1. Renal Physiology 3: Renal Clearance
Ahmad Ahmeda
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2. 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.

3. Glomerular Filtration Rate

4. 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 L/day

5. 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

7. Glomerular Filtration Rate
Measurement of creatinine concentration in a urine sample, urine flow rate and plasma creatinine concentration can be used to determine GFR

8. 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 human, effective over a range of BP from mmHg. Below 75mmHg, filtration falls and ceases altogether when MBP = 50mmHg.

9. 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:

10. 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

11. 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

13. 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).

14. Extrinsic Regulation 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.

15. Extrinsic Regulation
Physiological Stress: cold, deep anesthesia, fright, sever exercise, hypoxia and ischemia stimulate sympathetic NF leading to renal vasoconstriction and decrease in RBF.
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.

16. Normal
Afferent arteriolar constriction
Efferent arteriolar constriction
Efferent arteriolar dilatation
Afferent arteriolar dilatation

17. 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.

18. 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.

19. 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]plasma x glomerular filtration rate = [sub]urine x urine flow rate

21. 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.

22. For substances secreted by the kidney
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 What leaves the
into the nephrons nephrons
C = UV/P
Cs > Cin Secretion into nephrons is occurring

23. For substances absorbed by the nephrons
GFR.Ps = T + Us.V (T = amount transported)
What goes What leaves
Into the nephrons 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.

24. P.A.H.A Used to measure the RBF. Properties of P.A.H.A:
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.

25. 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.

27. Thanks