RENAL PHYSIOLOGY Origin of the Hyperosmotic Renal Medulla continuing from last time PHYSIOLOGY 451 RENAL PHYSIOLOGY Dr. Michael Fill, Lecturer mfill@rush.edu

Origin of the Hyperosmotic Renal Medulla Page 62 in the Renal syllabus Cortex Medulla mOsM 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Medulla is hyperosmotic but there is also an osmolarity gradient.

Origin of the Hyperosmotic Renal Medulla Cortex Medulla mOsM 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Countercurrent Multiplication H20 reabsorbed Na H20 Na+ reabsorbed The 3 Essential Elements: 1) Active Na+ transport in thick ascending limb of loop. ( Overall, the loop always reabsorbs more Na+ than H20 )

Origin of the Hyperosmotic Renal Medulla Vasa Recta Blood Osmolarity IN = OUT mOsM 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Hair-pin loop arrangement preserves medullary osmolarity Cortex Medulla The 3 Essential Elements: 1) Active Na+ transport in thick ascending limb of loop. ( Overall, the loop always reabsorbs more Na+ than H20 ) 2) Unique arrangement of medullary peritubular capillaries. ( The vasa recta loop down into the renal medulla)

Origin of the Hyperosmotic Renal Medulla Cortex Medulla mOsM 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Urea Recycling: Keeps “dumping” urea (solute) back into medulla. Rate of “dumping” depends on urea level in the tubular fluid (faster when higher). Urea Recycling The 3 Essential Elements: 1) Active Na+ transport in thick ascending limb of loop. ( Overall, the loop always reabsorbs more Na+ than H20 ) 2) Unique arrangement of medullary peritubular capillaries. ( The vasa recta loop down into the renal medulla ) 3) Recycling of urea between loop and collecting duct. ( Urea provides about half of the high medullary osmolarity )

Tubular Fluid Osmolarity Changes along Nephron Percent filtered H20 Remaining Iso-osmotic to plasma Dilute urine Conc. Approaches osmolatity of interstitium in cortex Approaches osmolatity of interstitium in medulla Hypo-osmotic to plasma

Regulation of Sodium and Water Excretion ( Lecture 5 … page 66, renal syllabus ) ….. essentially same as….. Regulating Plasma Volume and Osmolarity Kidneys excrete salt and water Since the amounts of salt and water in body define blood volume & osmolarity, Kidney’s control blood volume and body fluid osmolarity.

Renal Role in Blood Pressure Regulation Short Term BP Control: seconds/minutes classic baroreceptor reflex sympathetic output changes vascular resistance Medium Term BP Control: minutes/hours renin release renin promotes angiotensin II formation circulating angiotensin II changes vascular resistance Long Term BP Control: hours/days changes in total body salt & H20 changes blood volume The Kidney’s Role: 1) renin release (min/hrs) 2) controlling blood volume (hrs/days) CONCEPT: If you control Na, then you control blood volume. Blood volume changes when H20 moves in or out of the plasma. H20 always moves down osmotic gradients. Most abundant osmotically active particle in plasma is Na+. Control of Na = control of H20 movement = Control of volume

Regulation of Na+ & H20 Balance First a Conceptual Overview Parallel Bulk Handling Pressure Natriuresis Aldosterone ….. Na ADH ….. H20 Differential Hormonal Fine-Tuning

Regulation of Na+ Balance Pressure Natriuresis Definitions: Natriuresis =  Na+ excretion in Urine Pressure Natriuesis is caused by increased blood pressure & associated increase in GFR. More IN OUT Simply Hemodynamics: More IN = More OUT No independent treatment of Na+ & H20 Good for simple bulk volume control Some Murky Mechanism Details: Some evidence that increased BP some how down regulates Na reabsorption from the proximal tubule Higher hydrostatic pressure in peritubular capillaries reduces reabsorption from the proximal tubule. Pressure Natriuresis: 1) driven by simple hemodynamics 2) proximal nephron phenomenon 3) no sensors or circulating factors

