydrochlorothiazide (HCT)1 mg/kg b.w.

Mean of the twourinary values

Maximum urinary value obtained after HCT

FECl

• maximal excretion of FECl at any time after HTC administration

• minus the mean of the two basal FECl

FECl: 0.60%

t test dataControlGit AGit CBartterPseudob0.1110100

ControlSubjects

BartterSyndrome

Gitelman Syndrome

Adults Children

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5

20

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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 genefound in the Italian population

NH2

R

COOH

1 3 4 5 7 8 9 10 11 1262

Mutations demonstrated in patients subjected to HCT test

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 salt-losing 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