A New Perspective on A New Perspective on Hyponatremia Hyponatremia

by Steve Chenby Steve Chen

Director of Nephrology, Shin-Chu Branch of Taipei Veterans General Hospital

SodiumSodium

Reference Range:136 – 145 meq/L

SodiumSodium

Hyponatremia is Na+ < 135 meq/L

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Serum NaSerum Na++ < 135 meq/L < 135 meq/L– Symptoms due to brain edema: Symptoms due to brain edema:

headache & vomiting if headache & vomiting if NaNa++ < 120 meq/L < 120 meq/L

– CNS symptoms: CNS symptoms: convulsions if convulsions if NaNa++ < 113 meq/L < 113 meq/L

– CV symptoms: CV symptoms: CV collapse if CV collapse if Na < 100 Na < 100 meq/Lmeq/L

Hyponatremia

HyponatremiaHyponatremia

Causes an osmotic fluid shift from plasma into brain cells

Hyponatremic Hyponatremic encephalopathyencephalopathy

Hospital acquired: SIADH Post-operative state: 3-4 L hypotonic fluid in 2 days in female fatal Encephalitis in children: fatal

Risk factors: Children : non-osmotic stimuli of ADH ↑brain/intracranial volume Female: sex steroid inhibit brain adaptation Hypoxemia

Hyponatremic Hyponatremic encephalopathyencephalopathy

Outpatient : Medications Psychogenic polydipsia Water intoxification in infants Marathon runners Hip fracture S/P colonoscopy : ADH↑from bowel

manipulation + polyethelene glycol for bowel preparation Recreational drug: Ecstasy

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Pathophysiology: CNSPathophysiology: CNS– Water shifts into brain cellsWater shifts into brain cells

– ApathyApathy –– Altered Altered ConsciousnessConsciousness

– AgitationAgitation –– Convulsions Convulsions– HeadacheHeadache –– Coma Coma

– Risk of brain damage > during Risk of brain damage > during treatmenttreatment

– Cerebral demyelination syndrome(CDS)Cerebral demyelination syndrome(CDS)

Hyponatremia

Cerebral Demylination Cerebral Demylination Syndrome Syndrome

CDS risk factorsCDS risk factors Development of Hypernatremia ↑S-Na > 25 meq /L in 48Hrs Hypoxemia Hypokalemia Mal-nutrition Severe liver disease Alcoholism Severe burns Cancer U osm ≤ 150 Kg/L

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Serum OsmolalitySerum Osmolality– Number of osmoles (osmotically Number of osmoles (osmotically

active particles) in the serumactive particles) in the serum– Normal rangeNormal range

275 to 295 mosm/L275 to 295 mosm/L

Fluid Balance

2[Serum Na+] + ------------ + ------------Glucose BUN

18 2.8

ELECTROLYTE DISORDERSELECTROLYTE DISORDERSHyponatremiaHyponatremia

Flow of D.D.Flow of D.D.

Plasma Osmolality

Normal (275-295)Isotonichyponatremia

Low (< 275)Hypotonichyponatremia

High (> 295)Hypertonichyponatremia

Hypovolemic Hypervolemic Euvolemic

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypertonicHypertonic Hyponatremia Hyponatremia (P(Posmosm > > 295)295)– Large quantities of solute in ECFLarge quantities of solute in ECF– Water moves from ICF ECFWater moves from ICF ECF– HyperglycemiaHyperglycemia most common cause most common cause

Each 100 mg/dl plasma glucose will Each 100 mg/dl plasma glucose will serum Naserum Na++ by 1.6 meq/L by 1.6 meq/L

– TreatmentTreatment Volume replacementVolume replacement

Hyponatremia, hypertonic

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

IsotonicIsotonic Hyponatremia Hyponatremia (P(Posmosm 275 - 275 - 295)295)– ““PseudohyponatremiaPseudohyponatremia””– Artifact in serum NaArtifact in serum Na++ measurement measurement

2° High levels of plasma proteins and 2° High levels of plasma proteins and lipidslipids

