Tubular troubles:why Gitelman should be more famous

Fiona E Karet Frankl

UNIVERSITY OF CAMBRIDGE

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

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

?

? 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/ Bartter syndromes hypercalciuria

Diuretics

Renal tubular acidosis Conn syndromeproximal distal GRA - primary - with osteopetrosis K - hyperkalaemic BP

60%

25%

< 10%

2 - 3%

Renal sodium and potassium reabsorption

70%

secretion

15% but mostly

recycled

reabs/secretion

NBC1

NHE3Na

Na

H+

HCO3-

2-3%AT2

Renin

AT1

ACE

Angiotensinogen

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

< 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

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

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

Na

Shimkets et al. 1994

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

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

?

? 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

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

? 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

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 syndromesFred Bartter 1962; Hillel Gitelman 1966Hypokalemic alkalosis with enlarged JGAAutosomal recessiveMany candidate genes, much diagnostic confusionBettinelli 1992

/ 4

Deafness

/BSND1

Gitelman

Bartter I Bartter III

Bartter II Bartter IVBSND1

thiazide

loop

Gitelman vs Type 3 Bartter syndrome

mor

e co

mm

on

gene

test

s

Exclude diuretic abuseHigh renin and ?aldo

LATER:HTSometimes

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

Low potassium1. Redistribution2. GI losses3. Skin4. 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/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

NBC1

NHE3Na

Na

H+

HCO3-

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?

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

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

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