Gargus Flashcards
1
Q
1 L of water weighs?
A
1 kg
2
Q
Intracellular fluid contains how much of body fluid?
A
2/3 (largest component) Contained within the cell membrane
3
Q
Extracellular fluid contains how much of body fluid?
A
1/3
4
Q
Interititial fluid is how much of extracellular fluid?
A
3/4 Surrounds the cells but doesn’t circulate
5
Q
Intravascular fluid makes up how much of extracellular fluid?
A
1/4 Circulates as the extracelluar component of blood Contained by the capillary endothelium
6
Q
How do we measure volumes?
A
To measure fluid volumes, one needs markers that are confined, not degraded, evenly distributed & non-toxic Goal: put in a known amount, let distribute & measure the concentration to determine original volume Volume = amount/concentration
7
Q
Compartment volumes are determined by?
A
There are no barriers to water (there is never an osmotic gradient) & water moves in response to osmoles (the amount of a substance that dissociates in solution to form one mole of osmotically active particles) Quantity of osmotically active solute in a given compartment that determines its volume Wherever these are trapped, water flows; osmolarity is the same everywhere
8
Q
What is macroscopic electroneutrality?
A
Every compartment has macroscopic electroneutrality “ same number of anions (-) & cations (+)
9
Q
What determines ECF? How? What happens when increased?
A
Na+ determines ECF (balanced by Cl- & HCO3 -) & is excluded from cells by Na-K ATPase If a person eats salt without water, NaCl will be added to the ECF, increasing osmotic pressure & water will flow from the ICF to the ECF to balance
10
Q
What determines the ICF? How?
A
K+ determines the ICF (balanced by proteins) & is brought into the cells by the Na-K ATPase
11
Q
What determines the intravascular space fluid level?
A
Proteins determine the intravascular space
12
Q
What are Donnan effects?
A
Not all compartments have the same number of osmoles; some molecules that can’t cross the membrane are trapped (e.g. proteins) and thus a lot more permeant ions are also trapped
13
Q
Describe what happens with a polyvalent molecule trapped on one side of a membrane
A
At time infinity there’s always more permeable stuff where the macromolecule is (more osmoles) & thus also more water as a result
14
Q
What neutralizes polyvalent molecules?
A
protein (polyvalent anion) always associated with Na+ (charge neutralize); so Na+ always goes with it
15
Q
Where are Donnan effects most pronounced?
A
Interstitial < plasma < intracellular
16
Q
A 10 fold gradient of monovalent ion generates?
A
60 mV
17
Q
Why doesn’t a cell pop even though it has so much protein and DNA?
A
Pumps keep Na out of the cell
18
Q
How do we measure total body water?
A
Measure: drink D2O (heavy water) & blood sample, but messy since D2O is lost in sweat, expiration, etc. Easier to use daily weights to follow & see if a patient is tucking water away into another compartment
19
Q
How do we measure ECF?
A
Measure: provide a loading dose of inulin (inert, freely filtered & rapidly excreted), then adjust the infusion by fiddling with the IV to obtain a steady-state concentration (same amount in & out; determined by drawing samples & seeing if the concentrations are changing), then stop the infusion & begin to save urine; the total amount of inulin voided in the urine filled the ESF at steady-state
20
Q
How is plasma volume measured?
A
can be measured by tagging albumin (131-I) or RBC (51-Cr) because these are trapped in the vascular space
21
Q
Describe how we determine interstitial volume?
A
ISV=ECF-plasma volume
22
Q
Intracellular volume is determined by?
A
ICV=TBW-ECF
23
Q
Describe the units of solutes (weight, charge, osmolarity)
A
Units: each solute has a MW, eq/mol (# of charged components after dissociation) & osmol/mol (# of molecules) i.e. NaCl has a MW of Na+Cl, 2 eq/mol because it dissociates into 2 charged particles & osmol/mol of 2 i.e. Ca2+ has 2 eq/mol becuase it carries two charges but it is only 1 osmol/mol because just one molecule
24
Q
What is plasma osmolarity?
A
Number of particles per aqueous volume
25
Na+ yields what osmolarity?
1 meq/L yields 2 mosm/L because wherever there is Na there's an anion
26
Glucose yields what mosm?
mosm\_glu = mg/dl glucose / 18
27
BUN yields what mosm?
mosm\_BUN = mg/dl BUN / 2.8
28
P\_osm is calculated by?
P\_osm = 2 \* P\_Na + Pglu/18 + PBUN/2.8
29
What is effective osmolarity?
urea equilibrates across membranes & water equilibrates with all effective osmoles So Effective osmolarity = 2 \*(body Na + K)/TBW TBW=total body water or ~2PNa + Pglu/18
30
What to remember when giving IV fluids and thinking about fluid loses?
! Mentally always +/- solute & water sequentially ! Decide what compartment retains/loses solute ! Remember the water MUST move ! Remember no osmotic gradients ! We dont give IV water (use D5W) ! Don't give IV isotonic KCL (think twice about IV K+)
31
Infuse isomotic NaCl, response?
increase only the volume of ECF, equally between intersitial and intravascular (wont affect ICF)
32
Infuse hyperosmotic NaCl, response?
Increase ECF (equally between intersitial and intravascular), decrease ICF
33
Infuse hypoosmotic NaCl, response?
Increase all compartments
34
What is ECF? How is maintained?
ECF (1/3 TBW): nutrients/wastes pass into/out of cells & steady state volume is maintained by the kidneys
35
What are the 4 primary renal functions?
1) H2O & electrolyte balance " by varying rate of excretion of H2O/ions; controlled by negative feedback 2) Excretion of metabolic waste (i.e. urea, uric acid, creatinine, bili, hormones, drugs) " urine 3) Endocrine (renin [blood pressure], EPO, vit D metabolism) 4) Gluconeogenesis
36
Describe renal blood flow. Percent filtered?
Renal blood flow is 20% of the cardiac output; 20% of that gets filtered & 1 mL/min remains in the tubule (urine)
37
Describe renal circulation.
Renal circulation is a portal system (2 capillary beds in series) 1st capillary segment (Glomerulus) " Inc hydrostatic pressure due to geometry of renal artery (off aorta) & interposed between arterioles with muscles; envision pin prick in a hose & squeezing on either side)] 2nd capillary segment (Peritubular capillaries) " high flow & low pressure
38
What drives the glomerular filtration rate?
Glomerular Filtration Rate (GFR) is driven by the Starling forces (hydrostatic & oncotic pressures) operating across the capillary wall
39
What is the ultrafiltration pressure?
Puf = Delta P - Delta Pi where Puf = ultrafiltration pressure, P =hydrostatic pressure (BP) and pi = oncotic forces
40
What is the result of glomerular filtration?
a protein-free filtrate of plasma exciting the blood of the glomerular capillary into Bowman's space
41
What is the glomerular filtration rate? How is it estimated?
Filtration occurs at 125 mL/min which is a huge amount over a day (estimated by Cin or Ccr)
42
What is renal plasma flow?
Renal plasma flow (RPF) = RBF (1-hct) where RBF= renal blood flow & hct = hematocrit (estimated by Cpah)
43
What is the filtration fraction?
FF=GFR/RPF fraction of RPF that normally gets filtered (estimated Cin/Cpah) [typically 0.2]
44
What is the filter of the kidney composed of?
Capillary endothelium and kidney tubule endothelium
45
What are podocytes?
contain interdigitated processes that coat the glomerular capillary bed
46
What is tubular transport?
most filtrate reabsorbed, all metabolites (ex glu) reabsorbed; some wastes entirely secreted
47
Inulin and creatine are...
are filtered & not transported; thus, 20% is the filtration fraction
48
PAH is...
completely secreted & 100% is cleared
49
What is the significance of "don't stand in the urine"?
imagine yourself in the blood & resorption/secretion is relative to where you are
50
What is resorption?
moves out from tubule to plasma (primarily occurs in the proximal tubule)
51
TF/P changes as you progress along...?
TF/P (tubular fluid/plasma) changes as you progress along the proximal tubule
52
Glucose/AA/Bicarb do what as you move along the proximal tubule?
Drop to zero
53
What is secretion?
Moves in from plasma to tubule
54
Describe the anatomy of a nephron
Glomerulus (capillary bed 1) ! Proximal convoluted tubule (70% isotonicly resorbed) ! Loop of Henle (thick & thin) (20% resorbed, single effect) ! Distal convoluted tubule ! Collecting duct (10% resorbed, regulated) ! While there are 1 million nephons per kidney & there are 2 kidneys, we'll focus on single nephron
55
What is clearance?
Clearance is a ratio that is descriptive of the kidney excretion mechanisms
56
What is the exact definition of clearance?
the volume of plasma COMPLETLEY cleared of a constituent to YIELD the amount that is found in
the urine in a unit time
Clearance (ml/min) = rate of excretion (mmol/min) / plasma concentration (mmol/ml)
Note units are volume/time and never an amount or concentration
57
How do we calculate the rate of substance Z excreted?