– Etiology:Etiology: HyperlipidemiaHyperlipidemia HyperproteinemiaHyperproteinemia

Hyponatremia, isotonic

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypotonicHypotonic Hyponatremia Hyponatremia (P(Posmosm < < 275)275) Plasma Osmolality

Normal (275-295)Isotonichyponatremia

Low (< 275)Hypotonichyponatremia

High (> 295)Hypertonichyponatremia

Hypovolemic Hypervolemic Euvolemic

Hyponatremia, hypotonic

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypovolemicHypovolemic Hyponatremia Hyponatremia– RenalRenal Na Na++ loss loss

Urine NaUrine Na++ > 20 meq/L > 20 meq/L Etiology:Etiology:

– Diuretic useDiuretic use– Salt-wasting nephropathy (renal tubular acidosis, Salt-wasting nephropathy (renal tubular acidosis,

chronic renal failure, interstitial nephritis)chronic renal failure, interstitial nephritis)– Osmotic diuresis (glucose, urea, mannitol, Osmotic diuresis (glucose, urea, mannitol,

hyperproteinemiahyperproteinemia– Mineralocorticoid (aldosterone) deficiencyMineralocorticoid (aldosterone) deficiency

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypovolemicHypovolemic Hyponatremia Hyponatremia– ExtrarenalExtrarenal Na Na++ loss loss

Urine NaUrine Na++ < 20 meq/L < 20 meq/L Etiology:Etiology:

– Volume replacement with hypotonic fluidsVolume replacement with hypotonic fluids– GI loss (vomiting, diarrhea, fistula, tube suction)GI loss (vomiting, diarrhea, fistula, tube suction)– Third-space loss (burns, hemorrhagic pancreatitis, Third-space loss (burns, hemorrhagic pancreatitis,

peritonitis)peritonitis)– Sweating (cystic fibrosis)Sweating (cystic fibrosis)

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypovolemicHypovolemic Hyponatremia Hyponatremia– TreatmentTreatment

Re-expansion of ECF with Re-expansion of ECF with isotonic salineisotonic saline Correction of underlying disorderCorrection of underlying disorder

To calculate Na deficitTo calculate Na deficit

Sodium deficit = total body water X (desired Na - present Na)

TBW = body wt x 0.6 males 0.5 females

Sodium DeficitSodium Deficit

Na deficit= Vd of plasma Na x Na deficit per ﹝ ﹞liter

Vd of plasma Na = TBWa = 0.5 x LBW if ﹝ ﹞female =0.6 x LBW if man

60Kg woman, Thiazide 5 days, acute confusion, plasma Na = 108meq/L. If Na =120 is ﹝ ﹞ ﹝ ﹞safe, sodium deficit= 0.5x 60x﹙120-108 =360 ﹚

Urine Na> 40meq/L indicates Normovolemia restored

NS supplied for fear of postsupply overdiuresis

Post-N/S diuresis: turn off Post-N/S diuresis: turn off ADH ADH

U osm <100 mOsmInitial rate before P-Na targeted:

ongoing free water loss = UV x [ 1-( UNa+UK / PNa+PK ) ]

Later rate after P-Na targeted: free water loss = UV x [ 1-( UNa+UK-oral Na+K-IV Na+K / PNa+PK ) ]

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

EuvolemicEuvolemic Hyponatremia(1) Hyponatremia(1)– SIADHSIADH

Hypotonic hyponatremiaHypotonic hyponatremia Inappropriately elevated urine osmolality (usually > Inappropriately elevated urine osmolality (usually >

200 mosm/kg)200 mosm/kg) Elevated urine NaElevated urine Na++ (> 20 meq/L) (> 20 meq/L) Clinical euvolemiaClinical euvolemia Normal adrenal, renal, cardiac, hepatic, and thyroid Normal adrenal, renal, cardiac, hepatic, and thyroid

functionfunction

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

EuvolemicEuvolemic Hyponatremia(2) Hyponatremia(2)– Etiology:Etiology:

HypothyroidismHypothyroidism Pain, stress, nausea, psychosis (stimulates Pain, stress, nausea, psychosis (stimulates

