tubular troubles: why gitelman should be more famous fiona e karet frankl university of cambridge
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Tubular troubles:why Gitelman should be more famous
Fiona E Karet Frankl
UNIVERSITY OF CAMBRIDGE
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The post glomerular nephron
PCTReabsorption- Glucose- Na/Bic- Phosphate/Calcium- UrateReceptor-mediated endocytosisAmmoniagenesis LH
OsmolalityNa/K/Cl
AmmoniumCa/Mg
DCT
Na/ClCaMg
CD
Fine regulation- Osmolality- Na/K- Ammonium- Aid-base
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Case 1
A 33 year old woman complains of headaches andepisodic lethargy. She has recently split up with herpartner of 15 years. There was nothing to find on examination and her BP was 145/90 when GP saw her 3 weeks ago and thoughtshe was depressed. However, she returned with unremitting symptoms; BP was 170/110, and baseline investigations were:
Na 144 K 2.9 U 4.2 Cr 78
?
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? Next investigations
If K is low, you NEEEEEEED to know the bicarb
Then, you need to know where the K has gone
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Acidosis Alkalosis
PHA type 1 Liddle syndrome
Gordon syndrome Gitelman syndrome
Hypomagnesaemia/ Bartter syndromes hypercalciuria
Diuretics
Renal tubular acidosis Conn syndromeproximal distal GRA - primary - with osteopetrosis K - hyperkalaemic BP
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60%
25%
< 10%
2 - 3%
Renal sodium and potassium reabsorption
70%
secretion
15% but mostly
recycled
reabs/secretion
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NBC1
NHE3Na
Na
H+
HCO3-
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2-3%AT2
Renin
AT1
ACE
Angiotensinogen
Aldosterone
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? Next investigations
If K is low, you NEEEEEEED to know the bicarb
Then, you need to know where the K has gone
Renin and aldo may be helpful, also other hormones
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< 10%
2-3%
Confounders of renin / aldo levels
AT2
Renin
AT1
ACE
Angiotensinogen
Aldosterone
Lifton lab and others
Low K
Many BP drugs:
ACEI/ARB Renin up Aldo down
Beta blockers
Renin down
Diuretics
Renin up Aldo up
Aliskiren
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A (true) clinical story
17 year old female, hypertensive since age 14K had been 3.1 mmol/lNo other investigations at that time
Father, uncle and sister hypertensive
Renin and aldosterone both below detection limit, bicarb 29 mmol/L
Diagnosis: Liddle syndrome
Treatment: amiloride 5mg – excellent response
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Liddle syndrome very rare
Grant Liddle 1963Autosomal dominant, young onsetAppears like hyperaldosteronism: HT
volume expansion salt retention K+
However, low renin / aldoResponse to amiloride / triamterene (ENaC inhibitors)
must also be on low-salt diet
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Na
Shimkets et al. 1994
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Some C-terminal functions of ENaC
Ubiquitination via NEDD4.2Phosphorylation via ERK/CK2
SGK1 phosphorylates NEDD
….and other mechnisms Snyder, Rotin, Rossier, Schild
PY
Na
Knowing the molecular mechanism guides treatment:- spironolactone not useful- amiloride ideal- father’s care now being rationalised
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Case 2
A 33 year old woman complained of aches and pains and lethargy. She had recently split up with her partner of 5 years. There was nothing to find on examination and her BP was 125/70 when GP saw her 3 weeks ago and thought she was depressed. However, she returned with unremitting symptoms and baseline investigations were:
FBC normalNa 135 K 2.9 U 8.7 Cr 100
?
