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Mech of Disease Renal Disease


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what are the 4 main functions of the kidney/nephron?
1. reabsorb filtered nutrients 2. tubular secretion 3. eliminate/conserve H20 4. adjust plasma pH
Where does reabsorption take place?
proximal tubule
What are things that get reabsorbed?
Vitamins, glucose, minerals, amino acids
Where does secretion take place
in the renal tubular cells
what gets secreted
How does secretion take place?
via secretory/transport mechanisms in the tubular cells
how do the mechanisms work
tubular cells grab the substance from the peritubular capillaries and actively secrete them into the tubular fluid
Do drugs get filtered into the urine on their own
no- usually bind to plasma proteins like albumin
How is urine osmolality adjusted?
by eliminating or conserving H20
When the body is H20 deprived, what happens to osmolality?
increases: very concentrated urine (1200 milliosmoles/liter)
When there's too much water what happens?
decreases osmolality: urine contains more water
How is plasma pH adjusted?
by secreting H+ ions and making and conserving
bicarbonate ions
What's the normal pH in the plasma?
whats the NL [Na+] in plasma?
0.14 M
What causes many problems with the acid/base balance?
sulfuric acid breakdown
When acid/base problems arise, what do the kidneys do?
adjust the H+/HCO3- ions
When acid/base problems arise, what do the lungs do?
adjust by ventilating more or less
What hormone does the kidney secrete to produce RBC's
What is another hormone the kidney produces?
What does renin do?
end result= BP inc'd
What does aldosterone do?
inc's Na+ reabsorption in renal tubules and increases K and H+ secretion into tubular fluid.
What does the kidney have to do with Vitamin D?
it converts 25-OH Vitamin D (inactive form) to 1.25 (OH)2 Vitamin D (the active form)
What is the significance of this conversion?
1. increases Ca2+ absorption in the gut 2. assimilates dietary stuff into blood
What effect does parathyroid hormone have on the kidney?
causes increased Ca2+ reabsorption from tubular fluid; causes osteoclastic activity
When is it secreted?
decreased Ca2+ in plasma
What secretes ADH (vasopressin)?
posterior pituitary
What affect does ADH have on kidneys
when osmolality is too high (you get dehydrated) it causes kidney to increase H2O reabsorption in collecting ducts
What is the proportion of plasma to cells in blood flowing into the kidney?
55% plasma, 45% cells
trace the bloodflow thru the kidneys
afferent artery -> glomerular capillaries -> efferent artery -> peritubular capillaries
What is the structure of glomerular capillaries?
single fenestrated layer of endothelial cells on top of a basement membrane and foot processes of visceral podocytes
What features easily allow movement in and out
single layered and fenestrations
contractile, phagocytic cells that respond to complement cascade by secreting chemical junk; also secrete a matrix
mesangial cells
describe glomerular filtration barrier
triple layer of glomerulus with a negative charge
significance of neg charge?
keeps neg charged particles out of urine like albumin
definition of GFR
the amount of plasma filtered out of the capillaries into bowman's space
quantify the rate at which plasma is filtered
amt excreted = amt. filtered + amt. secreted - amt. reabsorbed
What was the basis for the inulin experiment?
inulin is neither secreted nor reabsorbed and is freely filtered; therefore the amt filtered = the amt excreted
What was the avg GFR determined to be?
125 mL of plasma/minute
does all plasma go thru glomeruli?
What is the ERPF?
effective renal plasma flow= the total amount of plasma going to the kidneys and thru the glomeruli
difference btw ERPF and GFR
GFR is only a fraction of total plasma flow, it represents only one glomerulus; ERPF represents the collective glomeruli
What substance was used to determine ERPF?
para-aminohippuric acid (PAH)
What was ERPF determined to be?
585 mL/min
How much of this goes out the efferent arteriole (not being filtered)?
585 - 125 = 460 mL/min
%age of renal blood flow that goes to glomeruli?
what is the total renal plasma flow-TRPF (amt delivered to whole kidney)?