Rate of substance Z excreted (mmol/min) = concentration of Z in the urine (mmol/ml) x urine flow rate (ml/min)
58
How do we calculate rate of substance z extracted?
Q\_z (extracted) = Plasma concentration \* Clearance of Z
59
If excretion is equal to extraction, what derivation do we have?
Clearance of Z = Concentration of Z in urine \* Urine flow rate / Plasma concentration of Z
60
What can be used to estimate GFR?
Clearance of inulin or creatining (Cin or Ccr)
Cin=CCr=GFR
61
What is the formula for GFR using inulin or creatinine in urine
GFR=Concentration of urine inulin \* Urine flow rate / Plasma inulin concetration = Cin = Ccr
62
Why can inulin be used to estimate GFR?
it freely crosses membranes but never enters cells
Small (freely filtered), not bound to proteins, nontoxic & not metabolized, easily measured,
contributes little to osmolality & is unable to pass in/out of the tubule by active or passive transport
Inulin is also NOT endogenous, must be loaded into patient
63
Why can creatinine be used to measure GFR?
It is a compound steadily made & eliminated only be filtration
64
What can clearance of PAH be used to estimate?
ERPF (effective renal plasma flow)
65
Describe the filtration of PAH
PAH filters freely & is secreted by the tubule; at low concentrations, secretion rate may be high enough to
eliminate ALL PAH in a single renal passage (note: PAH must be preloaded)
!
Since the amount of PAH that reaches the kidneys per unit time is almost totally excreted, it was contained
in almost all of the plasma that flows through the kidneys per unit time
66
ERPF is equal to?
Clearance of PAH
Note that RBF = RPF / (1-Hct)
67
Describe the clearance rate of PAH as a function of plasma concentration
slope is maximal at low PAH; as it rises, the slope
decreases & eventually approaches that of inulin because
secretion transport system becomes saturated
68
Describe the clearance rate of inulin as function of plasma concentration
the slope is constant & equal to its clearance
69
What is active resorption?
```
Active resorption (i.e. glucose) means that none is cleared
(clearance is zero) because you resorb 100%
```
70
Describe concentration of inulin in plasma as compared to urine
Concentration of inulin in the urine differs from the concentration in the plasma only because some of the water has
been resorbed; thus, water resorption can be estimated from the ratio
71
The fraction of filtered water present in urine is calculated by?
Plasma concentration of inulin / Urine concentration of inulin
72
The fraction of filtered water resorbed is calculated as?
1 - (Concentration of inulin in plasma / concentration of inulin in urine)
73
What is Tm?
Tm = tubular transport mechanism = maximum rate of tubular transport (varies for different solutes)
analogous to glucose E renal tubules can reabsorb glucose until a maximum rate is reached, above
which glucose is spilled in the urine
74
What is fractional excretion?
can tell whether something will be secreted, resorbed or filtered only
75
Cx/Cin = 1 means?
The substance will only be filtered
76
Cx/Cin \<1 means?
The substance X is resorbed
77
Cx/Cin \>1 means?
The substance X is secreted
78
Clearance ratio is measured how?
Clearance ratio can be obtained just by measuring the concentrations of inulin & solute in question in
plasma & urine; you do not need timed urine
Cx/Cin = (Ux/Px)/(Uin/Pin)
79
Fractional excretion of Na or Cl helps?
helps deconvolute regulation of urine volume from regulation of urine Na
80
Fractional excretion of urea and creatinine helps?
as GRF decreases, FE Urea decreases & FE Creatinine increases
! Normal BUN/Cr = 20; when BUN/Cr \> 40 it indicates hypovolemia (pre-renal azotemia)
81
What happens if one kidney is removed to the GFR and Pcr?
If 1 kidney is removed, the ! the GFR will contain the same amount but in ! the volume so the plasma
concentration will double (If GFR is halved, Pcr doubles)
82
What is the percent water composition for adult male and female as well as baby?
Male = 60%
Female = 50%
Baby = 75%
83
How does hyperlipidemia affect plasma sodium levels?
Machine sampling assumes that the plasma volume is water. If lots of fat, then the sodium level is much lower because water is less (replaced with fat)
84
How much of total CO goes to kidney? How much is filtered by the glomerulus?
1/5 of CO 1.1 L/min
1/5 of plasma is filtered
(625 mL/min to 500 mL/min so 125 ml/min is filtered)
85
How much of the glomerular filtered fluid is resorbed in the peritubular capilaries?
About 124/125 ml/min
1 mL per minute to urine
86
How many times is the ECF filtered daily?
15 times!
125/min leading to 180 L/d (this is equal to the clearance of inulin or creatnine)
87
What is the approximate renal plasma flow?
RPF=RBF (1-hct) = 1100 ml/min \* 0.57 = 625 mL/min
~Clearance of PAH
88
The filtration fraction is what approximately?
FF = GFR/RPF = 125/625 = 0.2 ~ Cin/Cpah
89
Describe the flow of fluid into the nephron
From artery through afferent arteriole through glomerular capillary then through the efferent arteriole then through the peritubuilar capillary and to vein
Resorbtion and Secretion happen at the Tubule (Tubule leads to urine excretion)
90
Describe the filtered amount and resorbed amount of:
Water
Sodium
Chloride
Potassium
Bicarb
Glucose
Urea
Water 180 L/d 99%
Sodium 630 g/day 99.5%
Chloride 680 g/day 99.5%
Potassium 28 g/day 94%
Bicarb 274 g/day 100%
Glucose 180 g/day 100%
Urea 56 g/day 50 %
91
As you move down the proximal tubule, what happens to inulin concentration?
Goes up because water is being filtered
92
Describe the anatomy of a nephron and the functions of each component
Glomerlus - initial capilary bed
Proximal convoluted tubule - 70% isotonic resorbiton
Loop of Henle (thin and thick) - 20% resorption, single effect (concentrated urine)
Distal convoluted tubule
Collection duct - 10% resorbed, regulated, lg gd
93
How many nephrons per kidney?
1 million
94
What happens at the macula densa?
Kiss back to the glomerulus. Separates the thick ascending limb of loop of henle and the distal convoluted tubule
95
Blood enters the glomerulus through? Exits through?
Enters through afferent arteriole
Exits via the efferent arteriole
96
What do both efferent and afferent arterioles have?
Contratile walls
97
What is a capillary tuft?
Between the renal arterioles is the capillary tuft with an usual water permeability
Hydraulic permeability 50-100x that of peripheral capillaries
98
What are mesangial cells? What is function?
Within the capillary loops & between capillaries are mesangial cells that provide structural support, act as
phagocytes (remove macromolecules that get stuck in the filter) & contain contractile myofilaments that respond to
signals by balling up the glomerular tuft & reducing the filtration area
99
The glomerular capillary tuft extends into?
Bowman's space (lumen of Bowman's capsule)
100
Bowman's space is continous with?
The proximal tubule
101
What covers the capillaries in the kidney glomerulus?
Podocytes which have tenticle processes konwn as pedicels which interdigitate with other neighboring podocytes
102
Where is the basement membrane of the glomerulus found?
Between the fenestrated membrane and the podocytes
103
Fundtion of capillary fenestrated endothelium?
Course pre-filter for cells
104
The function of the basement membrane in glomerulus?
Coarse filter that keeps junk away
105
Function of epithelial slit pores of podocytes?
true filter with anionic proteoglycans on the
surface; limits by size & charge (remember most important proteins are polyvalent
anions)
106
Small molecules are classifed as? how do they filter?
\<18 A, like inulin
Freely filter
107
What are large molecules classified as? Do they filter?
\>44 A, like globulins
Completely impermeant
108
Describe intermediate size molecule filtering
18 A
Have intermediate permeability Cx
Greater size = less permeable
109
Describe the relative filtering of cations, neutral molecules, and anions
Cations\>Neutral\>Anions
110
Describe the general characteristics of glomerular capillaries
high H2O permeability, low protein permeability & constant high hydrostatic pressure
111
What drives filtration?
hydrostatic pressure & osmotic pressure working together
112
What is the equation for stariling forcces?
F = Kf[(Pgc-Pt)-pi\*(gc t)]
Pgc = hydrostatic pressure in the glomerular capillary, constant & high; favors filtration
Pt = hydrostatic pressure in the tubule,constant & low; favors resorption
Pi\*gc=oncotic pressure in the glomerular capillary, increases as the protein
concentration rises while filtrate is forced through the capillary walls; favors resorption
NOTE THIS IS THE ONLY FORCE THAT CHANGES
!pi\*t = oncotic pressure in tubule, negligible
113
Describe the effect of hydrostatic pressure in the glomerular capillary
Constant and high, favors filtration
114
Describe the effect of hydrostatic pressure in the tubule
Constant and low, favors GFR
115
Describe oncotic pressure in the glomerular capillary
Increases as the protein concnetration rises while the filtrate is forced through the capillary walls
Favors resorption
This is the only force that changes really
116
Describe oncotic pressure in the tubule
Negligable
117
When hydrostatic pressure = oncotic pressure what happens?
