Potassium (only 2% of body K+ is in extracellular fluids and it has to be regulated tightly) Re-absorption by intercalated cells constantly Around 90% reabsorbed here, little regulation ATPases Excretion by principal cells - REGULATED ASC Aldosterone High tissue K+ increases K+ flow into cells thence out: Low K+ diets tyrP of apical K+ channels channels removed from membrane High K+ diets cause loss of tyrP and channels accumulate in membrane Data from Giebisch GH. (2002) A trail of research on potassium. Kidney Int. 62:1498-512

Potassium flux is sensitive to body pH: Re-absorption by intercalated cells constantly Alkalosis: H+ out-pumping by intercalated cells reduced, so less K+ re-uptake (AND apical K+ channel activity increased in Prinicipal cells and so is the Na+/K+ ATPase -> more K+ loss) hypokalaemia ATPases Acute acidosis: H+ out-pumping by intercalated cells increases so K+ reuptake increases. Also, apical K+ channels on Principal cells less active (by an effect on their intracellular regulation) so K+ secretion falls. hyperkalaemia Excretion by principal cells - REGULATED ASC (Chronic acidosis; Na pump less efficient in PCT, so urine more copious and helps flush K+ away) Aldosterone High tissue K+ increases K+ flow into cells thence out: Low K+ diets tyrP of apical K+ channels channels removed from membrane High K+ diets cause loss of tyrP and channels accumulate in membrane Data from Giebisch GH. (2002) A trail of research on potassium. Kidney Int. 62:1498-512

Diuresis: increasing the amount of water (+ salts) lost from the body through / of urine 65% salt and water PCT 0.08 0.29 H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Salt recovery Water reabsorption driven by hypertonic zone 1.4 Up to 1.4 (you have seen this before)

(Henle's) Loop Diuretics: (this still happens) 65% salt and water If we block SLC12A2, we stop the salt being moved into the interstitium PCT TAL: Renal corpuscle More NaCl (2-5%) Salt recovery SLC12A2 Water reabsorption driven by hypertonic zone (you have seen this before)

Features of loop diuretics: They are powerful (up to 20% of filtrate to bladder: usually around 0.4%)  They result in loss of Na+, K+ and Cl- because of failure to recover in the TAL of LoH  They can result in hypercalcuria – less pull for Ca2+ recovery – and kidney stones. More Na+ getting to the Coll Duct means more uptake there and more K+ loss 

Alternative diuretics: Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 0.29 H2O SLC12A3 Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Salt recovery You still loose some K+ for the same reason Water reabsorption driven by hypertonic zone (you have seen this before) 1.4 Up to 1.4

Alternative diuretics: Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 Potassium-sparing diuretics (amiloride etc) 0.29 H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 ASC Salt recovery "amiloride sensitive sodium channel" Water reabsorption driven by hypertonic zone 1.4 Up to 1.4 (you have seen this before)

Alternative diuretics: aldosterone Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 Potassium-sparing diuretics (amiloride etc) H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Spironolactone (problem – also antiandrogenic) Salt recovery Water reabsorption driven by hypertonic zone 1.4 Up to 1.4

Alternative diuretics: Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 Potassium-sparing diuretics (amiloride etc) H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Spironolactone Salt recovery Carbonic anhydrase inhibitors (more bicarb in lumen, resists egress of water osmotically) Water reabsorption driven by hypertonic zone 1.4 Up to 1.4

Alternative diuretics: Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 Potassium-sparing diuretics (amiloride etc) H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Spironolactone Salt recovery Carbonic anhydrase inhibitors Water reabsorption driven by hypertonic zone Osmotic agents (eg mannitol): stay in the lumen and resist water egress osmotically) Clinical use controversial 1.4 Up to 1.4

Alternative diuretics: Distal tubule diuretics ('thiazides') 65% salt and water PCT 0.08 Potassium-sparing diuretics (amiloride etc) H2O Renal corpuscle 0.1 More NaCl (2-5%) 0.29 Spironolactone Salt recovery Carbonic anhydrase inhibitors Water reabsorption driven by hypertonic zone Osmotic agents (eg mannitol): stay in the lumen and resist water egress osmotically) 1.4 Up to 1.4 Very high plasma glucose can exceed recovery capacity and act in this way: diabetic thirst because water lost by Na+ not lost as much -> hypernatraemia.

Diuretics summary slide: Carbonic anhydrase inhibitors Thiazides Amiloride, spironolactone Loop diuretics NB – this info is given from the point of view of basic understanding – the pharmacology vertical theme will give you the clinical details.

What can go wrong? – Hereditary disorders of tubule function. Bartter's syndrome (Type 1) – impaired SLC12A2 CLICKER QUIZ Effects (choose one) a) Loss of Na+, K+, hypocalcuria b) Loss of Na+ K+, H2O; hypercalcuria c) Na+ loss, K+ retention, high aldosterone d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension TAL cells:

What can go wrong? – Hereditary disorders of tubule function. Gitelman's syndrome – impaired SLC12A3 CLICKER QUIZ SLC12A3 Effects (choose one) a) Loss of Na+, K+ b) Loss of Na+ K+, H2O; hypercalcuria c) Na+ loss, K+ retention, high aldosterone d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension

What can go wrong? – Hereditary disorders of tubule function. Liddle's syndrome – hyperactive ASC (=ENaC) CLICKER QUIZ Effects (choose one) a) Loss of Na+, High K+, hypocalcuria b) Loss of Na+ K+, H2O; hypercalcuria c) Na+ loss, K+ retention, high aldosterone d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension ASC

What can go wrong? – Hereditary disorders of tubule function. Pseudohypoaldosteronism – inactive ASC (=ENaC) CLICKER QUIZ Effects (choose one) a) Loss of Na+, K+, hypocalcuria b) Loss of Na+ K+, H2O; hypercalcuria c) Na+ loss, K+ retention, high aldosterone d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension ASC

What can go wrong? – Hereditary disorders of tubule function. Inactivating Mutations of Aquaporins CLICKER QUIZ AVP + Effects (choose one) a) Loss of Na+, K+, hypocalcuria b) Loss of Na+ K+, H2O; hypercalcuria c) Na+ loss, K+ retention, high aldosterone d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension

What can go wrong? – Problems outside the kidney CLICKER QUIZ Addison's disease (destruction of adrenal glands) Effects (choose one) Loss of Na+, High K+, hypovolaemia Loss of Na+ K+, H2O; hypercalcuria c) Whole body hypo- osmolarity d) Diabetes insipidus (polyuria, polydipsia) e) Volume expansion (body), hypertension

What can go wrong? – Problems outside the kidney Psychogenic polydipsia CLICKER QUIZ Effects (choose one) Loss of Na+, K+, hypovolaemia Loss of Na+ K+, H2O; hypercalcuria c) Whole body hypo- osmolarity