Regulation of Na+ in Distal Nephron Aldosterone: Most important “H20-independent” controller of Na+ reabsorption & Na+ balance Steroid hormone produced by adrenal cortex Acts on principle cells of the collecting duct Circulating Angiotensin II stimulates its release Differential Hormonal Fine-Tuning Collecting Duct So…  BP trigger baroreceptor response … this in turn triggers renin release … renin leads to increased angiotensin II levels … this triggers aldosterone release … this stimulates Na reabsorption … this leads to increased blood volume … increased blood volume leads to  BP This is summarized in the next figure.

…  BP triggers baroreceptor response …  BP & sympathetic inputs trigger renin release from granular cells … renin enters circulation and leads to increased angiotensin II levels … angiotensin II triggers aldosterone release from adrenal cortex … aldosterone stimulates Na reabsorption from collecting duct … the retained Na leads to increased blood volume which raises BP Aldosterone is not the only hormone that regulates the body’s Na+ balance.

Atrial Natriuretic Peptide released from heart when atria stretch due to high blood volume ( BP) vasodilates afferent arteriole increasing GFR inhibits Na reabsorption in from collecting duct inhibits renin-angiotensin Atrial Natriuretic Peptide Now…. Let’s look at hormonal control H20 balance

Regulation of H20 Balance Key Hormone = Antidiuretic Hormone (ADH) sometimes called vasopressin Collecting Duct ADH : Peptide hormone Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly Released from posterior pituitary Increases H20 Permeability of apical membrane by promoting the fusion of vesicles containing an aquaporin

Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release

Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Baroreceptors

Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalmic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Osmoreceptors The cells that release ADH integrate the 2 input signals. “2 heads are better than 1”

Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalmic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Generally, osmolarity usually dominates unless there are very large changes in volume. Certain other brain level inputs can alter short-term ADH release (fear, pain, alcohol). Diabetes insipidus is due to abnormal ADH regulation. Origin could be brain problem or bad renal ADH receptors.

Free Water Clearance (CH20) means to access renal H20 handling, not the usual clearance calculation The CH20 determination considers urine as having 2 parts: Urine Volume solute-free H20 H20 with solute  This is the H20 “cleared” Volume in which solutes present would be iso-osmotic compared to plasma. v solute-free H20 H20 with solute Can be calculate as Osmolar Clearance COSM = UOSM · V POSM

Free Water Clearance (CH20) means to access renal H20 handling, not the usual clearance calculation The CH20 determination considers urine as having 2 parts: Urine Volume solute-free H20  This is the H20 “cleared” v H20 with solute Volume in which solutes present would be iso-osmotic compared to plasma. solute-free H20 Thus…. CH20 = V - COSM COSM = UOSM · V POSM H20 with solute Can be calculate as Osmolar Clearance

Free Water Clearance (CH20) means to access renal H20 handling, not the usual clearance calculation The CH20 determination considers urine as having 2 parts: Urine Volume solute-free H20  This is the H20 “cleared” v H20 with solute Volume in which solutes present would be iso-osmotic compared to plasma. Note: CH20 could be negative !! This is when very concentrated urine is being produced. solute-free H20 Thus…. CH20 = V - COSM COSM = UOSM · V POSM H20 with solute Can be calculate as Osmolar Clearance

Free Water Clearance (CH20) means to access renal H20 handling, not the usual clearance calculation The CH20 determination considers urine as having 2 parts: Urine Volume solute-free H20 H20 with solute  This is the H20 “cleared” Volume in which solutes present would be iso-osmotic compared to plasma. v Note: CH20 could be negative !! This is when very concentrated urine is being produced. solute-free H20 H20 with solute Can be calculate as Osmolar Clearance COSM = UOSM · V POSM Thus…. CH20 = V - COSM If… V = COSM Then… CH20 is zero If… V > COSM Then… CH20 is positive If… V < COSM Then… CH20 is negative