There's filtration arrest
118
What is the single nephron GFR?
SNGFR=Kf\*(deltaP-pi\_gc)
119
Changes in Pgc effect GFR how?
key regulation by changing the resistance of afferent/efferent arterioles
Increase Pgc, Increase GFR
120
Effect of RBF on GFR?
High flow and low increase in gc oncotic pressure leads to high GFR
121
Describe the interplay between GRF, RBF, and plasma oncotic presure
Plasma oncotic pressure has less time to rise as it rushes out of the glomerulus; thus, the average
change in oncotic pressure will be less, making the average filtration pressure more & GFR rises
122
Describe the distribution of renal blood flow
\>90% cortical
\<7% medullary
\<1% papillary
123
Where does the major pressure drop happen in the RBF?
At the efferent and afferent arterioles
124
How do changes in Kf affect GFR?
hormones can cause mesangial cells to contract d capillary SA available for filtration
125
Describe the relationship between GFR and plasma oncotic pressure
Plasma oncotic pressure is inversely related to GFR and changes in plasma oncotic pressure result from changes in protein metabolism outside the kidney (i.e. hypoproteinemia)
126
Describe the effect of change in plasma tubule hydrostatic pressure and GFR
increasing Pt decreases GFR; obstruction of the urinary tract will increase Pt
127
What is autoregulation of RBF?
RBF remains fairly constant as mean arterial blood pressure is altered over a wide range
128
Describe autoregulation
An intrinsic process composed of the myogenic reflex and the tubuloglomerular feedback
129
What is the myogenic reflext?
vascular smooth muscle contracts in response to stretch
130
Describe tubuloglomerular feedback
the tubule talks to the glomerulus & high flow [Cl] at the macula
densa produces constriction of afferent arteriole & decreased GFR
This prevents a run-away nephron spilling salt because decreases GFR
131
What is acute tubular necrosis?
renal blood flow stops (i.e. due to MI) then restarts and,
due to [NaCl], all nephrons constrict & blood flow stops; tubular cells die from ischemia
132
What is the key controller of kidney resistance to blood flow?
The afferent arteriole
133
Describe neurogenic control of RBF
Kidney is richly innervated by adrenergic fibers (NE) but there is no significant basal renal sympathetic tone
Increasing sympathetic activity REDUCES RBF (increases vascular resistance of both e and a arterioles)
Since GFR reduces more than RBF, filtration faction rises (or doesn't fall) FF=GFR/RPF
134
Describe effect of sympathetic, hypoprotinemia, or BP on the FF?
FF=GFR/RPF=Cin/Cpah
Increases with sympathetic increase or hypoproteinemia
Unchanged by BP
135
What is glomerulotublar balance?
Glomerular filtration and tubular reabsorption are linked
136
Describe Na resorbtion in the proximal tubule
PT resorbs a fixed percentage of the Na load presented
NOT a fixed amount and is INDEPENDENT of hormones/nerves
137
Do glomerular and peritubular capillaries communicate?
Si
138
Describe the balance of starling forces in glomerulotubular balance
Changes in the Starling forces in one capillary cause a reciprocal change in Starling forces in the other
Ex. Higher FF produces more Na in the tubule but also higher oncotic forces in the peritubular capillaries
139
Describe volume expansion in terms of glomerulotubular balance
Volume expansion leads to decreased efferent arteriole resistance which results in decrease in GFR and increase in RPF which leads to decrease in FF
Decreases oncotic and increases hydrostatic pressure entering the peritubular capillary
Thus fluid reuptake by the peritubular capillaries is decreased
140
Describe the effect of efferent arteriole constriction in terms of glomerulotubular balance
Efferent arteriole constricts (hypovolemic for example) leading to increased hydrostatic pressure in the glomerular capillary which leads to increased GFR and FF (decreased RPF)
Generates a larger load for the tubule. Peritubular hydrostatic pressure is decreased and the oncotic pressure of the pertibular capillary increases due to increased FF which favors resorption
141
Describe the epithelial layer of the tubules
sheets of cells (single layer in renal tubules) with 2 surfaces: Apical/luminal vs. basolateral/blood
142
Describe the boundary and coupling of epithelium in the tubules
Tight junctions define the boundary & cells are electrically coupled horizontally by gap junctions
143
Functions of the tubular epithelium
(1) Transport salts & nutrients (2) maintain gradients
144
Describe tight vs leaky epithelium for the tubules
Tight vs. Leaky Epithelia (depends on tight junctions)
Tight junctions that dont allow passage of water and ions is tight
Tight junctions that are very permeable to water/ions are leaky
145
Describe tight tubule epithelium
Distal tubule, collecting tubule
High gradients
High membrane potential (lumen negative 30-125 mV)
High resistance
Low salt/H20 permeability
NOT lanthanum premeable
146
Describe leaky tubular epithelium
Like proximal tubule
High flux
Low membrane potential (lumen positive or negative 5 mV)
Low resistance
High salt and water permeability
Tight junctions permeable to lanthanum
147
What are three passive transport mechanisms?
Diffusion, solvent drag, and facillitated diffusion
148
What is diffusion?
random molecular movement downhill (chemical or electrochemical gradient) via channels
149
What is solvent drag?
solute molecules being dragged/carried along with the flow of water (GFR)
150
Compare membrane potential for tight and leaky epithelium in tubule
Tight = lumen negative of 30-125 mV
Leaky = lumen positive or negative of 5 mV
151
What is facilitated diffusion? What is transported this way?
net movement down concentration gradient but requires a specific transport
proteins/carrier & thus exhibits specificity, saturability & substrate competition (Km, Vmax, M-M kinetics)
Ex. Urea, glucose
152
What are the two active transport mechanisms?
Primary active transport
Secondary active transport
153
What is primary active transport? Examples?
molecules transported against electrochemical gradient using energy from
hydrolysis of ATP (Ex. Na/K-ATPase, H-ATPase, H/K-ATPase, K-ATPase & Ca-ATPase)
154
What is secondary active transport?
coupled movement of 2 substrates; one substance is moving down its
chemical/electrochemical gradient & powers the transport of the other substance against its gradient; thus,
this process occurs without direct input of metabolic energy
155
What is cotransport?
A form of secondary active transport where movement of all substrates are in one direction
156
What is countertransport/antiport? Examples?
A type of secondary active trasnport where movement of substrates occurs in opposite directions
Ex. Na/K/Cl, Na/glu, Na/AA cotransporter, Na/H, Na/Ca antiport
157
What are the 5 common membrane properties of tubule epithelia?
1. Basolateral membrane with Na/K pump (extrudes 3 Na from the cell in exchange for 2 K+)
2. Electrical potential difference across the basolateral membrane is electrically negative (-60 mV)
3. Intracellular distribution of ions: increase K, decrease Na intracelluarly via pump, increase Cl in secretory or resorptive epithelia
4. Basolateral membrane is predominantly permeable to K; high PK determines the Em [resting membrane
potential] (low PNa & PCl [small permeabilities to Na & Cl])
!5. Apical membranes are specialized (no generalizations can be made)
158
What is the Ussing model?
model for transepithelial Na+ transport
159
Describe permeability of apical membrane versus the basolateral membrane in the Ussing model
Apical membrane is relatively permeable to Na+ & not K+ (high P\_NA) while the basolateral membrane is
relatively impermeable to Na+ but highly permeable to K+ (high P\_K)
160
Describe Na entrance and exit to cells in Ussing model?
Na+ enters the cell across the apical membrane down a net
electrochemical gradient (passive entry at apical face) & then
is extruded from the cell to the blood via a pump (pump at
basolateral face).
161
Extrusion of Na is linked to in the Ussing model?
This extrusion is linked to K+ uptake & this K+ leaves the cell
across the basolateral membrane producing a potential
difference
162
The lumen tubule is ... relative to the interstitum?
Negative
163
Apical and basolateral refers to what for tubule epithelium?
Apical is on the tubule and basolateral is bordering the intersititum
164
What is the Curran Double Membrane Model?
water movement without net driving force (i.e. osmotic gradient)
There are epithelia (like the proximal tubule) where there's no measureable osmotic gradient but which
reabsorb large volumes of fluid (isotonic uptake)
165
What is the reflection coefficient for the Curran double membrane model?
measure of the relative permeability of the membrane to solute using water as
the standard, varies from 0 (membrane is as permeable to the solute as to water) to 1 (impermeable)
Denoted by sigma
166
What is osmotic pressure in the curran double membrane model?
Denoted by pi and is between the left side of the left membrane and the middle of the membranes
Equal to sigma \* R\*T\*del\_Concentration
167
Describe the structure of the Curran Double Membrane Model?
