Muster Week 2 Flashcards
Filtered substances can be ____ or ____
REABSORBED or SECRETED as needed to maintian homeostasis
Amount filtrate into nephron PT
125 mL/min
SECRETION
peri-tubular capillary to lumen
REABSORPTION
lumen to peri-tubular capillary
proximal tubule is made of…
proximal tubule cell SINGLE CELL LAYER (but still cell membrane)
____ of all the filtered solute and water are reabsorbed within the proximal tubule!
2/3
goes in at 300 mosmol –> leaves as 300 mosomols = ISO-OSMOTIC
“literally sucking up what just put into it”
Mechanisms to move substances
- diffusion (generally down a gradient)
- channels
- transports (uniporters/multiporters) (active, 1* or 2*)
Primary active transport requres ______
ATPase, energy
Secondary active transport
one of solutes moves down EM/conc gradient, which drives other
“drag other along for the ride”
stoichiometry drives _____
charge difference
basolater Na/K transporter is ________ transport
ACTIVE transport
requires energy
ONLY ON BASOLATERAL (serosal, anti-luminal, blood side)
luminal Na+ channel is
PASSIVE
What is K+ doing?
RECYCLING
allows pump to keep moving/working
Na-glucose trnasporters are also known as…
SGLT (sodium-glucose linked transporters) in two flavors, 1 and 2
***90% of glucose reabsorbed in PT occurs via SGLT 2 (1:1)
2* active transport is regulated by:
- increased CO2
- increased angiotension II
- increased SNS drive
- decreased pH
= ACIDOSIS
Na/H pump responds directly to ______
acidosis
_____% of glucose is brought across at luminal border by _____
100% of glucose is brought across luinal border by SGLT 2 = NO GLUCOSE IN URINE
___, ___, and ___ are all being pumped UP their EM gradient
glucose, a.a.s, phosphorus pumped UP EM gradient by 2* ACTIVE TRANSPORT
- all facilitated by Na* transport (symporters)
High Na+ in interstitium drives _____
Na+ concentration gradient into peritubular capillaries
transport maximum (Tm)
Na+/glucose transporter saturation point…additional glucose will NOT be able to be reabsorbed and will REMAIN IN URINE
~15mM glucose
glucosuria
when Tm (or glu in urine?) reaches about 15mM = ABNORMAL
not a test for DM
Why isn’t glucosuria test for DM?
Becuase Tm is transport mediated, so could have totally normal serum [glu] but glu in urine = SOMETHING IS WRONG WITH TRANSPORTER IN PT (not just high glu everywhere)
osmotic diuresis
Na/glu transporter has reached Tm –> excrete rest of glu out –> H20 follows –> osmotic diuresis
Cl- transport, think
Cl- recycling
formate recycling
“that’s just the way Cl- is handled” it is recycled using FORMATE = FORMATE ANTIPORTERS = formate is recycling too
and PARACELLULAR TRANSPORT through tight junctions
late section of PT
- formate anti-porters
- favorable concentration gradient of Cl- for transcellular movement
- EM gradient allowing some para-cellular movement of sodium as well
CA is present two places
- brush border
2. in cell
HCO3- transport
1 DESTROYED: 1 RECLAIMED (put back in blood)
= BICARBONATE REABSORPTION/RECLAMATION
bicarb is created and put back into the blood stream
CA
CO2 + H20 –> H2CO3 –> HCO3- + H+
= makes bicarb and protons
the reaction occurs without carbonic anhydrase (CA) but CA cranks it up 100x
Na/HCO3- symporter
on capillary bed side –> 3 HCO3-: 1 Na+ BOTH GOING OUT
= puts bicarbonate back in blood
If PT defect…
see in urine:
- BICARB (ACIDOTIC)
- PHOSPHOROUS can’t be reclaimed
- VITAMIN D also
H20 transport in PT
- diffusion (minor player)
- aquaporins
- paracellular transport
*for all solute reabsorbing, water follows –> no change in osmolality
ATN
ACUTE TUBULAR NECROSIS
- damage to PTs –> Na+, Cl-, bicarb, glu = everything in pee that PT isn’t taking up
- see casts
As fluid leaves the glomerulus –> slight increase in oncotic pressure (filtration of solute and water)
slight increase in oncotic pressure (filtration of solute and water)
hydrostatic pressure within capillary drops due to
resistance
Net filtration pressure of capillary uptake
forces of filtration - forces of reabsorption
(P pc + PI i) - (P i - PI pc)
(20 + 6) - (33 + 3) = -10mmHg
NEGATIVE 10mmHg = OPPOSITE OF FILTRATION = REABSORPTION
____% of Na, Cl, H20, reabsorbed by end of PT
66%
____% glucose reabsorbed by end of PT
100%
____% HCO3 reabsorbed by end of PT
80%
Why need to filter 180L/day?
