1. Sodium Reabsorption, Diuretics, and Diet Vivek Bhalla, MD Division of Nephrology Stanford University School of Medicine September 14th, 2015

2. Anatomy of the Renal Block PhysiologyPathophysiologyUrology Body Fluids -1Glomerular Diseases – 3Histology Lab GFR, Clearance -1Acute Kidney Injury – 1Malignancy – 1 Sodium / Diuretics – 2 1Chronic Kidney Disease – 3 Potassium – 2Renal Lab -2 1 Acid – 2Transplant Pathology-1 Water – 2Vascular Diseases – 1/2 Steady State - 1Plumbing- 1/2

3. Learning Objectives (3) To understand how sodium is handled along the nephron To learn the 4 major classes of diuretics, their mechanisms of action, their relative potencies, and main side effects To understand what is meant by a “low-sodium” diet

4. Daily Sodium Reabsorption (ancient) GFR ≈ 100 mL/minGFR ≈ 100 mL/min ≈ 150 l/day [Na] ≈ 140 mEq/L[Na] ≈ 140 mEq/L Filtered load of [Na] ≈ 150 l/day x 140 mEq/LFiltered load of [Na] ≈ 150 l/day x 140 mEq/L ≈ 21,000 mEq/day ≈ 21,000 mEq/day Na excreted ≈ 1 to 50 mEq/dayNa excreted ≈ 1 to 50 mEq/day – (primitive)

5. Daily Sodium Reabsorption (today) The average American eats about 150 mmol of NaCl per day. Many Americans eat much more.

6. Sodium Reabsorption in Disease States (?) Sodium retention is prominent in: heart disease kidney disease 1.nono 2.yesno 3.noyes 4.yesyes

7. What is a diuretic? Diuretic = natriuretic blocks reabsorption of Na + and Cl - by the tubule increases excretion of Na + and Cl - into the urine presuming that osmolar control is normal, water will be excreted along with Na + and Cl, and the ECF volume will decline

8. Where would Diuretics act?

9. Classes of Diuretics Proximal Tubule Thick Ascending limb (of the loop of Henle) Distal convoluted tubule Collecting duct Carbonic anhydrase inhibitors “Loop” diuretics Thiazide-type diuretics Potassium-sparing diuretics

10. Classes of Diuretics Proximal Tubule Thick Ascending limb (of the loop of Henle) Distal convoluted tubule Collecting duct Osmotic diuretics (e.g. mannitol) Aquaretics (not natiuretics)

11. Classes of Diuretics Where’s the best place to block sodium reabsorption? 1. proximal tubule 2. thick ascending limb 3. distal tubule 4. collecting duct

12. What will be the side effect of acetazolamide: low serum HCO 3 - or high serum HCO 3 - ? Carbonic anhydrase Proximal tubule: carbonic anhydrase inhibitor -- acetazolamide

14. Thick ascending limb: Na-K-2Cl inhibitor-- furosemide

15. What will the side effects be? 1. low K +, low HCO 3 - 2. low K +, high HCO 3 - 3. high K +, low HCO 3 - 4. high K +, high HCO 3 -

16. principalintercalated Na+ K+ H+ HCO3- Furosemide causes more Na + and Cl - to be delivered to the downstream collecting duct. More K + and H + are exchanged for Na + in the collecting duct. More K + and H + are excreted in the urine. Na+ K+ H+ Aldosterone

18. Distal convoluted tubule: Na-Cl inhibitor– hydrochlorothiazide Na T What will the side effects be? 1. low K +, low HCO 3 - 2. low K +, high HCO 3 - 3. high K +, low HCO 3 - 4. high K +, high HCO 3 -

20. Collecting Duct: Na channel inhibition principalintercalated Na+ K+ H+ HCO3- Na+ K+ H+ Aldosterone Spironolactone Amiloride Triamterene

21. Osmotic Diuretics Act all along the tubule Not used for diuresis per se, but important to be aware of Mannitol: used commonly in neurologic injury (to minimize cerebral edema) Glucose: why poorly controlled diabetics have polyuria

22. Take Home Points: Diuretics Diuretic ClassSite of ActionPotencySide EffectsClinical Utility CA InhibitorsProximal TubuleLowLow HCO3-Used for contraction alkalosis LoopTALHHighLow K+ High HCO3- Drug of choice in CHF, more advanced renal failure ThiazideDistal Convoluted Tubule MediumLow K+ High HCO3- Good for essential HTN, but less effective with GFR < 30 ml/min Potassium Sparing Collecting DuctMediumHigh K+Great as adjunctive therapy

23. The ECF volume is increased: do you want to reduce it? A patient with heart failure comes into your clinic complaining of leg swelling. Physical exam is notable for a blood pressure of 120/70, a pulse of 90, a high central venous pressure, bibasilar rales, and 3+ pitting edema. Should you give a diuretic to reduce the leg swelling? 1. Yes 2. No

24. The ECF volume is increased: do you want to reduce it? A 5 year old boy is brought in by his mother who says he has gained 25% body weight over a few days and has swollen legs. Physical exam notable for BP 95/65, HR 88, 3+ pitting edema. Labs show Cr 0.6 mg/dL, UA with 3+ protein, albumin 2.0 g/dL. Should you give a diuretic? 1. Yes 2. No

25. Where will diuretics remove fluid from? 1.Plasma 2.Interstitial Fluid 3.Intracellular Fluid 4.All of the above

26. Where will diuretics remove fluid from?

27. The ECF volume is increased: do you want to reduce it? A patient with polycystic kidney disease has a blood pressure of 156/95, a central venous pressure of 7 mmHg, and no edema. Her serum creatinine is 1.8 mg/dL and she currently takes lisinopril 40 mg daily. Should you give a diuretic? 1. Yes 2. No

28. Diuretic Resistance (Refractoriness)? You give the stuff, and not much comes out.

29. Diuretic Resistance (Refractoriness)? _________________

30. Sodium in our Diet

31. Low-sodium diet (US recommended daily allowance) 100 meq Na+ = 100 mmol* 23 grams/mol = 2.3 grams Na+ (not NaCl)

32. Low Sodium Content in Natural/Raw Foods Bielamowicz MK, 2011 The Sodium Content of Your Food

33. High Sodium Content in Processed Foods Bielamowicz MK, 2011 The Sodium Content of Your Food Sauce Fries

34. Sources of Dietary Sodium in the American Diet

35. Sodium in our Diet Quiznos large turkey club sandwich in NYC 5820 milligrams NaCl = 5.82 grams / 58 grams / mol = ~100 meq Na

36. Sodium in our Diet Quiznos large turkey club sandwich in NYC 5820 milligrams NaCl = 5.82 grams / 58 grams / mol = ~100 meq Na

37. Learning Objectives (3) To understand how sodium is handled along the nephron To learn the 4 major classes of diuretics, their mechanisms of action, their relative potencies, and main side effects To understand what is meant by a “low-sodium” diet