disorders of sodium handlinga/nef6... · • physiology of sodium transport ... git lgitelman...
TRANSCRIPT
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Disorders of sodium handling
Detlef Bockenhauer
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Objecti esObjectives
• Physiology of sodium transport• Clinical consequences of disturbed
transporttransport
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Overview of renal salt handlingOverview of renal salt handling
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Biochemical “Fingerprinting”Biochemical “Fingerprinting”
• Disorders of tubular sodium handling are i t d ith ifi bi h i lassociated with specific biochemical
profilesp• Identification of these patterns help
t bli h ifi di iestablish a specific diagnosis
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The “Aldosterone fingerprint”The “Aldosterone fingerprint”
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?
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Biochemistry alone is not ysufficient
Diagnosis Bartter AME
Na (mmol/l) 140 142
BP (mmHg) 74/46 128/84
K (mmol/l) 2.2 1.9Cl (mmol/l) 98 95HCO3 (mmol/l) 27 29
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Another caseAnother case
• 10-day old baby referred by visiting nurse b f i ht l (2 275 k bi thbecause of weight loss (2.275 kg, birth weight: 2.280)g )
• Pregnancy complicated by IUGR• Born at 37+3 weeks
Family history: Two healthy siblings• Family history: Two healthy siblings. Parents are first cousins
• Examination: good peripheral perfusion, BP ? li i l i f d h d tiBP: ?, no clinical signs of dehydration
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Laborator In estigationsLaboratory Investigations
BloodNa [mmol/l] 133K [mmol/l] 7.4Cl [mmol/l]HCO3 [mmol/l] 16Creatinine [mcmol/l] 40Creatinine [mcmol/l] 40pH 7.25Osmolality [mmol/l]
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Diagnosis?Diagnosis?
• Congenital Adrenal Hyperplasia• Pseudohypoaldosteronism
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Sodi m transport in CDSodium transport in CD
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TreatmentTreatment
• Na-bicarbonate 13 mmol/kg/d• Na-Resonium 450 mg three times daily• NaCl 10 mmol (3 mmol/kg/d) added to iv• NaCl 10 mmol (3 mmol/kg/d) added to iv
fluids• Fludrocortisone 75 mcg
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S bseq ent co rseSubsequent course
• Develops significant hypertension (systolic BP 100 H ) b t i t tBP >100 mmHg), but persistent hyperkalaemia (>6 mmol/kg)yp ( g)
• What now?
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F rther in estigationsFurther investigations
• Normal synacthen test, urinary steroid fil CAH l d dprofile => CAH excluded
• Initial aldosterone level: 3480 pmol/lInitial aldosterone level: 3480 pmol/l (normal for neonate: <2000), repeat level ( t t t 758 l/l) i 0 3(on treatment: 758 pmol/l), renin:<0.3 nmol/lnmol/l
• Normal renal US, no evidence of UTI
Di i ?• Diagnosis?
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PHA2 (Gordon s ndrome)PHA2 (Gordon syndrome)
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Trial of H drochlorothia ideTrial of Hydrochlorothiazide
before On thiazidePlasma
Na [mmol/l] 133 134K [mmol/l] 6.6 3.2
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Blood press reBlood pressure
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Diagnosis?Diagnosis?
• PHA type 2 (Gordon syndrome)• Genetics: homozygous splice site mutation
in KLHL3: c 903G>A; p = (last base exonin KLHL3: c.903G>A; p. (last base exon 8)
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Disorders of renal salt handlingDisorders of renal salt handlingDisorder Gene(s) Corresponding drugDisorder Gene(s) Corresponding drugRenal FanconiSyndromes
EHHADH, SLC34A1, ….
