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Tubular troubles: why Gitelman should be more famous Fiona E Karet Frankl

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. CD

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Tubular troubles: why Gitelman should be more famous Fiona E Karet Frankl

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  1. Tubular troubles: why Gitelman should be more famous Fiona E Karet Frankl UNIVERSITY OF CAMBRIDGE

  2. The post glomerular nephron DCT Na/Cl Ca Mg • PCT • Reabsorption • Glucose • Na/Bic • - Phosphate/Calcium • Urate • Receptor-mediated • endocytosis • Ammoniagenesis • CD • Fine regulation • - Osmolality • Na/K • Ammonium • Aid-base LH Osmolality Na/K/Cl Ammonium Ca/Mg

  3. 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 ? 

  4. ? Next investigations If K is low, you NEEEEEEED to know the bicarb Then, you need to know where the K has gone

  5. Acidosis Alkalosis PHA type 1 Liddle syndrome Gordon syndrome Gitelman syndrome Hypomagnesaemia/ Bartter syndromes hypercalciuria Diuretics Renal tubular acidosis Conn syndrome proximal distal GRA - primary - with osteopetrosis K - hyperkalaemic BP

  6. < 10% 60% 70% 2 - 3% 25% secretion Renal sodium and potassium reabsorption reabs/ secretion 15% but mostly recycled

  7. NHE3 Na H+ Na HCO3- NBC1

  8. Angiotensinogen Renin AT1 ACE 2-3% AT2 Aldosterone

  9. ? 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 Low K Many BP drugs: ACEI/ARB Renin up Aldo down Beta blockers Renin down Diuretics Renin up Aldo up Aliskiren Angiotensinogen < 10% Renin AT1 ACE 2-3% AT2 Aldosterone Lifton lab and others

  11. 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

  12. Liddle syndromevery 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

  13.  Na  Shimkets et al. 1994

  14. Some C-terminal functions of ENaC  Ubiquitination via NEDD4.2 Phosphorylation 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 

  15. 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 ? 

  16. ? 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

  17. 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

  18. ? 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

  19. 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)

  20. 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

  21. Gitelman thiazide Bartter I Bartter III Bartter II loop BSND1 Bartter IV

  22. Gitelman vs Type 3 Bartter syndrome Exclude diuretic abuse High renin and ?aldo more common gene tests LATER: HT Sometimes

  23. 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 Amiloride Spironolactone RAS axis ACEI Beta blockade Vitamin D? ?’Good’: K > 3 Mg > 0.6

  24. Low potassium Redistribution 2. GI losses 3. Skin 4. Renal losses

  25. 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

  26. NHE3 Na H+ Na HCO3- NBC1

  27. 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 ? 

  28. 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 ? 

  29. 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

  30. 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

  31. TRPM6: EGF responsive Mutations cause hypomagnesemia with 2o hypocalemia Na/K-ATPase g-subunit mutations isolated hypomagnesemia EGF k/o: hypomagnesemia Ca Mg TRPV5 TRPM6 Ca Na/K ATPase K+ g Na+ Ca Calcium: Upregulated proximal reabsorption Distal convoluted tubule Mg - C l NCCT + N a

  32. 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!

  33. 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

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