52. Hypertension and Cardiac Failure

Question 1

How does blood pressure change with age?

Answer 1

It increases with age.

Question 2

Draw a graph of blood pressure against age.

Answer 2

Question 3

What is the equation for mean arterial blood pressure, relative to systolic and diastolic pressure?

Answer 3

Mean ABP = (1/3 x sysolic pressure) + (2/3 x diastolic pressure)

Question 4

How does short and long-term regulation of blood pressure occur?

Answer 4

• Short-term -> Baroreflex
• Long-term -> Kidneys

Question 5

What is the baroreflex?

Answer 5

• One of the body’s homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels.
• The baroreflex provides a rapid negative feedback loop in which an elevated blood pressure reflexively causes the heart rate to decrease and also causes blood pressure to decrease.

Question 6

Describe the receptors, ganglia and afferent nerves involved in the baroreflex.

Answer 6

Carotid sinus baroreceptors:

• Via the petrosal ganglia
• Glossopharyngeal nerve (IX)

Aortic arch baroreceptors:

• Via the nodose ganglia
• Vagus nerve (X)

Question 7

What type of receptors are involved in the baroreflex?

Answer 7

Baroreceptors -> These detect transmural pressure, not flow

Question 8

Where do the afferent nerves of the baroreflex synapse in the brain?

Answer 8

Nucleus tractus soltarius (NTS) -> This is in the medulla

Question 9

Describe the efferent target organs of the baroreflex.

Answer 9

Parasympathetic:

• Heart

Sympathetic:

• Heart
• Blood vessels
• Kidney

Question 10

Draw a summary of the baroreflex.

Answer 10

Question 11

Describe the negative feedback loop of the baroreflex.

Answer 11

Question 12

What is neuromodulation? Give some examples. How is it relevant to blood pressure control?

Answer 12

• The alteration of specific nerve activity by targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the bod
• Depending on the site, it can be used to treat various conditions
• The diagram shows some ways in which blood pressure could be modified

Question 13

Give some experimental evidence for neuromodulation.

[EXTRA]

Answer 13

(Sverrisdottir, 2020)

• An experiment involved use of dorsal root ganglion stimulation to ease chronic pain in a group of patients
• However, the researchers also found that the stimulation reduced sympathetic outflow and could therefore be used to lower blood pressure in patients with hypertension

Question 14

Which part of the brain is important in cardiovascular control?

Answer 14

The brainstem (midbrain, pons and medulla), since cardiovascular function is not under conscious control.

Question 15

Summarise the effects of the baroreflex in response to low blood pressure and how they contribute to blood pressure control.

Answer 15

• Sympathetic stimulation of the venous system and heart causes venoconstriction and increased heart rate -> This increases cardiac output
• Sympathetic stimulation of the arteries causes vasoconstriction -> This increases total peripheral resistance

In combination, these two effects increase blood pressure.

Question 16

Give some experimental evidence for which parts of the brain are involved in cardiovascular activity.

[EXTRA]

Answer 16

Aside from the nucleus tractus solitarius in the medulla, the subthalamus is also involved in cardiovascular control:

• This is evidenced by stimulation of the subthalamic nucleus (part of the diencephalon, between the thalamus and midbrain)
• This stimulation has been experimentally used to treat patients with motor dysfunction, such as in Parkinson’s disease
• However, it was also discovered to cause an increase in arterial blood pressure
• This logically makes sense, because if you want to move around, you are quite likely to want to increase your blood pressure also
• This also shows that the STN is an inhibitory part of the brain -> By injecting current, they are causing depolarising block, thus blocking the inhibition, so that movement can occur
• Similar effects were seen in the:
  
  • Thalamus
  • Substantia nigra

Question 17

What is the periaqueductal grey and how is it relevant to the cardiovascular system?

[EXTRA?]

Answer 17

• It is a nucleus within the midbrain
• It is divided into 4 sections: Dorsomedial, Dorsolateral, Lateral, Ventrolateral
• Primarily involved in nociception

(Carrive, 1991) found that:

• Activation of the lateral column -> Leads to hypertension
• Activation of the ventrolateral column -> Leads to hypotension

Question 18

What is some experimental relevance of the periaqueductal grey (PAG)?

[EXTRA?]

Answer 18

Removal of the PAG causes:

• Loss of consciousness
• Mutism
• Loss of CO₂ sensitivity
• Loss of muscle pressor reflex
• Respiratory failure

This suggests some of its functions.

Question 19

What are the main afferent pathways that feed into the brain and are involved in cardiovascular control (aside from the baroreceptors in the aortic arch and carotid sinus)?

[IMPORTANT]

Answer 19

• Cardiopulmonary receptors
  
  • In great veins, pulmonary artery and right atrium/ventricle
  • Detect filling of the heart
  • Inhibit heart rate and cause vasodilation, plus increased renal excretion -> Causing blood pressure and volume to fall
• Arterial baroreceptors
  
  • In aortic arch and carotid sinus
  • Detect arterial pressure
  • Inhibit heart rate and cause vasodilation -> Causing blood pressure to fall
• Muscle work receptors
  
  • Involve C fibres that are activated upon muscle activity (e.g. by potassium)
  • Increase heart rate -> Causing blood pressure to rise
• Arterial chemoreceptors
  
  • In aortic arch and carotid sinus
  • Respond to decreased pO₂ and pH, and increased pCO₂
  • Increase heart rate and sympathetic stimulation of vasculature -> Causing blood pressure to rise

Question 20

Draw a summary of the acute control of blood pressure.

