008_-_2.3_osmolality_regulation_-_dr._justin_cheng_-_updated_oct_10.pdf

Regulation of Body Osmolality Justin Cheng, MD FRCPC October 10, 2023 Slides adapted from Dr. R. Suneet Singh I would like to acknowledge that UBC’s Vancouver c...

Regulation of Body Osmolality Justin Cheng, MD FRCPC October 10, 2023 Slides adapted from Dr. R. Suneet Singh I would like to acknowledge that UBC’s Vancouver campus is situated on the traditional, ancestral, unceded territory of the Musqueam people Disclosure None. Objectives 1. Describe normal plasma osmolality and the forces that govern the movement of water between the intracellular fluid (ICF) and extracellular fluid (ECF) 2. Describe the kidney's process in water excretion and reabsorption 3. Describe the basic mechanisms that allow the kidney to be able to concentrate or dilute urine 4. Describe osmolality and the role of the arginine vasopressin (AVP) in determining the renal handling of free water 5. Describe the relationship between renal water handling and the plasma concentration of sodium 6. Describe the role of AVP in ECF volume regulation 7. Describe pharmacological agents that can manipulate the AVP system  The kidney presents in the highest degree the phenomenon of sensibility, the power of reacting to various stimuli in a direction which is appropriate for the survival of the organism; a power of adaptation which almost gives one the idea that its component parts must be endowed with intelligence. Ernest STARLING—1909  Why Study Osmolality Almost all patients admitted to the hospital will receive intravenous (IV) fluids Disorders of salt and water is extremely common Disturbances of extracellular fluid (ECF) and intracellular fluid (ICF) volume Volume depletion is among the most common cause of death globally Hyponatremia (low plasma sodium concentration) present in 25% of all hospital admissions Disorders of electrolytes Often preventable cause of morbidity and mortality  Critical Points Under most circumstances, salt and water regulation by the kidney are independent of each other Extracellular sodium total content determines ECF volume and is regulated by changes in urinary sodium excretion/reabsorption Extracellular sodium concentration is primarily affected by changes in urinary water excretion/reabsorption (output) and thirst (intake)  Key Distinction Volume Status: refers to the state of the extracellular fluid (ECF) compartment. A patient with an expanded ECF compartment is “volume expanded”. A patient with a reduced ECF compartment is “volume contracted”. Volume is determined by the sodium content It is regulated over hours to days Dehydration: a deficit of water compared to sodium Osmolality is regulated minute to minute  What is Osmolality Osmolality is the ratio of plasma solutes (in osmoles)/plasma water (in kg) normal is 275-295 mOsm/Kg water Plasma solutes primarily sodium (& anion) and small concentrations of others Can be measured with analytical equipment Osmolarity is the ratio of plasma solutes (in osmoles)/plasma water (in L) Estimated clinically by 2[Na] + [glucose] + [urea]  We can measure the plasma osmolality. Plasma, extracellular and intracellular osmolality are ALWAYS the same Why?  280 mOsm/kg 280 mOsm/kg 10.5 L Interstitial Osmolality 28 L H2O H2O = ECF solute /ECF volume = ICF solute /ICF volume 3.5 L H2O Intravascular = ECF solute + ICF solute /TBW Extracellular solute is primarily sodium Intracellular Extracellular Intracellular solute is primarily potassium Small solutes travel freely within the ECF compartment Water travels freely between ECF and ICF compartments  Tonicity Tonicity: effective plasma osmolality the force that drives the movement of water between ICF and ECF Effective osmoles – cannot cross cell membrane freely Sodium, mannitol Ineffective osmoles – able to cross cell membrane freely urea**, glucose*, ethanol We use tonicity to define intravenous solutions—such as “isotonic saline” or “hypotonic dextrose solution”. Both have similar osmolality, but different tonicity “Distribution” of the fluid is different, but beyond the scope of this lecture **exceptions in some clinical circumstances  Disturbances in Osmolality Disturbances occur easily: we do not consume salt and water at a fixed ratio It is up for the body to adjust for changes in serum osmolality By adjusting the osmolality of the urine By adjusting how much electrolyte-free water is inputted or excreted Osmolality disturbances are almost always due to losses/gains of water compared to concomitant losses/gains of sodium Sodium regulation should not result in osmolality changes** **exceptions in some clinical circumstances  More about Water Water intake fluctuates wildly Basic minimum is 400 ml/day, “normal” is 2-3 litres daily The brain influences intake The kidney regulates excretion/reabsorption of water by changing the concentration of urine Water Deprivation Goal: Conserve water Result: High osmolality/”concentrated” urine; low volume Water Excess Goal: Excrete water Result: low osmolality/”dilute” urine; high volume  Source Water intake Source Water output (ml/day) (ml/day) Ingested water 1400 Urine 1500 Water content of 850 Skin 500 food Products of Respiratory tract 400 350 oxidation Stool 200 Total: 2600 Total: 2600 Summary: Osmoregulation vs. Volume Regulation Osmoregulation Volume regulation Signal Plasma osmolality “Effective” circulating