Two membranes (1 & 2) with different sigma are in series
separated by a closed rigid compartment. Compartment
M has higher osmolarity than L
1. If osmotic pressure gradient (hydrostatic pressure due
to difference in solute concentration) is greater across
membrane 1 than 2, volume will flow from L to M
2. Since M is rigid, the initial volume flow will result in
hydrostatic pressure increase in compartment M
3. This hydrostatic pressure will be greater than the
osmotic pressure of the membrane with the lowest sigma and
less than the membrane with higher sigma
4. Hydrostatic pressure \> osmotic pressure against
membrane 2 produces a net flow from M to R
168
What is the Diamond model?
took the general model & applied it to an epithelium where M was the lateral intercellular space
169
Describe teh diamond model
In the new scenario:
1 = plasma membrane
M = lateral interspace
2 = PT Capillary membrane
Thus, the lateral interspace has higher osmolarity & so,
due to the osmotic pressure gradient, volume flows
from the interstitium across the plasma membrane into the lateral interspace
The increase in water in the lateral interspace
increases the hydraulic pressure &, since the capillary
membrane has a lower sigma, water flows from the lateral
interspace across the PT capillary membrane and into
the capillary
170
Regulation of epithelial transport is maintained by?
Supply of transported species
Permeability
Na/K Pump
Paracellular Shunt
171
Describe the supply of transported species in regard to regulation of epithelial transport
Flux of Na is low when concentration is low
172
Describe the permeability in regard to regulation of epithelial transport
Permeability of the membrane can influence transport by altering the rate of Na entry into the cell
Aldosterone increases apical PNa
Amiloride (diuretic) inhibits apical PNa
173
Describe the Na/K pump in regard to regulation of epithelial transport
Na/K Pump activity can be influenced by energy supply, direct effect on the pump (i.e. inhibitors),
modulation of the number of active pumps & isoforms
174
Describe the paracellular pump in regard to regulation of epithelial transport
leaky junctions can result in backflux of Na into the lumen resulting in decreased net
reabsorption
175
Effect of aldosterone on apical sodium permeability? Amiloride?
Aldosterone increase apical permeability to sodium
Amiloride decreases it
176
Describe the proximal tubule function
Where all most of the filtered water, Na, Cl & K is reabsorbed!
177
What percent of filtered sodium and water is resorbed at the proximal tubule?
65%
178
Describe Cl resorbtion at the proximal tubule
Less than Na and water
179
Describe glucose and AA resorption at the proximal tubule
All glucose and AA are reabsorbed
180
What is the epithelium of the proximal tubule?
Leaky epithelium (no osmotic gradient, near zero transepithelial pressure difference)
Water permability is so high that the osmotic gradient can't be established
181
Describe transport into the proximal tubule
Transport is driven by Na/K pump & reasborption of nearly every substance
is linked to this enzyme
All processes in the proximal tubule depend on resorption of Na
182
What are the 3 parts of the proximal tubule
Part 1: early part of the convoluted portion
Part 2: late part of the proximal tubule
Part 3: pars recta of the proximal tubule
183
Describe the electric potential of the proximal tubule
Inside the cell is negative with respect to either the
basolateral or apical surface, but the magnitude of the
apical potential is slightly less than the magnitude of
the basolateral membrane (due to the Na current)
Departing Na+ leaves excess negative behind in the
lumen
Transepithelial voltage is about 3 mV, lumen negative
184
What drives resorption of sodium in the proximal tubule?
Energy source driving all Na reabsorption is the Na/K ATPase found on the basolateral membrane
185
Describe entry of Na at the apical membrane in the proximal tubule
Passive Na entry at the apical membrane via Na leak or cotransport/exchange
Apical Na channel is voltage & TTX insensitive (tetrodotoxin)
Na moves down its electrical and chemical gradient
186
Describe the exchange of sodium at the basolateral membrane
At the basolateral membrane, 3 Na+ ions are pumped out for 2 K+ ions pumped in
187
Is there paracellular transport of Na in the proximal tubule?
Considerable paracellular transport through tight junctions of the leaky epithelium
188
Describe potassium in the basolateral membrane of proximal tubule
K+ leak in the basolateral membrane but not independent (crosstalk b/w apical & basolateral membranes)
189
Describe Na crossing the apical membrane in the proximal tubule
Na crossing the apical membrane:
Na concentration in the tubular fluid in the proximal tubule is
about plasma, but the Na concentration in the cell is very low &
so there's a huge driving force for Na to cross the apical
membrane (both because of the electrical potential drop & the
concentration gradient)
!
Na passively crosses the apical membrane
190
Describe Na crossing of the basolateral membrane in the proximal tubule
Na/K ATPase (3 Na out/2 K in)
! Note that if the K pumped in didn't leave the cell, it would pop, so
K+ leaks out via a K+ channel in the basolateral membrane
191
What is the net effect of sodium entry in the proximal tubule?
Net effect is on Na ion crossing the epithelium
192
What crosses the paracellular tight junctions in Na transport from the tubular lumen?
3 Cl-, one for each Na+ that crosses
193
Describe function of reabsorption of Cl
Without reabsoprtion of Cl-, there apical side would continue to be more negative due to loss of Na+ &
basolateral side would continue to become more positive due to accumulation of Na+
194
All long-term reabsorption is charge?
Neutral
195
What is reabsorpted along with Na in the proximal tubule?
Cl or bicarb
196
Most Cl- is reabsorbed in the proximal tubule via?
Most Cl- is absorbed through a paracellular pathway: Passes via leaky tight junctions of the proximal
tubule through lateral interspaces to the basolateral side of the tubule
197
Describe the net reabsorption of NaCl
Early on, Cl- is reabsorbed through a paracellular pathway
Na/K ATPase is the battery driving current
Current is carried one way by the Na & in the other direction by Cl (since
Cl is negatively charged, direction of current flow is opposite to the flow of the ion).
There's no new flow of current despite a very substantial flow of material
198
Describe the steps to bicarbonate reabsorption in the proximal tubule (7 steps)
1. Na cross the apical membrane via Na-H antiporter (Na ion in the lumen is exchanged for a H+ inside the cell)
2. Na+ is then kicked out the basolateral side by the Na/K ATPase
3. H+ in the tubule lumen combines with HCO3 to make H2CO3
4. Proximal tubule brush border has carbonic anhydrase that converts carbonic acid to H2O & CO2
(Note: this is highly unusual since carbonic acid is NOT usually present extracellularly
5. CO2 (small, uncharged GAS) & H2O rapidly equilibrate across the apical membrane
6. The cell needs more H+ & carbonic anhydrase inside the cell combines H2O & CO2 to form carbonic acid that dissociates
7. The proton replaces the one originally secreted & HCO3- goes down its electrochemical gradient through the basolateral membrane into the peritubular space. (via a 3HCO3 to Na pump)
NET: HCO3 reabsorption w/ no change in intracellular composition
Note: there's a Cl-HCo3 apical exchanger: cellular HCO3 is
exchanged for Cl- across the apical membrane & the Cl- exits via
the basolateral membrane
199
Describe the concentration changes of tubular fluid in the proximal tubule
concentration of bicarb decreases, while the concentration of Cl increases (because bicarb
reabsorption in slightly higher than Cl); the concentration of Na remains the same since it's isotonic resorption
200
Describe the type of exchange of sodium in the proximal tubule
ISOTONIC because passively reabsorbed through the apical membrane
201
As tubular fluid passes along the proximal tubule, what happens to the concentrations of bicarb and Cl?
Bicarb is preferentially reabsorbed such that tubular Cl\>plasma Cl
This results in a decrease of bicarb in the tubular fluid and a increase of chloride concentration
202
Describe chloride reabsoprtion via the Na/H antiporter
Bicarb make inside the cell by dissociation of carbonic acid doesn't exit the basolateral membrane and instead is exchanged for Cl across the apical membrane. Cl then exits via the basolateral membrane
203
Describe the lumen positive potential for the proximal tubule
Now the chloride concentration inside the proximal tubule is 132 meg/L, but the outside in the peritubular space is the same as the chloride concentration of plasma, 110 meq/L. There is thus a gradient of chloride. Because of the tight junctions of the proximal tubule are very permeable to Cl-, this gradient gives rise to a very small transepitheleial potential, on the order of 2 or 3 mV. But unlike the potential in the early proximal tubule, this potential is lumen positive.
Because of the very high permeability of the tight junctions of the proximal tubule, this small positive potential can drive an appreciable sodium flux through the lateral interspaces and the tight junctions.
Note that the chloride-generated lumenal potential also enhances the effectiveness of mechanisms for Na+ reabsorption we discussed previously.
204
Describe coupling of glucose and AA reabsorption
Glucose & AA are reabsorbed almost completely, and this reabsorption is coupled to Na gradient
Na/glucose co-transporter & Na-dependent AA uptake
205
Movement of glucose and AA back into the peritbular capillary generates?
Net movement of charge by Na
206
Describe membrane depolarization due to AA/glucose. Na permeability depends on?
Na permeability depends on the [glucose/AA]; increasing Na permeability of a membrane should
depolarize it SO glucose (an uncharged molecule) can depolarize an epithelial apical membrane in the
presence of Na+ by triggering an increase in Na conductance (ex. Galactose-induced depolarization
207
Membrane pumps and leak channels work..?
