Lecture 6: Renal Blood Flow, Glomerular Filtration and Assessment of Kidney Funtion Flashcards
What is ultrafiltration?
Formation of fluid from plasma that is nearly free of protein as result of effects of hydrostatic and oncotic pressure gradients applied across a semi-permeable membrane
-most important in glomerular filtration barrier of kidneys as this membrane as well as artificial membrane in dialysis
What is diuresis?
Technically refers to water excretion alone (with natriuresis indicating sodium loss) but often used to refer to both water and sodium excretion in urine
What is oncotic pressure?
The osmotic pressure resulting specifically the presence of nonpermeable macromolecules (such as albumin in plasma)
How much of total Cardiac Output goes to kidney?
20% of 1 L/min
Where do interlobar arteries extend?
Along columns of Bertin
What does the efferent arteriole give rise to?
A peritubular capillary network (vasa recta)
Drains into peritbular venous network
That then goes to renal veins
How do you tell difference between cortex
And medulla under the microscope?
Cortex has glomeruli
What is the difference between Renal blood flow
And Renal plasma flow? RBF vs RPF?
RBF = 20% of cardiac output = Renal plasma flow + renal RBC flow
Thus renal plasma flow is only ONE component of renal blood flow
RPF = RBF*(1-hematocrit) = 600 ml/min = 60% of RBF
What is the significance of renal plasma flow?
This is what is being removed from the blood at the level of the glomerulus
RPF = composition of ultrafiltrate
What are the three components of the glomerular filtration barrier?
- endothelial cells of glomerular capillaries
- glomerular basement membrane
- foot processes including many proteins on podocytes
What is the first step in formation of urine?
Ultrafiltration of plasma at the glomerulus
What gets absorbed at the proximal tubule?
2/3 of filtered Na, K, Cl and H20
80% of bicarb and phosphate
~100% of glucose and amino acids
What is GFR?
Amount of filtration per unit time
The amount of ultrafiltrate that passes through the glomerulus at a given minute
Expressed in ml/min or ml/min/1.73m^2
GFR of adults = 120 ml/min = 180 L/day … and urine volume is 2L/day
As one ages (>30 yo), GFR = 100/ml/min/1.73m^2
What is the significance of GFR?
Primary measure used experimentally and clinically to define the level of kidney function
What is UF/P?
Ratio of concentration of each solute in glomerular ultra filtrate (UF) to that in the plasma (P)
A ratio of 1 = no restriction to filtration
Any ratio less than 1 = restriction of filtration
Is there such a thing as Inulin?
YES
It is not insulin misspelled lmao
What molecules does the glomerular barrier (3 components) select for?
- small size
- neutral or positively charged
Examples: Na, K, urea, creatinine, glucose
What molecules usually can’t get through glomerular barrier?
Myoglobin, hemoglobin, albumin because they are too big/have negative charges
What prevents anions from passing through glomerular barrier?
Heparan sulfate is a negatively charged compound on the endothelium/fenestrations
Also negatively charged glycocalyx
What is analogy for glomerular filtration?
Strainer for spaghetti
Pouring water into spaghetti in bowl with small slits
So only water goes through and no spaghetti can go through
Disease = when spaghetti can squeeze its way through the bowl
What are the four forces that drive filtration across filtration barrier?
- Glomerular capillary hydrostatic pressure (promotes filtration)
- Bowman’s space oncotic pressure (close to 0 and promotes filtration)
- Bowman’s space hydrostatic pressure (opposes filtration)
- Glomerular capillary oncotic pressure (opposes filtration)
What are the two pressures that promote filtration at glomerulus?
- Glomerular capillary hydrostatic pressure
2. Bowman’s space oncotic pressure
What are the two pressures that oppose filtration at Glomerulus?
- Bowman’s space hydrostatic pressure
2. Glomerular capillary oncotic pressure
What are the characteristics of the Bowman’s space hydrostatic pressure?
It is low
Entire capillary sees the same low pressure along its entire length
Determined by rate of urine formation and flow of urine into proximal tubule
Can increase if there is urine backup
What are the characteristics of the capillary oncotic pressure?
