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RTA Hypotonia

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RTA Hypotonia Powered By Docstoc
					      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

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




- 60 - 30          0   30         60    90      120    150        180


 Mean of the two       Maximum urinary value obtained after HCT
 urinary values



        Plasma Na, K, Cl and
             creatinine
              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

                                           Control Gitelman Syndrome Bartter
                                           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
        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