585/0.9 = 650 mL/min
What is hematocrit (hct)
the fraction of blood composed of RBCs, usually 45%
approx amt of RBF-renal blood flow- total
1200 mL/min
what %age of total blood volume is filtered each time around
What is the macula densa? What does it do
-the part of the tubule that passes thru the branches of the afferent/efferent arterioles
-detects change in sodium concentration and triggers vasoconstriction of afferent arteriole
What detects a BP decrease
nearby granular cells with stretch receptors in teh afferent arteriole
trace flow of filtrate thru the nephron
glom caps release glomerular filtrate with enters the bowmans capsule then goes to PCT, the descending loop, the loop of Henle, the DCT, and then to the collecting duct
where is H2O reabsorbed
from the fluid in the descending interstitial tubule
it maintains a constant fraction of the filtrate reabsorbed by the tubule leading to a constant rate of Na+ reabsorption and excretion
action of Na+ and Cl- in ascending limb
Cl- pumped out actively and Na+ pumped out passively
What part of the nephron does ADH act on
the collecting duct
What does it do to the duct?
causes holes to be inserted to increase H2O reabsorption
how fast your kidney secretes a substance/drug is called
what organs are involved in clearance
kidneys and liver
why is it called virtual clearance
b/c it doesn't measure how much substance is actually in the urine but rather how many individual mL of blood are cleared of the solute they're carrying.
clearance equation
Cx = ([Ux] x V)/[Px]
clearance of x = concentration of x times volume of urine divided by plasma concentration of x
the volume of plasma cleared of X
why is creatinine used
b/c its not reabsorbed and it's freely excreted
where is creatinine normally found
striated skeletal muscles
easiest to measure: plasma creatine or urine creatinine
high conc of Cre plasma =
poor renal function
low conc of Cre plasma =
person is sick
does creatinine clearance measure GFR exactly
no- overestimates GFR slightly b/c it's slightly secreted
why is that important
b/c it can miss early renal failure
A decrease in GFR is often indicative of what
What does decreased GFR do physiologically
dec.'d urine production (anuria or oliguria), creatinine clearance, and urea clearance
dec'd creatinine clearance =
inc'd plasma creatinine
dec'd urea clearance =
inc'd BUN
inc'd plasma cre and inc'd BUN =
azotemia is indicitave of ---
NL urine output =
750-2000 mL/day
oliguria =
= <500 mL/day
anuria =
= <100 mL/day
polyuria =
= >2500 mL/day
What is the most important determinant of body fluid volume
how measured?
Fraction Excretion of Na+
Fractional Excretion of Na+ tells what
quantifies the percentage of filtered sodium that is actually excreted in the urine.
FE Na+ =
= (UNa x Pcre)/(Pna x UCre) x 100
FE Na+ when excess Na+ intake =
up to 5%
FE Na+ when too little Na+ intake =
low as 0.1%
sodium in the body fluid volume is a collective measure of...
Na+ in extracellular space, including the plasma
if little Na+ intake, filterted Na+ is ....
conserved (reabsorbed).
if too much Na+ intake....
it's excreted
Inc'd FE Na+ is usually a good indicator of ....
the presence of a physiologic stimulus for the retention of sodium by the kidneys
what are some physiolgical stimuli for Na+ retention?
dehydration, x-treme blood loss, heart failure
circulating fluid volume measures what?
blood perfusion
poor perfusion (an inc'd FEna) leads to
dec'd GFR, dec'd urine output and azotemia (in'd BUN and Cre plasma)
pre-renal failure or pre-renal azotemia
the kidneys are not getting enough blood flow to do their job of filtering the plasma
are the kidneys ill in pre-renal azotemia?
no- the kidneys themselves are still OK, but the stuff being delivered to the kidneys, the circulation, is inadequate.
what do kids do if they detect pre-renal azotemia?
start conserving sodium in order to pump up the circulating fluid volume, so FE Na goes down
FE Na in pre-renal azotemia =
< 1%
Intrinsic Renal Failure (Structural renal failure)
kidneys themselves are sick, but blood flow is adequate
post-renal failure (obstructive renal failure)
both the kidneys themselves and the circulation to them are both OK, but there is an obstruction to urine output
FE Na in renal azotemia
> 1%
if renal azotemia is intrinsic what happens to UNa and Uosm?
