Pathophysiology of Fluid Balance

Causes of Oedema

• Congestive heart failure: reduced ability of the heart to maintain cardiac output, leading to kidney response to hypovolaemic state to raise blood volume
• Nephrotic syndrome: damaged glomerular membrane, loss of protein reduces colloidal osmotic pressure, leading to aldosterone secretion through RAAS
• Hepatic cirrhosis: accumulation of fluid in the abdominal cavity
• Premenstrual oedema: fluid retention due to hormonal changes

Treating Non-Oedematous States

• Hypertension: reduce blood volume and dilate arterioles
• Hypercalcaemia: promote calcium excretion, infused with normal saline due to hypovolemia
• Diabetes insipidus: paradoxic treatment for polyuria and polydipsia, reduce plasma volume, decrease glomerular filtration rate, and increase sodium and water reabsorption

Classes of Diuretics

• Carbonic anhydrase inhibitors: act on proximal convoluted tubule
• Osmotic diuretics: act on descending limb of Henle and proximal convoluted tubule
• Loop diuretics: act on ascending limb of Henle
• Thiazide diuretics: act on distal convoluted tubule
• Aldosterone antagonists: act on collecting ducts, potassium-sparing diuretics
• ADH antagonists: act on collecting ducts

Carbonic Anhydrase Inhibitors

• Mechanism of Action: inhibit carbonic anhydrase, preventing exchange of Na+ for H+, resulting in mild diuresis
• Largely replaced by thiazides and loop diuretics
• Indications: long-term use for oedema, chronic treatment of open-angle glaucoma, high altitude disorders prophylaxis
• Adverse effects: metabolic acidosis, hypokalaemia, decreases uric acid secretion

Osmotic Diuretics

• Mechanism of Action: increase osmolarity of tubular fluid, preventing water reabsorption
• Regions affected: proximal tubule and descending limb of Henle
• Indications: maintain urine flow in acute toxic ingestion, acute renal failure patients
• Adverse effects: dehydration, headache

Loop Diuretics

• Mechanism of Action: inhibit Na+/K+/2Cl- symporter, decreasing reabsorption of sodium, potassium, and chloride
• Greatest diuretic effect of all diuretic drugs
• Indications: acute pulmonary oedema and renal failure, hypertension, hypercalcaemia, hyperkalemia
• Adverse effects: ototoxicity, hyperuricaemia, hypomagnesaemia, hypokalaemia, acute hypovolaemia

Thiazide Diuretics

• Mechanism of Action: inhibit Na+/Cl- symporter, decreasing reabsorption of sodium and chloride
• Indications: hypertension, mild congestive heart failure, idiopathic hypercalciuria, nephrogenic diabetes insipidus
• Adverse effects: orthostatic hypotension, erectile dysfunction, hypokalaemia, hyponatraemia, hyperuricaemia, hypercalcaemia, hyperglycaemia

Thiazide-Like Analogs

• Similar mechanism of action to thiazides
• Indapamide: lipid-soluble, long duration of action, decreases blood pressure, low doses, minimal diuresis

Aldosterone Antagonists

• Mechanism of Action: competitive antagonist of aldosterone, preventing sodium reabsorption and potassium secretion
• Indications: hypertension, heart failure, secondary hyperaldosteronism
• Adverse effects: hyperkalemia, gynaecomastia, menstrual irregularities, decreased libido, impotence

Potassium-Sparing Diuretics

• Mechanism of Action: directly inhibit epithelial Na+ channels, decrease Na+/K+ exchange
• Amiloride and triamterene: combinations with thiazides or loop diuretics, minimal diuresis
• Side effects: leg cramps, decreased folic acid, contraindicated in pregnancy

ADH Antagonists

• Mechanism of Action: decrease number of aquaporins, preventing water reabsorption
• Indication: syndrome of inappropriate ADH secretion (SIADH)
• Lithium and demeclocycline: non-selective, limited use

