Flashcards in Unit 4 - Renal Physiology and Diuretics Deck (96):
explain total body fluids (in 70 kg man)
TBW: 60% of body weight (42 L water)
intracellular: 40% body weight (28 L water)
extracellular: 20% body weight (28 L water)
what is the makeup of intravascular fluid?
7% of adult body weight (4.9 L)
-55% plasma (3 L)
-45% RBC, WBC, platelets (2 L)
how does TBW and ECF change in life?
TBW: 75% in neonate to 50% in advanced age
ECF: decreases from 50% TBW at birth to 30% in adults
what does puberty and being a woman do to TBW?
decreases water percentage of total body weight
what is the equation for BP?
BP = TPR x CO
what is the equation for CO? in a 70 kg man? what is it equivalent to? how much of it perfuses the kidney?
CO = HR x SV
-5-6 L/min (equivalent to 7% of body weight)
-20% of Co perfuses the kidney
what is renal blood flow VS renal plasma flow in a 70 kg man? how much of RPF is filtered in glomeruli?
RBF: 1-1.2 L/min; 1440-1728 L/day
RPF: 600-720 mL/min; 860-1040 L/day (55% of RBF)
-20% of RPF is filtered in glomeruli (125 mL/min, 180 L/day)
--entire ECF volume filtered every 2 hours
what is the GFR in a 70 kg man?
125 mL/min, 180 L/day (constant in all)
what is urine output in a 70 kg man?
14 L/day (if water volume is high)
what determines volume in ECF?
total amount of Na moles in ECF
-more Na = larger ECF volume (expansion)
-less Na = smaller ECF (contraction)
where are increases or decreases in ECF volume detected?
receptors in vasculature, CNS, liver, kidneys
-neural and humoral signals determine how kidneys respond by modifying V and composition of fluid in renal tubules
how much does GFR change in response to volume change?
normally, GFR will not change unless there is severe contraction (GFR)
what do the kidneys do in response to dietary sodium restriction?
kidneys increase magnitude of Na reabsorption over a period of several days until a lower level of urinary Na output is achieved
-Na balance is lower but still equivalent Na input/output
-osmolarity of ECF must remain constant
what does ECF volume expansion VS contraction do to the kidney?
increased ECF V: decreased tubular reabsorption --> increase of Na and water in urine
decreased ECF V: increased tubular reabsorption --> decrease in Na and water in urine
what is the definition of edema?
derangement in fluid distribution
what are causes of edema?
-hyperaldosteronism (excess accumulation of fluid in interstitial space due to cardiac, renal, hepatic, or endocrine dysfunction --> too much Na raises hydrostatic P)
-imbalance of hydrostatic and oncotic pressures across capillary wall --> shift in fluid distribution from intravascular to extravascular space (isotonic retention of Na and water, decreased circulating volume)
-decreased circulating volume decreases renal perfusion pressure and activates RAAS (increases Na+ retention to maintain edema)
what are edematous diseases?
-CHF (increased hydrostatic pressure)
-pulmonary edema (increased hydrostatic pressure)
-liver disease (decreased oncotic pressure)
-nephrotic syndome (oncotic pressure)
in general, what do diuretics do?
decrease vlasma volume by "forcing" increased elimination of Na and water in urine
-decreases hydrostatic pressure and increases oncotic pressure --> favors absorption of edematous fluid in interstitial space back into intravascular space to correct edema
handling of Na in nephron
PCT: 67% reabsorption
TAL: 25% reabsorption
DCT: 5% reabsorption
CD: 3% reabsorption
this, there's <1% excretion
what is plasma ultrafiltrate mate of?
plasma produced with similar solute composition but without protein
what is the raw material of urine?
