renal physiology Flashcards
in a healthy 70kg person, how many liters of fluid are held in each the extracellular fluid and intracellular fluid?
extracellular: 17L
intracellular: 25L
what is always held constant between intracellular and extracellular fluid?
osmolality (held at 290 Osmol)
electroneutrality
are solute concetrations equal in ECF and ICF?
no
how to roughly estimate serum osmolarity
2 x sodium concentration
define hypotonic
concentration of solutes is greater inside the cell than outside of it (high solutes, low water)
define hypertonic
concentration of solutes is greater outside the cell than inside it
(high water, low solutes)
define isotonic
concentration of solutes are same within and outside the cell
what kind of fluid is lost while sweating
hypotonic saline (low water, high solute)
what kind of fluid is D5W
isotonic glucose (same solute concentration as cells), once glucose is metabolized it is osmotically equivalent to drinking water
explain fluid shifts that occur during sweating without fluid replacement
sweating is the loss of hypotonic saline
extracellular volume decreases and osmolality increases
compensation: water moves into extracellular space
intracellular volume decreases and intracellular osmolality increases
explain fluid shifts that occur when D5W is administered intravenously
IV D5W enters extracellular fluid (
glucose is metabolized and water remains in ECF
extracellular volume increases and osmolality decreases
comensation: water enters cells
intracellular volume increase, intracellular osmolality decreases
equation for net driving pressure within capillaries (starlings law of the capillary)
net driving pressure = (capillary hydrostatic pressure - interstitial hydrostatic pressure) - (capillary oncotic pressure - interstitial oncotic pressure)
*note: this is the driving force of fluid out of capillaries into the interstitium
what is the main driving pressure on arterial side of capillaries
hydrostatic pressure of capilaries
net= +12 mmHg (into the interstitum)
what is the main driving pressure on venous side of capillaries
oncotic pressure of capillaries
net= -8 mmHg (into capillaries)
what is the result of disrupted Starling forces in capillaries
edema
what changes in pressures (starling driving forces) promote edema
increase oncotic interstitial pressure secondary to increased capillary permeability to proteins (ex. burns, trauma, infection- local inflammation)
decrease oncotic capillary plasma protein pressure (ex. liver disease, nephrotic syndrome)
increase hydrostatic capillary pressure (ex. left heart failure, cirrhosis -> hepatic portal hypertension, DVT)
blockage of lymph flow (ex. filariasis, lymph node remodeling)
define lymphedema
reduced lymph flow
*causes edema bc lymphatic drainage reduces interstitial fluid volume
define filariasis
parasitic obstruction of lymph flow
filtration fraction equation
GFR/RPF
normal GFR (%)
20%
nephron
glomerus + tubule
“functional unit of the kidney”
differentiate the two types of nephrons
cortical nephrons: 85% of nephrons in kidney, short loops of Henle, glomerulus in outer cortex
juxtamedullary nephrons: 15% of nephrons in kidney, long loops of Henle, large glomerulus near the medullary border
where is the majority of water absorbed in nephron
proximal tubule via osmosis
what are the sources of ADH/AVP
supraoptic and paraventricular nuclei of hypothalamus and is released from posterior pituitary
function of ADH
increases water reabsorption in the kidney by causing vesicles to fuse and insert aquaporins onto apical membrane of principal cells in the collecting duct
how does ethanol block ADH
inhibits calcium channles and inhibits ADH release
define plasma clearance
the volume of plasma which would produce the amount of that substance which is excreted in urine per unit time (ml/min)
4 requirements for a good substance in measuring GFR
- freely filtered by glomerulus
- neither reabsorbed nor secreted by renal tubules
- not be metabolized or produced in the kidneys
- physiologically inert (no effect on kidney function)
GFR equation for clearance of inulin