ADH)ADH) Drugs: ADH, nicotine, sulfonylureas, Drugs: ADH, nicotine, sulfonylureas,

morphine, barbs, NSAIDS, APAP, morphine, barbs, NSAIDS, APAP, Carbamazepine, Phenothiazines, TCAs, Carbamazepine, Phenothiazines, TCAs, Colchicine, Clofibrate, Cyclophosphamide, Colchicine, Clofibrate, Cyclophosphamide, Isoproterenol, Tolbutamide, MAOIsIsoproterenol, Tolbutamide, MAOIs

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

EuvolemicEuvolemic Hyponatremia(3) Hyponatremia(3)– Etiology:Etiology:

Water intoxication (psychogenic polydipsia)Water intoxication (psychogenic polydipsia) Glucocorticoid deficiencyGlucocorticoid deficiency Positive pressure ventilationPositive pressure ventilation PorphyriaPorphyria Essential (reset osmostat or Essential (reset osmostat or sick cell sick cell

syndromesyndrome))

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

Treatment of Severe Hyponatremia(4)Treatment of Severe Hyponatremia(4)– Indications:Indications:

Serum NaSerum Na++ < 120 meq/L < 120 meq/L Rapid development ( NaRapid development ( Na++ > 0.5 meq/L/hr) > 0.5 meq/L/hr) Patient in extremis (coma, seizures)Patient in extremis (coma, seizures)

– 3% Saline Solution (513 meq/L) @ 3% Saline Solution (513 meq/L) @ 25 - 25 - 100 ml/hr100 ml/hr NaNa++ should not exceed 0.5 – 1.0 meq/L/hr should not exceed 0.5 – 1.0 meq/L/hr

Time Classification of SIADH-Time Classification of SIADH-Hyponatremia Hyponatremia

Duration Clinical setting

Risk Therapy

Acute <48Hr Post-operative

Brain cell swelling

↑﹝Na by ﹞up to 5meq/L/H

Chronic Unknown

Or > 48Hr

Many Cerebral demyelination syndrome

↑﹝Na﹞<0.33meq/L/H

Therapy for SIADHTherapy for SIADH

Aggressive Tx only for Pts with coma/seizure: ↑ Na up to 5meq/L to control CNS S/S; then ﹝ ﹞↑ Na 8meq/L/D﹝ ﹞≦

Slow correction when brain cell size normal ↑ Na 8meq/L/D to prevent CDS ﹝ ﹞≦3% NaCl 1cc/Kg/Hr= ↑ Na 1meq/L/Hr﹝ ﹞

Even slower correction if manutrition or hypercatabolic state(poor availability of K or organic osmoles

SIADH with chronic SIADH with chronic hyponatremiahyponatremia

A 50Kg,SIADH due to tumor, plasma Na 120meq/L, asymptomatic﹝ ﹞

TBW=30L; ICF 20L Total ICF osmoles normally=20x2x140=5600 If ICF osmoles unchanged, ICF=5600/2x120=23.2L Time(hr)=140-120/0.5=40Hr

Therapeutic goal: To lose 3L of EFW within 40Hr

Treatment guidelinesTreatment guidelinesAdministration of oral or IV Na+ (3%)

SupplementsEncourage foods high in Na+

Fluid restrictionMonitor Neurological StatusNormovolemic hyponatremia:V2

antagonist– Vaprisol (conivaptan) – IV infusion– Samsca (tolvaptan) - PO

Renal water channels: AQP Renal water channels: AQP Aquaporins: AQP 0 ～ 12 AQP 0: Cataract AQP 1 in proximal & thin descending LOH: re-

absorption of most filtered fluid= partial NDI AQP 2 in apical of collecting duct: urine

concentration= NDI AQP 3 & 4 in baso-lateral of collecting duct: AQP 5: SS AQP 7 in apical of S3 proximal: 10% as water

route; glycerol re-absorption AQP 11 in intracellular vesicles: PCKD

Sei Sasaki: Tokyo Medical and Dental University

AQP 2 binding protein AQP 2 binding protein complex complex

Trafficking of AQP2 Mis-routing to baso-lateral

membrane instead of apical SPA-1: a GTP-ase activating protein

for Rap1 Cytoskeleton protein actin

Sei Sasaki: Tokyo Medical and Dental University

Urinary concentration Urinary concentration modulation modulation

↑c AMP

AQP2 trafficking and expression

Post-3%N/S free water Post-3%N/S free water diuresis diuresis

Psychogenic polydipsia DC of DDAVP Water intoxification in infants Hypotonic fluid plus DDAVP for

overcorrection of hyponatremia Case:

