Glomerular filtration rate (GFR)

Question 1

How many L of blood are filtered by glomeruli? How many are excreted in urine?

Answer 1

180L

only a small fraction of the filtrate (0.6-2.5 litres) is excreted as urine

Question 2

What is the FF? Is it a fixed number? What influences the FF?

Answer 2

The exact proportion between glomerular filtration rate (GFR) and the renal plasma flow (RPF) rate is not fixed but may vary depending on the magnitude of GFR, the composition of the blood and the condition of the glomerular capillary. The ratio of GFR/RPF is called the filtration fraction (FF).

Question 3

Explain Rudolf Heidenhain’s view of GF and what experiment he did to think this.

Answer 3

• Thought renal tubules secrete (things that are not needed by body)
• Experiment: Took rabbits and injected dyes indigo kurmin – taken up by renal tubules cells. When dissecting kidneys, he realized dyes went primarily in cells of proximal tubules at the beginning, and then in lumen of tubules later.

Question 4

Explain Carl Ludwig’s view of GF.

Answer 4

• Thought everything should be explainable in mechanistic terms using the laws of physics
• Said that kidneys must filter a large volume and then reabsorb the volume. But pretty inefficient?
• Would need to filter 70L of fluid per day to get rid of the amount of urea we have in our urine. But nature would never make something so inefficient…
• Truth: Urea is actually reabsorbed by renal tubules, so need to filter 180L per day!

Question 5

Does every species have glomeruli in their kidneys?

Answer 5

No, some fishes don’t have glomeruli but have a tubule

Question 6

What is the glomerular capillary wall made of? (3)

Answer 6

From the inside out:

• Endothelial cells
• The glomerular basement membrane (GBM)
• Visceral epithelial cells

Question 7

Name the 3 cellular components of the glomerulus

Answer 7

1. Epithelial cells (podocytes)
2. Endothelial cells (blood vessels)
3. Mesengial cells (pericytes)

Question 8

Name 2 functions of podocytes.

Answer 8

a. Synthesis of matrix components (in mesengium)

b. Maintenance of capillary wall permeability

Question 9

Name 1 function of the epithelial cells of the glomerulus.

Answer 9

a. Synthesis of matrix components (which go to basement membrane)

Question 10

Name 3 functions of pericytes.

Answer 10

a. Contain contractile elements and receptors for angiotensin II and other factors that regulate renal hemodynamics (thus they contract when stimulated by those different agonists)
b. Contribute to the synthesis of matrix components (which go to mesengium)
c. Have capacity for phagocytosis (cleaning function)

Strategically situated at the branchpoints of the capillaries – control diameter of capillary through contraction –> regulates blood flow; increases and decreases surface area

Question 11

What is a fenestra

Answer 11

spaces between endothelial layer which allow most small solutes to go through

Question 12

How many layers does the glomerular barrier have? what are they?

Answer 12

Glomerular barrier (basement membrane) is tri-layered

1. lamina rara externa,
2. lamina interna
3. lamina densa

Question 13

What is a slit diaphragm

Answer 13

Tight junctions in the glomerular epithelium (visceral epithelium) are specialized for filtration.
They have a pore in the center which discriminates molecules that can go through in terms of size. Smaller than albumin molecules; thus prevents filtration of big proteins
Epithelial cells have slit diaphragm and endothelial cells have fenestra.

Question 14

What synthesizes the components of the GBM and the mesengial matrix?

Answer 14

The epithelial, endothelial, and mesangial cells.

Question 15

Name 4 components of the GBM and mesengial matrix

Answer 15

• Type IV collagen (backbone of the GBM, and main molecular sieve)
• laminin (anchors cells to GBM collagen)
• fibronectin (cell attachment protein)
• heparan sulfate proteoglycan (electronegative barrier)

Question 16

What is type IV collagen? What is its structure? Function?

Answer 16

o distinct from interstitial collagens I, II and III
o triple helical, three domains
o Structural support; forms 2D mesh
o Pressure in glomerular barrier is 10x higher than blood everywhere else. Type 4 collagen allows structural support for higher pressures

Question 17

What is laminin? What is its function? Where is it located?

Answer 17

o Attachment protein
o Concentrated in lamina rara interna and externa
o Important connection for podocytes to GBM

Question 18

What is heparan sulfate proteoglycan ? What is its function? Where is it located?

