Disorders of ECF Homeostasis

Waleed AliDivision of Renal Diseases and Hypertension

University of ColoradoDenver, USA

ElementsBody fluid constituents Homeostatic mechanismsECF volume contractionECF volume expansion

(3.5 L)

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

Major effector homeostatic mechanisms

Extracellular Fluid Volume Depletion

Major causes of ECF volume depletion

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

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?

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.

• 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:1. D5W2. Isotonic sodium bicarbonate3. Hetastarch 6% (hydroxyethyl starch)4. Isotonic (normal) saline

• 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, HCO3 12, BUN 68, Cr 2.1. ABG: 7.23/100/36/14 on 40% FiO2

• What is the initial replacement fluid of choice:1. Isotonic (normal) saline2. Isotonic sodium bicarbonate3. D5W4. Hetastarch 6% (hydroxyethyl starch)

Extracellular Fluid Volume Expansion

• 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.

Pathogenesis-I

Pathogenesis-II

Primary Renal Sodium Retention

Secondary renal sodiumretention to reducedEABV (arterial underfilling)

Acute kidney injuryAdvanced chronic kidney diseasePrimary glomerular diseases

Cardiac failureCirrhosisNephrotic syndromeIdiopathic edemaDrug-induced edemaPregnancy

Mechanism, CHF

Mechanism, cirrhosis

Mechanism, nephrotic syndrome

Drug-Induced Edema

• Minoxidil and diazoxide• Dihydropyridine calcium channel blockers

Gustafsson DJ. Cardiovasc Pharmacol. 1987

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

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

• 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:

1. Eplerenone2. Chlorthalidone3. Bumetanide4. Mannitol

Management

• Achieve negative sodium balance:

–Restrict Na to <100 meq/day!!

–Use diuretics

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

Practically, how do you advise low salt diet?!

• Avoid processed and prepared foods/eat fresh fruits and vegetables!

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)

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”

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

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 1st-line agents in in liver cirrhosis with ascites and amiloride in the treatment of Liddle syndrome.

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

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

The End!Thank you