Medullary Gradient Physiology PDF

Lecture 72: Physiology - Medullary Gradient - Dilution & Concentration of Tubular Fluid Loop of Henle: TF entering the descending limb is isotonic → reabsorbate is hypertonic (ISF in medulla is hypertonic) → TF leaving ascending limb is hypotonic; sets up conditions to generate dilute or concentrate...

Lecture 72: Physiology - Medullary Gradient - Dilution & Concentration of Tubular Fluid Loop of Henle: TF entering the descending limb is isotonic → reabsorbate is hypertonic (ISF in medulla is hypertonic) → TF leaving ascending limb is hypotonic; sets up conditions to generate dilute or concentrated urine Corticomedullary gradient: ISF osmolality ↑ progressively from cortex to inner medulla Descending limb (DLH): permeable to H2O & some solutes, TF equilibriates w/ ISF → TF osmolality ↑ Thick ascending limb (TALH): impermeable to H2O, reabsorbs solute → TF osmolality ↓as fluid moves up limb (200 mOsm/kg gradient b/w TF in TALH, higher, and DLH, lower) Countercurrent multiplication: properties of TALH & DLH create 200 mOsm/kg gradient b/w limbs (see above) → TF flow in opposite directions (down DLH & up ALH) multiplies gradient (countercurrent multiplication) → ISF osmolality ↑ from cortex (~300 mOsm/kg) to inner medulla (1200-1500 mOsm/kg) Mechanism: as fluid moves down DLH, it absorbs ISF solute from ALH → gradient b/w TALH & DLH → as flow occurs, gradient b/w limbs multiplied to gradient from cortex to medulla Corticomedullary (CM) gradient: Loop of Henle: makes TF hypotonic & ISF hypertonic → sets up gradient for concentrated urine Final Uosm & urine flow rate (V): determined by proper function of the loop of Henle (dilution), amount of H2O reabsorbed downstream in collecting duct (concentration) & steepness of CM gradient Urinary dilution: TF is diluted across TALH (~100 mOSM/kg), may increase as distal tubule & collecting duct absorb additional solute (~50 mOSM/kg) Urinary concentration: by corticomedullary gradient formed due to active solute reabsorption by loop w/o H2O reabsorption, under the influence of ADH Factors that influence steepness of gradient: rate of solute reabsorption by TALH (directly), TF flow rate through loop of Henle (inversely), & rate of blood flow through vasa recta (inversely) Rate of reabsorption by TALH: ↓solute reabsorption → ↓gradient (opposite is also true); influenced by NKCC2 activity (see below), which is inhibited by diuretics to prevent formation of optimum gradient Na+/K+/2Cl- transporter (NKCC2): produces NET NaCl reabsorption (K leaks back out) Flow rate through hoop of Henle: ↓flow rate → ↑corticomedullary gradient (opposite also true) b/c slower flow leaves more time for transporters to reabsorb solute Paradox: ↓↓↓ flow rate → ↓gradient due to insufficient solute delivery to TALH to make it to ISF Flow rate through vasa recta: ↓flow → ↑corticomedullary gradient (opposite also true) Paradox: ↓↓↓flow → ↓gradient due to lack of nutrients (ATP) to support active solute transport Vasa Recta: surround tubules of loop of Henle to help maintain gradient & facilitate exchange of nutrients Blood characteristics: high Hct, low pO2, high osmolality → RBCs shrink (causes polymerization of sickle Hg → clogged capillaries → infarction of medulla) Changes to 3D arrangement: normally blood vessels packed densely around tubules; if medullary interstitium attacked (eg. interstitial nephritis due to medication allergy) → tubules & blood vessels get “pushed apart” → urine concentration & other tubular functions impaired Pericytes: compose walls of vasa recta in outer medulla, capable of contraction Fenestrations: present in vasa recta deeper in medulla to permit exchange of mat’l from ISF to lumen Solute reabsorption by TALH: basolateral Na+/K+ ATPase (moves Na+ to ISF), impermeable to H2O, Na+ & Cl- move down EC gradient (TF → ICF), K+ moves by 2° active transport to ICF but leaks back into TF via a K+ channel, Na+ also reabsorbed in exchange for H+ (but minimal CA on apical membrane), lumen voltage (+) drives paracellular cation (Na+, K+, Ca2+, Mg2+) movement (TF → ISF) Loop diuretics: act on the loop of Henle by inhibiting NKCC2 (eg. furosemide, bumetanide) → inhibit TF dilution & conc. by inhibiting solute reabsorption in TALH; prevents both maximum dilution (by inhibiting solute reabsorption) & maximum concentration (by ↓gradient) Diseases: in Bartter’s syndrome, mutations in NKCC2, the apical K+ channel, and/or the basolateral Cl- channel results in electrolyte abnormalities (K+ & HCO3-), volume issues leading to ↓BP, & inability to concentrate urine Role of urea: used by long loops of Henle to generate an even greater medullary gradient & for removal of nitrogenous waste Characteristics: freely filtered at glomerulus; reabsorbed by proximal tubule (paracellular) & inner medullary collecting duct (facilitated diffusion); secreted by proximal straight tubule, DLH, & tALH Transporters: urea transporters (UT1, UT2, UT4) Changing composition of medullary gradient: outer medulla = mostly ionic solutes, inner medulla = nearly equal parts of urea & ionic solutes Distal tubule & collecting duct: have the greatest impact on Uosm & V Vasopressin (ADH): controls H2O reabsorption by acting on principal cells of collecting tubules/ducts Minimum ADH: distal tubule & collecting duct are impermeable to H2O but some solute still reabsorbed → ↓TF osmolality (maximal dilution) → min Uosm (~40-50 mOsm/kg), max V (~28 L/day) Maximum ADH: distal tubule & collecting duct are permeable to H2O due to insertion of aquaporin 2 (AQP2) in apical membrane of principal cells→ H2O reabsorbed in distal tubule → TF flow↓ & osmolality↑ → H2O reabsorbed in collecting duct (hypertonic medullary gradient) → max Uosm (1200-1500 mOsm/kg), min V (~0.5 L/day) Average ranges: V averages ~1.5 L/day, Uosm ranges 50-1200 mOsm/kg