We are putting toxic waste metabolites into urine, NEED THIS COPING MECHANISM TO RID TOXINS
(otherwise would be very pointless and excessive)
Not all substances filtered have channels or transports, so they must either:
diffuse across cell membrane OR be excreted
Polar substances
have CHARGE
Non-polar substances
have NO charge
Polar substances’ fate
no transporter/channel/diffusion –> trapped in lumen –> “PEE OR POOP IT OUT, THAT’S IT!”
Non-polar substances’ fate
Non-polar CAN diffuse across cell membrane –> reabsorption
Ex: O2, steroid hormones, CO2, cholesterol
If given a toxic substance, would you want it to be polar or non-polar?
You would want it to be POLAR SO CAN EXCRETE IN URINE/POOP
Liver transformation is…
give dursg that are non-polar –> liver –> cyp450 –> polarized drug –> can excrete
If interaction to CYP450…have to do what to dosing?
Interaction with CYP450 –> decreased ability –> decrease dosing
WOA and WOB are both:
secreted AND reabsorbed
WOA and WOB we WANT to keep
monocarboxylic acids: pyruvate, ketone bodies, lactate
Keep WOA and WOB by…
adding carboxylate to them –> kidney recognizes carboxylic group –> allows to attach to transporter –> gets into cell –> pumped out
***this pump can become saturated, HAS A TM
OAT and OCT
organic anion transporter
organic cation transporter
*DEPENENT ON BOUND TO ALBUMIN
active transport
WOA and WOB transport into lumen…
facilitated diffusion
WOA and WOB into cell from blood…
active transport (OAT and OCT)
WOA and WOB (as MCA’s) into cell…
Na+/MCAs symporter
MCA’s back into capillary…
MCA transporter
orthostatic hypotension is a sign of ________
volume depletion
Key functions of Loop of Henle
- reabsorbs 25% of filtered sodium
(add to 66% Na reabsorbed in PT) - Na is reabsorbed IN EXCESS of water = JUST THE SOLUTE = INCREASES [H20]
–> allows for the excretion of urine with osmolality that is DIFFERENT than plasma
Parts of nephron NOT permeable to H20
Thin and thick ascending limbs of Loop of Henle, distal tubule
NO AQUAPORINS
PT mOsms
deep medullary space mOsms
end of thick ascending limb mOsms
PT: 300 mOsms Deep medullary space: 1400 mOsms (huge draw for H20 out of the tubule) (bottom of loop) End of thick ascending loop: 100 mOsms (ascending not permable to H20, but Na+/K+/CL- pump) (top of loop)
Thick ascending limb
channels set up nice gradient
- Na/K/2Cl carrier!
Important functions of Na/K/2Cl carrier:
- reabsorbs 20% of filtered Na!
(add to 66% from PT, 25 from loop of henle!) - all sites MUST be occupied
- Na+ reabsorption is NOT linked to organic solutes (glucose, phosphorous)
- affinity for Na+ and K+ is VERY HIGH –> Cl- is RATE LIMITING
Na/K/2Cl blocker
Lasix (furosemide)
Lasix indicated for
CHF
NaCl retensive patients
-give along with low Na+ diet so can affect this 25% reabsorption and make a difference
Na/K/2Cl transporter mutation
Bartter syndrome
- 25% more Na, K, and 2Cl are hitting urine than should
- genetic mutation
Bartter syndrome
- 25% more Na, K, and 2Cl are hitting urine than should
- genetic mutation
- present EARLY IN LIFE
- growth retardation
- mental retardation
- VOLUME DEPLETION with LOW BP
- HYPOkalemia
- METABOLIC ALKALOSIS
- normal or elevated urinary calcium excretion
Why get elevated urinary calcium excretion in Bartter syndrome?