volume Carotid sinus, large vein, atrial, Sensors Hypothalamic osmoreceptors and intrarenal receptors Antidiuretic Hormone (ADH), Renin/angiotensin, aldosterone, Effectors thirst sympathetic nerves, ANP, ADH Observed Urine osmolality, water intake Urinary sodium excretion responses  Renal Water Handling For renal excretion to vary between filtered substances, there must be differential transport within the tubular epithelium Proximal Tubule Loop of Henle Descending Limb Ascending Limb Distal Convoluted Tubule Early Late Collecting Duct  The Proximal Tubule 67% of filtered load Water flow is passive and follows the osmotic gradient established by Na reabsorption Sodium and water are absorbed iso-osmotically  Loop of Henle Descending thin limb Cortex Medulla Permeable to water Little sodium reabsorption Generates a hyperosmolar filtrate Thick ascending limb Impermeable to water Active sodium reabsorption Diluting segment  Loop of Henle Descending thin limb Permeable to water Little sodium reabsorption Generates a hyperosmolar filtrate Thick ascending limb Impermeable to water Active sodium reabsorption Diluting segment The loop of Henle reabsorbs 25% of filtered solutes and 20% of filtered water  Distal Convoluted Tubule and the Collecting Duct Distal Convoluted Tubule (DCT) Early DCT Peak urinary dilution Impermeable to water Further filtrate “dilution” via active solute transport Late DCT and Collecting Duct (CD) Variable water permeability Regulated by ADH Reabsorbs 8-17% of filtered load  Aquaporin and ADH Stored in intracellular vesicles in collecting duct epithelium Through cAMP-mediated signaling, vesicles move to apical membrane In absence of ADH, water channels are re- internalized Summary: Tubular Water Permeability ** ADH is the most important regulator of water balance Final Urine Osmolality Concentration is dependent on: 1. Interstitial gradient 2. ADH effect Maximal concentration ~1200 mOsm/kg water Minimal concentration ~50 mOsm/kg water Counter-Current Multiplication The perfect physiological-anatomical relationship between the tubules, their location in the kidney and their relationship with the blood vessels The vasa recta, “straight vessels”, has very low flow rates Unique to all other organs—some parts of the nephron are normally impermeable to water Requires NaCl and urea in the interstitium Urea transporters upregulated by ADH  Recap of Water Handling in the Nephron Proximal Tubule: water permeable, 67% of water is reabsorbed iso-osmotically with NaCl Loop of Henle Descending Thin limb: water permeable, passive reabsorption Thick Ascending Limb: water impermeable: diluted urinary space Distal Convoluted Tubule: water impermeable: diluted urinary space Collecting Duct ADH present: water reabsorption via aquaporins, concentrated urine ADH absent: limited water reabsorption, dilute urine Summary: Urine Osmolality and ADH Water Regulation: ADH Plasma Osmolality and ADH Urine Osmolality and ADH Nephron segment No ADH Max ADH Proximal tubule 300 300 Start of descending 300 300 thin limb Start of ascending thin 1200 1200 limb End of TAL 100 100 End of cortical 50-100 300 collecting duct Final urine 50 1200  ADH and Volume Status Primary stimulus: Osmolality Hypothalamic osmoreceptors Sensitive (1%) Setpoint Secondary stimulus: Hemodynamic Baroreceptors Insensitive (5-10%) but overriding ADH Receptors  Water Intake Excess water ingestion is managed by increased renal free water excretion Free water depletion is managed by both increased renal water reabsorption and water ingestion An intact thirst mechanism alone can prevent the development of significant free water depletion  Thirst Regulation Regulated by hypothalamic receptors: Subfornical organ Organum vasculosum Signals: 1. Osmolality 2. Hemodynamic sensing Independent from (but synergistic with) ADH secretion Also stimulated by angiotensin II Receptors in oropharynx and upper GI tract sense water intake Relief even before correction of osmolality ADH: Putting everything together ADH Activation  Hemodynamic ADH Release Late responder Very insensitive—requires >10% change in volume/pressure Sensors are baroreceptors in the venous and arterial side of the circulation Venous side—total body volume Arterial side—”effective circulating volume” In this setting, RAS is also activated which leads to sodium retention and thirst Net effect is salt (and water) and free water retention This occurs in disease—not in normal state Minimal Urine Output  Fundamentals for Clinical Medicine Sodium concentration does not tell you anything about ECF volume Sodium concentration has nothing to do with sodium content Sodium concentration tells you about the ratio of Na/water in the ICF and ECF Summary Osmolality regulation is synonymous with water regulation Complex renal mechanisms facilitate the concentration/dilution of urine to allow water movement in the kidney to be regulated Major hormone system is ADH Very quick regulation, most of the time it is completely distinct from the body sodium content and its’ regulation The clinical goal is to determine why the kidney is retaining extra water—why is ADH acting? What has happened in the feedback system.  Questions Email: [email protected] Reminder Please take a few minutes after this lecture to log into One45 and complete the Teacher Assessment form for this lecture. Your teachers do want your feedback!