It increases during transit along the capillary bed because of progressive extraction of water by ultrafiltration
This is a fail-safe mechanism to prevent too much plasma from being filtered
What are the characteristics of the capillary hydrostatic pressure?
The hydrostatic pressure in glomerular capillaries is nearly constant along their length because of regulation of the resistances of afferent and efferent arterioles
Can increase or decrease this capillary hydrostatic pressure (which promotes filtration) by vasodilating or vasoconstricting afferent and efferent arterioles
What is the net driving force favoring ultrafiltration (P_UF)?
Difference between forces favoring filtration and those opposing
P_GC + oncotic pressure of bowmans space – P_BS + oncotic pressure of glomerular capillary = P_UF
As one goes along the capillary, the pressure favoring ultrafiltration will decrease (since the opposing pressure of glomerular capillary oncotic pressure is increasing while everything else remains constant
What is the relationship between renal plasma flow and glomerular filtration rate?
Directly proportional with tapering off as it increases
A fall in renal plasma flow can reduce GFR and vice versa if RPF is increased
A fall in RPF will reduce GFR by a greater proportion than an increase in RPF will be able to raise GFR
What is the filtration fraction (FF)?
The fraction of arterial renal plasma flow (RPFA) that is filtered at the glomerulus
FF = GFR/RPFA
Or
GFR = FF*RPFA
Normal filtration fraction = 20% which means 80% of arterial renal plasma flow just goes through capillary network unfiltered
If patient were to take a medication that causes efferent arteriolar vasoconstriction, what happens to GFR?
Increases
What happens if you have higher afferent resistance compared to efferent arteriolar resistance? High Afferent resistance and Low Efferent resistance?
Decrease GFR because glomerular capillary pressure will decrease
What happens if you have lower afferent resistance as compared to efferent resistance?
Low afferent:High efferent?
Increase GFR because glomerular capillary pressure will increase
What happens to oncotic pressure as filtration fraction goes up?
They increase proportionally
What is glomerular capillary dictated by?
Glomerular capillary pressure Is dictated by ratio between Afferent and efferent resistance If ratio increases, you get less GFR If the ratio decreases, you get more GFR
What is the relationship between afferent arteriole
Resistance (AAR) to GFR, RPF and P_GC?
As afferent resistance increases
GFR decreases
RPF decreases
P_GC (pressure in glomerular capillaries) decreases
What is the relationship between efferent arteriole resistance (EFR) to GFR, RPF and P_GC?
As Efferent resistance increases
GFR starts to increase but eventually decreases (key finding)
RPF decreases
P_GC increases
P_GC increases because it encounters a more highly resistant exit
GFR increases because flow encounters more highly resistant exit
-theoretically will decrease because of less RPF (less blood flowing through because of vasoconstriction will lead to back up)
-however this effect is negligible clinically
What are the effects of angiotensin II on afferent/efferent tone?
Angio II will increase the resistance of both A/Efferent
However more effect on efferent
Therefore, angio II will serve to preserve GFR
Indicated for patients who are volume depleted (lack of sodium) and need more renal perfusion)
What effect does ARB or ACEinhibitors have in this setting?
Losartan and Enalapril (ARB and ACEi respectively) will decrease the effects of angio II, thereby making the efferent arteriole more vasodilated and DECREASE GFR (as said in lecture)
What effect does norepinephrine and epinephrine have on the kidney?
- Binds to alpha adrenergic on afferent arterioles for vasoconstriction
-reduces GFR and RPF - Binds to beta-1 receptor on JG cells to promote the secretion of renin
So both alpha and beta activity
What is the effect of endothelin-1?
Potent vasoconstrictor (NO and prostacyclin are the vasodilators) Causes such intense vasoconstriction of both afferent and efferent arterioles such that RPF and GFR both fall
What is the effect of PGE2 and prostacyclin?
Vasodilation
Dilates the afferent arterioles > efferent arterioles so you get more GFR
Thromboxane A2 is vasoconstrictive
Under basal conditions, PGE2 does not have significant impact on GFR but under pathophysiologic conditions, PGE2 can oppose the vasoconstrictive influences of catecholamines
What do NSAIDs do to afferent arteriole resistance?
