Renal system Flashcards
hypothalamic control of the posterior pituitary - water balance
- ADH stimulates an increase in water permeability of the collecting duct in the kidneys, allowing water to be reabsorbed
ADH secretion as a response to osmolality
- ADH secretion is stimulated by osmoreceptor neurone in the hypothalamus as a response to a rise in plasma osmolality and osmotic pressure (cell shrinks)
what do osmoreceptors stimulate
- thirst
- a greater AP frequency of ADH-producing neurone in the hypothalamus, leading to a greater release of ADH
stretch receptors and blood volume
- low blood volume is sensed by stretch receptors in the left atrium of the heart - increases ADH secretion
negative feedback loop fincreased blood osmolality
- blood osmolality increases
- thirst and increased ADH secretion by posterior pituitary
- drinking and water retention by the kidneys
- increased blood volume (and decreased osmolality)
what happens upon release of ADH into the blood stream
- helps to increase H2O reabsorption in the kidneys
- allows water to be reabsorbed in the collecting ducts of the kidney (returned to the blood)
- concentrated urine is secreted
what are the plasma osmolality htresholds
- for stimulating ADH secretion = 280mOsm/kg
- for stimulating thirst secretion = 290mOsm/kg
- changes in plasma osmolality are greatly affected by Na+, Cl- and K+ cocentrations
what happens to osmolality when you are overhydrated
- rise in blood volume stimulates stretch receptors in the left atrium and decreased plasma osmolality sensed by osmoreceptors
- leads to inhibited ADH secretion
- water is less effectively reabsorbed in the collecting duct of the kidneys (not returned to blood)
- dilute urine is secreted
ADH secretion: effects and stimulus
increased osmolality = increased ADH = urine vol decreased
decreased osmolality = decreased ADH = urine vol increased
increased blood vol = decreased ADH = urine vol increased
decreased blood vol = increased ADH = urine vol decreased
what happens If you don’t pee
- can possibly die from acute water intoxication
what happens if the ADH gene is mutated: rat model
- a frame shift mutation in Avp gene leads to deficient synthesis and release of ADH
- rats exhibit polyuria, excessive thirst and polydipsia
diabetes insipidus
central: caused by inadequate secretion of ADH
nephrogenic: caused by an inability of the kidneys to report to ADH
distinguished by…
- measuring plasma ADH levels
- diving a desmopressin challenge
the patients don’t take insulin
ADH and nocturnal enuresis (bedwetting)
- in healthy children: increased ADH secretion at night, increased reabsorption of water and decreased nocturnal production of urine
- with nocturnal enuresis these patters are messed up
- may be because of insufficient ADH production, insufficient response to ADH or impaired sensory input from the bladder
- treatment = desmopressin
body water contents: male vs female
male: more water than women because testosterone is anabolic
female: less water than men because they typically have more body fat
where is water stored in the body
- 2/3 intracellular
- 1/3 extracellular
- of the extracellular water 80% is in interstitial fluid and 20% is in blood plasma
if we take in 1.5-2.5L of water everyday how is most of it excreted
- majority from kidneys
- lungs
- skin (sweat glands)
- feces
what is water balance
water intake = water loss
water regulation in the Arabian camel: lipid humps
- lipid is stored In the hump of camels
- lipid metabolism can provide significant metabolic water
- > 1g water per 1g lipid
- much of the water produced is evaporated from the lungs during respiration = net loss of water
what was observed with suppression of cholesterol biosynthesis in the kidneys of the Arabian camel
- it facilitates their ability to retain water
- a decrease in cholesterol showed an increase in ion channel and transporter expression in the kidneys which increases water reabsorption
- includes aquaporin 2
water regulation in the Arabian camel: RBCs
- camel RBCs are able to withstand dehydration
- RBCs are oval shaped , smaller and circulate in larger numbers
- their Hb has a greater affinity for O2
- RBC properties allows passage through small blood vessels even hewn blood viscosity is high during dehydration
- RBCs can expand up to 240% original volume - prevents hemolysis when camels drink lots of water
water regulation in the kangaroo rat: adaptations
- can survive without any intake of water
- avoid harsh desert environment
- live in colonies underground - moist air in the burrows reduces respiratory water loss
- obtain water from seeds
- produce very dry feces
- kidneys concentrate urine to lose almost no water through it
salt content in water vs humans
fresh water = 0.1% dissolved salt
human body = 0.9% dissolved salt
seawater = 3.5% dissolved salt (4x more than blood)
what happens if we drink sea water?
