1. ELECTROLYTE
DISORDERS:
diagnosis and management
T.L.Nastausheva
October 22nd 2013
Moscow

2. Causes of Hyponatremia in
Children
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Hypovolemic
Normovolemic hyponatremia (DM)
Intestinal salt loss
Diarrheal dehydration
Vomiting,gastric suction
Fistulae
Laxative abuse
Transcutaneous salt loss
Cystic fibrosis
Endurance sport
Renal sodium loss
Mineralocorticoid defiency (or resistance)
Diuretics
Salt-wasting renal failure
Salt-wasting tubulopathies
Cerebral salt wasting
Perioperative
Third space losses (burns, septic shock,
sergery)
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Normovolemic or Hypervolemic
Increased body water
Parenteral hypotonic solutions
Tap water enemas
Compulsive water drinking
Nonosmolar release of antidiuretic hormone
Cardiac failure
Severe liver disease (mostly cirrhosis)
Nephrotic syndrom
Glucocorticoid deficiebcy
Drugs causing renal water retention
(hypotyroidism)
Syndrome of inappropriate antidiuresis
Classic syndrome of inappropriate secretion of
antidiuretic hormone
Hereditary nephrogenic syndrome of
inappropriate antidiuresis
Reduced renal water loss
Chronic renal failure
Oliguric acute renal failurei
Мario G.Dianchetti, Alberto Bettinelli, 2008

4. Objectives
 review the tubular handling of the major electrolytes
(Na⁺, K⁺, Ca⁺², Mg⁺²)
 understand the role of the tubular cells involved in
the handling of electrolytes:
1. Proximal tubular cell (PT)
2. Thick ascending limp cell (TAL)
3. Distal tubular cell (DT)
4. Collecting dust cell (CD)

6. Objective
 Illustrate the tubular functions via:
 Bartter syndrome
 Gitelman syndrome
 Pseudohypoaldosteronism

7. NA (Sodium)
 In adults more than 99% of filtered Na⁺ is reabsorbed
in the tubules
 20-30% reabsorbed in the thick ascending limb (TAL)
 5-10% is reabsorbed in the distal tubule (DT)
 5-10% is reabsorbed in the collecting dust (CD)

8. Sodium: TAL
 Na⁺ and cloride (Cl¯) enter the cell via the apical
electroneutral Na⁺-K⁺-2Cl¯ cotransporter (NKCC2)
 This is electrochemically favorable because of low
intracellular Cl¯ and K⁺ levels
 The low intracellular K⁺ levels are maintained by the
ROMK channel
 Low Cl¯ levels are maintained by CIC-Kb channel

10. Sodium: DT
 Sodium in the DT is reabsorbed at the apical
membrane via the thiazide sensitive
Na⁺- Cl¯ contransporter (TSC)
 At the basolateral surface Na⁺ and Ca⁺² compete for
reabsorption in the DT
 The more Na arrives at the DCT the less Ca is
reabsorbed and the greater the degree of
hypercalciuria

12. Sodium: CD
 Na⁺ is reabsorbed through ENaC located on the
apical membrane of principal cells
 ENaC activity and density is under the control of
aldosterone
 These channels are responsible for the final
modification of sodium excretion in response to oral
intake
 Each molecule of Na reabsorbed requires the
secretion of K⁺ (or H⁺) ion

14. Potasium
 Unlike Na⁺, K⁺ is both reabsorbed and secreted in the tubules
 25% is reabsorbed in the TAL via Na⁺-K⁺-2Cl¯ transported
 By the time the filtrate reached the DCT only 10% of filtered
K+ remains

15. Potassium - Secretion
 In the collecting dust K⁺ is secreted and not reabsorbed
 The basolateral Na⁺/K⁺ATPase activity drives the whole
process
 The magnitude of K⁺ secretion depends on: availability
of Na⁺(electrochemical gradient), serum K⁺,
aldosterone, urine flow rate

17. Calcium
 98-99% Ca⁺² reabsorbed in the tubules
 20% is reabsorbed in the TAL, which is driven by the
large positive transepthelial voltage difference
 This is in part regulated by the calcium sensing
receptor (CaSR)

18. Calcium: DT
 5 – 10% of Ca⁺² is reabsorbed in the DT
 In contrast to the proximal tubule and TAL most of the
Ca reabsorbed in the DT is transcellular (TRPV-5)

19. Magnesium
 Around 95% of filtered Mg is reabsorbed in the tubules
 70-75% in the TAL
 10% in the DT

20. Magnesium: TAL
 Mg⁺² absorption is passive and paracellular
 The main driving force is the transepithelial voltage
gradient
 The permeability of the paracellular pathway is
determined by proteins such as paracellin-1 (claudin 16)