GFR = (Ux * V)/Px
why are creatinine and inulin good for GFR measure, differentiate
freely filtered
not reabsorbed or secretely (actually creatinine is 10% secreted here so causes slight increase in GFR)
inert
minimally secreted
however creatinine is better used in clinic
GFR equation (not clearance equation)
GFR (mL/min/1.73 m2) = 175 x (serum creatinine - 1.154) x (age- .203) x (.742 if female) x (1.212 if african american)
azotemia
high levels of BUN
BUN when GFR decreases (increase or decrease)
BUN increases as GFR decreases
Cr when GFR decreases (increase or decrease)
Cr increases as GFR decreases
what alters BUN
protein intake and hydration
BUN when ADH increases
BUN increases as ADH increases (dehydration), increased urea transporters reabsorbing urea
- urea transporters are inserted in membrane
- hydration dependent
Cr when ADH increases
no change in Cr when ADH increases (not hydration dependent)
normal BUN/creatinine ratio
15 (range 10-20)
GFR reduction effect on BUN/Cr
proportional increase in both so ratio still 15
dehydration effect on BUN/Cr
increase in Cr but only slightly due to the slight decrease in GFR
greater increase in BUN by both GFR and urea reabsorption stimulated by ADH
ratio increases
in renal failure and dehydration how is BUN/Cr ratio effected
increased
effect of intravenous isotinic saline on body water spaces
solute stays in extracellular space
extracellular volume increases and osmolality stays the same
no osmotic gradient so fluid stays in ECF
IC volume and omsolality stay constant
autoregulation
allows renal plasam blood flow to stay stable despite changes in renal arterial pressure by constriction of the afferent arteriole
- myogenic response: pressure
- tubuloglomerular feedback: flow
myogenic control of afferent arteriole tone
increased arterial pressure –> stretch of afferent arteriole –> opening of mechanically gated Ma+ and K+ channels in smooth muscle –> negative charge of cell causes more influx of Na than eflux of K+ –> muscle cell depolarizes –> Ca++ voltage gated channels open –> Ca++ enters cell , binds calmodulin, activates MLCK, muscle contracts
tubuloglomerular feedback
increased RBF and GFR –> increased delivery of solutes to JG apparatus (sense by maculla densa) –> release of ATP and adenosine –> ATP binds P2X receptors, adenosine binds A1AR receptors–> Ca++ signaling –> incresed resistance of afferent arteriole –> decreased RBF and GFR
how does autoregulation correct GFR in response to BP
increased BP causes an increased GFR but through autoregulation, the resistance in afferent arteriole is increased, resulting in a less dramatic increase of RBF and therefore less dramatic increase in GFR
sympathetic regulation of RBF
only active in a stressed state (not always on)
mild stimulation: decreases RBF but GFR is unchanges (bc both arterioles constrict), increases filtration fraction (GFR/RBF)
strong stimulation: afferent constriction dominates, RBF dramatically decreased such that GFR decreases and blood is shunted to other tissues
- in the afferent arteriole: it acts on alpha 1 receptors of smooth muscle to preferentially constrict afferent arteriole cells thus decreasing GFR
- in the efferent arteriole: acts on beta 1 receptors of JG cells to increase renin secretion –> increase angiotensin II –> restriction of efferent arteriole leading to increased GFR
angiotensin II regulation of RBF/GFR
potenet vasconstrictor of both afferent and efferent however the efferent is more sensitive to it
at low levels: angiotensin II results in increased GFR and decreased RBF
at high levels: both are severely constricted and net decrease in GFR/RBF
ACE inhibitor regulation of RBF/GFR
ACE inhibitor leads to eferent dilation –> decreased GFR so must be careful with kidney patients
what part of nephron is most important site of regulation
collecting duct
sodium hanfling in proximal tubule
Na+/H+ contertransport is passive
angiotensin increases expression of these channels
osmotic diuretics block these actions (ex. mannitol)
sodium handling in the thick ascending limb
Na+/H+ passive, NA+/k+/2Cl- passive