- osmolality increases
- ADH secretion increases
- thirst increases
- kidneys increase water reabsorption to get rid of saline in blood plasma (Na+ bad for osmolality)
- cells will shrivel
- dehydration
water regulation in marine mammals
- obtains water from metabolism of food
- produce very concentrated urine
water regulation in baleen whales
- baleen whales don’t have teeth, they have baleen made of keratin
- baleen are arranged like the teeth of a comb
- whales open their mouth to fill it with water, then force the water out
- the mat on the inside of the baleen teeth catches plankton
water regulation in hibernating bears
- live completely off of stored fat reserves from the summer and fall
- burn 8000 calories a day
- do not eat defecate, drink or urinate
water regulation in hibernating bears: adaptations
- metabolic rate is but by 50-60% as the loss of body heat is slowed
- high insulating pelt - lower surface to mass ration
- metabolic water from lipid balances respiratory water loss
- decreased respiratory and heart rates
- urea produced from fat metabolism is broken down, resulting in nitrogen being used to build protein (sustained muscle mass)
what are the 4 main structures of the urinary system
- kidney
- ureters
- urinary bladder
- urethra
what do the kidneys regulate by forming urine
- the volume of blood plasma
- the concentration of waste products
- the concentration of electrolytes in plasma
- the pH of the plasma
- also secrete EPO to stimulate RBC production
basic pathway of urine from kidneys to the urethra
- urine produced in the kidneys is drained into the renal pelvis
- the urine is then channelled from the ureters to the urinary bladder by peristalsis
- the urinary bladder is a storage sac for urine
- the bladder is drained by the tubular urethra
shape of the bladder
empty = pyramid shaped
full = ovoid, bulges up into abdominal cavity
anatomy of the kidney: 2 zones of the renal parenchyma
renal cortex: outer part, contains many capillaries
renal medulla: inner part, contains microscopic tubules
anatomy of the kidney: moving from renal cortex to the renal pelvis
- extensions of the renal cortex form renal columns which divide the renal medulla into renal pyramids
- the boat face of the pyramids faces the cortex, the blunt point is called the renal papilla
- the papilla of each pyramid is nestled in a cup called a minor calyx (collects urine from each renal pyramid)
- 2 or 3 minor calyces converge into a major calyx
- 2 or 3 major calyces converge to form the funnel-like renal pelvis (one)
what is the renal pelvis
the renal pelvis is part of the kidney that is in continuation with the ureter to allow urine from the kidneys to get into them
what is included in one lobe of the kidney
one renal pyramid and overlying cortex
- about 6-10 lobes per kidney
what is the purpose of kidney circulation
filter out products from blood into the urine
how cardiac output is delivered to the kidneys
- kidneys receive about 21% of CO
- each kidney is supplied by the renal artery
- the renal artery divides into interlobar arteries that pass between the pyramids through the columns
- interloper arteries branch into arcuate arteries at the divide between the cortex and medulla
- interlobular arteries branch off the arcuate arteries into the cortex
- interlobular arteries subdivide into a series of afferent arterioles
order of arteries leading to the kidney (specifically nephron)
renal - interlobar - arcuate - interlobular - afferent arterioles
what happens when blood arrives at the afferent arterioles of the kidney (until efferent arterioles)
- each afferent arteriole supplies one nephron
- the afferent arteriole delivers blood into the glomerulus which is then drained by an efferent arteriole
how does blood get back to the heart after getting to the efferent arteriole
- efferent arterioles deliver blood into the peritubular capillaries (which surround the renal tubules)
- blood from the peritubular capillaries - interlobular vein - arcuate vein - interlobar vein - renal vein - inferior vena cava
brief events that happen when filtering blood at the kidneys
- blood enters at the glomerulus
- blood is filtered through the nephron
- a) urine leaves out the collecting duct (whatever remains in filtrate)
- b) blood leavers out the renal vein (anything filtered out of filtrate)
lobulated bovine kidney
- present in cattle (don’t have the simple kidney)
reticulate kidneys
- in hibernating and marine mammals
- has increased surface area (more renal pyramids and release more toxins/absorb more water)
what is the nephron
the functional unit of the kidney which is responsible for the formation of urine
