Physiology 28
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Osmolarity = amount of solute/volume of ECF
Total body water controlled by fluid intake, renal excretion of H2O
Kidneys can excrete dilute or concentrated urine independent of solute excretion
o ADH/vasopressin = primary effector of renal water excretion feedback
 When osmolarity increases (too concentrated), posterior pituitary secretes ADH
-> increased permeability of distal and collecting tubules to water
Mechanism for excreting dilute urine -> kidney reabsorbs solutes while failing to reabsorb water
o Proximal tubule -> solute and H2O reabsorbed proportionally (isosmotic to plasma ~300
mOsm/L)
o Descending loop of Henle -> H2O reabsorbed (osmosis) (hypertonic)
o Ascending loop of Henle (thick) -> Na, K, Cl avidly reabsorbed, impermeable to H2O
(hypotonic ~100 mOsm/L)
 Regardless of whether ADH is present or absent, fluid leaving early distal tubular
segment is hypoosmotic
o Distal tubule, cortical collecting duct, and collecting duct -> additional NaCl
reabsorption, impermeable to H2O without ADH (further dilutes, ~50 mOsm/L)
Water lost from body via lung evaporation, GI feces, skin evaporation and perspiration, urine
Water deficit -> kidney concentrates urine (solute excretion > H2O excretion)
o Maximum urine [] 1200-1400 mOsm/L
Max concentrating ability dictates urine volume excreted
o Ex. normal human excretes 600 mOsm/day and max urine concentrating ability is 1200
mOsm/L -> minimal volume to be excreted (obligatory urine volume) = 600/1200 =
0.5L/day
 Dehydration with ingestion of seawater because of high [] of solutes
approaching max concentrating ability + excretion of regular metabolites (urea)
-> net fluid loss
Urine specific gravity = clinical estimate of urine solute concentration (more [], higher s.g.
increasing linearly) -> measure with refractometer
o Determined by number and size of solute molecules
o Expressed in grams/ml and ranges 1.002-1.028 g/ml (↑ 0.001 for every 35-40 mOsm/L)
 Altered with high amounts of large molecules (glucose, radiocontrast,
antibiotics)
Requirements for concentrating urine = high level of ADH and high osmolarity of renal medullary
interstitial fluid (osmotic gradient for H2O reabsorption)
o Renal medullary interstitium normally hyperosmotic
Countercurrent mechanism depends on special anatomical arrangement of the loops of Hele and
the vasa recta (specialized peritubular capillaries of renal medulla)
o 25% of nephrons = juxtamedullary nephrons
Osmolarity of medullary interstitial fluid = 1200-1400 mOsm/L in pelvic tip of medulla
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Buildup of solute [] -> active transport of Na w/ cotransport of K, Cl, and other ions
(thick ascending limb); active ion transport from collecting ducts; facilitated diffusion of
urea; low diffusion of water
 TAL active and cotransport establishes 200 mOsm [] gradient (impermeable to
H2O)
Steps to hyperosmotic renal medullary interstitium:
o Loop of Henle fluid ~300 mOsm/L
o TAL established 200 mOsm/L gradient (~400 mOsm/L in interstitium)
o descending limb of loop of Henle and interstitial fluid reach equilibrium (osmosis)
o additional fluid from proximal tubule added (hyperosmotic DL fluid to AL)
o Ions pumped from AL into intersititum (200 mOsm/L gradient created again)
o Repeat until interstitium concentrated
 Gradually traps solutes in medulla and multiplies [] gradient -> interstitial fluid
osmolarity to 1200-1400 mOsm/L
 Repetitive reabsorption of NaCl by TAL and new NaCl from proximal tube =
countercurrent multiplier
Fluid is dilute at distal convoluted tubule (100 mOsm/L) -> further dilution in early distal tubule
o ADH affects late distal tubule and cortical collecting tubule
 Large amounts of H2O absorbed in cortex preserves high medullary interstitial
fluid osmolarity
o Medullary collecting duct reabsorbs less water carried away by vasa recta into veins
Urea contributes about 40-50% osmolarity of renal medullary interstitium (passively reabsorbed
from tubule)
o Ascending loop, distal and cortical collecting tubules -> impermeable to urea but with
high ADH, water reabsorbed and urea concentrated
o High [urea] in inner medullary collecting duct causes diffusion out (facilitated by urea
transporters, UT-A1 and UT-A3) -> high urea [] in tubule maintained tho
 UT-A3 activated by ADH
o High protein diet can concentrate urine much better
Rate of urea excretion determined by [urea] in plasma and the GFR
o Renal disease with reduced GFR -> plasma urea ↑ to return filtered urea load/excretion
rate to normal
Proximal tubule reabsorbed 40-50% of filtered urea
o Urea [] increases through tubules from H2O reabsorption and secretion into think loop
from medullary interstitium
 Secretion of urea into thin loop of Henle = urea transporter UA-A2
o TAL, distal and cortical collecting tubule impermeable to urea (may even ↑ urea [] if
ADH present) -> passive diffusion in medullary collecting duct
 Recirculation of urea additional mechanism to form hyperosmotic renal medulla
Excess water in body increases urine flow rate so [urea] in medullary collecting duct reduced
Special features of renal medullary bloody flow (preserve high solute []) = medullary blood flow
is low and vasa recta serve as countercurrent exchangers
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Vasa recta highly permeable to solutes except for plasma proteins -> concentrated
descending into medulla and less concentrated back up as H2O moves in
 Little dilution because of U shape -> vasa recta do not create medullary
hyperosmolarity by prevent it from dissipating