-proceeded by succeeding tubular segments to become urine
describe proximal tubule filtration
all of convoluted and most of straight are in cortex
-66% of filtered Na and most of filtered bicarbonate is reabsorbed
-most of filtered nutritive solutes are reabsorbed and returned to circulation of renal vein
-"leaky" epithelium, unable to maintain osmotic gradient
-reabsorbtion of solutes and water occurs isosmotically
describe Loop of Henle filtration
-thin descending and ascending limb are in medulla; thick ascending starts in medulla and ends in cortex
-25% of filtered Na is reabsorbed in TAL
-tdL permeable to water
-taL and TAL impermeable to water, even with ADH
-reabsorption of solutes (NaCl) w/o reabsorption of water, dilutes tubular fluid by reducing concentration and osmolarity of tubular fluid to values less than plasma (hypotonic)
-TAL is solute transport engine driving and maintaining counter current multiplication of interstitial solute concentration difference or solute concentration gradient extending from cortex to medulla surrounding collecting duct
describe distal tubule filtration
both early (convoluted) and late (straight) segment of distal tubule are located in renal cortexj
-6-8% of filtered Na is reabsorbed in DT; Na reabsorption in late DT; regulated hormonally by circulating levels of aldosterone
-early DT is impermeable to water (further dilutes tubular fluid); late DT is permeable to water when induced by ADH
describe collecting duct filtration
begins in outer cortex and extends to inner medulla
-ability of kidney to conserve water and defend against ECF volume contraction is ultimately determined in CT (water permeability and reabsorption is induced by ADH)
what is the equation for filtration fraction? the usual amount? what does this mean?
FF = GFR/RPF = 120 ml/min / 660 ml/min = 0.20
-this means 20% of plasma flowing through glomeruli is ultrafiltered to make tubular fluid (per day is 20x greater than ECF volume)
what happens to tubular fluid advancing through nephron?
most of filtered water and solute is reabsorbed and returned to renal circulation to exit kidney in renal vein
what is urine formed by?
fraction of filtered water and soluble NOT reabsorbed and by solute added to or secreted into tubular fluid flowing along nephron
what is the fractional excretion of water?
FE(water) = V(dot) / GFR = V(dot) / C(in) = P(in) / U(in)
-can be estimated from plasma to urine inulin concentration ratio
what is GFR estimated as?
measuring clearance of inulin (Cin)
what is solute clearance?
volume of plasma cleared of solute per unit time (ml/min)
what is the formula for amount of inulin filtered? excreted?
filtered: GFR x P(in)
excreted: V(dot) x U(in)
what is FE(Na) formula?
C(Na)/C(creat) = U(Na)P(creat) / U(creat)P(Na)
how much of filtered water and Na appears in the urine if there is water and Na balance? negative water balance? positive water balance?
dehydration: Fe(water) 5%; FE(Na) = 1%
what is fractional reabsorption?
fraction of filtered solute or water which is reabsorbed and doesn't appear in urine
-quantified as 1 - FE
-in balance, 99% of filtered Na and water are reabsorbed
what is the excretion in low K+ and high K+ diet?
low: 1% excretion = 100% filtration - 99% reabsorption + 0% secretion
high: 110% excretion = 100% filtration - 87% reabsorption + 97% secretion
freely filtered at glomerulus
K+ reabsorption and secretion along nephron
PT: 67% reabsorption
TAL: 20% reabsorption
CD: low K+ diet only will have 12% reabsorption
CD: variable secretion depending on dietary K+, aldosterone, acid-base, flow rate
what does aldosterone do for K+?
increases secretion in late DT and early CD
what does alkalosis do for K+? acidosis?
alka: increases K+ secretion
acid: decreases K+ secretion
why do (non-K+-sparing) diuretics increase K+ secretion?
increase in outwardly directed K+ gradient across luminal membrane
why is FE(K) dependent on Na+ reabsorption along nephron?
decrease in Na+ reabsorption in TAL induced by diuretic will cause more Na to be delivered downstream to DT and CD --> compensate by increasing Na+ reabsorption
-this is functionally linked to increase in K+ secretion
-increased Na+ reabsorption = increased K+ secretion
-risk of hypokalemia
ATPase in kidney?
all nephron epithelial cells have ATPase on basolateral side
TAL solute reabsorption
25% of Na, 20% of K reabsorbed in medullary and cortical TAL
-membrane-specific transporters at luminal (Na-K-2Cl cotransporter)and basolateral (ion-specific channels Cl and K, and Na/K ATPase) side of cell
-lumen positive potential difference serves as driving force for Ca and Mg reabsorption across TAL epithelium
what is the capacity of the kidney to make a dilute, hyposmotic urine dependent on?
functional integrity of TAL to mediate solute reabsorption in absence of H2O reabsorption
what generates counter current multiplication?
active reabsorption of solutes in medullary TAL extending form cortex to papilla
how does the osmolarity of the medullary interstitium do progressively?
increases upon descending from cortex to papilla and achieves max value (1200 mOsm/L) 4x the osmolarity of plasma
what is preservation of normal ECF volume achieved by?
ability of kidney to maximize (concentrate) or minimize (dilute) osmolarity of urine in response to ECF volume
what can the measurement of urine specific gravity be substituted for?
urine osmolarity except when glucosuria or proteinuria disproportionately increases the urine specific gravity more than urine osmolarity
when is the U/P osmolarity ratio =, >, < 1?