Una in's and Uosm dec's
What is ARF?
abrupt decline in renal fx: dec’d GFR and therefore dec’d excretion of nitrogenous waste, dec’d urine output
are most forms of ARF reversible
What is uremia?
azotemia w/ Sx
what are the sx of uremia? 11
-N/V and anorexia
-yellow pigmentation
-peripheral neuropathies (stocking, feet, and glove sensation loss; and loss of proprioception)
-anion gap acidosis
-lethargy, confusion, seizures, coma
What causes pre-renal ARF
hypotension or edematous states
what would cause hypotension
sepsis, volume depletion (blood loss, dehydration, hemorrhaging, untreated burns, diarrhea)
what causes edematous states?
CHF (loss of fluid volume into tissue), cirrhosis of the liver (hydrostatic pressure builds up, fluid leaves filling abdom cavity), nephrotic syndrome (xs protein in urine c/b leaky glomeruli; water leaves too and changes osmotic pressure)
What is affected in intrinsic renal failure
renal parenchyma
The types of intrinsic (5):
acute tubular necrosis, glomerulonephritis, interstitial nephritis, Infectious interstitial nephritis , and vasculitis (SLE)
causes of acute tubular necrosis
ischemia to kidney parenchyma, or nephrotoxic drugs
what are nephrotoxic drugs?
aminoglycosides (streptomycin and gentamicin) or radiocontrast drugs (no CT Scans!)
What is the major Sx of glomerulonephritis?
most common cause of post-renal failure:
uric acid stones
what causes uric acid stones?
hyperuricemia (i.e. from chemo)
other causes of post-renal failure:
nephrolithiasis or urolithiasis, tumors, BPH
The 3 mechanisms kids use to regulate blood flow:
myogenic, tubuloglomerulo-feedback, glomerulotubular balance
does myogenic mech control GFR?
how does myogenic work?
-Smooth muscles in vessels contract changing pressure and resistance.
-If P inc's arteriole muscle will contract and vessels constrict.
-Vessel constriction prevents inc'd P from causing inc'd blood flow
equation: P=
Flow x Vascular resistance
Which mech regulates GFR against momentary changes in BP?
Tubuloglomerlu feedback
what structure carries out tubuloglom feedback
Juxtaglomerular Aparatus (JGA)
components of the JGA=
macula densa, granular cells, extraglomerular mesangial cells, and sympathetic nerves
where is macula densa located
btw. the efferent and afferent arteries
what does macula densa do
detects even a slight inc in GFR due to increase in flow to distal tubule and increase in NaCl concentration
what happens when mac densa detect inc in flow rate?
sends signal to granular cells wich cause afferent arteriole to constrict causing GFR to decrease
what do extraglomerular mesangial cells do?
secrete chemical junk and respond to inflammation
what does the glomerulotubular balance mechanism do?
keeps amount of filtered solute (NaCl) constant; prevents increase in Na+ loss while GFR is temporariy inc'd (due to inc'd BP)
what are cause of acute changes in BP
posture changes (sitting/laying), or brief exercise
does kidney have parasympathetic innervation
no, sympathetic only
where do sympathetic fibers to the kidneys go?
to the smooth muscle cells in all arteries and arterioles
effect on arterioles?
branches of symp nerve fibers also innervate---
granular cells
activation of granular cells leads to what?
gran cells secrete renin, leading to angio II which is a powerful vaso constrictor
which two adrenergic receptors are involved in symp nerve stimulation
alpha 1 and beta 1
fx and location of alpa 1 receptors:
located mostly on renal arterioles; : Sympathetic fibers innervating renal arteries release norepinephrine and cause vasoconstriction of the arteries/arterioles via alpha receptors
what does this do to the renal blood flow (RBF) and GFR?
decreases both of them
where are beta 1 receptors located
in granular cells of JGA
beta 1 receptor fx:
norepinephrine is relased from symp nerve branches and binds to beta-1 receptors. The agonism of the B-1 receptor causes renin release from the granular cells.
what is end result of norep release
increase in Na+ reaborption to keep fluid volume up
4 functions of Sympathetic NS activity in kids:
1. regulate blood flow to kids
2. regulate GFR
3. regulate renin secretion
4. regulate salt/H2O reabsorption
does plamsa NLy get filtered into tubular fluid?