paracellular Ca2+ transport can only work in Na/K/2Cl pump works
Distal tubule key features
- reabsorbes about 5% of filtered sodium
(add to 66% in PT, 25 in loop of henle, 20% in ascending limb!) by NA-CL PUMP - tubular reabosroption of Na+ varies with Na+ delivery (limited if don’t have enough Na+)
- iMPERMEABLE TO WATER so contributes to URINARY DILUTION
- contribues to calcium reabsorption
NaCl transporter mutation
Gitleman syndrome
*better than mutation in Na/K/2Cl transporter because this one only takes care of 5% more Na+ reabsorption
Gitleman syndrome
- genetic mutation in NaCl transporter
- normal BP
- METABOLIC ALKALOSIS
- HYPOcalciuria
- HYPOmagnesemia
- HYPOkalemia
Na/Cl transporter blocker
hydrocholorothiazide
*will improve HTN but not to same degree as Lasix
Can manipulate kidney Na+ reabsorption for HTN tx because
Na+ = BV = BP
PIVOTAL
The collecting duct key features:
- variable sodium reabsorption
* **FIRST AREA that is DIRECTLY CONTROLLED to DETERMINE URINARY ELECTROLYTE CONCENTRATION - principal cell: BIG KAHUNA BURGER
- intecalated cell
primary role principal cell
BIG KAHUNA BURGER
- contributes to Na, Cl, and K reabsorption/excretion
- ENaC (epithelial Na+ channel)
- RMPK (renal outer medullary K+ channel)
primary role intercalated cell
- H+, HCO3-, and K+ reabsorption/excretion
Of filtered load of Na+, ____% is controlled
5%
If reabsorb 4.9% of controlled amount filtered load of Na+, excrete:
excrete 0.1% of filtered load = 1g Na+ (25mM)
If reabsorb 0% of controlled amount filtered load of Na+, excrete:
excrete 5% of filtered load = 50g Na+ (1250mM)
Primary mechanism of controlling salt reabsoption (that 5%) (and K+ secretion) in principal cells is via…
the hormone ALDOSTERONE
Primary regulator of this secretion of aldosterone is…
angiotensin I and ultimately, angiotensin II
RAAS SYSTEM
RENIN –> ANGIOTENSIN I –> ANGIOTENSIN II –> ALDOSTERONE
and ADH
3 primary physiologic signaling pathways that stimulate renin release:
- SNS (NE)
- decreased stretch in afferent arteriole
- decreased Cl- delivery to macula densa
Renin release stimulated by these clinical manifestations:
- hypovolemia
- low Na diet
- low body NaCl
- anything that causes high SNS
Primary actions of angiotensin II
- ULTIMATELY stimulates ALDOSTERONE
- systemic vasconstricotr
- stimulates PT reabsorption of Na+
- increases SNS
Aldosterone and principal cell key points:
- aldosterone stimulated by angiotensin II
- lipophilic so FREELY crosses cell membrane
- binds to intracellular Rec –> ultimately INCREASES TX OF CELLULAR PROTEINS
- proteins INCREASE ACTIVITY or NUMBER of both the luminal Na+channel ENAC and Kchannel ROMK and basolateral Na/K/ATPase
*renin responding to low Na+ state –> aldosterone –> more doorways –> reabsorbs as much Na+ as possible
aldosterone causes
- increased Na- reabsoprtion
- K secretion
aldosterone stimulus for release
- low Na+ states
- high K+ states
K+ sparing diuretics:
- amiloride
2. triamterene
disease of upregulation of ENaC
Little’s syndrome
- ENaC always on –> ramp up insertion when stimulated by aldo –> reabsorbing Na+ soo much –> no response to aldo any longer
- present: Na+ sensitive HTN
FENa
excreted / filtered x 100
clearance
excretion rate / plasma concentration
Cr cl in ____ Na+
high Na+
= trying to clear
NaCl = ____
volume
water follows
GFR (creatinine clearance) varies with salt intake:
high salt –> increased filtered load of Na+ –> increased Na+ excretion
aldosterone is stimulated by ___ salt stores
low salt stores
high salt –> reduced aldo –> fewer ENaC channels to reabsorb Na+ –> Na+ excretion increases
PT, Na+/H+ antiporter is regulated by RAAS:
high salt –> reduced renin –> reduced Na+ reabsorption –> Na+ excretion increases
Two primary functions of K+
- cell metabolism (protein and glycogen synthesis)
- (ratio of intracellular/extracellar potassium) PRIMARY DETERMINANT OF RMP (ie the necessary state for generation of APs)
___% of K+ is stored intracellularly
98%
key regulators of immediate/short term extracellular K+
- insulin (activate Na/K ATPase, promotes SKmus uptake)
2. catecholamines (beta-2 receptors stimulate Na/K ATPase)
cell and channels that facilitate renal excretion of K+
PRINCIPAL CELL Na/K ATPase pump ROMK channels (K+) ENaC channel (Na+) BK channel (K+)
location of K+ reabsorption and contribution of each tubular segment
