Glomerular Filtration and its Control

Question 1

List the main functions of the renal system.

Answer 1

• Regulation of ECF volume and blood pressure
• Regulation of osmolality
• Maintenance of ion balance
• Regulation of pH
• Excretion of waste
• Production of hormones

Question 2

Describe (and be able to draw) the structure of the nephron.

Answer 2

Nephrons are the structural and functional units of the kidneys.

Each nephron consists of a glomerulus, a tuft of capillaries associated with a renal tubule.
The cup-shaped end of the renal tubule, the glomerular capsule (or Bowman’s capsule ) is blind and completely surrounds the glomerulus (much as a well-worn baseball glove encloses a ball). Collectively, the glomerular capsule and the enclosed glomerulus are called the renal corpuscle.

Eventually, there are thousands of collecting ducts, each of which collects urine from several nephrons and conveys it to the renal pelvis.

For drawing of nephron, refer to lecture page 2, third slide.

Question 3

Describe the structure of the glomerulus and glomerular capsule, and their properties.

Answer 3

“The glomerulus is a ball of capillaries surrounded by the Bowman’s capsule into which urine is filtered. Blood enters the capillaries of the glomerulus by a single arteriole called an afferent arteriole and leaves by an efferent arteriole.”

The glomerular endothelium is fenestrated (penetrated by many pores), which makes these capillaries exceptionally porous. They allow large amounts of solute-rich, virtually protein-free fluid to pass from the blood into the glomerular capsule. This plasma-derived fluid or filtrate is the raw material that the renal tubules process to form urine.

The external parietal layer of the glomerular capsule is simple squamous epithelium. This layer simply contributes to the capsule structure and plays no part in forming filtrate. The visceral layer, which clings to the glomerulus, consists of highly modified, branching epithelial cells called podocytes (“foot cells”). The octopus-like podocytes terminate in foot processes, which intertwine as they cling to the basement membrane of the glomerulus. The clefts or openings between the foot processes, called filtration slits or slit pores, allow the filtrate to enter the capsular space inside the glomerular capsule.

Question 4

Define filtration membrane.

Answer 4

The filtration membrane lies between the blood and the interior of the glomerular capsule. It is a porous membrane that allows free passage of water and solutes smaller than plasma proteins.

Question 5

Define Juxtaglomerular apparatus and identify the components of the Juxtaglomerular apparatus of a nephron.

Answer 5

Each nephron has a region called a juxtaglomerular apparatus (JGA), where the initial portion of its coiling DCT lies against the afferent arteriole feeding the glomerulus. Both structures are modified at the point of contact.

The JGA is made up of:
1) Juxtaglomerular cells of the arterioles (enlarged, smooth muscle cells with prominent secretory granules containing renin. JG cells act as mechanoreceptors that sense the blood pressure in the afferent arteriole)

2) Macula densa cells of the distal tubule (group of tall, closely packed DCT cells that lies adjacent to the JG cells. These cells act as chemoreceptors (or osmoreceptors) that respond to changes in the solute content of the filtrate)
3) Mesangial cells (surrounding the glomerular capillaries, have phagocytic and contractile properties. The contractile state of these cells influences the total surface area of the capillaries available for filtration)

Question 6

Briefly identify the main parts of the renal tubule, stating where in the kidney each part lies.

Answer 6

It leaves the glomerular capsule as the elaborately coiled proximal convoluted tubule (PCT)- Renal Cortex

Makes a hairpin loop called the loop of Henle- Mainly in Medulla

Winds and twists again as the distal convoluted tubule (DCT)- Renal Cortex

Before emptying into a collecting duct- Medulla

Question 7

Describe the path of collecting ducts, stating where they drain.

Answer 7

The collecting ducts, each of which receives filtrate from many nephrons, run through the medullary pyramids and give them their striped appearance. As the collecting ducts approach the renal pelvis, they fuse to form the large papillary ducts, which deliver urine into the minor calyces via papillae of the pyramids.

Question 8

What are the main kinds of nephrons ?

Answer 8

Cortical nephrons represent 85% of the nephrons in the kidneys. Except for small parts of their loops of Henle that dip into the outer medulla, they are located entirely in the cortex.

The remaining juxtamedullary nephrons are located close to the cortex-medulla junction, and they play an important role in the kidney’s ability to produce concentrated urine. Their loops of Henle deeply invade the medulla, and their thin segments are much more extensive than those of cortical nephrons. (efferent arterioles serving the juxtamedullary nephrons tend not to break up into peritubular capillaries. Instead they form bundles of long straight vessels called vasa recta that extend deep into the medulla paralleling the longest loops of Henle. The thin-walled vasa recta play an important role in forming concentrated urine).

Question 9

Describe the main components of the microvasculature of the nephron, and their functions.

