L3 and L4 Measuring GFR And Renal Clearance Flashcards
GFR gives a rough measure of the number of …
Functioning nephrons
Decreased GFR is a key sign of renal disease
A reduction in GFR may indicate a disease progression, or development of a reversible problem
Grading of chronic renal insufficiency and dosages of drugs secreted by kidneys are based on…
GFR (glomerular filtration rate)
Experimentally, the polysaccharide ______ is often used to measure GFR
Inulin
Inulin clearance = GFR
If a material is neither reabsorbed or secreted by the nephron, then…
What goes in must come out
GFR = (Ux)(V)/Px
Where:
Ux = concentration of x in the urine
V = Urine rate
Px = concentration of x in the plasma
The perfect marker for GFR is freely filtered but neither _________ nor _________
Neither reabsorbed nor secreted
Inulin clearance is the gold standard but it is not commonly used clinically
_____________ clearance and plasma _____________ concentration are frequently used as indicators of GFR in clinical practice
Creatinine
Other techniques: EDTA, iothalamate clearance
Creatinine is produced by ____________ at a relatively constant rate from breakdown of ___________________.
Skeletal muscle, creatine phosphate
Why use creatinine to measure GFR?
It is freely filtered, not reabsorbed, and is only slightly secreted
It is also already at a steady-state concentration in the blood, if formation and excretion are stable
Blood creatinine levels can provide an estimate of …
GFR over the preceding hours
Calculation of GFR by determining creatinine clearance can be described by the following formula:
Ccr = (Ucr)(V)/Pcr ≈ GFR
Where:
Ccr = Creatinine clearance
Ucr = concentration of creatinine in urine (mg/100ml)
V = volume of urine (ml/min)
Pcr = concentration of creatinine in plasma (mg/100ml)
Normal Ccr ≈ 80-110 ml/min/1.73m2
Method for sample collection in order to properly measure GFR
Patient voids on arising at 7 am, urine discarded
Urine collected for 24 hours, including specimen on arising on the following morning at 7 am
Blood same also taken during the same 24 hour period
Ccr = (U x V) / P
Where U = concentration of Cr in urine
V = volume of urine
P = Concentration of Cr in plasma
If a patient’s
Urine flow (V) = 2.0 ml/min
Urine [Cr] = 0.6 mg/ml
Plasma [Cr] = 0.01 mg/ml
What is the patient’s GFR?
GFR = (U x V)/P = (0.6 x 2.0)/(0.01) = 120 ml/min
What if all you have is the plasma [Cr]?
You can estimate GFR based upon their inverse relationship.
Several algorithms exist for estimating GFR based on plasma creatinine, based on large data sets
The different algorithms used to estimate GFR based on plasma creatinine
Cockcroft-Gault equation
- requires age, weight, sex and Pcr
MDRD 4 (Modification of Diet in Renal Disease) - requires age, sex, race, and Pcr
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
- requires age, sex, race, and Pcr
What is Blood Urea Nitrogen (BUN)
Amino acid catabolism in the liver produces urea —> urea synthesis varies with protein intake and liver function —> about 1/2 of the filtered urea is reabsorbed (reabsorption increases when GFR is low)
________ is not a good GFR marker
BUN
__________ represents the volume of plasma that is cleared of a given solute per minute.
Clearance
Cx = (Ux)(V)/(Px)
Normal Cr clearance is ________ for females and _________ for males
≈85-125 ml/min for females
≈97-140 ml/min for males
Clearance of a secreted substance will be greater than Ccr, thus greater than GFR
Clearance of reabsorbed substances will be less than Ccr and less than GFR (ex: glucose, complete reabsorption, clearance is zero)
If GFR = 125 ml/min (from Cr plasma)
Px = 0.02 mg/ml
Ux = 0.10 mg/ml
V = 2.5 ml/min
Is Substance X secreted or reabsorbed?
Start with clearance:
Cx = (Ux x V)/Px = (0.10 x 2.5)/0.02 = 12.5 ml/min
12.5 < 125
Substance X is reabsorbed
If GFR = 125 ml/min
Px = 0.008 mg/ml
Ux = 2.5 mg/ml
V = 1.8 ml/min
Is Substance X secreted or reabsorbed?
Cx = (2.5 x 1.8)/0.008 = 562.5 ml/min
562.5 > 125
Substance x is secreted
If GFR = 125 ml/min
P(ur) = 0.15 mg/ml
U(ur) = 3.9 ml/ml
V = 2.5 ml/min
Is Urea secreted or reabsorbed?
C(ur) = (3.9 x 2.5)/0.15 = 65
65 < 125
Approximately 1/2 of filtered urea is reabsorbed
For glucose: GFR = 125 ml/min P(glucose) = 1.0 mg/ml U(glucose) = 0 mg/ml V = 2.5 ml/min
Is glucose reabsorbed or secreted?