on each pass through the glomeruli, some of the plasma gets filtered into the tubular fluid
active secretory/transport mechanism of tubular cells does what to drugs/toxins
"sucks" them out of the peritubular capillaries & interstitium and secrete them into the tubular fluid (early urine)
why are many toxins not readily filtered into the tubular fluid by the glomeruli
b/c they bind to albumin
what do lungs do in acid-base disturbances
they increase or decrease ventilation (i.e blowing off or retaining CO2
what do the kids do in acid base disturbances
adjust the secretion and reabsorption of H+ and HCO3-ions
what does aldosterone do
increases Na+ reabsorption (Na conservation) and increases K and H secretion into tubular fluid
What happens if theres too much aldosterone
plasma Na increases, leading to water retention and an increase in the total circulatory fluid volume⬦and at the same time K+ and H+ are being secreted and dumped, so hypokalemia and increased plasma pH (alkalemia) both occur
In dehydration, how high is the plasma osm?
> 290mosm/L
How does the hypothalamus monitor osmolality?
--the preoptic/periventricular nuclei of the hypothalamus fire action potentials down their axons to their ends in the posterior pituitary
--upon arrival, they stimulate the release of ADH from the axon terminals into the blood
--Then, ADH travels to the peritubular capillaries where it causes the development of new pores in the collecting ducts, through which excess water in the collecting duct fluid can be reabsorbed and retained by the body
what is diuresis
denotes increased Na and water excretion by the kidneys
T/F it takes several days without enough dietary calcium intake to signal the parathyroid to produce PTH
F- less than a day
During filtration, fluid and substances filtered into the proximal tubule are quickly reabsorbed by the proximal tubule cells and carried back into the circulation by the what?
peritubular capillaries
When the charge in the glomerular barrier disappears due to glomerulitis, the filtration barrier becomes excessively leaky to what?
RBCs and plasma proteins.
Why is PAH used to determine ERPF?
because all of the PAH in the plasma (from the collective afferent arterioles) gets into the tubular fluid (and urine), whether by filtration or secretion
about what percentage of the plasma flow thru the collective glomeruli is being filtered?
approx 21%
What happens to H2O in the descending limb of the loop of Henle
it's passively reabsorbed
What happens to Na in the ascending limb?
its passively reabsorbed
What does the passive reabsorption of both Na and H2O do?
it removes water and traps Na (and urea) in the interstitium surrounding the bottom of the loop of Henle
what is this cyclic mechanism called?
a counter current multiplier system
What does the counter current multiplier system do to osmolality
It creates very high interstitial osmolality, 1200 mOsm, at the bottom of Henle’s loop (especially deep within the kidney..the medullary area), which is at about the same renal tissue depth as much of the collecting duct.
When ADH is released and H2O is sucked out of the collecting duct, is the high osmolality diluted?
no, because the peritubular capillaries take it away, and because the countercurrent multiplier mechanism works to maintain the high osmolality. Without maintenance of the high osmolality, and without ADH, we would all more easily come close to dangerous levels of dehydration.
What are the units by which renal clearance is expressed?
T/F Since creatinine is produced at a constant rate, plasma concentration of creatinine should also be constant if clearance of creatinine is also constant and in the correct range
What specifically, causes prerenal azotemia?
burns, hemmorhage, dehydration, edema, CHF, renal stenosis, sepsis
what is a common cause of acute tubular necrosis
blood loss during trauma or surgery
What are the 3 edematous states that cause prerenal ARF?
CHF, liver cirrhosis, and nephrotic syndrome
a specialized segment of the thick ascending limb of the nephron which passes
macula densa
Sum up the kidney's response to a decrease in BP
*Kidney puts out renin -> Angiotensin II production -> systemic vasoconstrictor increases BP.
*In addition to causing vasoconstriction, Angiotensin II also has the following effects:
**Angiotensin II -> causes release of ADH from posterior pituitary -> increased water reabsorption in the collecting duct -> increased circulating fluid volume ->increases BP
**Angiotensin II -> increases aldosterone from the adrenal cortex -> increased sodium reabsorption in the renal tubules, which itself causes more water to be reabsorbed from the tubular fluid
if you reclaim an extra 2% of total filtered Na per day, how much circulating fluid would that occupy?fluid
T/F the renin-angiotensin II aldosterone mechanism is a short term regulator of BP
F- a long term regulator
what are the four functions of sympathetic NS activity?
