Download (Renal Clearance)

Renal Physiology 3:
Renal Clearance
Ahmad Ahmeda
[email protected]
Cell phone: 0536313454
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Learning Objectives
• Describe the concept of renal plasma clearance.
• Use the formula for measuring renal clearance.
• Use clearance principles for inulin, creatinine etc.
for determination of GFR.
• Explain why it is easier for a physician to use
creatinine clearance Instead of Inulin for the
estimation of GFR.
• Describe glucose and urea clearance.
• Explain why we use of PAH clearance for
measuring renal blood flow.
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Glomerular Filtration Rate
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Substances Used to Measure GFR
• Inulin, a polymer of fructose, is used in research to
precisely measure GFR
– Freely filtered into the Bowman’s capsule
– Not reabsorbed, secreted or metabolized by the nephron
– Non-endogenous, has to be infused intravenously
• Assume:
– [Inulin]urine = 30 mg/ml
– [Inulin]plasma = 0.5 mg/ml
– urine flow rate = 2 ml/min
• GFR = 120 ml/min or 172.3 L/day
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Substances Used to Measure GFR
• Clinically, creatinine, endogenously released into
plasma by skeletal muscle, is used to measure GFR
– Not as accurate as inulin as a small quantity is
secreted into the proximal tubule
– amount excreted > amount filtered
– Reasonably accurate measurement of GFR
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Substances Used to Measure
GFR
• The usual analytical method for creatinine
measurement (alkaline picrate method) also
detects substances in the plasma other than true
creatinine, leading to increase in plasma
creatinine value.
• Thus, these two errors usually cancel each other
and gives a correct estimate of GFR.
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Glomerular Filtration Rate
• Measurement of creatinine concentration in a
urine sample, urine flow rate and plasma
creatinine concentration can be used to
determine GFR
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GFR
• Only 15 – 20 % of plasma entering glomerulus filtered
• Composition of filtrate:
Similar to plasma BUT NO large proteins or cells
• Determined by filtration barrier:
- size: < 20 Å
- between 20 – 40 Å depends on charge
- electrical charge: -ve charged proteins not filtered
(i.e. most plasma proteins)
- > 42 Å not filtered
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Regulation of GFR & RBF
• Intrinsic Autoregulation:
- Renal vasculature also exhibits a well developed
intrinsic ability to adjust its resistance in response
to changes in arterial BP and thus to keep BF and
GFR essentially constant = autoregulation.
- In man, effective over a range of MBP from 75160mmHg. Below 75mmHg, filtration falls and
ceases altogether when MBP = 50mmHg.
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Regulation of GFR & RBF
• If mean arterial P , there is an automatic  in afferent
arteriolar constriction, preventing a rise in glomerular
pressure . Dilatation occurs if P falls.
• Autoregulation is independent of nerves or hormones,
occurs in denervated and in isolated perfused
kidneys.
• 2 mechanisms are responsible for the autoregulation:
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1) Myogenic mechanism
• normal response of
vascular smooth muscle
• that is, increased stretch
due to pressure rise
depolarises the cells,
calcium enters and
causes a vasoconstriction
• well developed in the
kidney
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2) Tubuloglomerular feedback
• [NaCl] dependent mechanism
• macula densa cells in JGA detect [NaCl] send signals
to afferent arteriole
• e.g.  GFR =  [NaCl] filtrate
• sensed by JGA  arteriole constricts
• (resistance    blood flow)
mediator unknown ?? Adenosine/Renin
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Sympathetic Regulation of GFR
• Stimulates
vasoconstriction of
afferent arterioles.
– Preserves blood volume
to muscles and heart.
• Cardiovascular shock:
– Decreases glomerular
capillary hydrostatic
pressure.
– Decreases urine output
(UO).
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Extrinsic Regulation
1) Neurogenic factors
 Sympathetic Nerve Fiber: is the major NF to kidney.
Stimulation of sympathetic NF causes renal
vasoconstriction and results in decrease of RBF and
GFR.
 There are some parasympathetic NF to efferent
arterioles, most predominantly to juxtamedullary
nephrons and sphincters of vasa recta. Stimulation
of parasympathtic NF causes renal vasodilation and
results in increase in RBF and GFR.
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Extrinsic Regulation
2) Humoral and pharmacological factors:
 Epinephrine, Nor-Epinephrine, Angiotensin II,
Prostaglandin (F), and Thromboxane cause
renal vasoconstriction and results in decrease in
RBF and GFR.
 Acetylcholine, Bradykinin, Prostaglandin (D, E,
and I), and bacterial pyogens cause renal
vasodilation and results in increase in RBF and
GFR.
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Extrinsic Regulation
3) Physiological Stress: cold, deep anesthesia, fright,
sever exercise, hypoxia and ischemia stimulate
sympathetic NF leading to renal vasoconstriction and
decrease in RBF.
4) Posture: RBF increase in supine than sitting than
standing.
Changing the posture from lying to standing leads to a
decrease of about 15% in RBF due to the stimulation
of sympathetic NF.
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• Normal
• Afferent arteriolar
constriction
• Efferent arteriolar
constriction
• Efferent arteriolar
dilatation
• Afferent arteriolar
dilatation
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Plasma Clearance
Definition:
– The clearance value of a certain substance 
(means the vol. of plasma which is cleared from
this substance by the kidney (in urine) /min.
Calculation:
– It is calculated by applying the formula U x V /
P where:
• (V) = Vol. of urine (ml) /min.
• (U) = Conc. of the substance mg/ml urine.
• (P) = Conc. of the substance mg/ml plasma.
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Plasma Clearance
Any exogenous substance used in plasma
clearance tests should have the following
properties:
• Stays in the plasma i.e. does not enter the
RBC’s.