Because U = 0, and C = (UxV)/P so C = 0
100% of the filtered glucose is reabsorbed
Clearance ratios allow us to compare the clearance of any substance with…
Inulin clearance
Clearance ratio = C(x)/C(inulin)
If C(x)/C(inulin) = 1.0 the substance must also be a GFR marker (filtered, but neither secreted nor absorbed)
C(x)/C(inulin) < 1.0 —> Either substance is not filtered, or it is filtered and reabsorbed
C(x)/C(inulin) > 1.0 —> The substance is filtered and secreted
What does Para-Aminohippurate (PAH) tell us about renal plasma flow?
Since all the blood is cleared of PAH, C(PAH) is an estimate of RPF.
PAH in plasma —> some PAH is filtered —> all the remaining PAH is secreted —> all of the PAH is excreted in urine, none is left in the plasma
C(PAH) = (Upah x V)/Ppah = (540ml/min)(1)/(1) = 540 ml/min ≈ RPF
If we use PAH to estimate RPF, how can we determine renal blood flow (RBF)?
RBF = RPF/(1-Hct)
If Hct = 0.4 and RPF = 540 ml/min (from previous example):
RBF = (540)/(1-0.4) = 900 ml/min
The process by which a protein-free filtrate that is otherwise identical to plasma is produced
Glomerular filtration
The process by which waste products, metabolites, toxins etc are removed from the peritubular capillaries into the lumen of the tubule
Tubular secretion
The process by which valuable molecules (glucose, amino acids, etc) are moved from the tubular lumen back to the peritubular capillaries
Tubular reabsorption
_________ ≠ secretion, but is simply the loss of a substance from the body in the urine
Excretion
The amount of a material in the glomerular filtrate is referred to as the …
Filtered load (FL, units are mg/min)
FL = (GFR)(Px)
The amount of a material lost in urine is referred to as the …
Excretion rate (ER, units are mg/min)
ER = (Ux)(V)
The amount of material added to (secreted) or removed (reabsorbed) from glomerular filtrate
Transport rate (Tx, units = mg/min)
Tx = FL - ER
If transport rate is positive, then some material was …
Removed from the filtrate by reabsorption
If transport rate is negative, then some material was …
Added to the filtrate by secretion
Renal handling of different plasma constituents
Substance % Reabsorbed
Na+ 99.4
K+ 93.3
Cl- 99.2
HCO3- 100
Urea 53
Glucose 100
Total solute 98.9
Water 99.4
The two routes for reabsorption
Paracellular (between cells in the “leaky” epithelium)
Transcellular (across the luminal membrane and basolateral membrane)
Different mechanisms for facilitating transcellular reabsorption
Simple diffusion (usually via pores)
Facilitated diffusion (carrier mediated)
Primary active transport (NaK-ATPase, H+-ATPase, H/K-ATPase, Ca2+-ATPase)
Secondary active transport (reabsorption of AAs, glucose, lactate, citrate, phosphate, etc coupled to Na+ gradient)
Endocytosis
By what mechanisms is glucose reabsorbed?
1) at the luminal/apical membrane, Glucose is transported into the cell by secondary active transport. (Note, much more glucose is moved than Na+)
2) at the basolateral membrane, glucose is transported into the ISF via facilitated diffusion
______% of Na+ in the filtrate is reabsorbed in the __________.
67% in the proximal tubule
(Via Active Transport)
25% is reabsorbed in the LOH via active transport
8% is reabsorbed in the distal tubule and collecting duct via active transport (but subject to control by aldosterone)
______% of water is reabsorbed in the ______
65% in the proximal tubule (via passive transport, or solute-linked)
15% in the LOH (also passive or solute-linked)
20% in distal/collecting duct but NOT solute linked - regulated by ADH
In the distal tubule and collecting duct, ______ reabsorption is controlled by aldosterone and ______ reabsorption is regulated by ADH.
Na+ = aldosterone Water = ADH
Na+ is transported across the basolateral membrane back into the peritubular capillary by …
The Na+/K+-ATPase.
Water follows Na+ passively via diffusion
What drives fluid movement from the nephron lumen into the peritubular capillaries?
1) Active transport of Na+ across the basolateral membrane
2) Slight osmotic gradient then “pulls” water from the nephron lumen into the basolateral compartment
3) Anions (Cl- etc) follow Na+
4) π(PC) is the primary force driving fluid movement from the BL compartments into the peritubular capillaries
Reabsorption of water and electrolytes is considered to be __________ in the proximal tubule
Isosmotic
Mechanisms for reabsorbing Na+, Cl-, glucose, phosphate, citrate, lactate, and amino acids in the proximal tubule
Na+ enters PT cells via cotransport w/ organic and Na+/H+ antiport
Cl- enters peritubular capitallry via paracellular routes (and other routes)
Na+ leaves the cell by Na+/K+ ATPase or via contransport with HCO3-
How does Angiotensin II influence Na+ reabsorption by the proximal tubule?