Bartter syndromes SLC12A1, KCNJ1, CLCNKB, BSND
Loop diuretics
Git l SLC12A3 thi idGitelman SLC12A3 thiazideEAST/SESAME KCNJ10PHA1 SCNN1A B G NR3C2 A il id / i l tPHA1 SCNN1A,B,G, NR3C2 Amiloride/spironolactoneHypoaldosteronism CYP11B2, PHA2/Gordon WNK1 WNK4 CULL3 tacrolimusPHA2/Gordon WNK1, WNK4, CULL3,
KLHL3tacrolimus
Liddle SCNN1B,G,AME HSD11B2 licoriceHyperaldosteronism CYP11B1, KCNJ5, fludrocortisoneyp , ,
CACNA1D,H, CYP11B2
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Key message 1Sodium transport determines
blood pressure/volume homeostasis
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There is onl one organThere is only one organ…
d it k th h lt…and it works through salt
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Ph siologPhysiology
From: Hoenig &Zeidel, CJASN 2014;9(7):1272-1281
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Key aspects of disorders of y psodium transport
• Primarily affects volume homeostasis• Rarely affects plasma sodium concentration• Molecularly linked to other transport• Molecularly linked to other transport
processes
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Pathoph siologPathophysiology
• 2-week old neonate transferred to GOSH l drenal ward
• Born at 32-wk gestationBorn at 32 wk gestation • Pregnancy complicated by
polyhydramnios (2 amniocentesis)Postnatal: polyuria (200 ml/kg/d) and• Postnatal: polyuria (200 ml/kg/d) and severe electrolyte disturbancey
• 3rd child of healthy parents, 1st cousins
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E aminationExamination
• Decreased peripheral perfusion• Wt: 1.68 kg • Length: 44 cm• Length: 44 cm• HC: 29 cm• BP: 68 mmHg systolic
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BiochemistriesBiochemistries
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DiagnosisDiagnosis
• Bartter syndrome• Also has sensorineural deafness• Bartter type 4• Bartter type 4• Homozygous mutation in Barttin yg
p.Pro151Leufs*27
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Pathoph siologPathophysiology
CLCNKB/ABarttin
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TreatmentTreatment
• Salt! up to 14 mmol/kg/d• Potassium up to 13 mmol/kg/d• NSAID (indomethacin celecoxib)• NSAID (indomethacin, celecoxib)
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F rther co rseFurther courseparameter min maxNa (mmol/l) 116 173Na (mmol/l) 116 173K (mmol/l) 1.4 6.9Cl (mmol/l) 56 125CreatinineCreatinine (mcmol/l) 29 182
H 7 58 7 90pH 7.58 7.90
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“Renal Apnoea”“Renal Apnoea”
• Recurrent desaturations• Inability to extubate after GA for central
line insertionline insertion
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Pol somnographPolysomnography
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More complicationsMore complications
• Hypophosphataemic rickets
test Value [unit]PO4 0.3 mmol/lPTH 56 pmol/lALP 1226 IU/lTmP/GFR <0.8 mmol/l
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and more complications….and more complications
• Severe developmental delay• Failure-to-thrive• Stuck in hospital• Stuck in hospital
S DIUMTRANSPORT
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Homer said it allHomer said it all
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Ho to mo e for ard?How to move forward?
• Palliative care• Titration with HCl• Nephrectomy(ies)• Nephrectomy(ies)• amiloride
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Amiloride actionAmiloride action
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Pathoph siologPathophysiology
??
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Bartter syndrome affects tubuloglomerularfeedbackfeedback
• MD cells are TAL cellsMD cells are TAL cells• chloride reabsorption
leads toleads to renin/angiotensin activation viaactivation via ProstaglandinsCOX 2• COX-2
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Amiloride j stificationAmiloride justification
• JG apparatus is “short circuited” as noJG apparatus is short circuited , as no chloride reabsorption
• => prostaglandin=>renin=>aldosterone independent of volume statusindependent of volume status
• Volume homeostasis must be maintained by adequate salt supplementation
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C iCourse since
• Blood pH <7.6I d l• Improved mental state
• No further phosphate supplementationp p pp• Discharged home age 12 months (2 months after
starting amiloride)starting amiloride)
• Severe developmental delay• CKD stage 3 (eGFR 30 ml/min)• CKD stage 3 (eGFR 30 ml/min)
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Concl sionsConclusions• Renal salt handling regulates volume• Renal salt handling regulates volume
homeostasis• Renal sodium transport is molecularly linked
t lti l th t t thto multiple other transport pathways• Volume homeostasis “rules”!Volume homeostasis rules !• Disorders of renal sodium handling clinically
manifest with altered BP and secondary electrolyte abnormalitieselectrolyte abnormalities
• They rarely affect plasma sodium concentration