21. Magnesium: DT
 Responsible for 10% of Mg⁺² reabsorption
 Recent evidence suggests that the TSC interacts with
the TRPM6 (Mg⁺² transporter) in the DT and causes
Mg⁺² wasting

23. Bartter/Gitelman Syndrome
 Both characterized by renal salt wasting,
hypokalemia, and metabolic alkalosis
 Bartter syndrome (BS) is associated with
hypercalciuria and normal serum magnesium levels
 Gitelman syndrome typically associated with
hypocalciuria and hypomagnesemia

24. Bartter/Gitelman Syndrome
 The different phenotypes are the result of genetic
defects causing impaired channel activity at different
locations within the nephron
 Bartter syndrome = Defective TAL
 Gitelman syndrome = Defective DT

25. Genetics of Bartter/Gitelman
syndromes
TYPE
GENE
Gene
Product
Bartter I
SLC12A1
NKCC2
Neonatal BS
Bartter II
KCJN1
ROMK
Neonatal BS
Bartter III
CICKB
CIC-Kb
Classic BS
Bartter IV
BSND
Barttin
Neonatal BS/
Deafness
Gitelman
Syndrome
SLC12A3
TSC
Gitelman
Phenotype

27. Clinical
 Neonatal Bartter Syndrome
(BS type I, II, IV)
 Neonatal or fetal presentation
 Severe polyhydramnios
 Prematurity (usually 27-35 weeks)
 Severe intravascular volume depletion/dehydratation
 Polyuria
 Growth retardation
 Rarely Deafness

28. Clinical
 Classic Bartter Syndrome (Type III)
 Usually presents under the age of 6
 Salt craving
 Polyuria/dehydration
 Emesis/constipation
 Failure to thrive
 Rarely periodic paralysis/rhabdomyolysis

29. Clinical
 Gitelman Syndrome
 May present anytime but usually in adolescence or early
adulthood
 Muscle weakness/spasms/tetany
 Paresthesias
 Salt craving
 Polydipsia/polyuria
 Joint pains (chondrocalcinosis)
 Rarely cardiac arrhythmias
 Rarely periodic paralysis/ rhabdomyolysis

30. Bartter syndrome
 The renin - aldosterone system is activated in an
attempt to counteract the volume/Na+ loss
 This stimulating excess K⁺ and H⁺ excretion in the
collecting dust
 In the BS the profound hypovolemia and hypokalemia
further stimulate excessive prostaglandin E2
production
 This amplifies to the defect in Na⁺ and H2O
reabsorption

32. Hypercalciuria in Bartter syndrome
 The potential difference maintained across the TAL is
lost and therefore calcium is not able to be reabsorbed
paracellularly
 There is decreased calcium reabsorption in the DT
because it normally competes with sodium which is
now more abundant

33. Gitelman syndrome and
hypocalciuria
 Decreased entry of Cl¯ through the TSC and leakage
of Cl¯ out the basolateral membrane hyperpolarizes
the membrane and opens TRPV-5 channels
 Na⁺ and Ca⁺² competes for reabsorption in the DT.
Less Na reabsorption promotes greater Ca
reabsorption

34. Pseudohypoaldosteronism
 Type I (cortical collecting tubule)
 Autosomal recessive: reduced sodium channel activity
 Autosomal dominant: mutations in gene for
mineralocorticoid receptor, phenotype mild and
transient
 Type II (familial hyperkalemic hypertension or Gordon
syndrom)

35. Genetics of Pseudohypoaldosteronism
TYPE
GENE
Gene
Product
Phenotype
Type I (AR)
S NCCLB,
SNCCLA,
16p12, 12p13
ENaC
Severe PHA
Type I (AD)
MRL, 4q31.1
Mineraloc.rec.
Mild and
transient PHA
Type II
WNK1, WNK4, NCC
KLYL3, CCUL3
PHA + AH

37. PHA
 < Na, <Cl in serum
 > K in serum, metabolic acidosis
 Hypertension (PHA type II)

38. Clinical
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Neonatal or later presentation
Prematurity
Vomiting, poliuria, dehydration
Crams
Growth retardation

40. Bartter syndrome
Treatment
 Correction of the volume and electrolytes: Na, K
 Indometacin 1 mg/кg/day

41. Gitelman syndrome
Treatment
 Correction of electrolytes: К, Mg, Na
 Mg 10-20 мg/кg
 К (3.0 – K)x weight x 0.04 = К mMoll

42. Pseudohypoaldosteronism
Treatment
 Correction of electrolytes: К, Na
 Na bicarbonate
 Thiazides 0.04 – 0.12 mg/кg/day

43. Thank You for attention