Membrane pump-leak regulation (cross-talk) occurs between the basolateral & apical membranes
208
Describe efficiency of glucose clearance
Normally, glucose clearance is zero (100% reabsorbed); in diabetes, threshold is exceeded & patient spills
209
Describe SGLT2
SGLT2 (Sodium-dependent GLUcose Transporter): 1:1 Na/Glucose co-transport, only in kidney (mutated
in familial renal glucosuria) (100:1 concentration ratio of sugar)
210
What is SGLT1?
SGLT1 is a 2:1 Na/Glucose co-transport, works with glucose & galactose, found in the kidney & gut
10,000:1 concentration ratio of sugar
211
SGLT1 works with what sugars?
Glucose and galactose
212
What is GLUT?
GLUT facilitated transporter is found in the basolateral face & transport glucose to peritubular space
213
What do Na coupled transporters of AA work like?
SGLTs
214
Describe organic acid secretion to the proximal tubule
occurs via active transport from interstitium & then out to lumen via a family of exchangers
215
Describe water transport in the proximal tubule
Proximal tubule DOESNT regulate final urine concentration; fluid recovered is isomotic/isotonic to plasma
216
Describe regulation of water transport in the proximal tubule
No regulation: unregulated water channel protein (ADH-insensitive water channel, AQP1 (aquaporin 1)
!
Note: all of the regulation occurs in the distal tubule
217
Describe water transport according to the diamond model
1. Reabsorption of Na & other substrates causes an increase in the osmolarity of the lateral space
between the cells (steady-state Na gradient in the lateral interspaces created by Na/K pumps)
2. Because the lateral space is hyperosmotic with respect to the tubular fluid, water moves through
the tight junctions & tubular cells by osmotic pressure
3. Accumulation of water in this space increases the hydrostatic pressure in this compartment,
driving the fluid out into the basal space & into the capillaries
218
Water resorption follows?
Reabsorbed fluid is?
Water reabsorption follows the solute transportation & reabsorbed fluid is essentially isotonic to tubular fluid
219
What is the driving force for water transport in proximal tubule?
Driving force for water is probably developed by a combination of the slight (immeasurable) luminal
hypertonicity, axial anion asymmetry & a standing gradient of osmolality in the lateral interspaces
220
Describe the function of the loop of henle
Loop of Henle normally reabsorbs 25% of the filtered Na+ & Cl+ and only about 15% of the water (not isosmotic)
221
Water resorption in the loop of henle is?
NOT isomotic
222
Percent of Na and Cl resorbed in the loop of henle?
25%
| (15% of water)
223
Describe ratio of Na/Cl to water resorption in loop of henle
More NaCl than water (not isosmotic)
224
Thick ascending limb functions to?
Thin ascending limb?
Thick ascending = resorption of ions
Thin descending = resorption of water
225
Describe the spatial separations of the loop of henle permeabilities
Thin descending limb resorbs water; impermeable to ions/Urea/Na (predominated by Na/K/Cl cotransport
Thin ascending limb passively resorbs Na (high PNa), impermeable to water & moderate Purea
Thick ascending limb resorbs ions & is impermeable to water (don't understand how it is tight to water)
! Predominated by passive transport
226
The thin descending limb of loop of henle functions to?
Resorb water
Impermeable to ions/urea/Na
227
The thin ascending limb of the loop of henle functions to?
Passively resorbs Na (high permeability), imperable to water, moderate permeability to urea
228
The thick ascending limb of the loop of henle functions to?
resorbs ions & is impermeable to water
Predominated by passive transport
229
Describe how the thick ascending limb transports ions
BL Na/K pump sets up a gradient (low intracellular Na, electrochemical
gradient favors the movement of Na from the tubular fluid into the cell)
Na/K/2Cl cotransporter: moves Na+ across the apical cell membrane
Na/K exchanger also mediates Na+ apical uptake
At the apical surface, K+ tends to leak out of the cell back into the lumen
230
Na/K/2Cl cotransported is important where? What does it move?
Thick ascending loop of henle
Na is moved from tubule lumen down concentration gradient into the cell
K and 2 Cl are moved into cell AGAINST concentration gradient
231
Ion transport into the thick ascending loop of henle is?
Electroneutral - no electrical potential generated across the celll
232
Loop diuretics function to?
Inhibit the Na/K/2Cl cotransported which increases the Na load to the rest of the system
233
Bartter syndrome affects?
The Na/K/2Cl cotransporter
234
Na/H exchanger is importatn where in addition to the proximal tubule? What does it do?
Ascending thick limb of loop of henle
Mediates Na apical uptake
H secretion leads to HCO3 reabsorption too
Na exits via the Na/K ATPase and K,Cl, HCO3 passively exit the cell
235
At the apical surface, what happens to K in the thick ascending loop of henle?
Tends to leak back into the tubule lumen
236
What meadiates K leak at the apical surface of the thick ascending loop of henle?
ROMK channel
237
Why is the lumen positive at the thick ascending loop of henle?
Na/K/2Cl moves into the cell
K leaks back out via ROMK channels
This is a net positive lumen
238
The lumen positive thick ascending loop of henle drives what?
Positive voltage drives resorption of all cations via the paracellular pathway
239
What is the diluting segment?
The reabsorption of solutes, along with the relative impermeability of
the thick ascending limb to water reduces the osmolarity of the tubular
fluid & thus the thick ascending limb presents a dilute fluid (ALWAYS
hypotonic to plasma) to the distal nephron; thus, the thick ascending
limb is also called the diluting segment
240
Function of the thin loop of henle?
vital role in formation of concentrated urine, but active transport properties are dull
241
Properties of the thin descending limb of the loop of henle? (Permeabilities)
Relatively permeable to water: Medullary interstitium is hypertonic, there's a drive force for the
passive resorption of water; the high water permeability ensures rapid passive water resorption
! Relatively impermeable to salt & urea
242
Properties of the thin ascending limb of the loop of henle
Relatively impermeable to water
Relatively permeable to salt & urea: hypertonicity of the medullary interstitium provides an inward
driving force for urea & outward driving force for the flow of salt
243
Thick ascending limb of the loop of henle is the prime mover for?
creating the single effect that sets up the osmotic gradients in the kidney
which are tapped efficiently to produce dilute/concentrated urine & thus keep the body in water balance
244
Na and water absorption at the distal convoluted tubule and collecting duct?
Na & water resorption continues so that the final urine contains less than 1% of the filtered Na/Cl
245
The distal convoluted tubule and collecting duct secrete?
K and H
246
Describe the epithelium for the distal convoluted tubule and the collecting duct
Tight epithelial
Increased transepithelial membrane potential and resisitance
Decreased water and salt permeability
247
What is the main function of the distal convoluted tubule and the collecting duct?
Main function is to maintain gradients set up in earlier segments
This is where the final control of the composition of the urine is exerted
248
The distal nephron varies?
reabsorption of the fluid, providing sufficient control range to maintain water
249
Describe the membrane potential of the distal convoluted tuble and the collecting duct
Transepithelial potential is larger & lumen is negative
The apical face is more depolarized due to higher Na permeability
250
The distal tubule transport mechanisms do what?
Receives dilute urine and continues to dilute it
251
Describe the pump mechanics of the distal tuble
Basolateral Na/K pump sets up gradient
Apical Na/Cl cotransporter (sensitive to Thiazie-diuretics) allows Na entry
Also there are regulated apical Na channels (sensitive to amiloride, a K+ sparing diuretic)
Cl reabsorption is both passive (driven by luminal negative transepithelial potential) & secondary active
cotransport (see above)
In some cells, Cl- reabsorption is mediated by an apical HCO3/Cl exchange
252
Apical Na/Cl cotransporter in the distal tubule is sensitive to?
Thiazide diuretics
253
Los of Na/Cl cotransporter in the distal tubule leads to?
Gitelman's syndrome
(hypocalcemia & magnesemia, mild phenotype, salt wasting & secondary hypoaldosteronism, no HTN)
254
Apical Na channels in the distal tubule are sensitve to?
Amiloride, a K sparing diuretic
255
The last segment of the distal tubule and the collecting duct are characterized by?
Principal cells and intercalated cells
256
What are principal cells
More abundant in the distal distal tubule and collecting duct
Primarily absorb Na and Water and Secrete K
257
Describe the channels of the principa cells
Na channel allows resorption (amiloride sensitive)
K channel allows secretion
Aldosterone inserts both channels (by encouraging new protein synthesis)
258
What are intercalated cells?
secrete H+ and reabsorb HCO3- (acid base regulation)
In the distal distal tubule and the collecting duct
259
Carbonic acid does what in the intercalated cells?
CA generates protons that are secreted across the apical membrane against its electrochemical
gradient & through an H-ATPase
HCO3- leaves the basolateral membrane into the blood
260
What does aldosterone do?
controls Na resorption in the distal nephron (regulates volume)
261
How does aldosterone function?
