Tubular troubles:
why Gitelman should be more famous
Fiona E Karet Frankl
UNIVERSITY OF
CAMBRIDGE
The post glomerular nephron
DCT
Na/Cl
Ca
Mg
PCT
Reabsorption
- Glucose
- Na/Bic
- Phosphate/Calcium
- Urate
Receptor-mediated
endocytosis
Ammoniagenesis
LH
Osmolality
Na/K/Cl
Ammonium
Ca/Mg
CD
Fine regulation
- Osmolality
- Na/K
- Ammonium
- Aid-base
Case 1
A 33 year old woman complains of headaches and
episodic lethargy. She has recently split up with her
partner of 15 years.
There was nothing to find on examination and her BP
was 145/90 when GP saw her 3 weeks ago and thought
she 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
? Next investigations
If K is low, you NEEEEEEED to know the bicarb
Then, you need to know where the K has gone
Acidosis
Alkalosis
PHA type 1
Liddle syndrome
Gordon syndrome
Gitelman syndrome
Hypomagnesaemia/
hypercalciuria
Bartter syndromes
Diuretics
Renal tubular acidosis
proximal
distal
- primary
- with osteopetrosis
- hyperkalaemic
Conn syndrome
GRA
K
BP
Renal sodium and potassium reabsorption
< 10%
reabs/
secretion
60%
70%
2 - 3%
25%
15%
but mostly
recycled
secretion
NHE3
Na
H+
Na
HCO3-
NBC1
Angiotensinogen
Renin
AT1
ACE
2-3%
AT2
Aldosterone
? 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
Confounders of renin / aldo levels
Low K
Angiotensinogen
< 10%
Renin
AT1
ACE
2-3%
Many BP drugs:
ACEI/ARB
Renin up
Aldo down
AT2
Beta blockers
Renin down
Aldosterone
Diuretics
Renin up
Aldo up
Lifton lab and others
Aliskiren
A (true) clinical story
17 year old female, hypertensive since age 14
K had been 3.1 mmol/l
No 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
Liddle syndrome
Grant Liddle 1963
Autosomal dominant, young onset
Appears like hyperaldosteronism:
very rare
HT
volume expansion
salt retention
 K+
However, low renin / aldo
Response to amiloride / triamterene (ENaC inhibitors)
must also be on low-salt diet


Na

Shimkets et al. 1994
Some C-terminal functions of ENaC


PY
Ubiquitination via NEDD4.2
Phosphorylation via ERK/CK2
Na SGK1 phosphorylates NEDD
….and other mechnisms

Snyder, Rotin, Rossier, Schild
Knowing the molecular mechanism guides treatment:
- spironolactone not useful
- amiloride ideal
- father’s care now being rationalised
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 normal
Na 135 K 2.9 U 8.7
? 
Cr 100
? Missing information
Always ask about drugs
Always take a family history
Always take a dietary history
? Next investigations
24 h urine K
Mg, Ca,
24 h urine Ca, FE Mg
FE anything
(%)
Spot urine and parallel blood
Ux
____ x
P cr
____
Px
U Cr
x 100 ( % )
(remember micro vs millimoles)
Never zero!!
Meaningless in respect of tubular dysfunction
if plasma value is normal
Divide by 0.7 for Mg
> 4% = renal loss
For urate, must have decent function
? Missing information
Always ask about drugs
Always take a family history
Always take a dietary history
? Next investigations
24 h urine K
Mg, Ca,
24 h urine Ca, FE Mg
If alkalotic, consider measuring urine chloride
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)
Diuretic
K
U Ca
Mg
Loop


()
Thiazide



K-sparing



Bartter and Gitelman syndromes
Fred Bartter 1962; Hillel Gitelman 1966
Hypokalemic alkalosis with enlarged JGA
Autosomal recessive
Many candidate genes, much diagnostic confusion
Bettinelli 1992
/4
Deafness
/BSND1
Gitelman
thiazide
BSND1
Bartter I
loop
Bartter III
Bartter II
Bartter IV
Gitelman vs Type 3 Bartter syndrome
Exclude diuretic abuse
High renin and ?aldo
Sometimes
LATER:
HT
Gitelman / Type 3 Bartter syndrome
Management:
TRICKY
INDIVIDUALIZE
Aggressive K and Mg replacement (need both)
KayCeeL
Mg glycerophosphate
(Sando K)
Mg lactate (Durbin pharmaceuticals)
Slow K
K-sparing agents
RAS axis
Vitamin D?
Amiloride
Spironolactone
ACEI
Beta blockade
?’Good’: K > 3
Mg > 0.6
Low potassium
1.
2.
3.
4.
Redistribution
GI losses
Skin
Renal losses
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/ARB
Gordon syndrome (PHA2)
very rare
look for funny teeth
renin too high for K
autosomal dominant
WNK1, WNK4, cullin or Kelch-3 mutations
Rx thiazide
NHE3
Na
H+
Na
HCO3-
NBC1
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
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
? 
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
What do you think his Mg was?
Hyperkalaemia + hypomagnesaemia
CNIs
Poorly controlled diabetes
Diuretics (combination)
Hypokalaemia + hypomagnesaemia
Diuretics (loop / thiazide)
Amphotericin
Gitelman / Type 3 Bartter spectrum
Conn syndrome
PPIs
Hypomagnesaemia + hypocalcaemia
PPIs
Post parathyroidectomy (hungry bones)
TRPM6 and claudin 16 mutations
Distal convoluted tubule
TRPM6: EGF responsive
TRPM6
TRPV5
NCCT
Mg
Ca
Mg
Ca
Cl-
Na+
K+

Na+
Na/K
ATPase
Mutations cause
hypomagnesemia with 2o
hypocalemia
Na/K-ATPase -subunit mutations
isolated hypomagnesemia
EGF k/o: hypomagnesemia
Ca
Calcium:
Upregulated proximal reabsorption
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!
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…)
fek1000@cam.ac.uk