Answer 18

o Anionic site of the GBM
o Consists of core protein and glycosaminoglycan
o Polypeptide with many sugar groups on them (which are modified to have sulfate – negatively charge)
o Confers charge to whole barrier. Thus the barrier selects not only on the size but also on the charge. We mostly want to avoid filtering negatively charged molecules.
o Distributed throughout the GBM but concentrated in the lamina rara interna and externa
o N-linked and O-linked glycosylation

Question 19

Solutes up to molecular weights of ___ pass quite freely through the glomerulus for filtration

Answer 19

10,000 Da

Question 20

Name 7 examples of molecules that go easily through the glomerulus. Name 4 examples of molecules that don’t. Name 1 exception to the rule.

Answer 20

PASS EASILY:

• E.g. small ions like Na, K and Cl- pass very easily (v. small) – relative concentration in filtrate vs. plasma is 1.0 –> no selection
• Urea, glucose, sucrose, polyethylene glycol –> relatively small too

DON’T PASS EASILY:

• E.g. lysozyme, myoglobin, lactoglobulin, albumin
• Exception: Bence jone protein since it is secreted as a 22kDa protein and then forms a dimer in the urine
• Serum albumin has extremely low permeability because important for oncotic pressure of plasma

Question 21

Name 2 molecules that are nor filtered because of charge. Name a molecule that passes easier than neutral molecules of the same size.

Answer 21

-: plasma protein and sulfated dextrans

+: diethylaminoethyl (DEAE) dextrans

Question 22

Where are molecules restricted to pass in the glomerulus?

Answer 22

there is little if any restriction to the passage of macromolecules by glomerular endothelial cells. Negatively charged macromolecules penetrate only into the proximal layer of the GBM. For neutral and cationic molecules, permeability is progressively enhanced, but passage of most of these molecules is restricted at the GBM. The remainder are restricted by the glomerular epithelial cells at the filtration slit diaphragms. However, it should be noted that in experimental models, injury of only glomerular epithelial cells (with no damage of the GBM) leads to a marked increase in glomerular permeability.

Question 23

What is membraneous glomerulopathy?

Answer 23

We make antibodies against basement membrane components –> can clog up GBM, and mesangial cells can have trouble keeping up with phagocytic needs.

Question 24

What are the 2 starling forces (forces driving filtration)?

Answer 24

1. Hydrostatic pressure (~40-50 mmHg)
   o Difference between BP and pressure within Bowman’s space
2. Colloid osmotic pressure (~15-30 mmHg)
   o Due to proteins in plasma

–> Net pressure ~ 15 mmHg (45-30)

Question 25

What factors are considered in the GFR calculation?

Answer 25

GFR = KF x PUF = KF (PGC -PT -(pi)GC) ``` KF = ultrafiltration coefficient; includes factors of hydraulic permeability and surface area for filtration PUF = net ultrafiltration capillary ``` ``` PT = hydraulic pressure in bowman's space piGC = oncotic pressure in the glomerular capillary plasma ```

Question 26

How do the hydrostatic and colloid osmotic pressures change during filtration?

Answer 26

Whereas the hydrostatic pressures in the capillary and in Bowman's space remain virtually constant, the plasma oncotic pressure increases as a direct consequence of ultrafiltration.

Question 27

How does glomerular capillary hydrostatic pressure stay constant throughout the capillary length?

Answer 27

Capillaries have large cross-sectional areas compared to the afferent arteriole, so relatively little resistance = no pressure drop

Question 28

Describe the pressure changes when going from the afferent arteriole to the efferent arteriole

Answer 28

Afferent arterioles and efferent arterioles create a hydrostatic pressure drop by creating a resistance point. Bowman’s capsule doesn’t empty immediately so it can create some sort of back pressure. So, the hydrostatic pressure shown in the image is P (in lumen) – P (in Bowman’s capsule) The net hydrostatic pressure stays relatively constant through capillaries (as Ludwig had guessed), then pressure drops after resistance in entry of efferent arteriole. Oncotic pressure starts low then increases gradually. Doesn’t reach equilibrium (we’re not sure) Everything reverses in efferent arteriole: High oncotic P but low hydrostatic P.

Question 29

Name 2 pathways that can influence GFR.