Answer 20

Question 21

What is another name for cardiopulmonary baroreceptors?

Answer 21

Low-pressure baroreceptors

Question 22

When is the only time that the cortex of the brain is involved in the cardiovascular system?

Answer 22

It is indirectly involved via fainting. When you are shocked/scared by something, there is a massive drop in the vagus activity, so that blood pressure drops very much and you may faint.

Question 23

Give a small summary of the innervation of the heart.

Answer 23

Question 24

Do you need to know much about the brainstem pathways involved in control of blood pressure?

Answer 24

Not really, most of it is RHS content:
“Central pathways of the baroreflex: role of the brainstem”

Question 25

Describe the different parts of the medulla involved in the baroreflex.

[EXTRA]

Answer 25

Question 26

What are some ways to test for the baroreflex in a patient?

Answer 26

• Vasoactive drugs (e.g. NO) -> These dilate the peripheral blood vessels, stimulating sympathetic activity to constrict the vessels
• Blood loss
• Neck suction
• Change in posture
• Lower body negative pressure

These are all things that trigger the baroreflex, allowing it to be assessed.

Question 27

What are some problems with using vasoactive drugs (e.g. NO) to test for the baroreflex?

Answer 27

Aside from dilating the peripheral blood vessels, thus stimulating the baroreflex, these also increase the heart rate, which is a confounding effect.

Question 28

What is the heart’s response to haemorrhage? What is some experimental evidence for this?

Answer 28

• The drop in blood pressure causes activation of the baroreflex
• This leads to tachycardia and an increase in blood pressure
• Experimentally, this can be demonstrated in animal models where there is denervation of the heart and the blood pressure drops very fast

Question 29

Describe the physiological changes (and response) when standing up, then starting to walk.

[IMPORTANT]

Answer 29

When going from lying to standing:

• When you stand, about 0.5L of blood pools in your legs, causing a drop in venous return
• This causes a drop in atrial pressure (preload), so the cardiac output drops and so does the arterial blood pressure
• The body’s response involves activation of the sympathetic nervous system via the:
  
  • Cardiopulmonary reflex (first) -> Leads to splanchnic vasoconstriction, increasing blood pressure and preserving blood for the vital organs
  • Baroreflex (second) -> Leads to tachycardia and vasoconstriction

When starting to walk:

• Skeletal muscle pump -> Moving of muscles causes blood to be pushed back to the heart (venous return)
• Breathing also increases, which helps blood pressure to increase also

Question 30

What are the two main reflexes involved in maintaining orthostasis?

Answer 30

• Cardiopulmonary reflex (i.e. using low-pressure baroreceptors)
• Baroreflex (i.e. using arterial baroreceptors)

Question 31

Draw the main structures in the brain involved in sympathetic control of the cardiovascular system.

Answer 31

ADD NOTES ON THIS - EXTRA?

Question 32

How is blood pressure control applicable to astronauts taking off in a rocket?

[EXTRA]

Answer 32

• When accelerating, the astronauts experience lots of g’s
• This causes pooling of blood in the lower limbs, leading to hypotension
• This can be combatted by:
  
  • Use of pressure suits that aid venous return
  • Placing the astronauts in a more lying-down position, so that the venous pooling is not as pronounced

Question 33

What are some changes that happen when you enter microgravity (e.g. in space)?

Answer 33

• Fluid shifts towards the head due to lack of gravity
• This causes an increase in puffiness of the face and cardiac engorgement
• The CVP and therefore ABP are increased
• The response includes a baroreceptor response, slowing down the heart, as well as urine loss
• Eventually, after about 24hrs the body is acclimatised

Question 34

What happens to the baroreflex during exercise?

Answer 34

It shifts to higher operating pressure, by inhibition of vagus activity by an unknown mechanism. This is important, or otherwise the increase in heart rate would immediately be counteracted.

Question 35

What are two conditions that the risk of is increased in individuals with hypertension?

Answer 35

• Coronary heart disease
• Stroke

Question 36

Draw and reference a graph to show the relative risk of mortality (from CHD and stroke) according to arterial blood pressure.

[IMPORTANT]

Answer 36

(Lipp, 2015)

Question 37

What is an equation for blood pressure?

Answer 37

Blood pressure = Cardiac output x Systemic vascular resistance

Question 38

What are the two main factors involved in the control of blood pressure?

Answer 38

• Cardiac output
• Systemic vascular resistance

Question 39

Draw a simple mathematical model of the circulation.

Answer 39

Question 40

What is the equation for the systemic resistance in this diagram?

Answer 40

This is equivalent to Ohm’s law.

Question 41

How can this model of the circulation be modified to show the properties of the arteries and veins?