NSAIDs decreases PGE2 and thus vasoconstricts the afferent arteriole
Thereby decreases GFR
How does kidney autoregulate itself?
- By modulating afferent and efferent resistance in response to mean arterial pressure (MAP)
- As RBF increases, afferent arteriolar resistance increases and efferent arteriolar resistance decreases
- If renal blood flow is too low (below 70mmHg), the GFR starts to drop and afferent arteriolar pressure begins to decrease (vasodilate)
- however at 40 mmHg, resistance is no longer able to be manipulated and GFR just drops off a cliff
- For the most part, when renal arterial pressure fluctuates from 80 to 180, GFR is maintained at a constant due to changes in afferent and efferent arteriolar pressure
- Autoregulation is mediated largely by myogenic response
- as afferent arterioles are stretched by increased MAP, stretch-activated cation channels respond by contracting the SMCs (smooth muscle cells)
What are the two ways that GFR is regulated?
- Intrinsic myogenic response (as seen above with afferent/efferent arterioles)
- Tubular glomerular feedback (as discussed below)
What is the tubuloglomerular (TGF) reflex?
The observation that a change in flow (change in chloride concentration) in tubule flowing past macula densa is followed by changes in afferent arteriolar constriction
Modulates RBF and GFR
What is the mechanism of tubuloglomerular feedback?
- Chloride and sodium are taken up by the Na-K-2Cl symporter
- Increased adenosine (ADO) production
- Adenosine binds to adenosine receptor (A1) on the extraglomerular mesangial cells (MC)
- binding of adenosine to A1 on mesangial cells will trigger cascade of cytosolic calcium
- Increase in Ca in the cytoplasm of
i. renin releasing cells
ii. smooth muscle cells - Thus increase in Ca leads to decreased renin secretion and vasoconstriction of the Afferent arteriole
So what are the final effects of the tubuloglomerular feedback when there is too much chloride concentration?
Decrease renin secretion
Vasoconstrict afferent arteriole to decrease GFR and PBF
What is the connection between flow rate and NaCl concentration in fluid?
If you have increased flow rate, you have decreased NaCl reabsorption at the level of the thick ascending LoH. Thus, when you get to the distal tubule, you will have an increased amount of NaCl, thereby triggering the TG feedback respons
At what GFR do complications of kidney failure start to arise?
GFR<30ml/min
What GFR indicates kidney transplant or dialysis?
GFR <10-12 ml/min
What is clearance?
The term used to characterize and quantify the ability of the kidney to transfer a substance from blood to urine
What is the equation for kidney solute mass balance?
Arterial input into the kidney = Venous output + Urine output
Arterial input = solute in arterial blood * arterial renal plasma flow RATE
Venous output = solute in venous blood *venous renal plasma flow RATE
Urine output = solute concentration in urine * urine flow RATE
What goes into kidney must come out (conservation of mass)
What is urine output?
solute concentration in urine * urine flow RATE
OR
Urine output = Amount filtered (GFR*P_x) – Reabsorption + Secretion
What is filtered load?
Determined by the GFR * the plasma concentration of solute “x”
So Filtered Load = GFR*P_x
Describes the amount delivered into Bowman’s space per unit time
Will adjust for protein binding by multiplying by corrective unit
What is SNGFRs?
Single Nephron GFRs
What is total GFR? Significance?
The sum of all single nephron GFRs or the sum of all SNGFRs
Rapidly declining GFR = acute kidney injury
Slowly declining GFR = chronic kidney injury
What are the characteristics of an ideal GFR marker?
- Inert/non-toxic
- Freely filtered
- Not metabolized
- Not secreted
Example: Inulin
What is the best example of an IDEAL GFR marker?
Inulin
Which is inert, freely filtered, not metabolized and not secreted
What is inulin?
An ideal GFR mrker
It is NOT insulin
A fructose polysaccharide extracted from Jerusalem artichoke
Not absorbed nor secreted
What are the factors influencing relationship between a GFR “Indicator” and true GFR?
