This document discusses hyponatremia (low sodium levels in blood). It begins by defining hyponatremia as a sodium level below 135 meq/L. It then describes the causes and symptoms of hyponatremia, which can include headache, vomiting, seizures and coma depending on severity.
The document categorizes hyponatremia based on plasma osmolality as hypertonic, isotonic or hypotonic. It discusses the various types in more detail including hypovolemic, euvolemic and hypervolemic causes. Treatment depends on the specific cause but may involve sodium supplementation, fluid restriction or medications. Chronic hyponatremia requires especially slow correction to avoid
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New Perspectives on Hyponatremia and its Causes
1. A New Perspective onA New Perspective on
HyponatremiaHyponatremia
by Steve Chenby Steve Chen
Director of Nephrology,
Shin-Chu Branch of Taipei Veterans General Hospital
7. Hyponatremic encephalopathyHyponatremic encephalopathy
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
8. Hyponatremic encephalopathyHyponatremic encephalopathy
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:
9. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
Pathophysiology: CNSPathophysiology: CNS
– Water shifts into brain cellsWater shifts into brain cells
– ApathyApathy –– Altered ConsciousnessAltered Consciousness
– AgitationAgitation –– ConvulsionsConvulsions
– HeadacheHeadache –– ComaComa
– Risk of brain damage > during treatmentRisk of brain damage > during treatment
– Cerebral demyelination syndrome(CDS)Cerebral demyelination syndrome(CDS)
Hyponatremia
10. Cerebral Demylination SyndromeCerebral Demylination Syndrome
CDSCDS
risk factorsrisk 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
11.
12. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
Serum OsmolalitySerum Osmolality
– Number of osmoles (osmotically activeNumber of osmoles (osmotically active
particles) in the serumparticles) 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
14. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
HypertonicHypertonic HyponatremiaHyponatremia (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 causemost common cause
Each 100 mg/dl plasma glucose will serumEach 100 mg/dl plasma glucose will serum
NaNa++
by 1.6 meq/Lby 1.6 meq/L
– TreatmentTreatment
Volume replacementVolume replacement
Hyponatremia, hypertonic
15. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
IsotonicIsotonic HyponatremiaHyponatremia (P(Posmosm 275 - 295)275 - 295)
– ““PseudohyponatremiaPseudohyponatremia””
– Artifact in serum NaArtifact in serum Na++
measurementmeasurement
2° High levels of plasma proteins and lipids2° High levels of plasma proteins and lipids
– Etiology:Etiology:
HyperlipidemiaHyperlipidemia
HyperproteinemiaHyperproteinemia
Hyponatremia, isotonic
21. 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
22. 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
23. Post-N/S diuresis: turn off ADHPost-N/S diuresis: turn off ADH
U osm <100 mOsm
Initial 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
28. ELECTROLYTEELECTROLYTE
DISORDERSDISORDERS
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 - 10025 - 100
ml/hrml/hr
NaNa++
should not exceed 0.5 – 1.0 meq/L/hrshould not exceed 0.5 – 1.0 meq/L/hr
29. Time Classification of SIADH-Time Classification of SIADH-
HyponatremiaHyponatremia
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
30. 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
31. SIADH with chronic hyponatremiaSIADH with chronic hyponatremia
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
32. Treatment guidelinesTreatment guidelines
Administration of oral or IV Na+
(3%)
Supplements
Encourage foods high in Na+
Fluid restriction
Monitor Neurological Status
Normovolemic hyponatremia:V2 antagonist
– Vaprisol (conivaptan) – IV infusion
– Samsca (tolvaptan) - PO
33. Renal water channels: AQPRenal 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
34. AQP 2 binding protein complexAQP 2 binding protein 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
36. Post-3%N/S free water diuresisPost-3%N/S free water 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
42. Hypouricemia in hyponatremiaHypouricemia in hyponatremia
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
43. Trickle-down hyponatremiaTrickle-down hyponatremia
Oh 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+a
lcohol;
↓Protein+
NaCl
↑Water Oh et al,
1997
44. Beer PotomaniaBeer 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
45. Basal water channels(BWC)Basal water 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↑
46. BWC>>AQP2BWC>>AQP2
Halperin 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
47.
48. The Janus effect: 2 faces ofThe Janus effect: 2 faces of
AldosteroneAldosterone
Chronic L-NAME
50. Aldosterone/Vasopressin in CDAldosterone/Vasopressin in CD
E Na C Na K ATP ase
Na
K
V2R
Aquaporin
H2O
MR
ATP
c AMP
PKA
Nedd4-2
Aldosterone
Sgk
Nedd4-2: neural precursor cell expressed developmentally down-regulated 4-2
Sgk: serum and glucocorticoid inducible kinase
52. Angiotensin II in CNT and CCDAngiotensin II in CNT and CCD
E Na C
ROMK1
Na K ATP ase
Na
K Protein
tyrosine
kinase(c-
Src)
V2R
AT1R
A candidate for an aldosterone-independent mediator of K preservation
during volume depletion
53. Clinical correlation of ENaCClinical correlation of ENaC
Vivek Bhalla et al: JASN 19: 1845-54,2008
55. Corin: new insights into ANPCorin: 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 mice
Single nucleotide polymorphism→
African Americans with HTN and cardiac
hypertrophy Q Wu et al: KI 75: 142-146, 2009
56. 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)
57. PseudoHypoAldosteronism: PHAPseudoHypoAldosteronism: PHA
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
59. Variants of Bartter’s syndromeVariants of Bartter’s syndrome
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
60. Bartter’s syndrome in THALBartter’s syndrome in THAL
NKCC
ROMK
Na K ATP ase
Ca, Mg pH
Na/K
K
2Cl
CaSR
Negative
Positive
ClC-Kb
2
1
3
61. Bartter with Sensori-NeuralBartter with Sensori-Neural
DeafnessDeafness
BSND
Barttin 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
62.
63. Gitelman’s / Bartter’s syndromeGitelman’s / Bartter’s syndrome
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 ↓
64. Thiazide-induced hyponatremiaThiazide-induced hyponatremia
Renal salt wasting: via TSC in DCT
Water 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 intake
No calcium wasting
65. Salt transport in DCTSalt transport in DCT
TSC
Na
2Cl
V2R
Inactive
TSC dimer TSC
monomer
AT1R
MR
SPAK
Osmotic gradient develops across blood brain barrier causing water to move into brain. -Two protective mechanisms: - Movement of interstitial fluid into the CSF - Loss of cellular potassium and organic osmolytes Acute hyponatremia (Na < 120) developing < 24 hours OR rate of fall of > 0.5 meq/L per hour: -Muscular twitching, seizures, coma Acute severe hyponatremia with CNS changes – mortality rate 50%. CPM – correction of hyponatremia faster than the brain can recover solute.
Movement of water from ICF to ECF dilutes the ECF. Volume replacement with sodium containing fluids.
Results in intracellular volume expansion with derangement of cellular function. Obtain serum and urine electrolytes Obtain plasma and urine osmolality
Clinical manifestations due to volume deficit rather than hyponatremia.
Unequal loss of electrolyte and water loss produces a contracted ECF volume with hyponatremia. Maintained by effect of volume depletion on kidneys inhibiting free water excretion. - Decreased GFR. - Increased proximal tubular resorption of solute and water. - Decreased deliver of fluid to the diluting segment of the nephron. - ADH released by nonosmotic stimuli.
CHF – perceived as low flow state, stimulates ADH Nephrotic Syndrome – low serum protein due to urinary loss Cirrhosis – low intravascular oncotic pressure due to decreased protein production