- each kidney contains over a million nephrons
- made up of tubules and associated small blood vessels
- fluid formed by capillary filtration enters the tubules and the resulting fluid that leaves is urine
what are the 2 types of nephrons
- Juxtamedullary nephrons (20%)
- originate in the inner 1/3 of the cortex
- longer nephron loop
- important for producing concentrated urine - cortical nephrons (80%)
- originate in the outer 2/3 of the cortex
- shorter loops - don’t extend as deep into adrenal medulla
what are the 4 regions of the nephron
- Bowmans/ glomerular capsule
- proximal convoluted tubule (PCT)
- loop of Henle (consists of a descending and ascending limb)
- distal convoluted tubule (DCT)
how does filtrate leave the DCT
- the DCT is in direct contact with the glomerulus and arterioles
- filtrate drains from the DCT into the collecting ducts where we have secretion of ADH for water reabsorption
true or false: all regions of the nephron are associated with networks of peritubular capillary vessels
true
what are the 3 transport processes that affect renal clearence
- filtration
- reabsorption
- secretion
what is filtration
- movement of molecules and ions from the glomerular capillaries into glomerular tubules (lumen of nephrons)
- type of bull transport that only occurs in the renal corpuscle
what is the renal corpuscle
glomerulus + Bowmans capsule
what is reabsorption
- movement of particular molecules/ions from the filtrate into the blood
- involves membrane transport by means of carrier proteins
what is secretion
- membrane transport process that moves select molecules/ions from peritubular capillaries (plasma) into the filtrate
what is evidence that we reabsorbed a high portion of what gets filtered out of filtrate
- we have filtration of 180L of fluid/day but only excrete 1.5L of fluid/day as urine
what is excretion rate
(filtration rate + secretion rate) - reabsorption rate
what is glomerular filtration rate
- the volume of filtrate produced by both kidneys per minute
excretion rate = reabsorption rate
(before molecules are reabsorbed)
what are fenestrae
- large pores within the endothelial cells of the glomerular capillaries
- prevent entry of RBC, WBC, platelets and majority of albumiin
what allows for the autoregulation of blood pressure in the kidney
the afferent arteriole is larger than the efferent arteriole
what are the layers of filtration in the renal corpuscle
- fenestrae
- glomerular basement membrane (most restricts the rate of fluid flow into the capsule lumen
- alit diaphragm (found in between foot processes)
Filtration membrane of the renal corpuscle
- the visceral inner layer of the Bowman’s capsule is made up of podocytes
- intricate interdigitation of the foot processes are filtration diaphragms - act as filters
- filtration slits are negatively charged to prevent plasma proteins from entering filtrate
proteins in urine
- mutations in slit proteins results in proteinuria
- proteins in urine show there is an issue with the kidneys (mainly from glomerulus)
- plasma protein = 7% vs filtrate (urine) protein = 0.03%
average GFR for men and women
men = 125mL/min
women = 115 mL/min
- total blood volume is 5-5.5L , therefore it is equivalent to the entire blood volume being filtered every 40 minutes
what is blood hydrostatic pressure
- the pressure that forces blood plasma out of the glomerulus into the Bowmans capsule
- 60mmHg
- promotes filtration
what does hydrostatic pressure of fluid in the bowman’s capsule do
- opposes blood hydrostatic pressure, therefore opposes filtration
- 18mmHg
what does the colloid osmotic pressure of plasma do
- greater colloid osmotic pressure of plasma promotes the osmotic return of filtered water to glomerular capillaries
- 32mmHg
- opposes filtration
what is the net filtration pressure
10mmHg
60 - 32 - 18 = 10
how does the permeability and high SA of glomerular capillaries affect net filtration pressure
- a modest net filtration pressure produces a large volume of filtrate
regulating GFR
- GFR is largely affected by the glomerular and blood hydrostatic pressure in the glomerular capillaries
- a relatively stable GFR ensures a constant flow of glomerular filtration - achieved by changing the diameter of the AFFERENT arteriole
what happens of GFR is too high or low
too high: fluid flows through renal tubules too quickly - can’t reabsorb water or solutes
too low: fluid flows sluggishly through the tubules - reabsorb wastes that should be eliminated
- therefore we need GFR to remain constant
what is renal autoregulation
- the ability to maintain a constant GFR with fluctuations in blood pressure