impermeable to water “diluting segment” which generates a medullary osmotic gradient
loop diuretics block Na+/K+/2Cl- here (ex. furosemide, ethacrynic acid)
sodium handling in distal convoluted tubule
Na+/Cl- cotransport
impermeable to water”diluting segment” the tubular fluid is now hypotonic compared to plasma
thiazide diuretics block Na+/Cl- channels here (hydrochlorothiazide)
sodium handling in late distal tubule and collecting duct principal cells
N+ ENAC channels, K+ ROMK channels (secreting) whcih are both upregulated by aldosterone and aquaporins which is upregulated by ADH
potassium sparing diuretics effect either by blocking the ENAC directly or blocking aldosterone receptor
what is the rate limiting step for RAAS activiation in most circumstances
renin release from kindeys
regulation of renin release
stimulation is caused by:
- decreased blood pressure in afferent arteriole
- decreases Na+ and Cl- in macula densa
- increased sympathetic activity on the alpha 1 receptors on jg cells
- decreased ANP
mechanism of macula densa sensing
increased flow and delivery of Na causes macula densa to release ATP which decreases GFR to maintiain normal filtered low and decrease renin secretion to allow more Na+ excretion
decreased flow and decreased Na+ delivery to macula densa causes macula densa to release NO and prostaglandins which increases GFR to maintain filtered load and increase renin secretion to conserve body’s Na
actions of angiotensin II
- increse peripheral vasoconstriction
- aldosterone release from adrenal gland
- increase renal arteriole constriction (mostly efferent)
- increased activity of Na+/H+ counter-transport in proximal tubule
- increased AFH synthesis and thirst in hypothalum and posterior pituitary gland
regulation of aldosterone
increased angiotensin II and increased plasma K+ both increase synthesis of aldosterone, independtently of eachother
increased ANP decreases aldosterone release
actions of aldosterone
increase ENAC Na+ channels in principal cells
increase activity of K+ channels in principal cells
increase activity of Na/K ATPase of principal cells
increase activity of H+ ATPase of intercalated cells
addisons disease
lack of glucocorticoid and aldosterone which leads to hyponatremia and hyperkalemia
Conn’s syndrome
hyperaldosteronism
hypertension
hyperattremia
hypokalemia
mecahnism of aldosterone increasing ENAC expression
aldosterone binds Aldo receptor which signals synthesis for SGK1 which inhibits Nedd4
Nedd4 degrades ENAC in the absence of aldosterone
how does the SNS have on Na+ excretion when stimulating alpha 1 vs beta 1 receptors
alpha 1 receptors stimulate vasoconstriction of afferent arteriole under mild stimulation which decreases GFR which decreases Na+ excretion
alpha 1 receptors also stimulate increase tubular Na+ reabsortion by increasing Na/K ATPase activity
beta 1 receptors activate renin release from JG cells activating RAAS which increases Na+ reabsorption
regulation of natriutetic peptide release
released from atrial (ANP) and ventricular (BNP) myocardial cells when stimulated by increased vascular volume
natriuretic peptide effects on sodium excretion
decreases sodium reabsorption from deep medullary collecting duct and increases GFR and RBF via afferent arteriolar dilation and efferent arteriolar constriction
decreases renin, aldosterone, and ADH release
how is K+ absorbed/secreted in each part of the nephron
proximal tube: passive secondary to Na and H2O
thick ascending: actively reabsorbed Na/K/2Cl pump
collecting duct intercalated cells: actively reabsorbed H/K ATPase
collecting duct principal cells: secreted passive ROMK channels (regulated by aldosterone)
what is the major regulation of K+ excretion
K+ excretion depends on the rate of K+ secretion by principal cells
how does aldosterone regulate K+
increased K intake stimulated adrenal cortext to secrete aldosterone, aldosterone upregulates ENAC, ROMK
increases ENAC causes increases sodium re absorption so the cell takes in more K to balance the electrogradient, the increased sodium causes increased stimulation of the basolateral Na/K ATPase so more K+ is being pumped out of blood into cells to be excreted into the lumen