70Kg, TBW 35, S-Na 110meq/L 1L 3% NaCl 11.2 meq/L↑ by closed system equation 22 meq/L if 3L free water diuresis

Post-3%N/S natriuresisPost-3%N/S natriuresis

SIADHCerebral salt wasting Case:

SIADH with fixed urine osmolality 600 1L 3% NaCl 11 meq/L ↑ by a closed system equation 7 meq/L ↑ if 1L urine Na+K =250 meq/L

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypervolemicHypervolemic Hyponatremia(1) Hyponatremia(1)– Without advanced renal insufficiencyWithout advanced renal insufficiency

Urine NaUrine Na++ < 20 meq/L < 20 meq/L Cirrhosis, ascites, CHF, Nephrotic syndromeCirrhosis, ascites, CHF, Nephrotic syndrome

– Advanced acute or chronic renal Advanced acute or chronic renal insufficiencyinsufficiency Urine NaUrine Na++ > 20 meq/L > 20 meq/L Renal failure (inability to excrete free Renal failure (inability to excrete free

water)water)

ELECTROLYTE DISORDERSELECTROLYTE DISORDERS

HypervolemicHypervolemic Hyponatremi(2) Hyponatremi(2)– TreatmentTreatment

Optimize treatment for underlying disorderOptimize treatment for underlying disorder Judicious salt and water restrictionJudicious salt and water restriction ++ Diuretics Diuretics ++ Dialysis Dialysis

Hypouricemia in Hypouricemia in hyponatremiahyponatremia

volume mechanism Reference

SIADH N/↑ water↑

Thiazide-induced hyponatremia

↑/↓ water↑ Fichman et al, AJM 1971

Polydipsia-induced hyponatremia

↑ water↑ Hanihara et al, JCP 58, 256-260, 1997

CSW ↓ ANF →Proximal tubule

Maesaka et al, CN 33, 1990

Hyperbilirubinemia severe

↓ Cholaemia → Proximal tubule

Tinatul et al, JMAT 1970

Trickle-down hyponatremiaTrickle-down hyponatremiaOh et al, JASN 8: 108A, 1997Oh et al, JASN 8: 108A, 1997

subgroups ↓Solutes ↓ADH Reference

I. Tea/Toast potomania

Toast: ↓ Protein; Thiazide for HTN: ↓Nacl

Tea: electrolyte-free water

Boulanger et al, NDT 14: 2714-15, 1999

II. Slim potomania

Low protein intake/NaCl; Exercise

↑Water Thaler et al, AJKD 31: 1028-31, 1998

III. Beer potomania

↑CHO+fat+alcohol;

↓Protein+ NaCl

↑Water Oh et al, 1997

Beer Potomania Beer Potomania cH2O= Solute excretion/ Uosm 1-Uosm/ ﹙

Posm﹚ Dependence of water clearance on daily

solute excretion at low urine osmolality(<100)

Uosm=80mOsm/kg(<100) solute 300mOsm; cH2O=2.7L; solute 600, cH2O=5.4; solute 900, cH2O=8.1L

Total solute excretion = urea + 2x Na+K ﹙ ﹚ urea= 50x7+100 ～ 150=450( for 70g protein intake) Thaler et al, AJKD 1998

Basal water Basal water channels(BWC) channels(BWC)

Vasopressin-independent water permeability high in the inner MCD Lankford et al, AJP 261: 554-566, 1991

Hereditary DI in rat Edwards et al, AJP 239: 84-91, 1980

A different AQP: severe impaired urinary concentrating ability in transgenic mice lacking AQP1 water channels Ma et al, JBC 273:4296-99,1998

