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1-3. Electrolyte disorders. Tatyana Nastausheva (eng)


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1-3. Electrolyte disorders. Tatyana Nastausheva (eng)

  1. 1. ELECTROLYTE DISORDERS: diagnosis and management T.L.Nastausheva October 22nd 2013 Moscow
  2. 2. 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
  3. 3. 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)
  4. 4. Objective  Illustrate the tubular functions via:  Bartter syndrome  Gitelman syndrome  Pseudohypoaldosteronism
  5. 5. 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)
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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)
  12. 12. 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)
  13. 13. Magnesium  Around 95% of filtered Mg is reabsorbed in the tubules  70-75% in the TAL  10% in the DT
  14. 14. 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)
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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)
  26. 26. 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
  27. 27. PHA  < Na, <Cl in serum  > K in serum, metabolic acidosis  Hypertension (PHA type II)
  28. 28. Clinical      Neonatal or later presentation Prematurity Vomiting, poliuria, dehydration Crams Growth retardation
  29. 29. Bartter syndrome Treatment  Correction of the volume and electrolytes: Na, K  Indometacin 1 mg/кg/day
  30. 30. 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
  31. 31. Pseudohypoaldosteronism Treatment  Correction of electrolytes: К, Na  Na bicarbonate  Thiazides 0.04 – 0.12 mg/кg/day
  32. 32. Thank You for attention