Aldo increases Na resorption by increasing the number of apical Na channels (by insertion only)
262
Are apical Na channels amiloride sensitive?
Yes, highly
263
Increasing Na resorption via aldosterone does what?
produces a high negative potential difference with the lumen negative that drives
anion (Cl-, HCO3-) resorption & H/K secretion
264
What are diseases of teh apical Na channels of the distal nephron?
Alpha,beta,gamma loss of function mutations lead to pseudo-hypoaldosteronism
Beta,gama gain of function mutation leads to Liddle's syndrome (severe HTN, pseudo-hyperaldosterone state)
265
What equation represents the transport of ions in the entire nephron?
[Na]reabsorbed=[Cl]reabsorbed + [H+K]secreted
266
Describe water permeability in the distal convoluted tubule
Very low, little H20 movement in this segment
267
Describe water permeability of the collecting duct
Water permeability of the collecting duct is subject to physiological control & may vary depending on the conditions
Note: even at its most permeable state, it's never as high as that of the proximal tubule
268
What is antidiuretic hormone (ADH)? What does it regulate?
```
Antidiuretic hormone (ADH) (aka vasopressin) from posterior pituitary & is the main determinant of H2O
permeability in the collecting ducts (regulates osmoles)
```
269
What two functions does ADH have?
ADH increases arterial blood pressure (by arteriole constriction) & works against dieresis (high urine volume)
270
In absence of ADH, what is collecting duct doing?
In the absence of ADH, H2O permeability in the collecting ducts is very low & little H2O is resorbed
271
In the presence of ADH, what is the collecting duct doing?
In the presence of ADH, H2O permeability can be quite large, allowing reabsorption of H2O from the tubule
272
What does ADH act upon?
ADH acts on principal cells by increasing the apical membrane water permeability by inserting water
channels contained in subapical membrane vesicles
273
Describe the mechanism of ADH action
ADH binds a basolateral receptors in principal cells (G protein coupled, adenyl cyclase, cAMP)
Increased cAMP causes downstream effects culminating in the fusion of the vesicles with the apical membrane & water channel insertion
Aquaporin water channel is ADH regulated in the principal cell but there are unregulated forms
found in the rest of the tubule & most other tissues
274
When is ADH secreted into the blood?
Osmoreceptors in the brain sense & the peptide is released into the blood
275
All regulation of water permeability in the collecting duct is controlled by?
ADH
276
Regulation of water resorption int the renal tubules does what?
Regulation of water resorption by the renal tubules is essential to the maintenance of normal body water content
277
What is beind controlled in order to affect urine production?
Plasma osmolality (not urine!) is being controlled & normal human urine can be very dilute or very concentrated
278
What is diuresis? antidiuresis?
Diuresis = high urine volume vs. antidiuresis = low urine volume
279
Give overview of water movement
Glomerulus: filtered
Proximal tubule: 2/3 resorbed, isotonic, unregulated
TAL: separates salt from H2O (impermeable to H2O), hypotonic, excess osmoles in interstitium
ADH allows collecting tubule fluid to osmotically equilibrate with interstitium (normally hyperosmotic), resorb
H2O ; without ADH, dilute distal tubule fluid leaves rather diluted
Note: ADH also renders the late collecting duct permeable to urea (helps produce concentrated urine)
280
What is countercurrent multiplication?
Countercurrent multiplication is essential to establish hypertonic interstitium & hypotonic distal tubular fluid
281
Countercurrent multiplication operates in conjuction with?
Countercurrent exchange
282
Countercurrent multiplication/exchange is achieved by?
Both are achieved by separating salt from water at the thick ascending limb (the single effect that's multipled)
Salt is removed from the ascending limb (impermeable to water) & those excess osmoles
accumulate around the descending limb (impermeable to salt) & draw water into interstitium
The single effect of the countercurrent multiplication process is the separation of solute & water
and the resultant osmotic gradient between descending & ascending limbs
283
Describe the steps of the countercurrent multiplication/exchange
Start with isotonic fluid & turn on single effect thick ascending limb
Salt is actively transported out into the interstitium
!Eventually back-flux will counterbalance active resorption & a
steady-state limiting gradient will be established
!
Ascending limb osmolarity is less than the interstitium
Due to the high PH2O of the descending limb, water flows into
the interstitium until the osmolaties of the descending limb &
interstitium are equivalent
(water reabsorption by the descending limb is driven by salt reabsorption of the ascending limb)
Now let the tubular fluid flow
Salt is transported out from the ascending limb
Gradient is achieved
Water is drawn out of the descending limb
284
The countercurrent effect is capable of generating what?
A 200 mosm gradient
285
The countercurrent multiplier is?
system in which a small concentration difference created by an active pump
(single effect) between 2 adjacent limbs of a loop is longitudinally enhanced (multiplied); requires:
Hairpin structure/loop arrangement
Specific properties of the membrane separating the two limbs
An energy input that generates the single effect
286
The concurrent multipler/exchange is characterized by?
1. Fluid leaving the loop is hypoosmotic as compared to fluid intering the loop
2. The osmolarity increases progressively from the top of the medulla to the bottom; the difference between
the top & bottom is larger than the single effect
3. At any horizontal level, the concentration in the ascending limb is lower than that in the descending limb
287
Imagine you put hypertonic urea deep in the papilla & using standard tubule properties (thin desc
permeable to water, thin asc permeable to urea/Na) see what happens:
Fluid descends & water leaves, thus the fluid gets more concentrated (salt concentration increases)
Fluid ascends & Na leaves passively due to concentration gradients & increases the salt
concentration of the medullary interstitium
Urea also leaks in, increasing the urea concentration in the tubule fluid
Then permeability properties change again such that only water can pass through the walls & so
fluid equilibrates with the hypertonic medullary intersitium & passes out very hypertonic
! Reabsorbed water is carried off by the vasa recta
288
NaCl is reabsorpted ... in the loop of henle to produce...?
hpertonically, the hypotonic fluid presented to the distal nephron
289
Fluid from the ascending limb is... to fluid in the descending limb
Hypoosmotic
290
ADH increases...at the collecting ducts
Water permeability
291
What is diabetes insipidus?
ADH isn't present or tubules are unresponsive; hypoosmolarity of the distal
tubule fluid/urine indicates that ADH alters collecting duct permeability to water
292
In additon to ADH collecting duct water permeability effect, what else is done by ADH?
ADH also alters collecting duct permeability to urea of deep papillary collecting ducts (and this is
what makes the magic urea box work)
293
Describe the passive equilibrim model of the concentrating mechanism
Tubular fluid leaves the proximal tubule isotonic with plasma but as it enters the distal tubule it is hypotonic
Urine leaves the papulla with an osmolarity dictacted by TBW balance as effected by ADH
The portion beyond the proximal tubule (descending & ascending limb of Henle, distal tubule & collecting duct)
underly the concentrating/diluting mechanism of the kidney
Thick ascending loop of Henle has an Na/K/Cl cotransporter with a BL Na/K pump that allows the cotransporter to
keep actively transporting NaCl out of the tubular fluid into the medullary interstitium, producing both hypotonic
tubular fluid that retains most of its urea and enrichment of osmolyte in medullary interstitium
```
In antidiuresis (+ADH), the distal tubule & collecting duct are highly permeable to water & allow contined water
extraction from the descending tubular fluid via passive osmotic equilibration with the increasingly hypertonic
intersitium
```
As urea permeability is low until the inner medullary collecting duct is reached, the tubular urea becomes more
concentrated
! Finally, at the inner medullary collecting duct where urea permeability is high, the now concentrated urea flows
down its concentration gradient into the papillary interstitium
The interstitial urea with the interstitial NaCl provide the osmotic driving force for passive water resorption from the
highly water permeable/solute impereable descending loop of henle, resulting in a passive concentration of
the impermeant NaCl in this segment
In addition, this NaCl-rich tubular fluid that has osmotically equilibrated with the interstitial NaCl & urea as it passes
through the descending limb, encounters a region of high NaCl permeability/relatively low urea permeability in the
thin ascending limb, tubular NaCl is permitted to passively run down its activity gradient into the interstitium
```
In dieresis (-ADH), the hypotonic urine is found in the distal tubule would now descend in the now-waterimpermeant
collecting duct, continuing to undergo solute extraction & exit as hypotonic fluid
```
Preservation of the axial medullary osmotic gradient (papilla most hypertonic) is made possible by the architecture
of the blood flow of the medulla, especially the countercurrent exchange between the ascending & descending vasa
recta & by the strict regional localization of urea permeability to the terminal portion of the collecting duct; both
serving to prevent a washout of the interstitial osmolyte & trapping it at the deepest regions of the medulla
294
Desscribe blood supply to the area with the hyperosmotic gradient
The hairpin loop anatomy of the vasa recta
Blood entering the descending limbs of the vasa recta are isoomsotic
As this blood flows through interstitial fluid of increasing osmolarity, ir progressively acquires the osmolarity
of the interstitium, reaching the maximum at the bend of the vessel
In the ascending limbs of the vasa recta, the reverse takes place because of the decreasing interstitial
osmolarity
Due to the high blood flow rate, the blood leaving the medulla is slightly hyperosmotic & hence the vasa
recta extract some solute/water from the medulla
The extraction of the salt into the capillaries is balanced by the addition & this is replaced by addition from
the tubules, yielding a steady-state situation
295
The vasa recta remove fluid that has been reabsorbed from the tubules how?
