a new perspective on hyponatremia
DESCRIPTION
A comprehensive and concise review of hyponatremia with multiple pictures easy to understand for deep learners and medical studentsTRANSCRIPT
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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
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SodiumSodium
Reference Range:136 – 145 meq/L
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SodiumSodium
Hyponatremia is Na+ < 135 meq/L
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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
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HyponatremiaHyponatremia
Causes an osmotic fluid shift from plasma into brain cells
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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 ) ]
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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
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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
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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))
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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
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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
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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
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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
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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
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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
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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
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Urinary concentration Urinary concentration modulation modulation
↑c AMP
AQP2 trafficking and expression
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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
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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
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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)
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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
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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
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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
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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
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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↑
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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
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The Janus effect: 2 faces The Janus effect: 2 faces of Aldosterone of Aldosterone
Chronic L-NAME
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Sodium Channel: ENaC Sodium Channel: ENaC Modes of ENaC regulationModes of ENaC regulation
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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
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Aldosterone/Vasopressin/Aldosterone/Vasopressin/CaSR in CD CaSR in CD
E Na C
ROMK
Na K ATP aseDepolarize
+
Aldosterone+
Na
KV2R
AquaporinH2O CaSR
CaSR
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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
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Clinical correlation of Clinical correlation of ENaCENaC
Vivek Bhalla et al: JASN 19: 1845-54,2008
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Processing of natriuretic Processing of natriuretic peptidepeptide
ConvertaseSignal peptidase
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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
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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)
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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
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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
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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
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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
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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
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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 ↓
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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
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Salt transport in DCT Salt transport in DCT
TSCNa
2Cl
V2R
Inactive TSC dimer TSC
monomer
AT1R
MR
SPAK
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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
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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
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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↓
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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
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