how do loop and thiazide diuretics effect K+ excretion
vascular volume depletion from the diuretics activates the RAAS system which increases K+ excretion via increased ROMK and increasing Na+ reabsorption in prinicpal cells which increases K+ excretion
decreased sodium reabsorption in the loop and distal tubule increases Na delivery to collecting duct which increases Na reabsorption in principal cells which increases K excretion
cause hypokalemia
how do K sparing diuretics effect K excretion
amiloride and triamterene block principal cell Na+ channels which decrease Na reabsorption in principal cellls which decereases K+ secretion
spironolactone blocks aldosterone receptor which decreases both Na reabsorption and K secretion in principal cells
henderson hasselbalch equation for pH in body
pH =pK + log10 (HCO3/.03 X PaCO2)
how does the kidney function normally to maintain pH
non volatile acids cannot be excreted by the lung as CO2 can, they must be compensated through the kidneys so the kidneys excrete a H+ which pushes a HCO3 into the blood and neutralizes charge from acids
how is H+ excreted from the kidney
inorder to not make the urine too acidic (ouch) H+ is excreted as a titratibile acid like H2PO4 which comes from the filtrate or in the form of ammonium (NH4) which is synthesized in the kidney
how much HCO3 is reabsorbed in the nephron
99.99% of filtered bicarb is reabsorbed
explain “new” bicarb vs “recycled” bicarb absorption
if secreted H+ binds with a filtered bicarb they are broken down as H20 and CO2 and reabsorbed, a bicarb transfered into interstitium (bc boop) which replaces the filtered bicarb so no net bicarb is gained
if secreted H+ binds with HPO4 or NH3 to be excreted as titratible acid, the bicarb transfered into interstitum (bc boop) is an extra/new bicarb because no bicarb was lost in the excretion of H+
H+ secretion in proximal, thick ascending, and early distal tubule
H/Na antiporter pump out H on apical side while HCO3/Na co transport on basolateral side for boop rule
metabolic acidosis renal tubular acididosis type II
failure in proximal reabsorbrion of HCO3
H+ in alpha intercalated cells
H+ ATPase and K/K ATPase secrete H into lumen while HCO2/Cl antiporter on basal side for boop
metabolic acidosis renal tubular acidosis type I
failure of distal H+ secretion
H+ in beta intercalated cells
secrete HCO3 into lumen via CL/HCO3 antiporter and H+ATPase pumps H+ into blood for boop
where and how is NH4 made in the kidneys
primarily made in PCT, glutamine enters cells from both lumen and capilaries via cotransporters
glutamin broken down and releases NH4 –> NH3 + H+ , the NH3 diffuses and captures H+ in lumen
NHE3 exchanger in PCT secretes NH4 into lumen as well
glutamine breakdown products participate in gluconeogenesis and generates 1 glucose and 1 HCO3 which covers boop
regulation of glutamine transport into kindeys
acidosis increases glutamin retention, glutaminase and glutamine dehydrogenase
alkalosis increases return of glutamine to bloodstream
NH4 in thick ascending loop
collects NH4 produced by PCT through ROMK ( NH4 has same structure and charge as K basically) then forms NH3 within the cells which crosses membrane and interstitium into the interstitial medulla to accumulate NH4+ to be used by collecting duct alpha intercalated cells to form urinary ammonia (excreted by Rhcg)
carbonic anhydrase, necessary for 3 roles in the kidney
HCO3 reabsorption, titratable acidity, and ammonium excretion
types/sites of carbonic anhydrase
CAIV is in apical membrane which is important for bicarb reabsorption
CAII is in cytosol of tubular cells and important in formming titratable acid and ammonium excretion
CA inhibitors
block HCO3 breakdown, Na+ and water increase in proximal tubule and result in alkaline urine
used as diuretic
can cause metabolic acidosis
acetazolamide
CA inhibitor used to treat high altitude respiratory alkalosis (hyperventilation) or decrease metabolic alkalosis
what happens to most H+ that is secreted?