1. regulate blood flow to the kidneys
2. regulate GFR
3. regulate renin secretion
4. regulate salt and water reabsorption
what are the 2 mechanisms that regulate BP long term
angiotensin II, aldosterone/ADH
which of these induces vasoconstriction
angiotenin II
which of these regulates circulation of fluid volume
What are the three primary detectors to control renin secretion
high pressure baroreceptors in the carotid sinus and aortic arch, intrarenal baroreceptors, macula densa cells
What happens when high pressure baroreceptors in the carotid sinus and aortic arch detect inc'd BP?
causes an increase in sympathetic activity, which causes granule cells to release renin, leading to angio II production and thus global vasoconstriction which inc's BP and renal blood flow
What else does Angio II cause?
aldosterone secretion by the zona glomerulosa of the adrenal glands which causes inc'd renal sodium reabsorption, thus inc'ing circulating fluid volume and inc'ing BP
intrarenal baroreceptors are also called what
granular receptors
how do granular cells detect pressure changes
stretch receptors
what do they do if low BP is detected?
renin secretion, etc. (as before)
what do macula densa cells do
detect a decrease in tubular flow and NaCl content
what happens when they detect changes?
they decrease the release of chemical junk transmitters that NLy inhibit the release of renin from the granular cells resulting in an inc in renin, etc (as before)
increased vasoconstriction
angio II
increased Na reabsorption
increased reabsorption of H2O into collecting duct
what percentage of all of the filtered Na does aldosterone control?
how many mEq can be reclaimed by aldosterone
504 mEq
how do the kids play a role in CHF?
a failing LVent causes a decrease in CO which dec's renal perfusion
what do the kids do in response to decreased renal perfusion?
secrete renin-angio II-vasoconstriction-inc total peripheral resistance (TPR)- inc BP
An increase in TPR also causes what?
increased ventricular work leading to increased cardiac sympathetic tone that's needed to help the failing LV able to handle pumping CO thru inc'd resistance. inc'd sympathetic tone also causes inc's renal sympathetic tone, causing renin secretion--viscious cycle
Angio II further complicates CHF by releasing aldosterone. what does this do?
inc's Na and Cl reabsorption in collecting ducts inc'ing circulating volume which leads to pulmonary edema, peripheral edema (ascites). this edema means a high vascular resistance packed tight w/ extra fluid leading to weight gain.
Angio II further complicates CHF by releasing ADH. what does this do?
inc's H2O reabsorption which inc's circulating volume (and thus BP)
how do you treat CHF?
diuretics and blood vessel dialators
how does the nephron deal with glucose
by co-transporting with Na or a.a.'s
how much gluc is reabsorbed by the proximal tubule
what causes gluc to not be reabsorbed
when the plasma load causes the filtered load to exceed the transport max (Tm) for glucose
what is the Tm for glucose
375 mg glucose/min
plasma glucose in a NL person=
1 mg/mL
filtered load=
volume of flow x concentration = 585 mL/min x 1 mg/mL
plasma load=
585 mL of glucose/min
filtered volume of glucose
125 mg/min of glucose get into tubular fluid
T/F if the amt of filtered glucose per minute does not exceed the transport max, there will be zero glucose in the urine
how much glucose will go in the afferent arteriole and back out the efferent arteriole per minute
460 mg
how much will get filtered (and also reabsorbed)
what does extra glucose in the tubules do?
leads to osmotic diuresis causing polyuria, polydipsia, and polyphagia
T/F kidney regulates the plasma glucose concentrations
F- insulin and pancreas do that
T/F a.a.'s are too large to be filtered
F- they are small enough and they get loosley bound to Na
What proteins get into the tubular fluid and why in the case of multiple myeloma? What happens to the transport max?
Bence-Jones proteins--b/c They are small enough that they are easily filtered. it causes Transport max for protein reabsorption to be exceeded so the excess over the max is released in the urine
What is the result of xs sodium intake
inc's extracellular fluid volume (ECFV) slightly b/c NaCl holds H2O
what are the 4 major results of an inc in ECFV
1. decreased tubular reabsorption of Na (inc'd sodium excretion by the tubules)
2. pressure natruresis
3. decreased BP
4. increased GFR (and thus pressure natruresis)
What causes dec'd tubular reabsorption of Na?
