Extracellular fluid homeostasis

Lecture presented by Dr. Elwaleed Ali, Nephrologist in Denver, CO in July 2011 in SMSB, Khartoum, Sudan

1. Disorders of ECF Homeostasis Waleed Ali Division of Renal Diseases and Hypertension University of Colorado Denver, USA

2. Elements Body fluid constituents Homeostatic mechanisms ECF volume contraction ECF volume expansion

3. (3.5 L)

4. Effective Arterial Blood Volume “The blood volume that is detected by the sensitive arterial baroreceptors in the arterial circulation” The EABV can change independently of the total ECF volume and can explain the sodium and water retention in different health and disease clinical situations

5. Major effector homeostatic mechanisms

6. Extracellular Fluid Volume Depletion

7. Major causes of ECF volume depletion

8. Lab Evaluation of ECF Volume Depletion Hemoconcentration and hyperalbuminemia BUN/creatinine >10 (mg/dl) or 40 ( mmol /l) ↑Urine osm and specific gravity ↓ Urine Na and FeNa FENa = [ UNa × Pcreat Ucreat × PNa ] ×100

9. Therapy for Extracellular Volume Contraction Replace deficit + ongoing losses with similar fluids Assess clinically &/or invasively Replacement fluid: Crystalloids: 1/3, 2/3 Human albumin (5% and 25%) and hetastarch (6% hydroxyethyl starch) Remain within the vascular compartment (if transcapillary barrier not disrupted by capillary leak states (MOF, SIRS) Outcome difference?

10. Therapy for Extracellular Volume Contraction Crystalloids or colloids?* High, normal or low serum Na? Sodium chloride or bicarbonate? *Wilkes et al. Ann Intern Med. 2001;135:149-164. * Finfer et al. N Engl J Med. 2004;350:2247.

11. A 34 yom presents to the ER with a few days duration of severe nausea, vomiting and watery diarrhea. Physical exam reveals a sick patient with PR of 110/BP of 106/56, and dry axillae . What is the initial replacement fluid of choice: D5W Isotonic sodium bicarbonate Hetastarch 6% ( hydroxyethyl starch) Isotonic (normal) saline

12. A 56 yof with presents to the ER with a few days duration of RUQ abd pain, fever and lethargy. Physical exam reveals an obtunded patient with Temp of 39.6, PR of 120, BP of 84/40, with general abdominal tenderness. Lab studies show Na 130, K 4.6, Cl 100, HCO 3 12, BUN 68, Cr 2.1. ABG: 7.23/100/36/14 on 40% FiO 2 What is the initial replacement fluid of choice: Isotonic (normal) saline Isotonic sodium bicarbonate D5W Hetastarch 6% ( hydroxyethyl starch)

13. Extracellular Fluid Volume Expansion

14. ECF volume expansion refers to excess fluid accumulation in the ECF compartment. Generalized edema results when an apparent increase in the interstitial fluid volume takes place. It may occur in disease states most commonly in response to cardiac failure, cirrhosis with ascites, and the nephrotic syndrome.

15. Pathogenesis-I

16. Pathogenesis-II Primary Renal Sodium Retention Secondary renal sodium retention to reduced EABV (arterial underfilling) Acute kidney injury Advanced chronic kidney disease Primary glomerular diseases Cardiac failure Cirrhosis Nephrotic syndrome Idiopathic edema Drug-induced edema Pregnancy

17. Mechanism, CHF

18. Mechanism, cirrhosis

19. Mechanism, nephrotic syndrome

20. Drug-Induced Edema Minoxidil and diazoxide Dihydropyridine calcium channel blockers Gustafsson DJ. Cardiovasc Pharmacol . 1987

21. Drug-Induced Edema Thiazolidinediones : Can cause fluid retention and CHF exacerbation Activation of peroxisome proliferator - activated receptor γ ( PPARγ ) -> stimulation of ENac NSAIDs: ↓ vasodilatory prostaglandins of the afferent arteriole. Guan et al. Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC -mediated renal salt absorption. Nat Med. 2005;11:861

22. Therapeutic Approaches Recognizing and treating the underlying cause Attempting to achieve negative sodium balance, judiciously : Dietary sodium restriction Diuretics Specific measures: Cirrhosis: large-volume paracentesis with albumin, TIPS Ultrafiltration

23. A 72 yom with known CHF 2/2 ischemic CM is seen at the clinic. He had noticed ↑SOB and ↓exercise tolerance over the past few weeks. O/E distended neck vein and bibasilar crackles, and +1 LEE. Labs: Na: 132, K 5.1, BUN 38, s. Cr 1.9. The initial diuretic of choice in this case: Eplerenone Chlorthalidone Bumetanide Mannitol

24. Management Achieve negative sodium balance: Restrict Na to <100 meq /day!! Use diuretics

25. What does “Na to <100 meq /day” mean?!! Calculate the molecular weight of NaCl Na = 23 Cl = 35 NaCl = 58 Therefore: 40% of NaCl is Na I Mole of NaCl = 58 grams 1Equivalent of NaCl = 58 grams 1mMole = 58 mg 1 meq NaCl = 58 mg; this provides 1 meq Na and 1 meq Cl 100 meq NaCl ~ 6000 mg, 40% of which is Na ~ 2300 mg ~ I teaspoon of table salt

26. Practically, how do you advise low salt diet?! Avoid processed and prepared foods/eat fresh fruits and vegetables!

27. Diuretics Diuretic tolerance Decreased action 2/2 distal nephron hypertrophy and enhanced Na reabsorption proximally Diuretic resistance edema that is or has become refractory to a given diuretic CKD Arterial underfilling -> ↑ RAAS (↑proximal Na reabsorption -> ↓ distal delivery) NSAIDs (↓ PG-mediated ↑ in RBF, ↑ expression of Na-K-2Cl cotransporters in TAL)

28. Loop diuretics Most potent since block absorption of loop where 25% of Na reabsorption occurs Short elimination T ½ , -> dosing interval needs to be short to maintain adequate levels (avid Na reabsorption may result in post diuretic retention) “Threshold drugs”

29. Distal Convoluted Tubule Diuretics Inhibit Na/ Cl absorption in DCT, 5% of filtered load is reabsorbed ->less potent than loop diuretics. Have long T ½ -> can be administered QD/BID

30. Collecting Duct Diuretics (K-sparing) Amiloride, triamterene ( ENaC blockers), and spironolactone and eplerenone (aldosterone antagonists) Are weak diuretics because they block only a small part (3%) of the filtered Na -> most commonly used in combinations to augment diuresis or to preserve potassium Are considered 1 st -line agents in in liver cirrhosis with ascites and amiloride in the treatment of Liddle syndrome.

31. Proximal Tubule Diuretics Acetazolamide is a blocker of Na-H + -> sodium bicarbonate excretion. Are weak since the loop has a large reabsorptive capacity that captures most of the Na/ Cl escaping Generates a hyperchloremic metabolic acidosis particularly with prolonged use. Rarely used as a single agent, this diuretic is most commonly used: in combination with other diuretics In the treatment of metabolic alkalosis accompanied by edematous states, and in chronic obstructive pulmonary disease

32. Approaches to manage resistance Restricting dietary salt Increasing the dose Administering more frequent doses Using combination therapy to sequentially block more than one site in the nephron Ultrafiltration

33. The End! Thank you