- decreased blood pressure = afferent arterioles dilate
- increased blood pressure = afferent arterioles constrict
what mechanisms are responsible for renal autoregulation
- myogenic mechanisms
- locally produced vasoconstriction and vasodilation chemicals
renal autoregulation: myogenic mechanisms
- stretching of vascular smooth muscle cells of the afferent arteriole leads to increased intracellular calcium in these cells by mechanoreceptors
- increase in calcium stimulates vasoconstriction
- maintains a constant GFR
renal autoregulation: locally produced chemicals (structure)
- a process called tubuloglomerular feedback
- the DCT loops back and comes into contact with the afferent and efferent arterioles in the renal cortex
- within this region of the DCT is a group of specialized cells known as the macula densa
- the macula densa are part of the juxtaglomerular apparatus
what is the juxtaglomerular apparatus
- structure in the kidney that regulated the function of each nephron
- includes granular cells and macula densa
- regulates the rate of filtrate formation and controlling systemic blood pressure
renal autoregulation: locally produced chemicals (mode of action)
- increase in arteriole blood pressure leads to increased delivery of NaCl and H2O to the DCT
- this is sensed by Na+K-2Cl- transporters and causes the macula densa to release ATP
- ATP and adenosine receptors are activated in afferent arteriole smooth muscle cells
- leads to an increase in intra-cellular calcium and ultimately vasoconstriction
- works in tandem with myogenic response
Regulation of GFR: what happens when afferent arterioles receive innervation from sympathetic nerve fibers
- causes an increase in sympathetic nerve activity
- afferent arterioles constrict
- divert blood to muscles and the heart to preserve blood volume
- this decreases GFR, therefore decreasing urine production and increasing blood volume
how can exercise and a decrease in blood pressure have the same effect on GFR
- decreased BP (causes the baroreceptor reflex) and exercise increases sympathetic nerve activity
- leads to vasoconstriction of afferent arterioles in the kidneys which DECREASES GFR
- this decreases urine production and increases BV
- in the process, increases sympathetic nerve activity also increases cardiac output and causes vasoconstriction in the skin and GI tract
cells of the juxtaglomerular apparatus
granular (G) cells: cells in the afferent arteriole that secrete the enzyme renin
macula densa (MD) cells: sensory cells in a region of the DCT
Mesangial (M) cells: communication cells, connect G and MD cells via gap junctions
events that trigger the RAAS to become active
- the secretion of renin from granular cells initiates the RAAS
- low blood osmolality inhibits ADH secretion which decreases water reabsorption
- this increases urine excretion while decreasing blood volume/pressure
- this fall in blood VOLUME stimulates renin secretion
- the fall in blood PRESSURE stimulates granular cells
- the pathway is stimulated by the SNS (B1-adrenergic receptors in the granular cells)
The RAAS pathway
- blood pressure/volume falls
- Renin is secreted by the granular cells of the afferent arteriole
- Renin catalyzes angiotensinogen (blood plasma protein) and turns it to angiotensin I
- Angiotensin 1 becomes angiotensin II my the enzyme ACE (angiotensin-converting enzyme)
- Angiotensin II stimulates vasoconstriction of afferent arterioles (AND stimulates thirst and aldosterone secretion from the adrenal cortex)
- results in an increase in BV and BP
what does RAAS stand for
the renin - angiotensin - aldosterone system
- functions to increase blood volume and pressure
the effect of angiotensin II on aldosterone in the RAAS
- angiotensin II stimulates the adrenal cortex to secrete aldosterone
- aldosterone stimulates Na+ reabsorption and K+ secretion
- aldosterone stimulates Na+/K+ ATPase activity in cells of the collecting duct
- this increases the electrochemical gradient for the passive movement of Na+ from the filtrate through Na+Cl- co-transporters in the blood
- all Na+ is reabsorbed –> H2O follows (passive reabsorption) which increases blood volume
true or false: like ADH, aldosterone affects blood osmolality
FALSE - aldosterone does not affect it
what does an increase in angiotensin II result in in the RAAS
- stimulates the thirst centre in the hypothalamus
- stimulates the adrenal cortex to secrete aldosterone, leading to Na+ reabsorption in the blood
- stimulates vasoconstriction of afferent arterioles
how can the RAAS clinically be used to treat hypertension
- we can pharmacologically target the RAAS to lower the blood pressure in hypertensive patients
