Renal Plasma Clearance

Question 1

List the forces controlling the filtration rate.

Answer 1

FAVOURING FILTRATION:
- glomerular capillary pressure (Pgc) = 60 mmHg

OPPOSING FILTRATION:

• hydrostatic pressure in the Bowman’s space (Pbs) = 15 mmHg
• osmotic force of plasma proteins (πgc) = 29 mmHg

Pgc - Pbs - πgc = 16 mmHg (net filtration pressure)

Question 2

Why is the GFR important?

Answer 2

• the GFR contributes to the rapid removal of waste products
• the GFR is around 180 L/day, and the plasma volume is about 3 L, meaning that the entire plasma can be filtered around 60 times a day
• the GFR is determined by a combination of factors (such as hydrostatic and oncotic pressures across the capillary membranes, and the permeability of the capillary filtration barrier and the surface area available)
• a change in any of these factors will change GFR

Hence, the GFR is an important clinical indicator of functioning of nephrons (renal function).

Question 3

How do we measure GFR?

Answer 3

We measure it using a substance that is freely filtered, but neither reabsorbed nor secreted. Hence, its excretion rate is equal to the rate at which it is filtered (eg. creatinine).

Question 4

What is the inulin method?

Answer 4

Inulin is an inert polysaccharide, with a molecular weight of about 5000.
It filters freely through the glomerular membrane. It is not absorbed, secreted or metabolised.

Question 5

Using the inulin method, what is the equation for measuring GFR?

Answer 5

GFR = (Uin x V*)/ Pin

GFR is in ml/min, Pin is plasma inulin concentration in mg/ml, Uin is urine inulin concentration in mg/ml and V* is urine flow rate in ml/min.

Question 6

What is the definition of renal clearance?

Answer 6

The renal clearance of a substance is the volume of plasma that is completely cleared of the substance by the kidney per unit of time (ie. excreted in the urine each minute, expressed in ml/min).

Question 7

What is the renal clearance formula?

Answer 7

Cs = (Us x V*) / Ps

Cs is the clearance rate of a substance, Ps is the plasma concentration of the substance, Us is the urinary concentration of the substance and V* is the urinary flow rate.

Question 8

List some drawbacks of the inulin method, and name the other method normally used instead.

Answer 8

• it has prolonged infusion
• we need repeated plasma samples
• it has difficult routine clinical use

Instead, we would clinically use creatinine for GFR measurement.

Question 9

List some advantages and disadvantages of using the creatinine method for measuring GFR?

Answer 9

ADVANTAGES:

• an intrinsic inert substance
• release at a steady level into the plasma from the skeletal muscle
• no infusion needed
• freely filtered
• not reabsorbed in the tubule

DISADVANTAGES:

• some is secreted into the tubule
• thus the GFR would be slightly higher (at 150 ml/min, rather than 125 ml/min)

Question 10

Describe how trimethoprim affects creatinine serum levels.

Answer 10

Trimethoprim competes with creatinine for the same transporters that secrete creatinine from the tubular blood into the urine, thus increasing the serum levels of creatinine.

Trimethoprim competitively inhibits renal tubular creatinine secretion and may cause an artificial increase in serum creatinine, particularly in patients with a pre-existing renal insufficiency. However, the GFR is unchanged.

Question 11

Using the creatinine method, what is the equation for measuring GFR?

Answer 11

GFR ≈ Ccr = (Ucr x V*) / Pcr

Ccr ∝ 1/Pcr

Question 12

How is GFR affected with age?

Answer 12

There is a decline in GFR with age.

To measure GFR, necessary adjustments need to be made for the age, gender, weight, etc.

Question 13

What is eGFR?

Answer 13

eGFR is the estimated Glomerular Filtration Rate.
Sometimes, we use blood tests, age, sex and sometimes other information to estimate the GFR from the MDRD equation.

This isn’t as good as measuring it (eg. 24hr urine collection), but it is much simpler as it requires just one blood test.
It is being used increasingly to spot kidney diseases earlier that would be possible using creatinine measurements.

Question 14

What are some problems faced when using eGFR?

Answer 14

It is only an estimate; a significant error is possible.
eGFR is most likely to be inaccurate in people at extremes of the body (eg. malnourished, amputees, etc.).
It is also not valid for pregnant women, patients older than 70 years old or children.

Also, some race groups may not fit the MDRD equation well, as it was originally validated for American black and white patients.

Question 15

Describe the different stages of CKD, and the treatment at each stage.

Answer 15

STAGE 1: GFR = 90+
There is normal kidney function but the urine, findings, structural abnormalities or genetic traits point to kidney disease.
TREATMENT: observation, control of blood pressure.