U/P = 1 isotonic
U/P < 1 dilute, hypotonic (ECF expanded)
U/P > 1 concentrated, hypertonic (ECF contracted)
what is the definition of "free water"?
water not osmotically obligated to remain in tubular fluid due to presence of solutes
what happens to ADH when there is an increase or decrease in osmolarity?
increased osmolarity: increased ADH, retention of free water by kidney --> hypertonic urine
decreased osmolarity: decreased ADH, elimination of free water by kidney --> hypotonic urine
what are the equations for free water clearance and osmotic clearance?
C(H2O) = V(dot) - C(osm)
C(osm) = U(osm)*V(dot) / P(osm)
what is free water clearance when urine is isotonic?
free water clearance = 0
-kidney neither adds nor removes free water from ECF
-osmotic clearance equal to urine flow
what is free water clearance when urine is hypertonic?
free water clearance < 0 (negative; volume of distilled water (free of solutes) must be added to make the hypertonic (concentrated) urine isotonic to plasma)
-kidney retains free water (to add to ECF)
-osmotic clearance greater than urine flow
-ADH increases, so H2O permeability increases and H2O reabsorption increases
what is free water clearance when urine is hypotonic?
free water clearance > 0 (positive; volume of distilled water (free of solutes) that must be removed to make hypotonic (dilute) urine isotonic to plasma)
-kidney eliminates free water (taken from ECF)
-osmotic clearance less than urine flow
-ADH decreases, so H2O permeability decreases and H2O reabsorption decreases
DT and CD solute clearance?
early: luminal Na-Cl cotransporter and basolateral Na/K ATPase with Cl-specific ion channel
-insensitive to ADH
late: luminal Na+ ion channel (in) and K+ ion channel (out); basolateral Na/K/ATPase
what is the NaCl cotransporter in early distal tubule targeted by? how?
-competitively interact with Cl for occupancy of binding site in NaCl cotransport protein
-NaCl reabsorption is inhibited, resulting in more NaCl remaining in tubular fluid and delivered to late DT and CD
how does ADH affect the early DT?
it doesn't (is impermeable to water even in presence of ADH)
-mediates solute reabsorption w/o water reabsorption (dilutes tubular fluid)
--cortical diluting segment = early DT and TAL
what is aldosterone? what does it do?
steroid hormone secreted from adrenal cortex
-acts on late distal tubule and CD (and sweat glands/intestine)
-low levels: positive Na balance where Na consumption exceeds Na excretion (less Na reabsorption b/c more Na+ consumed)
-high levels: negative Na balance where Na consumption is less than Na excretion (more Na reabsorption b/c less Na+ consumed)
how does aldosterone exert its effect?
diffuses into cell from bloodstream across the basolateral membrane, binds to intracellular receptor to form receptor-aldosterone complex
-enters nucleus and induces transcription of mRNAs coding for membrane transport PRO mediating transcellular Na reabsorption
why does aldosterone also affect K+ secretion?
because Na reabsorption in late DT and CD is functionally couplex to K+ secretion
-increased aldosterone --> more Na+ reabsorption --> increased K+ secretion
what do amiloride and triamterene target?
Na+ channel in luminal membrane of late DT and CD
-block and decrease Na+ uptake in tubular fluid --> decreases transcellular Na reabsorption --> increases Na+ in urine
-inhibits K+ secretion, which decreases K+ in urine ("K+ sparing")
what does spironolactone target? what is required to make it work
blocks Na+ reabsorption and blocks K+ secretion in late DT and CD
-"K+ sparing" by competing with aldosterone for complex formation with intracellular aldosterone receptor --> decreases synthesis of mRNAs and PRO necessary to maintain transcellular Na+ reabsorption and K+ seccretion
-requires high amounts of aldosterone (low Na+ diet) to have an effect
what are the different classes of diuretics? examples?
aquaretics: Lithium, fluoride (methoxy flurane), demeclocycline, vaptan family of ADH receptor antagonists
saluretics: loop, thiazide, K+ sparing
osmotics: mannitol, excess glucose, urea, isosorbide
what is the mechanism of aquaretics?
decrease ability of ADH to increase water permeability of late DT and CD (decrease ADH-induced water reabsorption)
-analagous to copious, dilute urine in diabetes insipidus
what is the mechanism of saluretics?