- we can either target ACE or angiotensin II
targeting the RAAS: ACE inhibitors
- ACE inhibitors prevent the conversion of angiotensin I to II
- this reduces the ability of angiotensin II to stimulate vasoconstriction (can treat hypertension)
targeting the RAAS: angiotensin receptor blockers
- angiotensin receptor blockers can inhibit the binding of angiotensin II to its receptor (AT1) on vascular smooth muscles
- this reduces vasoconstriction (can treat hypertension)
what are the peritubular capillaries
- blood flows in from the efferent arteriole into the peritubular capillaries
- after the glomerulus, blood vessels keep winding around the nephron, sending in and drawing out more water/solutes from the nephron
- about 85% of the 180L of glomerular filtrate formed per day is reabsorbed into the peritubular capillaries
locations of filtration, reabsorption and secretion
filtration: occurs in the glomerulus (afferent arteriole to efferent arteriole)
reabsorption: majority at PCT, some at loop of Henle
secretion: mostly at the DCT
of the 85% getting reabsorbed from filtrate, where in the nephron does it occur
- 65% of the salt and water in the original glomerular filtrate is reabsorbed across the PCT and returned to the vascular system
- 20% is returned to the vascular system by reabsorption through the descending limb of the loop of Henle
- reabsorption is not subject to hormonal regulation
types of reabsorption
transcellular: substances pass through the cytoplasm, depend on active transport and facilitated diffusion
paracellular: substances pass between epithelial cells
why does most reabsorption occur at the PCT
- it contains abundant mitochondria that provide ATP for active transport (transcellular reabsorption)
how does the concentration of Na+ in fluid entering the PCT affect reabsorption
- Na+ in the fluid entering the PCT is much greater than in the cytoplasm of the epithelial cells
- the steep concentration gradient favours facilitated diffusion of Na+ into epithelial cells
- Na+ moves into the interstitial fluid by Na+/K+ ATPase active transport
- the electrical gradient created from Na+ reabsorption causes Cl- to follow
what is the purpose of accumulated NaCl in interstitial fluid
- leads to the reabsorption of H2O by osmosis
Glucose reabsorption from filtrate
- glucose is normally 100% reabsorbed in the PCT - occurs via glucose-Na+ co-tansporter
- these co-transporters have a transport maximum = saturable
- blood plasma glucose in its normal range = carriers not saturated
how does elevated blood glucose affect glucose reabsorption
- the rate of glucose filtration > transport maximum
- this leased to glucose in urine (glucosuria) because we can’t reabsorb all of it
- sign of diabetes millitus
what is the concentration of fluid leaving the PCT
300mOsm
why does fluid leaving the PCT remain isosmotic with the blood
- because membranes in the PCT are freely permeable to H2O - salt and water are removed in PROPORTIONATE AMOUNTS
how are we able to get concentrated urine if salt and water are removed in proportionate amounts
- the loop of henle sets up a hyper osmotic environment in the renal medulla so that urine concentration can occur
4 players…
1. thicker walled ascending limb
2. thin walled descending limb
3. vasa recta
4. the collecting ducts
concentrating urine: structure of the ascending loop of Henle
- divided into thick and thin segments
- thick segment actively gets rid of 20-25% of filtered NaCl from the lumen into the interstitial fluid
- accomplished by Na+K+2Cl- co-transporter
- the walls of the ascending limb are IMPERMEABLE to water, therefore water cannot follow NaCl
what happens as a result of the ascending loop of Henle being impermeable to water
- water cannot follow NaCl out into the interstitial fluid - concentration decreased
- filtrate entering the DCT in the cortex is hypotonic (100mOsm)
- interstitial fluid in the medulla will be hypertonic
steps in extruding NaCl from filtrate in the ascending loop of henle
- 1Na+, 1K+ and 2Cl- enter the epithelial cells via secondary active co-transport
- Na+ actively transported into interstitial space and Cl- passively follows
- K+ passively diffuses back into the filtrate
concentrating urine: the descending loop of Henle
- as filtrate enters the descending limb from the PCT, it gets very concentrated, increasing from 300-1200mOsm as it reached the loop turn
- the walls of the descending limp are PERMEABLE to H2O and impermeable to NaCl
- because interstitial fluid is hypertonic, H2O is drawn out of the descending limb by osmosis