Predominant in the neonatal stage : physiological DI in water load≧20ml/Kg→water diuresis

Chlopropamide↑

BWC>>AQP2BWC>>AQP2Halperin et al, Clinical Nephrology 56: 339-345, 2001Halperin et al, Clinical Nephrology 56: 339-345, 2001

In the neonatal stage Trickle-down hyponatremia:

Low volume delivery to MCD low GRF/↑ re-absorption of filtrate in proximal tubule ↑water permeability in cortical distal nephron low solute excretion rate: Urea+NaCl low protein diet (low urea)

low NaCl intake ± large non-renal or prior renal NaCl loss ADH suppression

The Janus effect: 2 faces The Janus effect: 2 faces of Aldosterone of Aldosterone

Chronic L-NAME

Sodium Channel: ENaC Sodium Channel: ENaC Modes of ENaC regulationModes of ENaC regulation

Aldosterone/Vasopressin in Aldosterone/Vasopressin in CD CD

E Na C Na K ATP aseNa

KV2R

AquaporinH2O

MR

ATP

c AMP

PKA

Nedd4-2

Aldosterone

Sgk

Nedd4-2: neural precursor cell expressed developmentally down-regulated 4-2Sgk: serum and glucocorticoid inducible kinase

Aldosterone/Vasopressin/Aldosterone/Vasopressin/CaSR in CD CaSR in CD

E Na C

ROMK

Na K ATP aseDepolarize

+

Aldosterone+

Na

KV2R

AquaporinH2O CaSR

CaSR

Angiotensin II in CNT and Angiotensin II in CNT and CCD CCD

E Na C

ROMK1

Na K ATP aseNa

K Protein tyrosine kinase(c-Src)

V2R

AT1R

A candidate for an aldosterone-independent mediator of K preservation during volume depletion

Clinical correlation of Clinical correlation of ENaCENaC

Vivek Bhalla et al: JASN 19: 1845-54,2008

Processing of natriuretic Processing of natriuretic peptidepeptide

ConvertaseSignal peptidase

Corin: new insights into ANP Corin: new insights into ANP

Corin: a transmembrane serine protease identified in the heart

Convert pro-ANP to active ANP Lack of corin →

Salt sensitive HTN in miceSingle nucleotide polymorphism→

African Americans with HTN and cardiac hypertrophy Q Wu et al: KI 75: 142-146, 2009

Mutations of renal Na channelsMutations of renal Na channels Liddle syndrome: β and γ subunits of amiloride-sensitive

ENaC Gordon syndrome: WNK1 and WNK4 kinases Glucocorticoid remediable aldosteronism: aldosterone

synthase/11 β hydroxylase Adrenal hyperplasia: 11α hydroxylase/β hydroxylase Apparent mineralocorticoid excess: mineralocorticoid

receptor, 11 βhydroxystreoid dehydrogenase Progersterone induced hypertension: mineralocorticoid

receptor Psuedo-hypoaldosteronism (PHA)

PseudoHypoAldosteronism: PseudoHypoAldosteronism: PHAPHA

Bonny et al, JASN 13: 2399-2414, 2002Bonny et al, JASN 13: 2399-2414, 2002

Clinical Gene Defects

Type I: AR

AD

Renal: salt wasting/hypo-Na

Hyper-K

Metabolic acidosis

PAC↑/PRA↑

Extra-renal: chest, GI, skin

Renal : spontaneous remission

ENaC

Mineracorticoid receptor

Type II: AD ( Gordon syndrome )

Renal: HTN

Hyper-K

HCMA

normal PAC; PRA↓

A: 1q31-q42

B: WNK4

C: WNK1

Type III: Acquired (obstructive nephropathy; UTI; lead; amyloidosis)

GFR↓; Excessive salt loss

Hyper-K

HCMA

PAC↑/PRA↑

Transient PHA

Chloride channel: CLCChloride channel: CLC

hCLC-Ka(rCLC-K1)

hCLC-Kb(rCLC-K2)