Stimulates Na+/H+ exchange a rose the apical membrane (NHE family of transporters)
Increases Na+ reabsorption and H+ secretion
How does sympathetic nerve activity influence Na+ reabsorption by the proximal tubule?
Stimulates Na+ reabsorption
How does Parathyroid Hormone influence Na+ reabsorption by the proximal tubule?
Inhibits Na+/phosphate cotransport
Increases urinary excretion of phosphate
The tubular fluid to plasma concentration ratio (TF/P) for freely filtered solutes in Bowman’s capsule is…
1
Because the only thing that doesn’t get filtered is proteins, so the tubular fluid and plasma concentrations for every other filterable solute is the same
Water and solutes are reabsorbed along the length of …
The proximal tubule (PT)
The TF/P ratio for ________ shows that the volume of the tubule fluid is decreasing
Inulin
Because inulin is neither secreted nor reabsorbed, its TF/P ratio rises at a constant rate as the you move down the proximal tubule
________ can produce very small TF/P ratios
Reabsorption
If TF/Px (tubular fluid to plasma concentration) = 1.0, then …
Reabsorption has been exactly proportional to the reabsorption of water
If TF/Px (tubular fluid to plasma concentration) < 1.0, then …
Reabsorption of the substance has occurred to a greater extent than water
If TF/Px (tubular fluid to plasma concentration) > 1.0, then …
Reabsorption of the substance has been less than water, OR there has been net secretion of the substance
TF/P(inulin) (tubular fluid to plasma concentration of inulin) is used as a marker because:
Because it is only filtered (neither secreted nor reabsorbed), it’s concentration in the tube is solely determined by the movement of water
In renal transport systems, the maximal rate at which a particular solute can be transported is referred to as the
Tubular Maximum (Tm)
Below the Tm, all of the filtered load is reabsorbed
The portion of the load above Tm is excreted
Tubular maxima are primarily found in the ___________.
Proximal tubule, due to saturation of membrane transport proteins
Tm for glucose describes the…
Maximum rate at which glucose can be reabsorbed.
Above Tm, glucose begins to appear in the urine (is excreted).
For glucose the ___________ refers to the plasma concentration where glucose first appears in the urine
Threshold
Depends on the GFR and Tm
Due to the heterogeneity of nephrons, not all nephrons have the same Tm, which can be visualized on the glucose titration curve as …
Splay
Changing the GFR does not effect the _____ but it does effect _____.
Does not effect Tm (transport maximum is a constant)
DOES effect Threshold
Example:
Decreasing GFR increases the threshold (plasma concentration at which you will see the substance in urine)
Increasing GFR decreases the threshold
Examples of solutes that have Transport Maxima (Tm)
Sugars (glucose, fructose, galactose) Amino acids Metabolic intermediates (lactate, ketone bodies, kreb’s cycle intermediates) Phosphate ions Water-soluble vitamins Proteins and peptides
An excess amount of an unreabsorbed solute (ie mannitol) __________ osmotic water flow from lumen to basolateral spaces
Inhibits
This is how osmotic diuretics like mannitol work)
Causes sodium back-diffusion into the lumen of the tubule —> increased loss of water and electrolytes in the urine
__________ can result in a rapid loss of sodium and water (polyuria)
Osmotic diuresis
Example: mannitol, a non-reabsorbed carbohydrate can be given IV to induce an osmotic diuresis
Can accompany:
A high filtered load of urea
When the glucose load exceeds Tm in diabetic patients, the excess glucose in filtrate drives osmotic diuresis
The two main transport mechanisms for tubular secretion are:
One transporter for organic cations
One transporter for organic anions
Both very non-specific
How do the kidneys know to secrete metabolites, waste products, or foreign chemicals?
They are “tagged” (conjugated) by the liver, turning them into cations/anions
Organic anions are secreted via …
Tertiary active transport
At the basolaminar membrane, the Na/K ATPase allows for the secondary transport of alpha-KG into the cell via secondary tranport. The aKG then is exchanged for PAH via the OAT (organic anion transporter), making it a tertiary active transport system.
The PAH then leaves the cell on the apical side via a PAH-anion antiporter
Most organic anion secretion involves OAT-1 and OAT-3 transporters located in the…
Basolateral membranes of proximal tubule cells
Organic cation transport is handled by…
Several OCT transports, also located in the proximal tubule
Organic anion transporters (OAT) and cation transporters (OTC) exhibit…
Saturation kinetics, and therefore have a Transport Maximum (Tm)
Most secretion occurs in the …
Late proximal tubule
True for both organic cations and anions