what happens as a result of the descending loop of Henle being permeable to water (impermeable to NaCl)
- concentration of filtrate is increased
what is the countercurrent multiplier system
- enables the kidney to produce urine that is more concentrated than the blood, essential for regulating water balance in the body
- creates a concentration gradient that enables efficient water reabsorption
steps in the countercurrent multiplier system
- extrusion of NaCl from the ASCENDING limb makes the surrounding interstitial fluid more concentrated. multiplication of this concentration occurs because…
- … the descending limb is passively permeable to water, which makes the concentration in the tubule more concentrated
- the deepest region in the medulla reaches a concentration of 1200mOsm
what is the vasa recta
- a specialized slow-moving blood supply that parallels the loop of henle in juxtamedullary nephrons
- it is freely permeable to H2O AND NaCl
- it flows opposite to the flow of filtrate in the loop of henle
- maintains the hypertonicity of the renal medulla by the countercurrent exchange mechanism
what is the counter current exchange mechanism
a process where the vasa recta maintains the concentration gradient in the renal medulla created by the countercurrent multiplier system
concentrating urine: role of the vasa recta (countercurrent exchange)
- blood within the vasa recta will approach osmotic equilibrium with the interstitial fluid that surrounds each level of the renal medulla
- solutes that leave the ascending limb and enter the interstitial fluid, then the descending vasa recta
- H2O that leaves the descending limb enters the interstitial fluid and then the ascending vasa recta
- the same solutes that entered the descending vasa recta now leave the ascending vasa recta - completes countercurrent exchange
where is the vasa recta most concentrated
the bottom of the loop
what is the significance of recirculating and trapping solutes in the medulla
- allows us to maintain the concentration gradient of the medulla AND deliver blood at an isotonic concentration to the cortex
countercurrent multiplier vs exchanger
multiplier: established the osmotic gradient
exchanger: maintains the osmotic gradient
the collecting ducts in reabsorption
several nephrons main into each collecting duct - the filtrate that passes into the collecting duct in the cortex is hypotonic
- the collecting duct in the medulla is impermeable to NaCl
- the collecting duct MAY be permeable to H2O - depends on the number of aquaporin channels present in the PM (regulated by ADH)
the osmotic gradient and the collecting ducts
- the osmotic gradient created by the countercurrent multiplier provides the force for water reabsorption from the collecting ducts
- therefore, although the countercurrent osmotic gradient is constant, the rate of osmosis across the collecting duct can vary
the role of ADH in the collecting ducts
- determines If they are permeable to water or not
- ADH binds to membrane receptors in the collecting duct which stimulates cAMP production
- vesicles with AQP2 in the membrane fuse with the PM
- AQP2 are permeable to water and only function with ADH present
- without ADH, AQP2 are removed by endocytosis
function of the ureters
- urine moves from the renal pelvis to the ureter
- smooth muscles in the walls carry out peristalsis
- peristalsis waves move urine towards the bladder
- back flow of urine id prevented by a flap valve
what happens with a dysfunctional flap valve
- causes VUR by blocking the bladder
- causes the urine to back flow up the ureters
- often causes UTIs and incontience
Lilies and nephrotoxicity in cats
- all parts of the lily are nephrotoxic to cats (flower extract more toxic than the leaf)
- suggests a feline-specific water-soluble toxic metabolite is responsible for this
- renal failure due to necrosis of the renal tubular epithelial cells
symptoms of nephrotoxicity in cats post ingestion of lilies
- 1-3 hours: salivation, V+, anorexia
- 12-30 hours: polyuric renal failure - increased output of urine due to impaired ability to concentrate urine (reabsorb fluids)
- eventually leads to dehydration and anuria
- metabolic wastes and toxins will accumulate during this time = severe uremia
- may cause seizures
grapes and nephrotoxicity in dogs
- Grapes, grape skins and raisins are nephrotoxic to dogs
- independent of their weight, lacks a dose-response
- dried grapes have a higher rate of fatality
- mechanism of toxicity may be related to tannin intolerance, contamination or ingestion of excess vitamin D
- primary injury occurs in the proximal tubular epithelium (necrosis)
- renal failure 24-72 hours post-ingestion