Blood entering the descending limbs has high colloid-osmotic pressure & some residual hydrostatic
pressure which is higher in the descending than ascending limb
The net Starling forces are such that in the descending limb the Starling forces are approximately in
balance but in the ascending limb there definitely is colloid-osmotic uptake of fluid in the blood vessel
Result is that more blood volume emerges from the ascending limb than entered into the ascending limb
296
What is osmolar clearance?
Cosm=Uosm\*V/Posm
Cosm tells you in one minute, X mL of plasma was cleared of osmoles
297
What is solute free water clearance (free water clearance)?
CH20=V\_dot - Cosm
CH20 tells you X mL of water with no solute are removed from the plasma every minute
Note that CH20 can be negative
298
Describe H20 Balance
H2O balance: Inputs (food water content, oxidation of food, drinking) & outputs (insensible loss, sweat, feces, urine)
299
AH is a .... system
Osmoregulating system
300
Describe ADH structure and creation
ADH is an octapeptide synthesized by the hypothalamus & stored in the posterior pituitary
301
ADH acts on?
ADH acts on the distal nephron to inser water channels throughout & urea carriers in papillary CT
302
What are the three stimuli for ADH release
Ventricular osmoreceptors
Vascular strech receptors
Angiotensin II
303
Describe venticular osmoreceptors and ADH
Na receptors sense increased CSF [Na+] and release ADH
Provides tonic control because it's more sensitive and predominates at the +/- 1% range
304
Describe vascular strech receptors and ADH
Respond to increased blood volume
Emergency stronger resposne than osmoreceptors but aren't as sensitive +/- 10%
Can override osmosensors
305
Describe angiotensin II and ADH response
Released as part of the emergency response & affects ADH production
Promotes drinking by stimulating the thirst center
306
Describe ADH regulation of water when excess water is ingested
Excess H2O ingested
ECF osmolarity decreases as water increases
Osmoreceptors mediate reflex to decreased ADH secretion
Plasma ADH decreases
Tubular permeability to water decreases
Water resorption goes down and secretion goes up
307
Describe the emergency response (blood loss)
Plasma volume down by ~10%
Venous, atrial, arterial pressures go down
Reflexes mediated by cardiovascular baroreceptors (angiotensin II) leading to increased ADH secretion
Plasma ADH goes up
Tubular permeability to water goes up
Increase water reabsorption and decrease excretion
308
Describe acute dehydration
Decrease plasma volume ~10 percent leads to inhibition of baroreceptors & increased angiotensin II, leads to
increased thirst & increased H2O consumption
Decreased plasma osmolarity ~1% stimulates osmoreceptors to increase ADH secretion and increase plasma ADH leading to increased H20 permeability of the collecting duct, increased water reabsorption and decreased excretion
!Together this returns body to normal volume & osmolarity
309
Describe ethanol effect on water
Hypo-ADH relative to needs resulting in high plasma osmolarity &
abstraction of water from the ICF/cellular dehydration & hangovers (Rx: force water)
310
What is SIADH
```
(syndrome of inappropriate ADH): Results from head trauma & stimulates excess ADH release;
develop hyponatremia (Rx: H2O restriction)
```
311
What is diabetes insipidus?
copious non-sweet urine, rare genetic defect resulting in defective ADH receptor or
more commonly from loss of ADH production; hypernatremia (Rx: force water)
312
Describe Na intake vs output
Na: intake (oral E unregulated) vs. output (urine [key, controlled], small fecal loss, small sweat loss)
Nalost = Nafiltered E Naresorbed = GFRxPna E regulated Na sodium resorption
313
What are the three steps of sodium regulation
GFR
Renin-Angio-Aldo
Starling forces in peritubular capillary
314
Describe GFR effect of Na
1) GFR" increases osmolarity & plasma volume, should increase GFR but has a small effect
RBF constant due to autoregulation & thus GFR is constant with constant RBF
Prevented by myogenic reflex & tubuloglomerular feedback (high flow at macula
densa results in contraction of afferent arteriole)
Autoregulation tries to minimize the impact of GFR attempting to regulate plasma
Na
Increase load compensated by gt balance (fixed % resorbed at proximal tubule)
315
What is the first step in the renin angio aldo pathway?
Renin cleaves 4 AA crom angiotensinogen making angio I which is converted to angio II in the lung
316
What is angio II?
Angio II is a powerful vasoconstrictor, releases NE, stimulates thirst, aldo & ADH release
317
Aldo stimulates?
Na resorption & K/H secretion
318
The renin angio aldo pathway is stimulated by?
I. Intrarenal baroreceptor reduced stretch of the granular cells causes renin release
II. Renal sympathetic nerves (increased B-adrenergic outflow to granular cells in
response to reduced mean perfusion pressure)
```
III. Low flow sensed at the tubular sodium receptor in macula densa stimulates
renin release (note: opposite to TG feedback for high flow)
```
319
What is the main targed of the renin angio aldo system?
All of these work together!
Angiotensin serves broadly to protect volume but Aldo is primary (volume balance via Na
resorption)
Note: Angiotensin II also has some ADH release but this PALES IN COMPARISON to
ALDO!!! The main target is ALDO!!!
320
Aldosterone controls?
Na uptake in the distal tubule
321
How does aldo affect Na uptake?
Aldo increases the number of apical amiloridesensitive Na channels in Principal
cells by insertion only which produces a high negative PD that drives anion
resorption & K/H secretion
322
What balances the effect of aldo?
Aldo stimulates Na absorption
Has to increase secretion of H and K
Nar = Clr + [H + K]s
323
Reduced aldo balances with?
Increased Na intake
324
What is factor I in volume control?
GFR, small control
325
What is factor II in volume control?
Decrease Aldo
Aldo made in adrenal, Angio II is a major stimulus
Factor 2.5) ANF is a moderate stimulus & plays a MINOR ROLE
ANF is released from atrial cells stimulated by stretch
Increased ANF reduces renal vascular resistance and increase GFR
Increased GFR (macula densa) reduces renin, angio I and II, aldosterone & collecting duct Na channels
Aldo inserts amiloride sensitive Na channels in Principal cells
High Aldo balances low Na
326
What is Factor IIII in volume control?
Starling Forces in the Peritubular Capillary
Proximal Na resorption occurs from the tubule into this sink (peritubular capillary)
High peritubular capillary oncotic pressure decreases renal interstitial volume
This decreases renal instersitial hydraulic pressure & increase Na/H2O resorption
High hydrostatic pressure & low oncotic pressures may reduce uptake
327
What is the primary cause of hyperalosteronism?
Adrenal tumor: see mainly effects on K and H, but third factor escapes (no edema)
328
Secondary hyperaldosteronism is from?
Primary insult and is characterized by edema and volume expansion
CHF leads to decreases CO, decreases baroreceptor stretch; Na is retained in an attempt to expand
what is sensed as reduced volume; Na expands ECF & thus interstitial as well resulting in edema
Cirrohis leads to failure to synthesize albumin & hepatic scarring (blocks venous outflow, blood shifte)
Nephrosis leads to excess albumin loss, decreased oncotic pressure & mal-distribution of the ECF into
interstitial compartment producing generalized edema
Hypoalbuminemia
Clinical approach to: Hyponatremia " Rx: Decrease water vs. Hypernatremia " Rx: Add water
329
What is the normal pH?
7.35 to 7.45 (35-45 nM protons)
330
Why is normal urine acidic?
Acid load is higher so kidneys must excrete protons & normal urine is acidic
331
Bicarbonate resorption is where mostly?
Proximal tubule
332
Describe bicarb resorption
Na enters the cell on Na/H antiport
H is secreted don't acidify urine because they become water
Carbonic anhydrase diuretics " prevent resorption of HCO3 which in turn reduces Na resroption
which results in reduces amount of isotonically absorbed water
CO2 rapidly diffuses into cells where it combines with water in a rxn catalyzed by CA to form bicarb & H
Net result is bicarb resorption
!
Inverse relation with tubular Cl " HCO3 inside can exchange for Cl- on apical side
333
What are the four factors affecting bicarb resorption?
pCO2
Plasma Cl
Plasma K
Aldosterone
334
Describe pCO2 effect on bicarb resorption
increased HCO3 resorption with increased plasma CO2 concentration
335
Describe plasma Cl effect on bicarb absorption
as plasma Cl rises, more Cl is filtered, less HCO3 is resorbed & plasma bicarb
concentration falls
336
Describe plasma K effect on bicarb resorption
apparent H/K exchange into cells
!