Answer 29

1. elevating blood pressure above the autoregulatory range. 2. an intrarenal mechanism that senses correlates of flow through the distal tubule acts to reduce the filtration rate of the same nephron - the so-called "tubulo- glomerular feedback" mechanism. The macula densa cells of the distal tubule are thought to be the sensing site in the feedback pathway, since they are immediately adjacent to the vascular pole of the glomerulus of the same nephron.

Question 30

What is clearance?

Answer 30

How much of a substance can be removed from the plasma in a given period of time (often 1 minute) Measure of renal function

Question 31

Name 3 advantages of the clearance calculations

Answer 31

1. Simple 2. Gives overall assessment of renal handling of the solute (can use the clearance of a marker) 3. Virtually the only in vivo method available for use on patients

Question 32

Name 3 disadvantages of the clearance calculations

Answer 32

1. Provides no information regarding location of the transport process (i.e. which segment; where are things happening?) or mechanism (active? Passive?) 2. Provides a minimum estimate for transport (secretion then absorption? We don’t know because we only see the net effect) 3. Flux could be active or passive

Question 33

What measures does clearance measures involve?

Answer 33

measuring the concentration of a substance in the plasma and urine and the volume of urine flow.

Question 34

What is the clearance calculation? What is its unit?

Answer 34

Clearance = ([X]u x Vu) / [X]p ``` [X]U = concentration of substance X in urine (mg/ml) V = urine flow rate (ml/min) [X]P = concentration of X in plasma (mg/ml) ``` Thus, clearance has the units ml/min. It is the minimum volume of plasma from which the kidney could, in one minute's time, remove all substance X.

Question 35

From calculating the clearance rate of a substance, what can you do to know if they are absorbed or secreted?

Answer 35

The clearance rate of inulin provides a measure of glomerular filtration rate (GFR) and can be compared with that of other substances to assess whether they are absorbed or secreted.

Question 36

What is the formula to calculate the amount reabsorbed? secreted?

Answer 36

Reabsorbed: (GFR • Ps) = Us • V + Ts Ts = (GFR • Ps) – Us • V Secreted: Us • V = (GFR • Ps) + Ts Ts = Us • V - (GFR • Ps

Question 37

Name examples of molecules that are: 1. Filtered only 2. Filtered and absorbed 3. Filtered ans secreted 4. Filtered, reabsorbed and secreted

Answer 37

1. Inulin 2. Glucose 3. PAH 4. Potassium

Question 38

What is inulin? Why is it useful?

Answer 38

Inulin a polysaccharide that is not absorbed or secreted (not even found in body normally), therefore its clearance provides an accurate measurement of GFR. It is: - Able to get through the glomerular barrier without hindrance (small enough) - Not reabsorbed or secreted Provides a very good marker of the filtration rate. Clearance of inulin = GFR

Question 39

What is creatinine? What is it useful for?

Answer 39

Creatinine, a product of muscle metabolism that is constantly produced and excreted, is a clinically useful indicator of renal failure because its steady-state concentration in plasma varies directly with GFR.

Question 40

What is puraminohypurate and what is it useful for?

Answer 40

Puraminohypurate: inorganic acid, similar to benzoate (soft drinks) – filtered and secreted by proximal tubule. Relatively efficiently secreted. Clearance = rate of presentation to kidney. More PAH = more secreted. Used as a marker for renal plasma flow.

Question 41

The amount of any substance filtered per unit time is given by which formula?

Answer 41

the product of the GFR and the filterable plasma concentration of the substance

Question 42

The concentration of calcium in Bowman’s capsule is 3 mM, whereas its plasma concentration is 5 mM. How do you explain this?

Answer 42

The calcium ion is small, but approximately 40% is bound to proteins and so is not filterable.

Question 43

An increase in the plasma concentration of inulin causes which of the following in the renal clearance of inulin: a) Increase b) Decrease c) No change

Answer 43

No change. CIn = UInV/PIn . When PIn increases, there is no change in CIn because inulin is freely filtered and neither reabsorbed nor secreted, therefore UIn rises by an identical amount. Thus the mass of inulin filtered and excreted increases, but the volume of plasma supplying this inulin, i.e., completely cleared of inulin, is unaltered.

Question 44

How does clearance change in diabetic nephropathy?

Answer 44

In diabetic nephropathy there is a reduction in the fractional clearance of neutral dextrans of radius < 40 angstroms, but an increase for dextrans > 45 angstroms (Fig. 2.6). A similar pattern has been observed in several human glomerulonephritides.