Answer 9

Microvasculature of the nephrons consists of two capillary beds separated by intervening efferent arterioles. The first capillary bed (glomerulus) produces the filtrate. The second (peri-tubular capillaries) reclaims most of that filtrate.

1) GLOMERULUS, in which the capillaries run in parallel, is specialized for filtration. Both fed and drained by arterioles–the afferent arteriole and the efferent arteriole, respectively. The afferent arterioles arise from the interlobular arteries that run through the renal cortex. Because (1) arterioles are high-resistance vessels and (2) the afferent arteriole has a larger diameter than the efferent, the blood pressure in the glomerulus is extraordinarily high for a capillary bed and easily forces fluid and solutes out of the blood into the glomerular capsule. Most of this filtrate (99%) is reabsorbed by the renal tubule cells and returned to the blood in the peritubular capillary beds.
2) PERITUBULAR CAPILLARIES arise from the efferent arterioles draining the glomeruli. These capillaries cling closely to adjacent renal tubules and empty into nearby venules. They are low-pressure, porous capillaries that readily absorb solutes and water from the tubule cells as these substances are reclaimed from the filtrate.

Question 10

Describe the blood pressure existing at various points in the nephron, including the implications of such blood pressures on the peritubular capillaries.

Answer 10

Blood flowing through the renal circulation encounters high resistance, first in the afferent and then in the efferent arterioles. As a result, renal blood pressure declines from approximately 95 mm Hg in the renal arteries to 8 mm Hg or less in the renal veins. The resistance of the afferent arterioles protects the glomeruli from large fluctuations in systemic blood pressure. Resistance in the efferent arterioles reinforces the high glomerular pressure and reduces the hydrostatic pressure in the peritubular capillaries.

Question 11

Identify the cell populations which play important roles in regulating the rate of filtrate formation and systemic blood pressure.

Answer 11

JG cells

Macula densa cells

Question 12

Identify the main components of the filtration membrane. Which types of cells does each component prevent/allow the entry of ?

Answer 12

Its three layers are:

(1) the fenestrated endothelium of the glomerular capillaries (allow passage of all plasma components but not blood cells)
(2) the visceral membrane of the glomerular capsule made of podocytes
(3) the intervening basement membrane composed of the fused basal laminae of the other layers (restricts all but the smallest proteins while permitting most other solutes to pass + seems to confer electrical selectivity on the filtration process: most of the proteins in the membrane are negatively charged glycoproteins that repel other macromolecular anions and hinder their passage into the tubule. Because most plasma proteins also bear a net negative charge, this electrical repulsion reinforces the plasma protein blockage imposed by molecular size. Macromolecules that do manage to make it through the basement membrane may still be blocked by thin membranes (slit diaphragms) that extend across the filtration slits)

Question 13

What happens to macromolecules which get “hung up” in the filtration membrane ?

Answer 13

They are engulfed by podocytes and degraded.

Question 14

Explain how the glomerular filtrate is produced, identify the forces responsible for this filtration process, and explaining how different size molecules pass or do not.

Answer 14

♦ Glomerular filtration is a passive, nonselective process in which hydrostatic pressure forces fluids and solutes through a membrane.

♦ The net filtration pressure (NFP), responsible for filtrate formation, involves Starling forces acting at the glomerular bed:

1) Glomerular hydrostatic pressure (HP g), essentially glomerular blood pressure (the chief force pushing water and solutes out of the blood and across the filtration membrane). Value is + 55 mm Hg.
2) Colloid osmotic pressure in the intracapsular space of the glomerular capsule (theoretically “pulls” the filtrate into the tubule, but this pressure is essentially zero because virtually no proteins enter the capsule). Value is 0 mm Hg.
3) Colloid osmotic (oncotic) pressure of glmerular blood (OP g) (drive fluids back into glomerular capillaries). Value is 30 mm Hg.
(4) Capsular hydrostatic pressure (HP c) exerted by fluids in the glomerular capsule (drive fluids back into glomerular capillaries). Value is 15 mm Hg.

Thus, the NFP responsible for forming renal filtrate from plasma is 10 mm Hg (Note: net hydrostatic pressure in Bowmans also drives fluid round the tubule)

♦ Triple barrier allows:

• Free passage of solutes up to ~60 kDa (e.g. water, glucose, amino acids, and nitrogenous wastes) from the blood into the renal tubule.
• Cells and larger molecules pass with greater difficulty, and those larger than 7-9 nm are generally barred from entering the tubule.
• Negatively charged molecules are filtered less easily than positively charged molecules

Question 15

Does filtrate formation consume metabolic energy ?

Answer 15

Filtrate formation does NOT consume metabolic energy, so the glomeruli can be viewed as simple mechanical filters.

