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