ELECTROLYTE DISORDERS:diagnosis and management
T.L.Nastausheva
October 22nd 2013
Moscow
Causes of Hyponatremia in Children
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)
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
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)
Objective
Illustrate the tubular functions via:
Bartter syndrome Gitelman syndrome Pseudohypoaldosteronism
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)
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
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
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⁺ ⁺
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
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
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)
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)
Magnesium
Around 95% of filtered Mg is reabsorbed in the tubules
70-75% in the TAL
10% in the DT
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)
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⁺
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
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
TYPE GENE Gene Product Phenotype
Bartter I SLC12A1 NKCC2 Neonatal BS
Bartter II KCJN1 ROMK Neonatal BS
Bartter III CICKB CIC-Kb Classic BS
Bartter IV BSND BarttinNeonatal BS/
Deafness
Gitelman Syndrome
SLC12A3 TSC Gitelman
Genetics of Bartter/Gitelman syndromes
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
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
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
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
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
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
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)
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, KLYL3, CCUL3
NCC PHA + AH
Genetics of Pseudohypoaldosteronism
PHA
< Na, <Cl in serum > K in serum, metabolic acidosis Hypertension (PHA type II)
Clinical
Neonatal or later presentation Prematurity Vomiting, poliuria, dehydration Crams Growth retardation
Bartter syndromeTreatment
Correction of the volume and electrolytes: Na, K
Indometacin 1 mg/кg/day
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
PseudohypoaldosteronismTreatment
Correction of electrolytes: К, Na
Na bicarbonate
Thiazides 0.04 – 0.12 mg/кg/day
Thank You for attention
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