Ceiling Effects

• Low ceiling diuretics: thiazides, increasing dose does not increase diuretic response
• High ceiling diuretics: loop diuretics, increasing dose increases diuretic capability, substantial diuresis

Diuretic Tolerance and DDI

• Short-term tolerance: decreased response after first dose, nephron primed to reabsorb sodium after drug levels decline
• Long-term tolerance: gradual return of sodium chloride to electroneutral level, persistent volume removal triggers long-term RAAS activation
• Diuretic resistance and DDI: NSAIDs, ACE-inhibitors, beta-blockers, K+ supplements, heparin, inadequate dosage, poor absorption, hypoalbuminuria, low cardiac output, and poor renal perfusion### Kidney Functions
• Regulates ionic composition and urine volume through active reabsorption of water
• Five functional zones of the nephron: proximal convoluted tubule, descending loop of Henle, ascending loop of Henle, distal convoluted tubule, and collecting duct
• 1.4 × 10^6 nephrons in each kidney
• Functions include regulation of water and electrolyte content, retention of vital substances, maintenance of acid-base balance, excretion of waste products, and endocrine functions

Reabsorption

• Where Na+ goes, H2O follows
• Na+ leaves the tubule via active transport, anions follow Na+ across the electrochemical gradient
• Water follows through diffusion from an area of low concentration to an area of high concentration (osmosis)
• Low volume due to loss of water increases the concentration of K+ and other ions which follow if permeable to the membrane

Transporters

• Symporters: transport protein binds more than one substance, facilitating transport across the membrane together (e.g., Na+/K+/2Cl- symporter, K+/Cl- symporter)
• Uniporters: transport only one substance (e.g., renal medullary potassium channel (ROMK): ATP-dependent)
• Antiporters: exchange one substance for another (e.g., Na+/H+ antiporter, Na+/K+ ATPase antiporter)

Proximal Convoluted Tubule

• Kidney cortex
• Passive flow: epithelium permeable to water and ions
• Reabsorption of two-thirds of Na+, Na+/H+ antiporter, and Na+/K+ ATPase (basolateral membrane)
• Carbonic anhydrase modulates bicarbonate reabsorption
• Organic acid and base secretory systems

Loop of Henle

• Descending limb: highly water permeable, paracellular transport, osmolarity increases along descending portion
• Ascending limb: low permeability to water, active salt reabsorption via Na+/K+/2Cl- symporter, Na+/K+ ATPase in basolateral membrane

Distal Convoluted Tubule

• Kidney cortex
• Low permeability to water
• Na+ and Cl- (10%) reabsorbed via Na+/Cl- symporter
• Calcium reabsorption into interstitial fluid via Na+/Ca2+ exchanger

Collecting Ducts

• Principal cells: sodium (ENaC), potassium (ROMK), and water transport, stimulated by aldosterone
• Intercalated cells: α and β, acid-base homeostasis, hydrogen secretion
• Sodium reabsorbed via Na+/K+ ATPase
• Secretion of H+ and K+

Diuretics

• Drugs that increase excretion of salt and water
• Saluresis: urinary excretion of sodium and chloride ions
• Treat oedematous and non-oedematous states
• Most diuretics act on a single anatomical region of the nephron

Oedema

• Rate of fluid formation exceeds that of reabsorption
• Sodium chloride reabsorption is too high, resulting in water retention
• Increased blood volume and expansion of extravascular fluid compartments

Classification of Diuretics

• Carbonic anhydrase inhibitors (e.g., acetazolamide): act on proximal tubule, inhibit Na+/H+ antiporter
• Osmotic diuretics (e.g., mannitol): act on proximal tubule and descending limb, freely permeable to water
• Loop diuretics (e.g., furosemide): act on ascending limb, inhibit Na+/K+/2Cl- symporter
• Thiazide diuretics (e.g., hydrochlorothiazide): act on distal tubule, inhibit Na+/Cl- symporter
• Aldosterone antagonists (e.g., spironolactone): act on collecting tubule, inhibit ENaC