Increased K plasma leads to decreased H cytoplasm & H secretion is harder so decreased release
& decreased bicarb resorption
337
Describe aldosterone effect on bicarb resorption
generates extra Na channels in the distal nerphon
Nar = Clr + [H+K]s
Depolarization of apical membrane decreased gradient for K or H secretion & easier H release
! Increased Aldo = increased HCO3 resorption
338
Bicarbonate production is stimulated by?
Excretion of titratable acid
Excretion of ammonia
339
Describe excretion of titratable acid and new bicarb production
Inorganic phosphate is titrated, H+ remains in urine & new HCO3 returns to blood
Changes pH of urine
Low capacity " pump stalls at pH 4.4
340
Describe excretion of ammonia and new production of bicarb
Glutamine split into NH4 & HCO3, and the uncharged NH3 diffuses across the membrane & is
trapped by secreted protons such as NH4+
Think of it as a N/H exchange and NH3 diffusion
High capacity & generates non-acidic urine
341
New bicarb production functions to
Restore lost bicarb from acid load (resorption does not do this)
342
What is diffusion trapping?
```
neutral molecules (weak acids/base) cross the membrane & then become charged & trapped on
the other side
```
343
Describe urine trapping and urine
Neutral molecules can cross membranes faster than charged molecules
Ammonia example
Acid urine pH 4.5 " allows 1000/1 proton gradient which results in efficient trapping of weak bases
Alkaline urine pH8.2 " Can only create a 10/1 proton gradient promoting acid trapping
Urine alkalinized to treat salicytic acid poisoning
Alkaline urine traps acids & acid urine traps bases
344
Describe the changes in the buffering along the nephron
H+ is secreted in all segments; however, pH acidifies only at the collecting tubule when buffer is depleted
In the proximal tubule, tubular fluid is buffered by bicarbonate which is almost totally resorbed by the time
the fluid reaches the collecting duct
In the distal tubule, the buffer is PO4 concentrated following henle
! When all buffer is titrated, pH falls
Na/H stalls, H+ stalls " only H+ secretion can occur if immediately titrated by a buffer & in practice this
means that maximal proton excretion is limited by ammonia production
345
Describe the contributions of the tubular segments to acid balance
PT " resorbs most filtered bicarb & produces/secretes ammonium
TAL " resorbs most remaining bicarb
DT & CD " final controlled contributions
A-type Intercalated Cells " apical H-ATPase & basolateral anion exhcnage
Complete resorption of all remaining bicarb & produce titratable acids
Acidic pH created in lumen trapps ammonium allowing it to be excreted in urine
B-type Intercalacted Cells " secrete bicarb
346
What happens in acute acid load?
Rapid fall in plasma bicarb
UpH falls \< 5.5 (due to decreased bicarb filtrate & stimulate A-type intercalated cell H+ pumping)
Maximal titratable acid secretion is achieved in 1 day
Create new bicarb begins to allow the plasma bicarb to rise & urine pH to rise
Acidemia stimulates increase in NH3 delivery to the CD which takes 3-5 days to reach maximum
347
What happens in alkali load (vomiting)?
Loss of HCl leaves excess HCO3 in the plasma
Plasma & filtrate HCO3 rise
Cl loss produces hypochloremia
Volume loss creates hypovolemia
Both generate more Cl resorption by the kidney
In retaining Cl, the kidney loses the anion HCO3 so urine bicarb increases
Force K loss ([Na]r = [Cl]r + [K + H]s)
1 day after vomiting stops, bicarb disappears in the urine & it becomes acidic again
Paradox because plasma is still alkaline
Volume depletion, reduced GFR & increasing Aldo set the statge
348
What is the urine anion gap?
useful way to estimate urine ammonium excretion (which indicates new bicarb formation)
349
What is the formula for urine anion gap?
UNa+UK-Ucl=-UNH4
350
Urine anion gap helps distinguish?
This allows one to distinguish NORMAL renal response to acid vs. Abn renal Fx causing acidosis
351
Describe GI loss versus renal tubular acidosis in regarts to ammonium excretion
GI loss " renal tries to correct, HIGH negative gap
RTA (renal tubular acidosis) " renal causes acidosis via wasting, NO Gap
352
What is RTA: Hyperchloremic acidosis?
1. Proximal RTA (Fanconi Syndrome): proximal tubule damage, defective HCO3 resorption so spill HCO3
! Low PHCO3 can acidify
2. Distal RTA " defect in A-type intercalated cell, never get urine pH \< 5.5, no bicarb wasting (normal
proximal function) but low H+ secretion causes high K+ secretion resulting in hyperCl & hypoK
3. Aldo deficiency leads to decreased Na resorption leading to decreased K and H secretion, salt wase, acidosis and hyper K and Cl
353
Describe the levels of body potassium and function
98% of total body K+ is in the cells but the tiny plasma fraction plays a critical role in maintaining membrane
potentials of cells & allowing excitable tissues to function normally
! Plasma K sets the Nernst potential for K [Ek] & Ek sets membrane potentials that keep you alive!
354
What is the key regulation to K homeostasis?
The key regulation is via INTRACELLULAR BUFFERING modulated by Aldo, insulin & epi
355
Describe intracellular buffering of K
Epi (via B-adrenergic receptor) drives K+ into cells (probably compensates for K+ loss from damaged cells
in fight/flight response)
!Insulin (via receptor) drives K+ into cells (probably helps clear postprandial load)
! Used clinically in emergent hyperkalemia
Aldo drives K+ into cells (secreted in response to high K hyperkalemia)
356
Hyperkalemia will cause?
Alkalosis will cause
Acidosis will cause
Hypokalemia will cause?
Relevant to K
Hyperkalemia will secondarily cause plasma H concentration to rise (pH to fall) as the cell attempts
to buffer K
Alkalosis (high pH) will secondarily cause plasma K to fall as the cells release H into the plasma
Acidosis (low pH) will secondarily cause hyperkalemia as the cells try to buffer the acid
Hypokalemia will secondarily cause plasma H to fall (pH to rise) as the cells release K into plasma
357
Describe renal secretion of K
! K+ freely filtered & usually most resorobed though net secretion is possible
! K+ recycles in the medullary intersistial fluid
! 50% passively resorbed in proximal tubule with fluid resorption (downhill)
! Passively secreted into descending Henle down gradient from medullary fluid into tubule
! TAL reabsorbs another 40% of filtered (secondary active Na/K/Cl)
! Distal tubule always receives 10% of the filtered load & does little to it; therefore no K homeostatic
regulation of the nephron prior to the collecting duct
! Regulation achieved by CCT (cortical collecting tubule?) principal cell
! At high K, PC actively secrete all urine K
! At low K, PC turn off and theres constitutive intercalated cell K resorption
! MCT always resorbs K, creating the medullary gradient that drives passive secretion into
descending Henle
358
CCT principal cell does what?
Regulate Na
Regulate K
! K secretion via apical K channel
! Driven by the K gradient set up by the Na/K pump
! Site of Aldo & ADH action
! Aldo increases apical membrane Na & K channels
! Chronic aldo increases BL Na/K pump density
359
What does hyperkalemia do to CCT?
Directly stimulates CCT secretion
! Directly stimulates adrenal cortex to secrete ALDO
360
What does hypokalemia do to CCT?
Directly slows CCT secretion
Directly slows adrenal cortex ALDO secretion
361
How does aldo self regulate?
Aldo plays a critical role in volume regulation [Na balance] & K homeostasis
! Na load creates 2 stimuli via volume expansion
! Increase GFR " increase distal flow
! High flow tends to increase K loss
! Decrease renin " decrease ALDO
! Low ALSO tends to decrease K loss
! Thus, K loss is balanced which is good since it was never an issue!
! Low ALDO/low K channel balances high flow/high flux
362
Describe the difference between K sparring and K wasting diuretics
All diuretics that act BEFORE the collecting tubule must in turn deliver excess Na to the distal tubule (i.e.
block Na transport mechanism) & this process would serve to waste K (PD changed by Na transport would
favor K+ transport)
! All loop diuretics (i.e. furosemide) block Na/K/Cl cotransporter (which resorbs K when active)
! Act AT the CCT
! Channel or Aldo blocker " decrease Na transport, decrease PD & less K is secreted/wasted
363
Describe hypokalemia
Kidney will try to compensate for loss when it's not at fault, but kidney dyregulation can cause
hypokalemia
! Insufficient input/non-renal K loss " low body K, normal renal response, less K+ excretion
! Renal K loss " low body K, abnormal renal response & more K+ excretion
! Arrhythmia is the fatal complication & so be alert for early EKG signs: progressive PR lengthening, low T
waves overridden by U waves & then T inversion with prominent U
! Relative refractory period is elongated & reentry is possible
! Muscle weakness (gut & skeletal) can also occur " weak, constipated & digitalis is toxic
364
Describe hyperkalemia
Causes: spurious, increased K load, decreased renal K excretion, etc.
! EKG " progressively higher peaked T waves, loss of P waves & broadening of QRS
365