decrease solute reabsorption in one+ segments of nephron
-either direct interaction w/ solute transport proteins in luminal membrane, or by interaction with intracellular receptors regulating expression of solute transport proteins
what is the mechanism of osmotics?
enter tubular fluid by glomerular filtration; neither reabsorbed nor secreted
-increases osmolarity to oppose water and solute (primarily Na) reabsorption along nephron w/o specific interaction w/ solute transport proteins (thus there is a change in Na concentration)
-lower concentration in PT fluid allows lower reabsorption in rest of nephron --> disproportionately more water and Na eliminated
what does desmopressin do?
anti-aquaretic analog of ADH, and ADH receptor agonist absorbed into circulation by application as spray to nasal mucosa
-used to treat polyuria in diabetes inspidus
what do diuretics do to ECF?
change volume and ion composition/concentration of ECF
-by changing volume and ion composition/concentration of urine
what diseases are diuretics used to treat?
-HTN (increase vascular wall compliance)
-correct hypo/hypercalcemia/kalemia (decrease/increase amt of Ca++ or K+ in urine)
-prevent brain tissue damage (decrease CSF volume and pressure)
-prevent ocular damage in glaucoma (decrease IOF volume and pressure)
-improve localized imbalances in lung fluid distribution in children with respiratory disease
what do carbonic anhydrase inhibitors do to the PT?
decrease tubular fluid reabsorption by decreasing Na and bicarb reabsorption
-creates increased alkaline urine volume w/ Na+, K+, and bicarb
-less CO2 formed in tubular fluid, and less intracellular carbonic acid
-less intracellular H+ for recycling back across luminal membrane via Na/H exchange
what is aminophylline? how does it work?
phosphodiesterase inhibitor diuretic (combo of methylxanthine theophylline and ethylene diamine)
-increases cAMP levels in PT cells --> activates PRO kinase A --> increased phosphorylation of apical membrane Na/H exchanger (inhibition)
-decreases PT Na+ and bicarbonate reabsorption, isosmotic fluid reabsorption (thus more in urine)
-modest diuresis, but used more to prevent and relieve inflammation and bronchospasm in patients with asthma
what do diuretics that act on PT do?
induce maximal fractional excretion of Na of 5% or less (instead of normal 66%
-due to lack of potency of diuretics acting on PT and to compensatory increases in Na reabsorption in nephron segments downstream from PT
how do high-ceiling (loop) diuretics work?
on TAL; max diuresis (largest volume of excretion)
-decrease reabsorption of Na, K, and Cl (by blocking transporters) from tubular fluid resulting in increased delivery of solutes downstream to late DT and CD
-significantly increases urine osmolarity and osmolar clearance (initial weight loss, but upon ceasing diuretic, will cause less Na+ excretion and regain)
what do diuretics that act on TAL do?
increase FE(Na) to 25% (equivalent to total amt of Na normally absorbed in TAL
-only observed when increased amt of Na is delivered from PT
-significantly increases amt of K+ in urine
how do thiazide diuretics work?
decrease NaCl reabsorption from tubular fluid in cortical TAL and early DT, thus increasing reabsorption in late DT and CD, without effect on urine concentrating ability
-increased delivery of NaCl in late DT and CD, and increassed time necessary for kidney to correct ECF volume expansion
-increase FE(Na) up to 8%
-some inhibit PT carbonic anhydrase activity (bicarb may be increased in urine)
-induce increased K+ secretion in late DT and CD (increase K+ in urine)
how do K+ sparing diuretics work?
decrease Na and tubular fluid reabsorption and K+ secretion in late DT and CD
-increase FE(Na) up to 2%
-produce smallest diuresis (least efficacious); must be combined with loop or thiazide diuretics to induce larger diuretics with minimal increase in urine K+
-decrease in Na+ reabsorption to K+ secretion and K+ in urine
what do loop diuretics do if someone is volume expanded VS volume contracted?
-volume expanded: decrease free water clearance --> increase in osmolar clearance --> less positive free water clearance and increase in time necessary to return ECF to normal
-volume contracted: increase free water clearance --> decrease in osmotic clearance --> less negative free water clearance and impaired ability to defend against dehydration and ECF concentration
what do thiazide diuretics do if someone is volume expanded?
volume expanded: decreased positive free water clearance --> increased osmolar clearance
which patient is more at risk for hyponatremia? thiazide or loop diuretic?
thiazide diuretic, b/c loop diuretic patients are equally balanced in inability to take water in excess of solute from ECF when volume expanded, and add water in excess of solute to ECF when volume depleted
what drugs act on the PT?