Question 16

Which factors make the glomerulus a more efficient filter than other capillary beds ? What is the implication of this ?

Answer 16

The glomerulus is a much more efficient filter than are other capillary beds because

(1) its filtration membrane has a large surface area and is thousands of times more permeable to water and solutes, and
(2) glomerular blood pressure is much higher than that in other capillary beds (approximately 55 mm Hg as opposed to 18 mm Hg or less),

Resulting in a much higher net filtration pressure. This is why the kidneys produce about 180 L of filtrate daily, in contrast to the 3 to 4 L formed daily by all other capillary beds of the body combined.

Question 17

Identify the main processes that occur in the nephron.

Answer 17

Step 1: Filtration by glomerulus
Step 2: Obligatory absorption and secretion by proximal tubule
Step 3: Generation of osmotic gradient by loop of Henle
Step 4: Regulated absorption and secretion by distal tubule
Step 5: Regulation of water uptake by collecting ducts

Question 18

Comment on the relative concentrations of a) small solutes
b) plasma proteins
in blood and glomerular filtrate.

Answer 18

a) Usually show similar concentrations in the blood and the glomerular filtrate, because free passage of small solutes from blood to filtrate.
b) Much higher concentration in blood than glomerular filtrate, because molecules larger than 7-9 nm are generally barred from entering the tubule. This maintains the colloid osmotic (oncotic) pressure of the glomerular blood, preventing the loss of all its water to the renal tubules.

Question 19

Define, and give a value for Renal Blood Flow (RBF). How much is that relative to total CO ?

Answer 19

Total amount of blood that traverses renal artery or vein per unit time = 1100ml/min (1 – 1.2 L/min). (20 – 25% of cardiac output)

BUT intra-renal differences may occur between nephrons in the cortex and medulla and change with hydration state.

Question 20

Define, and give a value for Renal Plasma Flow (RBF) if haematocrit is 45%.

Answer 20

• Total amount of plasma that traverses renal artery or vein per unit time.
• If Haematocrit = 45%, R.P.F = 55% x 1100 = 600 ml/min

Question 21

Define GFR. State the normal range of this. What factors affect GFR ?

Answer 21

Glomerular filtration rate (GFR)= volume of filtrate formed each minute by the combined activity of all 2 million glomeruli of the kidneys
– normally 125-130 ml/min when the size of the body is corrected for.

Factors governing filtration rate at the capillary beds are (1) total surface area available for filtration, (2) filtration membrane permeability, and (3) NFP.

Because glomerular capillaries are exceptionally permeable and have a huge surface area, huge amounts of filtrate can be produced even with the usual modest NFP of 10 mm Hg. The opposite side of this “coin” is that a drop in glomerular pressure of only 15% stops filtration altogether.

Question 22

How does size and age affect GFR ?

Answer 22

Larger bodies = larger GFR

Higher age = lower GFR

Question 23

What are possible effects of changes in the pressures acting at the filtration membrane on GFR ?

Answer 23

Because the GFR is directly proportional to the NFP, any change in any of the pressures acting at the filtration membrane changes both the NFP and the GFR. An increase in arterial (and glomerular) blood pressure in the kidneys increases the GFR, whereas dehydration (which causes an increase in glomerular osmotic pressure) inhibits filtrate formation.

Question 24

Why is keeping a relatively constant GFR important ?

Answer 24

Maintaining a fairly constant GFR is important because reabsorption of water and other substances from the filtrate depends partly on the rate at which it flows through the renal tubules. If massive amounts of filtrate form the flow is too rapid for needed substances to be reabsorbed fast enough and some are lost in urine. When filtrate is scanty and flows slowly, nearly all of it is reabsorbed, including most of the wastes that are normally disposed of. In either case, a diseased state exists.

Question 25

Describe how glomerular filtration rate is controlled.

Answer 25

GFR is held relatively constant by both intrinsic (renal autoregulation) and extrinsic (neural and hormonal) controls which regulate renal blood flow.

1) INTRINSIC (RENAL AUTOREGULATION): By adjusting its own resistance to blood flow, a process called renal autoregulation, the kidney can maintain a nearly constant GFR despite fluctuations in systemic arterial blood pressure.
Two types of controls:

a) Myogenic mechanism
Increasing systemic blood pressure causes the afferent arterioles to constrict (because stretch, sensed by stretch receptors in arterioles, results in smooth muscle contraction), which restricts blood flow into the glomerulus and prevents glomerular blood pressure from rising to damaging levels. Declining systemic blood pressure causes dilation of afferent arterioles and raises glomerular hydrostatic pressure. Both responses help maintain a normal GFR.