ECFV increase stretches pressure receptors in the R. atrium and pulmonary vessels wich signals the brain to decrease sympathetic activity which dec's renin which dec's angio II which causes dec's na reabsorp
How does increased ECFV cause pressure natruresis
it inc's BP so pressure natriuresis is due to slightly increased GFR despite regulatory mechanisms that try to maintain GFR stable. This helps excrete some of the excess NA.
What does this slight increase in BP do?
decreases renin/angioII/aldosterone/ADH which all dec BP
How does the increase in BP lead to pressure natruresis?
incd' BP signals barorecptors to inhibit sympathetic tone which dilates afferent arterioles and inc's the GFR causing pressure natruresis
what happens to GFR if arterioles are dilated
what happens to GFR if efferent arteriole is constricted
increases: increases the filtration pressure in the glomerular capillaries so the GFR increases (think of a garden hose)
what is an ACE inhibitor
they cause dilation of the EFFERENT ARTERIOLE which decreases filtration pressure in the glomeruli
How does glucose normally reenter the blood?
Tubular cells pump glucose, co-transported with Na, back into the interstitium and glucose reenters the blood
how is the rate of glucose clearance from the blood determined?
Glucose Clearance = Ugluc * volume of urine / Pgluc
T/F in a normal person, all of the glucose remaining in the plasma would be taken up by brain tissue and skeletal muscle with the aide of insulin
T/F It is normal for 250 mg/min of glucose to be in the urine
F- shouldn't be there
in treating CHF, what do diuretics do?
they inc. excretion of Na, and therefore water leading to decreased BP & dec'd edema and less difficult for heart to pump
What kind of CHF drugs dilate blood vessels?
Calcium channel blockers, ACE inhibitors, and Angiotensin Receptors Blockers (ARBs)
What do Ca channel blockers do?
block the contraction of arteriolar smooth muscle which causes vasodilation--making it easier for heart to pump blood to kidneys and elsewhere
What do ACE inhibitors and ARBs do?
block production or function of Angiotensin II. – so also block the production of aldosterone and ADH
when aldosterone causes retention of sodium, why is a proportional amount of water retained also by the kidneys?
in order not to increase plasma osmolality beyond the normal 280-290 mOsm/Lt
T/F When the kids secrete renin and create the whole Angio II- aldosterone-ADH cascade, the rest of the body is not affected
F- they do it to serve themselves but it affects are systemic
T/F kidneys eliminate volatile acid
T/F lungs eliminate volatile acid
T/F H2CO3 is a volatile acid
T/F H3SO4 and H2PO4 are nonvolatile acids
What happens when the lungs get rid of CO2
it forces the recombnination of H+ and HCO3-, forming H2CO3 again.
H2O + CO2 yields what
H2CO3 --> H+ + HCO3
What is the net result of nonvolatile acids in daily metabolism?
1mEq H+/kg of body weight/day (50-100mEq/day)
Where does SO4 come from?
amino acid side chains- metabolism from our daily diet produces H2SO4
What would happen if the kidneys could not eliminate this nonvolatile acid?
[H+] would increase 60,000 times to .0024M (a pH of 1-2)
what is normal tissue pH and H+ concentratiom?
7.4 or .00000004M
What do the kids do if plasma/body pH decreases?
inc's H+ secretion/excretion, inc reabsorption of bicarbonate, and inc creation of new bicarbonate
What do the Na/H antiporters do?
secrete H+ into tubular fluid and reabsorb Na+
T/F this is a uni-directional exchange
F- bidirectional
Where are the Na/H antiporters located?
proximal tubule
where are the intercalated cells located
in the collecting duct
what are intercalated cells
a type of tubular epithelial cell
What lies on either side of the intercalated cells?
interstitium and tubular lumen
What type of pump is located in the intercalated cells?
proton pump
What does the proton pump do?
pumps H+ ions up their gradient (from interstitium to tubular fluid)
How high can the urinary concentration of H+ be before the pump fails?
1000 times normal (3 pH units)
What else is necessary for the pump to work?
a buffer in the tubular fluid
What are examples of buffers in this case?
NH3 and HPO4-

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