• Does not affect the renal functions.
• Not metabolized by the kidney.
• Easily measured in plasma & urine.
• Non toxic.
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Renal Clearance
• If the substance is freely filtered at the glomeruli and
is not reabsorbed, secreted or metabolized in the
nephron, then
– amount filtered per minute = amount excreted per minute
– [sub]urine x urine flow rate = [sub]plasma x glomerular filtration
rate
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Renal Clearance
Advantages:
• Plasma clearance tests can be used for:
– Measurement of the glomerular filtration rate.
– Measurement of the renal plasma flow rate (&
from there we can calculate the renal blood
flow rate).
– Determining the renal handling of the different
substances; whether or not the substance is
reabsorbed or secreted by the renal tubules.
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• Clearance measurements are also used to examine
renal management of substances absorbed or
secreted by the kidney.
For substances secreted by the kidney
• GFR.Ps + T
= Us.V
(T = amount transported)
What goes
into the nephrons
What leaves the
nephrons
• C = UV/P
Cs > Cin Secretion into nephrons is occurring
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For substances absorbed by the nephrons
• GFR.Ps
=
What goes
Into the nephrons
T + Us.V
(T = amount transported)
What leaves
the nephrons
GFR.Ps - Us.V = T
C = UV/P
Csubs< Cinulin Absorption from nephrons is occurring
Us.V = normally zero for glucose & amino acids.
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P.A.H.A
• Used to measure the RBF.
Properties of P.A.H.A:
1) When present below a certain conc. in the blood
– They are completely removed by a single circulation
through the kidney. This is because:
• They are easily filtered.
• They are secreted by renal tubules.
• They are not reabsorbed after filtration.
2) Not enter RBC’s or other tissue cells.
3) Not metabolized by tissues. 4) Not toxic.
5) Not adsorbed to the unfiltrated plasma proteins.
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Urea Clearance Test:
•
•
•
•
The patient evacuates his bladder, then drinks a glass of water.
After 1 hr  blood & urine samples are taken & he drinks another glass of
water.
After 2 hrs  another urine sample is taken.
The urine vol. /min. is calculated.
– If it is above 2 ml /min  we get the maximal urea clearance.
MC = (U) x (V) / (P)
= 75 ml /min. (normally).
– If it is below 2 ml /min  we get the standard urea clerance.
SC = (U) x (V) / (P) = 54 ml /min. (normally)
(U) = Conc. of urea in 1 ml urine.
(V) = Vol. of urine /min.
(P) = Conc. of urea in 1 ml plasma.
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Filtered Load
• Filtered load
– Quantity filtered at the glomerulus per min
• Filtered load of S = [S]plasma X GFR
• Normal [Glucose]plasma = 100mg/100ml
• Filtered load of glucose = 100mg/100ml x 125ml/min
= 125mg/ml
• [Glucose]plasma a Filtered load of glucose
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• WHAT GOES INTO THE NEPHRONS
• Amount of substance filtered /min
• GFR x [Plasma] Substance = TUBULAR (FILTERED)
LOAD (UNITS = mg/min)
Plus
What is secreted into the nephron tubules
WHAT COMES OUT OF THE NEPHRONS
Tubular load + amount secreted
Minus
• amount absorbed by nephrons into renal vein.
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Renal Threshold
• When the plasma concentration of the substance is
beyond it  the substance begins to appear in urine.
• At this level  the filtered load exceeds the
absorptive capacity of the tubules.
• Substances of high threshold: glucose, amino acids &
vitamins.
• Substances of medium threshold: K+ & urea.
• Substances of low threshold: phosphate & uric acid.
• Substances of no threshold: creatinine, mannitol &
inulin.
Renal Threshold
Notice:
•Appearance of glucose in urine before the
transport maximum is reached is termed “Splay”
and results from:
– Nephron variability: “in glomerular size & tubular
length”.
– Variability in the number of glucose carriers & the
transport rate of the carriers.
Tubular transport maximum
• Definition:
It is the maximal amount of a substance (in
mg) which can be transported (reabsorbed
or secreted) by tubular cells/min.
Tubular Transport Maximum
• Many substances are reabsorbed by carrier
mediated transport systems e.g. glucose, amino
acids, organic acids, sulphate and phosphate ions.
• Carriers have a maximum transport capacity (Tm)
which is due to saturation of the carriers. If Tm is
exceeded, then the excess substrate enters the
urine.
• Glucose is freely filtered, so whatever its [plasma]
that will be filtered.
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Tubular Transport Maximum
• In man for plasma glucose up to 10 mmoles/l, all will be
reabsorbed. Beyond this level of plasma [glucose], it
appears in the urine = Renal plasma threshold for
glucose.
• (If plasma [glucose] = 15 mmoles/l, 15 will be filtered,
10 reabsorbed and 5 excreted.)
• Kidney does NOT regulate [glucose], (insulin and
glucagon). Normal [glucose] of 5 mmoles/l, so Tm is set
way above any possible level of (non-diabetic) [glucose].
Thus, ensure that all this valuable nutrient is normally
reabsorbed. The appearance of glucose in the urine of
diabetic patients = glycosuria, is due to failure of insulin,
NOT, the kidney.
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a = Renal Threshold G
b = T maximum glucose (TmG)
(b)
(a)
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Tubular Transport Maximum
• For amino acids, Tm also very high  no urinary
excretion occurs.
• However, kidney does regulate some substances by
means of the Tm mechanism, eg sulphate and
phosphate ions. This is because Tm is set at a level
whereby the normal [plasma] causes saturation so
any  above the normal level will be excreted,
therefore achieving its plasma regulation. (Also
subject to PTH regulation for phosphate, PTH 
reabsorption).
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