b) Tubuloglomerular feedback mechanism (nephrogenic)
“directed” by the macula densa cells of the juxtaglomerular apparatus. These cells, respond to filtrate flow rate and osmotic signals. When the macula densa cells are exposed to slowly flowing filtrate or filtrate with low osmolality, their signals promote vasodilation of the afferent arterioles. This allows more blood to flow into the glomerulus, thus increasing the NFP and GFR. On the other hand, when the filtrate is flowing rapidly and/or it has a high sodium and chloride content, or high osmolality in general, (in conditions of high filtrate flow in the tubule there is an increase in the Na+ and Ca2+ concentrations), the macula densa cells prompt generation of a vasoconstrictor chemical that causes intense renal vasconstriction. This hinders blood flow into the glomerulus, which decreases the GFR and allows more time for filtrate processing. The macula densa cells also send a signal to the JG cells of the juxtaglomerular apparatus that sets the renin-angiotensin mechanism into motion.

2) EXTRINSIC

a) Nervous
When the volume of the extracellular fluid is normal and the sympathetic nervous system is at rest, the renal blood vessels are maximally dilated and renal autoregulation mechanisms prevail. However, during extreme stress or emergency when it is necessary to shunt blood to vital organs, neural controls may overcome renal autoregulatory mechanisms. Norepinephrine, released by sympathetic nerve fibers (and epinephrine released by the adrenal medulla) acts on alpha-adrenergic receptors on vascular smooth muscle, strongly constricting afferent arterioles, thereby inhibiting filtrate formation. This, in turn, indirectly trips the renin-angiotensin mechanism by stimulating the macula densa cells. The sympathetic nervous system also directly stimulates the JG cells to release renin,

b) Hormonal
- Reninangiotensin mechanism is triggered when various stimuli cause the JG cells to release renin. The enzyme renin acts on angiotensinogen, to release angiotensin I, which is converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II, a potent vasoconstrictor, activates smooth muscle of arterioles throughout the body, raising mean arterial blood pressure. By binding to receptors on the luminal membranes of the kidney tubule cells, angiotensin II activates a Na + /H + exchanger, thus increasing Na + reabsorption in the PCT cells. It also stimulates the adrenal cortex to release aldosterone, which causes the renal tubules to reclaim more sodium ions from the filtrate. Because water follows sodium osmotically, blood volume and blood pressure rise. Because the afferent arterioles sport fewer angiotensin receptors than do the efferent arterioles, angiotensin II causes the efferent arterioles to constrict to a greater extent, thereby increasing the glomerular hydrostatic (blood) pressure. This defensive mechanism partially restores the GFR to normal levels. Angio-tensin II also targets the mesangial cells associated with the glomerulus, causing them to contract and reduce the GFR (and afferent BF) by decreasing the total surface area of glomerular capillaries available for filtration.
- Sympathetic nerves release norepinephrine, and circulating epinephrine also result in vasoconstriction (which results in decreased afferent blood flow)
- Renal prostaglandins and Atrial natriuretic peptide result in vasodilation (which results in increased afferent blood flow)

Question 26

Autoregulation maintains blood flow over what BP ranges ?

Answer 26

Autoregulatory mechanisms maintain a relatively constant blood flow through the kidneys over an arterial pressure range from about 80 to 180 mm Hg. Consequently, large changes in water and solute excretion are prevented. However, the intrinsic controls cannot handle extremely low systemic blood pressure, such as might result from serious hemorrhage (hypovolemic shock). Once mean systemic blood pressure drops below 90 mm Hg, autoregulation ceases.

Question 27

State what happens to GFR upon constriction and dilation of both afferent and efferent arterioles.

Answer 27

AFFERENT ARTERIOLES
Constriction- Reduces filtration P, so GFR falls.
Dilation- Increases P driving ultrafiltration, so GFR increases.

EFFERENT ARTERIOLES
Constriction- Causes P to back up within capillary. GFR increases.
Dilation- Allows blood to easily escape the capillary and P falls. GFR falls.

Question 28

Draw a diagram showing change in RBF and GFR with changing Arterial BP.

Answer 28

RBF essentially constant over wide range of BP. Hence GFR essentially constant over wide range of BP.

Refer to lecture slides, page 7 second slide.

Question 29

Identify factors which can result in the release of renin (and therefore trigger the renin-angiotensin mechanism as part of the extrinsic control of GFR).

Answer 29

1) Reduced stretch of the granular JG cells. A drop in mean systemic blood pressure below 80 mm Hg (as might be due to hemorrhage, dehydration, etc.) reduces the stretch of the JG cells and stimulates them to release more renin.
2) Stimulation of the JG cells by input from activated macula densa cells. Under conditions in which the macula densa cells prompt a reduced release of the vasoconstrictor chemical (promoting vasodilation of the afferent arteriole), they also stimulate the JG cells to release renin.
3) Direct stimulation of JG cells via b1-adrenergic receptors by renal sympathetic nerves.