PT: 55-67% via tight junctions
thick ascending limb/loop of henle: 25%
principal cell in distal tubule: 10%
alpha-intercalated cell in collecting: 10% (actively reabsorbed)
location of Ca++ reabsorption and contribution of each tubular segment
PT: 65% paracellular across tight junctions
thick ascending limb/loop of henle: 20-25% paracellular
distal tubule: 10% transcellular
actions of hormones that stimulate K and Ca secretion
ALDOSTERONE
- increases activity of Na/K ATPase pump
- increases presence of ROMK channel
- occurs in normal or mildly elevated K+ (directly)
PTH
- directly release Ca++ from bones
- increase from kidneys
- activates increased absorption of Ca++ in gut
***increased angiotensin II activates increase in aldo
clinical stimuli of hormones that stimulate K and Ca
HIGH K+ STATES/DIET: aldo secreted, also BK channels open (two channels facilitating excretion of K)
LOW K+ DIETS: limited stimulation of aldo, no activity of BK channel, limited/decreased presence ROMK
actions of PTH on bone
a. DIRECTLY stimulates immediate release of stored skeletal Ca++ ==> increase serum [Ca++]
b. stimulates bone reabsorption (preserve trabecular bone at expense of cortical bone)
* this DIRECTLY releases PO4- as well as Ca++
actions of PTH on kidney
a. increased production of ACTIVATED VIT D
* this increases gut reabsorption of Ca++
b. increases Ca++ reabsoprtion
c. DECREASES renal PO4- absorption (INCREASES EXCRETION/SECRETION PO4-) –> activates make more vit D
actions of PTH on intestines
a. increased activated VIT D from kidney –> ULTIMATELY increases gut reabsorption of Ca++
cellular mech of Ca++ reabsorption
- activated PTH
- stimulates more Ca channels to open (from lumen)
- Ca++ NEEDS TO BIND TO CALBINDIN
- Ca++ through calcium ATPASE
difference between ROMK and BK channels
ROMK: ALDO increases presence RMOK
*inhibited by Mg++
BK: always there, not usually open
**ONLY OPEN WHEN HAVE LOTS K+ THAT NEEDS TO GET OUT (high K+ states = diets)
clinical situation when ROMK channels present
volume depleted
–> ang II –> aldo –> ROMK –> K out to lumen
clinical situation when BK channels present
d
***BK channels NOT present: low K+ diets
clinical presentations/dz when all intracell K suddenly released
- digitalis OD
- rhabdomyalisis (breaks down SK muscle, which holds K+_ –> release K
- crushed SK muscle
- femoral clot –> opened –> K+ flooded = REPERFUSION = hyperkalemia –> renal failure
control K by:
- distributing between spaces (hiding it)
2. control excretion
factors that regulate the Na/K ATPase pump
- insulin (eat –> increase insulin –> activate pump –> increase K in)
- catecholamines
- plasma K
- exercise –> sudden increase K released from myocytes
- cell breakdown
- chronic diseases
other factors that regulate K in short term
- plasma concentration: cellular uptake increased when serum K is up
- exercise: myocytes release K during exercise
- pH: increase in systemic H+ (metabolic acidosis) –> H+ into cells –> K+ out –> hyperkalemia
sequelae of active reabsorption of K+ in alpha intercalated cell
- K+ is exchanged for H+ ====> free floating H+ in lumen = ACIDIC PEE
- lots of H+ must be processed reabsorb K+
- also requires the reabsorption of bicarb!
= hard work to reclaim K+, has a price (acidic urine, increased HCO3-)
___% of all Ca++ bound to _____
40% of all Ca++ is bound to ALBUMIN
___% of Ca++ is bound to other stuff
10% (like phosphate, citrate)
___% of Ca++ is available as ionized Ca++ (free calcium) (unbound)
50%
- this is the amount Ca++ (free calcium) body is trying to manage
- PTH responds to free calcium, not total body calcium
You eat _ mM calcium a day, but only absorb ___ mM
eat 20mM a day, only absorb 4mM
risk factors for calcium oxalate stone formation
- high salt diet
- maybe calcium supplements
- reducing dietary calcium can increase stone formation…
reduced iCa++ stimulates production of…
PTH
primary hyperparathyroidism
increase in PTH = ROUGE PTH always on (separate from sensing Ca++) - trashes bone --> increase Ca++ release - increased PO4- excretion --> decreased [PO4-] - increased gut absorption - increased vit D - serum [Ca++] high
other reasons have increased Ca++, decreased PO4-, but normal/unchanged PTH
- cancer (mimics PTH)
- granulomatous disease (converts + vit D –> so much calcium with elevated vit D) (eg sarcoidosis)