- exogenously administered substance can take its pick of the three components of total body water
i. Plasma
ii. interstitial fluid
iii. Intracellular fluid - Once it is in the plasma, it can be
i. extrarenally secreted
ii. secreted by tubules
iii. or filtered through glomerulus - When inside the nephron, GFR indicator can be reabsorbed
How do you determine GFR with inulin?
Since inulin is not absorbed or secreted, then the following equation holds true
GFRP_x (x being inulin) = urine soluteurine volume flow rate
Thus GFR = U_in*V/P_in
V = urine flow rate = amount of volume excreted/unit time
What is the endogenous equivalent of inulin?
Creatinine
How much plasma must be cleared in order to achieve normal type of urine excretion rate?
2 ml/min because each ml of plasma contains 50 mg of solute so it would take 2 ml’s of plasma to excrete 100 mg of solute in a given minute
What is clearance equal to?
Net filtration – reabsorption + secretion
However, if there is no reabsorption and secretion, clearance = GFR
That’s why inulin is nice wit it
Clearance = (U_x * V)/P_x = GFR
When does urinary excretion rate = plasma removal rate?
A solute that is not synthesized or catabolized in kidney but may be reabsorbed or secreted
What happens when solute > GFR?
Means there was secretion
Must compare to inulin clearance
What happens when solute < GFR?
Means there was reabsorption
Must compare to inulin clearance
What are the two ways clearance can be zero?
- if it is not filtered
2. if all of it is reabsorbed
What is creatine?
A metabolic product of urea cycle
Stored in muscle
Produced as creatine-phosphate donates a phosphate to ADP to make ATP in muscle
How is creatine converted to creatinine?
By adding water
How much creatinine do we make a day?
20-25 mg/kg of muscle
Occurs through breakdown of muscle
What is the significance of creatinine?
Creatinine production rate is constant
Freely filtered across the glomerulus
However 10% of creatinine gets secreted into the tubule
What is the relationship between clearance of creatinine and GFR?
Clearance of Creatinine (CCr) > GFR
Because 10% of creatinine is secreted by the proximal tubule
What is relationship between clearance of urea and GFR?
Clearance of urea < GFR due to reabsorption of urea
That’s because urea is reabsorbed at level of collecting ducts
Measured as BUN (blood urea nitrogen)
A poorer indicator in comparison to creatinine because its production rate is inconsistent and gets reabsorbed due to fluid flow rate
How is GFR measured?
- creatinine clearance
2. Urea clearance (seen as blood urea nitrogen or BUN)
What happens to creatinine clearance as GFR decreases?
You get more and more creatinine that is secreted by proximal tubule
Thus the less GFR you have, CCr»_space;> GFR due to secretion by tubules
Normal kidney, creatinine secretion = 10%
Diseased kidney, creatinine secretion = 45%
therefore creatinine clearance is WORSE GFR indicator the lower the GFR becomes
What are drugs that inhibit creatinine secretion?
- Cimetidine
- Trimethoprim
- Probencid
All three antagonize organic cation transporters
How do you get GFR clinically with just creatinine and urea?
Since urea underestimates and creatinine overestimates, you can just take the average of the two!
Giving a high dose of cimetidine to a patient with a creatinine clearance of 30ml/min at baseline will do which one of the following?
Make creatinine clearance a better predictor of true GFR
You do NOT reduce GFR…just the measured amount of GFR (nahmean?)
Why is creatinine an ineffective predictor of GFR?
Because changes depending on race and gender
What is cystatin?
A 13 kD protease produced in all nucleated cells
Free filtered across the glomerulus
100% Absorbed in proximal tubule and metabolized in plasma
So use plasma volume to predict GFR
More sensitive than creatinine based GFR predicitons
Produced endogenously
What is fractional excretion?
How much of solute appears in the urine vs how much solute was filtered
So FE = UV/PGFR =
UV = amount appearing in urine
PGFR = amount filtered
So if FE is greater than 1, then you have secretion of solute
If FE is less than 1, you have reabsorption of the solute
FE = (Una/Pna)/(Ucr/Pcr)
What is the relationship between change in GFR and change in plasma creatinine concentration?
Creatinine concentration must be in STEADY state or else GFR measure is off
If creatinin levels fluctuate, you will have inaccurate readings of creatinine