STAGE 2: GFR = 60-89
There is mildly reduced kidney function; this and other findings (as in Stage 1) point to kidney disease.
TREATMENT: observation, control of blood pressure and risk factors.

STAGE 3A/3B: (3A) GFR = 45-59, (3B) GFR = 30-44
There is moderately reduced kidney function.
TREATMENT: observation, control of blood pressure and risk factors.

STAGE 4: GFR = 15-29
There is severely reduced kidney function.
TREATMENT: planning for end-stage renal failure.

STAGE 5: GFR = <15, or on dialysis
It is very severe, or end-stage kidney failure (sometimes called established renal failure).
TREATMENT: treatment choices.

Question 16

Compare different clearances.

Answer 16

By comparing the clearance of a substance to inulin (and in effect, GFR) you can tell a lot about the renal handling of that substance.
The clearance of inulin (GFR) is about 125 ml/min in the adult male and 10% less in females.

For a substance with clearance = inulin (= GFR), it’s probably antibiotics, such as streptomycin or gentamycin.
For a substance with clearance < inulin (< GFR), it’s not filtered freely, or it’s reabsorbed from the tubule.
For a substance with clearance > inulin (> GFR), it is secreted into the tubule.

Question 17

What does it tell you about a substance when the clearance < GFR?

Answer 17

1) Either the substance is not freely filtered …
For example, albumin clearance is 0 ml/min. This is similar to drugs bound to albumins, such as digoxin and warfarin.

2) … or the substance is reabsorbed.
This means that is filters freely but is usually absent from the urine as it is completely reabsorbed. For example, the glucose clearance is also 0 ml/min.

Question 18

Describe the glucose handling of the kidney.

Answer 18

15 mM is the renal threshold. Above this threshold, glucose starts to appear in the urine, and then the reabsorption line falls short of the filtration line.

The reabsorption line plateaus at 22 mM. This is known as the Transport Maximum (Tm) for glucose ie. the rate at which the carrier mechanism is fully saturated.

Question 19

List some other substances that are actively reabsorbed and passively reabsorbed.

Answer 19

ACTIVELY REABSORBED:
- all amino acids
- Ca2+, Na+, PO4 2-, Mg2+
- water-soluble vitamins
(all of the above display Tm)

PASSIVELY REABSORBED:

• Cl-
• urea
• some important drugs

Substances that are passively reabsorbed DON’T display Tm because their rate of transport is determined by the other factors (eg. electrochemical gradient, permeability, etc.).

As the glomerular filtrate flows down the tubule and more of the water is reabsorbed, the solutes are concentrated, providing a concentration gradient down which they diffuse. However, only the lipid-soluble substances can cross the tubular wall, so lipophilic drugs tend to return to the bloodstream whilst hydrophilic drugs are lost in the urine.

Question 20

What can we tell about a substance that has its clearance > GFR?

Answer 20

We can tell that it is a substance that is secreted.

• it filters freely
• it is secreted actively against the electrochemical gradient
• endogenous substances would include weak organic acids and bases, adrenaline, dopamine, steroids, etc.
• exogenous substances would include penicillin, probenecid, para-amino hippuric acid (PAH), etc.

Question 21

Describe RPF (renal plasma flow) and RBF (renal blood flow).

Answer 21

RPF is the rate at which plasma flows through the kidney.
The blood consists of about 55% plasma and about 45% cellular components (mostly RBCs).

Estimating the RPF through the kidneys can allow you to estimate the rate of total blood flow through the kidneys.

Question 22

Describe PAH (para-aminohippurate acid).

Answer 22

PAH is a weak acid metabolite found in horse’s urine. It is filtered freely and enters the glomerular filtrate. However, there is still a large amount in the plasma.

The majority of it is secreted back into the proximal convoluted tubule and excreted into the urine. This makes it suitable as a marker to measure renal plasma flow.

Question 23

With PAH secretion, describe the different transport mechanisms across the different membranes.

Answer 23

Active transport occurs in the basolateral membrane.

Passive transport occurs across the luminal membrane into the tubule.

Question 24

With PAH, what is the equation for RPF?

Answer 24

As plasma concentration becomes < 0.12 mg/ml, the PAH-secreting process can completely remove PAH from the capillaries (because the Tm = 80 mg/min)/ The PAH is cleared by a combined process of filtration and secretion.

In other words, the amount of PAH delivered to the kidneys in the blood is equal to the amount excreted in the urine. So:

RPF = (Upah x V*) / [PAH]

Question 25

How do we calculate the renal filtration fraction?

Answer 25

GFR and RPF can be used to calculate the filtration fraction.

Filtration Fraction = GFR/RPF

GFR is determined from inulin clearance, while RPF is determined from PAH clearance.