-CAI: acetazolamide, methazolamide, dichlorphenamide
-osmotic diuretics: mannitol, excess glucose, urea, isorbide
what drugs act on the medullary and cortical TAL?
loop or high ceiling diuretics: furosemide, bumetanide, torsemide, ethacrynic (dichlorophenoxyacetic) acid
-inhibitors of Na/K/2Cl symport
what drugs act on the early DT?
-thiazide diuretics: chlorothiazide, hydrochlorothiazide
-thiazide-like diuretics: chlorthalidone, quinethazone, metolazone, indapamide
-all inhibit Na/Cl symport
what drugs act on the late DT and CD?
-renal epithelial Na channel inhibitors: amiloride, triamterene
-aldosterone receptor antagonist: spironolactone
-K+ sparing diuretics
-induce moderate reduction in ECF volume, possible hypokalemia, and possible metabolic acidosis (corrects metabolic acidosis by becoming refractory to CAis)
-ASE: hepatic encephalopathy (contraindicated in cirrhosis), bone marrow depression, skin toxicity, allergic RXN
how is mannitol used?
administered via IV (not absorbed from GIT)
-doesn't cross cell membrane, and volume of distribution is limited to ECF (increased osmotic pressure drawing water from intracellular to extracellular space)
-metabolically inert; clearance from ECF due only to renal filtration and urine elimination
what are therapeutic uses of osmotics?
-treatment of drug overdoses (hastens clearance b/c eliminated in urine at rates related to urine flow)
-minimize risk of acute renal failure in shock or major surgery (help kidneys to keep work)
-treat oliguria (abnormally low rate and volume of urine flow)
--there is risk fo pulmonary edema
-reduce intraocular and intracranial pressure (increase ECF osmotic pressure, inducing absorption of water from IO and IC space, reducing volume and hydrostatic pressure)
what are side effects of loop diuretics?
-hyperuricemia (due to volume contraction)
-contraction alkalosis (hyperbicarbonatremia alkalosis)
-decreased clearance of creatinine
-hyponatremia, hypokalemia, hypomagnesemia (corrected by water restriction)
-clinical destabilization of patients with preexisting DM
-ototoxicity (decreased hearing loss if use aminoglycoside antibiotics)
-increased contraction of clotting factors in intravascular space (change dose of warfarin, NSAIDs)
clinical uses of loop diuretics?
-reverse acute episodes of pulmonary edema quickly
-correct edema from CHF, cirrhosis, and renal disease
-hypercalcemia (increases Ca in urine)
-drug toxicities (increased renal flow --> increased clearance)
side effects of thiazide diuretics?
-hyperuricemia, hypercalcemia (increased Ca++ resorption compared to others)
-hypomagnesemia, hyponatremia, hypokalemia
-increased BUN w/o or w/o increase in serum creatinine
clinical uses of thiazide diuretics
-HTN (alone or in combo with HTN medications)
--contraction of ECF volume including decrease in IV volume to decrease BP
-compensate for water and solute retention induced by other hypertensives
-reverse idiopathic hypercalcuria
-nephrogenic insipidus (contract ECF volume to induce decreased volume of tubular fluid arriving in later DT and CD, thus volume of voided urine due to reduction in GFR)
--don't compromise concentrating ability of kidney b/c don't inhibit solute reabsorption in medullar TAL compared to loops
side effects of lithium?
complicated by onset of nephrogenic diabetes insupidus (resistant to ADH)
-Li reversibly inhibits increase in water permeability of CD in response to ADH, and effect of Li to induce tubular interstitial damage
-can be fixed by thiazide diuretics
when are thiazide diuretics less effective?
-taking NSAIDs or antibiotic amphotericin B
-GIT absorption diminished by bile sequestrants
clinical uses of K+ sparing diuretics
-in combo with thiazide or loops
-alone or in combo with other diuretics to control edema from CHF, cirrhosis, and nephrotic syndrome
-spironolactone: treat aldosteronism, CHF
-amiloride: idiopathic hypercalciuria, nephrogenic diabeties insipidus from Li (inhibit luminal uptake of Li by DT and CD)
contraindications of K+ sparing diuretics
-hyperkalemia (opposite of loop/thiazide)
-triamterine: megaloblastic anemia if cirrhosis of liver
-spironolactone: gynecomastia, ED, loss of libido (men); amenorrhea, oligomenorrhea, breast soreness