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? Next investigations
24 h urine KMg, Ca, 24 h urine Ca, FE Mg
? Missing information
Always ask about drugsAlways take a family historyAlways take a dietary history
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FE anything (%)
Spot urine and parallel blood
U x P cr____ x ____ x 100 ( % ) (remember micro vs millimoles)
P x U Cr
Never zero!!Meaningless in respect of tubular dysfunctionif plasma value is normal
Divide by 0.7 for Mg > 4% = renal lossFor urate, must have decent function
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? Next investigations
24 h urine KMg, Ca, 24 h urine Ca, FE Mg
? Missing information
Always ask about drugsAlways take a family historyAlways take a dietary history
If alkalotic, consider measuring urine chloride
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Urine chloride
Normal: 100-250 mEq per 24 hours
Increased: Bartter syndrome Gitelman syndrome Drugs eg Corticosteroids
Diuretics
Decreased: Chloride depletion due to Gastrointestinal Loss Vomiting Colonic villous adenoma Diuretics
(Congenital chloride diarrhoea)
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Diuretic K U Ca Mg
Loop ()
Thiazide
K-sparing
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Bartter and Gitelman syndromesFred Bartter 1962; Hillel Gitelman 1966Hypokalemic alkalosis with enlarged JGAAutosomal recessiveMany candidate genes, much diagnostic confusionBettinelli 1992
/ 4
Deafness
/BSND1
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Gitelman
Bartter I Bartter III
Bartter II Bartter IVBSND1
thiazide
loop
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Gitelman vs Type 3 Bartter syndrome
mor
e co
mm
on
gene
test
s
Exclude diuretic abuseHigh renin and ?aldo
LATER:HTSometimes
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Gitelman / Type 3 Bartter syndrome
Management: TRICKYINDIVIDUALIZE
Aggressive K and Mg replacement (need both)KayCeeL Mg glycerophosphate(Sando K) Mg lactate (Durbin pharmaceuticals)Slow K
K-sparing agents AmilorideSpironolactone
RAS axis ACEIBeta blockade
Vitamin D?
?’Good’: K > 3 Mg > 0.6
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Low potassium1. Redistribution2. GI losses3. Skin4. Renal losses
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Case 3
A 45 year old woman complained of lethargy and palpitations. She had recently been started on antihypertensives. There was nothing to find on examination and her BP was 145/95. Baseline investigations were:
Na 135 K 6.4 U 8.7 Cr 120
? ACEI/ARBGordon syndrome (PHA2) very rare look for funny teeth renin too high for K autosomal dominant WNK1, WNK4, cullin or Kelch-3 mutations Rx thiazide
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NBC1
NHE3Na
Na
H+
HCO3-
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Case 4
A 45 year old woman complained of lethargy and abdo pain. There was nothing to find on examination and her BP was 145/95. Abdominal u/s showed a kidney stone.Baseline investigations were:
Na 135 K 3.0 U 8.7 Cr 145 Bicarb 19
?
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Case 4
A 45 year old woman complained of lethargy and abdo pain. There was nothing to find on examination and her BP was 145/95. Abdominal u/s showed a kidney stone.Baseline investigations were:
Na 135 K 3.0 U 8.7 Cr 145
?
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Case 5
A 35 year old asymptomatic man was recalled from transplant clinic, 2 weeks after first cadaveric transplant. BP was 145/95.
Rx: prednisolone 15mg od septrin 1 MWF FK506 3 mg bd nystatin 1mg qds MMF 500 mg bd fluconazole 50 mg od
Biochemistry:Na 135 K 7.9 U 8.7 Cr 145 Bicarb 17
?
? Mx
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What do you think his Mg was?
Hypokalaemia + hypomagnesaemiaDiuretics (loop / thiazide)AmphotericinGitelman / Type 3 Bartter spectrumConn syndromePPIs
Hyperkalaemia + hypomagnesaemiaCNIsPoorly controlled diabetesDiuretics (combination)
Hypomagnesaemia + hypocalcaemiaPPIsPost parathyroidectomy (hungry bones)TRPM6 and claudin 16 mutations
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Cl-
Na+NCCT
Distal convoluted tubule
Mg
K+
Na+
TRPM6: EGF responsive
Mutations cause hypomagnesemia with 2o hypocalemia
Na/K-ATPase -subunit mutationsisolated hypomagnesemia
EGF k/o: hypomagnesemia
TRPM6
Na/KATPase
Mg
Ca
Ca
Calcium: Upregulated proximal reabsorption
CaTRPV5
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Some things to remember about Mg…
- kidney is major regulator, 0.5 – 80% excreted
- mainly handled in TAL and DCT
- 90% is ‘invisible’. In circulation, 30% is protein bound
- low in GS, sometimes in T3BS
- isolated hypoMg due to EGF/γNaKATPase mutations
- often low post Tx
- PPIs may be the culprit
- FEMg is easy to measure!
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Don’t forget:
Try to get measurements before / off replacements
Always take a family history
Bicarb measurement is useful
It may or may not be the kidneys’ fault
Rarerenal.org may help you (in time…)