it is used to reclaim filterd bicarb
how is HCO3 reabsorbed
destroyed in lumen by CA and reformed in tubule cell after absorption
what ultimately dictates the bicarb levels in blood
H+ secretion
how is titratable acidity altered to compensate alkalosis and acidosis
alkalosis: decreased
acidosis: increased
how is NH4+ excretion altered to compensate alkalosis and acidosis
alkalosis: decreased
acidosis: increased
how is HCO3- excretion altered to compensate alkalosis and acidosis
alkalosis: increased
acidosis: decreased (although basically 0 at normal pH so not really a change)
how is total new HCO3 added altered to compensate alkalosis and acidosis
alkalosis: decreased (HCO3 is actually is actually excreted not added)
acidosis: increased
how is urine pH altered to compensate alkalosis and acidosis
alkalosis: increased
acidosis: decreased
list factors that stimulate H+ excretion in nephron
increased CO2 (more substrate to push equation towards HCO3 and H+)
decreased arterial pH (more H+, stimulates Na/H transporter, moves transporters to membranes that promote H+)
increased plasma aldosterone (increased H+ ATPase and Na reabsorption in principal cells so H leaves intercallated cells to balance potential difference in lumen)
increased plasma angiotensin II (increased Na/H exchanger in PCT and TAL)
hypokalemia (increases K/H ATPase activity
list factors that inhibit H+ excretion in nephron
decreased PCO2 (less substrate to make H+)
increased arterial pH
decreased plasma aldosterone
decreased angiotensin II
which is likely to be hypokalemic and which is likely to be hyperkalemic- acidosis, alkalosis
explain
acidosis: hyperkalemic
alkalosis: hypokalemic
ex. in acidosis, the cells have high concentrations of H+ and K+ leaves those cells to create electroneutrality. K is usually 98% stored in the ICF so this “small” shift in ICF has significant effects on ECF and the ECF will be considered hyper kalemic
ex. in alkalosis, H+ leave the cells to bc low H+ concentration in blood, K+ balances charge gradient by entering cells, this causes ECF to be hypokalemic
mechanism of K+ excretion in acute and chronic alkalosis
alkalosis causes H+ to leave body cells so K+enters as charge buffer which causes and increase in K+ concentration in principal cells so they increase K secretion
alkalosis causes H+ to leave principal cells which increases Na+/K+ ATPase and K+ channel activity to increase K secretion
enhances hypokalemia
mechanism of K+ excretion in response to acute acidosis
acidosis causes H+ to enter body cells which K+ leave to buffer charge gradient resulting in decreased K+ concentration in principal cells so principal cells decrease K excretion
acidosis causes H to enter principal cells which decreases Na/K ATPase and K channel activity which decreases secretion of K
further enhances hyperkalemia
after several days, though, metabolic acidosis stimulates K+ secretion
mechanism of K excretion in response to chronic metaboolic acidosis
in chronic metabolic acidosis the proximal tubule has decreased Na/K+ ATPase activity which decreases the water and Na reabsorption this increases flow to the collecting duct which increases K secretion
decreases hyperkalemia
this is less pronounced in respiritory acidosis because kidneys are more able to compensate pH and decrease inhibition of NaK ATPase
how does increased flow in collecting duct increase K secretion
increased flow bends cilia on principal cells in collecting duct which activates PKD/PKD2 and Ca+ entry
increased Ca+ activates ROMK
ROMK lets K leave cells
mechanism of loop diuretics/thiazide diuretics increasing H secretion
loop/thiazide diuretics decrease blood pressure –> increase renin –> increase angiotensin II –> increase Na/H countertransport in PCT and increase alsosterone –> increase Na reabsorption (H+ leaves to balance charge), increase K+ secretion from principal cell, increase H+ secretion from alpha intercalated cell
