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

PHA type 1 Gordon syndrome Hypomagnesaemia/ hypercalciuria Renal tubular acidosis proximal distal - primary - with osteopetrosis - hyperkalaemic

Alkalosis

Liddle syndrome Gitelman syndrome Bartter syndromes Diuretics Conn syndrome GRA K BP

Renal sodium and potassium reabsorption 60% 70% < 10% reabs/ secretion 25% 15% but mostly recycled 2 - 3% secretion

NHE3 H + Na Na NBC1 HCO 3 -

2-3% Angiotensinogen

Renin

AT1

ACE

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

< 10% Confounders of renin / aldo levels 2-3% Angiotensinogen

Renin

AT1

ACE

AT2 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 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

very rare

Grant Liddle 1963 Autosomal dominant, young onset Appears like hyperaldosteronism: 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 U x P cr ____ x ____ x 100 ( % ) (remember micro vs millimoles) P x U Cr 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 Loop Thiazide K-sparing K

  

U Ca

  

Mg (



)

 

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 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) Slow K Mg lactate (Durbin pharmaceuticals) K-sparing agents RAS axis Amiloride Spironolactone ACEI Beta blockade Vitamin D?

?’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 H + Na Na NBC1 HCO 3 -

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 MMF 500 mg bd nystatin 1mg qds 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

TRPM6 TRPV5

NCCT Distal convoluted tubule Mg

Ca

Cl Na +

K + 

Mg Ca

Na + Na/K ATPase Ca TRPM6: EGF responsive Mutations cause hypomagnesemia with 2 o hypocalemia Na/K-ATPase  -subunit mutations isolated hypomagnesemia EGF k/o: hypomagnesemia 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 kidney s’ fault Rarerenal.org may help you (in time…) [email protected]