CLC-5

Location TALH, basolateral

TALH, DCT, αIC basolateral

PCT, αIC intracelluar shunt by H ATPase

Disease NDI, DDAVP-insensitive (Clcnk1)

Tyep III Bartter syndrome (CLCNKB)

Mixed Bartter-Gitelman (CLCNKB)

XLR nephrolithiasis (Dent’s: CLC-5)

↓Receptor-mediated endocytosis

Variants of Bartter’s Variants of Bartter’s syndromesyndrome

Israel Zelikovic, NDT 18: 1696-1700, 2003Israel Zelikovic, NDT 18: 1696-1700, 2003 Defective transporter/protein

Clinical Locus

Type I NKCC2 (TAL) Antenatal 15q

Type II ROMK (TAL/CD) Antenatal 11q

Type III ClC-Kb (TAL,DCT) Classic 1p36

Type IV Barttin (β of CIC-Ka/CIC-Kb)

BSND

(Deafness)1p31

AD Hypercalciuria

CaSR (PT/TAL/DCT/CD)

Hypocalcemia 3q

Bartter’s syndrome in THAL Bartter’s syndrome in THAL

NKCC

ROMK

Na K ATP ase

Ca, Mg pH

Na/K

K

2Cl

CaSRNegative

Positive

ClC-Kb

2

1

3

Bartter with Sensori-Neural Bartter with Sensori-Neural DeafnessDeafness

BSNDBarttin forms heterodimers

with ClC-Ka in thin ALH with ClC-Kb in thick ALH→ NDI with ClC-K in marginal cells of stria vascularis (inner ear) & vestibular dark cells

Gitelman’s / Bartter’s Gitelman’s / Bartter’s syndromesyndrome

Gitelman’s Bartter’s

Molecular level ↓TSC in DCT ↓NKCC, ROMK, or Cl

Age at onset Teenage Children

Clinical Tetany Failure to thrive

Mimicked by Thiazides Loop diuretics

Plasma Mg ↓ ↓

D.D. Hypocalciuria Hypercalciuria

Uosm ↓

Thiazide-induced hyponatremiaThiazide-induced hyponatremia

Renal salt wasting: via TSC in DCTWater retention:

hypovolemia-induced ADH release direct effect of ↑distal water reabsorption ( via PGE2↓; indomethacin↑) Magaldi et al, NDT 15: 1903-5, 2000

↑thirst and water intakeNo calcium wasting

Salt transport in DCT Salt transport in DCT

TSCNa

2Cl

V2R

Inactive TSC dimer TSC

monomer

AT1R

MR

SPAK

Vasopressin/CaSR in DCT Vasopressin/CaSR in DCT

TSC

TRPV5

Na K ATP ase

pH pH

Na

Ca

2Cl

CaSRPositive

PositiveCaSR

CaATPase

NCX

V2R

Kinase SPAK

Salt-losing nephropathySalt-losing nephropathySalt-losing nephropathy with inappropriate

secretion of ANP( 10 ～ 47fmol/ml): no cardiac or cerebral abnormality pseudo-bartter syndrome: concentaring power highly-conserved; normokalemic metabolic alkalosis; no response to indomethacin therapy

Granulomatous interstitial nephritis&uveitis: non-caseating granuloma 6-M steroid therapy

Primary renal candidiasis: caseating renal granuloma→medullary destruction

Chronic milk-alkali syndrome

Milk alkali syndromeMilk alkali syndrome

↑Free P-Ca++ /Mg++ CaCO3 in duodenum + ferment H+ → Free Ca++ in lumen; if low HPO4 in GI (poor intake) → Free P-Ca++ ↑ via para-cellular route

Hypercalcemia GFR↓

Anorexia nervosa + AntacidsAnorexia nervosa + AntacidsMitchell Lewis HalperinMitchell Lewis Halperin

P-Na=118mM ; U-Na 44mM pH=7.2; P-HCO3=9 P-K=2.0mM; U-K=17mM K deficit >120 P-Ca 2.56mM; P-alb 2.7g/dl UV>6L; Uosm=150 P-Mg 1.5mM