Vasodilators and increased AP ↑ medullary BF “washing out” solutes and reducing
concentrating ability
Proximal tubule -> 65% electrolyte reabsorption with osmosis (no change in fluid osmolarity)
Descending loop of henle -> H2O absorbed (osmolarity increases)
Thin Ascending loop of Henle -> impermeable to H2O, some NaCl reabsorption and passive
diffusion (osmolarity decreases), urea secretion (recycling)
Thick Ascending Loop o Henle -> impermeable to water, high Na, Cl, K and ion active transport
(osmolarity decreases)
Early distal tubule -> solutes reabsorbed, H2O remains (further dilution)
Late distal tubule and cortical collecting tubule -> dependent on ADH, urea not permeant
(increased [urea])
Inner medullary collecting ducts -> dependent on ADH and medullary interstitium osmolarity,
specific urea transporters
o The kidney can, when needed, excrete highly concentrated urine that contains little NaCl
(other solutes, urea, contribute to hyperosmolarity)
 Occurs in dehydration with low Na intake (stimulates renin-angiotensinaldosterone)
o Large quantities of dilute urine can be excreted without increasing the excretion of Na
(decreased ADH secretion)
o Obligatory urine volume (dictated by urine [] ability)
Total clearance of solutes from blood = osmolar clearance (Cosm)
o Cosm= Uosm x V/Posm , (V is urine flow rate)
Free water clearance (CH2O) = V – Cosm
o Rate at which solute-free water is excreted by the kidneys -> positive = water>solute
clearance, negative = solute>water clearance
o Whenever urine osmolarity is greater than plasma osmolarity, CH2O is negative
Disorders of urinary concentrating ability:
o Inappropriate secretion of ADH
o Impairment of countercurrent mechanism
o Inability of distal tubule, collecting tubule, and collecting ducts to respond to ADH
Central Diabetes Insipidus = inability to produce or release ADH from posterior pituitary
o Large volume of dilute urine -> thirst mechanism activated so continue to drink H2O but
severe dehydration can occur if insufficient H2O intake
o Treatment -> desmopressin (synthetic ADH analog) selective for V2 receptors
Nephrogenic Diabetes Insipidus = tubules don’t respond to ADH or failure of countercurrent
mechanism
o Large volume of dilute urine
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Causes: renal diseases, impaired loop of Henle (diuretics like furosemide), drugs (lithium
and tetracyclines impaire distal nephron response)
o Distinguished from central by desmopressin administration (lack of effect)
o Treatment -> underlying cause eliminated, low-Na diet, diuretic enhancing Na excretion
(thiazide)
Plasma Na [] regulated between 140-145 mEq/L
o Posm estimated from plasma Na []
 Posm = 2.1 x Plasma [Na]
o For more accuracy, include glucose and urea []
o Na, HCO3 and Cl = 94% of extracellular osmoles
Primary systems regulating [Na] and ECF osmolarity = osmoreceptor ADH-system and thirst
mechanism
Osmoreceptor-ADH feedback system:
o High ECF osmolarity causes osmoreceptor cells in anterior hypothalamus to shrink ->
sends signals in supraoptic nuclei relaying down to post pituitary -> release ADH (water
reabsorption and excretion of concentrated urine)
Hypothalamus contains magnocellular neurons that synthesize ADH in the supraoptic and
paraventricular neuclei -> extend into posterior pituitary (ADH stored in secretory granules)
Anteroventral region of the third ventricle (AV3V region): upper part = subfornical organ and
inferior part = organum vasculosum of lamina terminalis; between is median preoptic nucleus
o Lesions of AV3V region cause deficit in ADH secretion, thirst, Na appetite, and BP
o Osmoreceptors are in vicinity
o Lack BBB allowing solutes to cross and rapidly respond to change
Arterial baroreceptor reflexes and cardiopulmonary reflexes control ADH, too (originate in aortic
arch, carotid sinus and cardiac atria) -> signal through CN IX and X through tractus solitarus ->
hypothalamic nuclei
o ↓ arterial P and blood volume trigger ADH secretion (only when 10% decrease)
 ADH more sensitive to small osmolarity change
Nausea = potent ADH stimulus
Nicotine and morphine stimulate ADH, alcohol inhibit ADH (thus marked diuresis)
AV3V region + preoptic nucleus = thirst center
o Organum vasculosum of lamina terminalis involved in sensing CSF osmolarity
Stimuli for thirst:
o Increased ECF osmolarity causes
o Angiotensin II
intracellular dehydration of
o Dryness of mouth/esophagus
thirst centers
o GI and pharyngeal stimuli
o Decreased ECF volume and AP
Na above 2 mEq/L of normal = threshold for drinking
If either ADH or thirst mechanism fail, the other system can compensate reasonably but if both
lost, poor control of Na [] and osmolarity
Angiotensin II and aldosterone -> increase amount of Na in ECF and ECF volume via osmosis
o have little effect on Na concentration except under extreme conditions
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Even without functional aldosterone feedback system, plasma [Na] well regulated
ADH-thirst mechanism overshadows angiotensin II-aldosterone system (even in primary
aldosteronism [Na] increases only 3-5 mEq/L above normal)
o In extreme conditions (adrenalectomy or Addison’s disease) loss of Na by kidneys can
reduce plasma [Na] -> thirst mechanism triggered but only ↑ H2O reabsorption so more
dilution
Humans can survive with only 10-20 mEq/day of Na
o Salt appetite = behavioral drive when Na deficiency (important in Addison’s disease)
o Primary stimuli that increase salt appetite = association with Na deficits and ↓ blood
volume/BP (circulatory insufficiency)
o Neuronal mechanism analogous to that of thirst mechanism (AV3V region)