Answer 41

• The height of each tube shows the pressure in the arteries and veins
• The width of each tube shows the compliance of the arteries and veins

Question 42

Who was the first person to measure arterial blood pressure?

Answer 42

• Stephen Hales in 1733
• He connected a vertical glass tube to the carotid artery of a horse lying down. Then he measured how high up the tube the blood moved up.

Question 43

What is the name for the blood pressure in the circulation system if there is no pump?

Answer 43

Mean circulatory filling pressure (P_mcf)

Question 44

What is the importance of the mean circulatory filling pressure?

Answer 44

• It is the pressure throughout the circulatory system when there is no pump
• Therefore the arterial and venous pressure can be considered as diverging from the P_mcf due to the heart pumping blood from the venous to arterial circuit

Question 45

According to this model of the circulation, how can hypertension be treated?

Answer 45

• Drugs that reduce cardiac output (e.g. beta-blockers)
• Drugs that reduce systemic vascular resistance

However, this neglects that circulation is an open system, so that pressure can also be regulated via:

• Intake via the gut
• Output via the urine

Question 46

How can the intake and loss of fluid be incorporated into this diagram of the circulation?

Answer 46

Question 47

How does fluid loss via the kidney change as blood pressure changes?

Answer 47

The urine production is proportional to the increase in blood pressure, so that the pressure is kept constant.

Question 48

Give some experimental evidence for the action of the kidney in maintaining a constant blood pressure.

[EXTRA]

Answer 48

(Hall, 1980)

• Several dogs were each assigned a diet with a different sodium intake, which came entirely from their solid feed
• They were free to drink as much water as they wanted
• No matter the salt intake, the blood pressure remained almost constant, showing that the kidneys filtered out fluid and salt proportionally to the arterial blood pressure

Note: This graph is usually presented with the axes flipped.

Question 49

Draw how hypertension, normotension and hypotension caused by the kidney be represented in this model.

Answer 49

Question 50

Describe some experimental evidence demonstrating how hypertension and hypotension can be induced in a kidney.

Answer 50

(Hall, 1980)

• Several dogs were each assigned a diet with a different sodium intake, which came entirely from their solid feed
• They were free to drink as much water as they wanted
• In the control group, the dogs had constant blood pressure over a range of sodium intakes
• In the angiotensin II group, the dogs showed elevated blood pressure, most pronounced at high salt intakes
• In the ACE inhibitor group, the dogs showed hypotension, most pronounced at low salt intakes

Note: This graph is usually presented with the axes flipped.

Question 51

What can we deduce from this experiment?

Answer 51

• We can deduce that the kidney on its own will display a hyperbola-shaped curve on the ABP-sodium intake graph
• It is the renin-angiotensin system that shifts the curve up or down depending on the salt intake, so that the blood pressure remains constant regardless of the salt intake
• This results in the flat control line

Note: This graph is usually presented with the axes flipped.

Question 52

Explain this graph.

[IMPORTANT FOR UNDERSTANDING]

Answer 52

• The renin-angtiotensin system is responsible for ensuring that the kidney excretes more fluid when the arterial blood pressure rises -> This means that the blood pressure is kept constant
• Therefore, when it is blocked:
  
  • At high salt intakes, function is basically normal, since not much angiotensin II is required (since there is little need for lowering pressure).
  • At low salt intakes, the lack of angiotensin II means that the kidney’s inherent filtering activity is too high, so that the blood pressure drops.
• When there is an excess of angiotensin II:
  
  • At low salt intakes, function is basically normal, since the excess angiotensin II is required anyway to reduce salt and water loss.
  • At high salt intakes, the excess of angiotensin II means that the kidney’s inherent filtering activity is too low, so that not enough salt and water are filtered, and blood pressure increases.

Question 53

Why is the “normal” line straight and vertical here?

[EXTRA]

Answer 53

The inherent activity of the kidney means that it actually has a curved line with a gradient, showing that its filtration rate is not inherently proportional to the blood pressure. However, the renin-angiotensin system is used to ensure that no matter what the salt intake (and therefore the blood pressure), the curve shifts so that the filtration rate is proportional to the salt intake (and therefore blood volume), so that the blood pressure remains constant.

[CHECK THIS]

Question 54

Give some examples of antihypertensive drugs.

Answer 54

• Certain vasodilators
• Beta-blockers
• Diuretics

Question 55

Describe the effect of using vasodilator drugs to treat hypertension.

[IMPORTANT]

Answer 55

• Vasodilators reduce systemic vascular resistance, so the blood pressure drops
• However, as the arterial pressure drops, so does the loss of fluid in the kidneys (this is how the kidneys work)
• Therefore, it is only a matter of time before intake of fluid exceeds loss, so that the circulation slowly fills back up to the previous pressure and the hypertension is renewed.
• HOWEVER, if the afferent arteries supplying the kidney are targetted and vasodilate significantly, it may be possible to maintain sufficient renal perfusion at the decreased mean arterial pressure. Therefore, the loss of salt is maintained at a lower MAP.

(Note: This might be a controversial view)

Question 56

Describe the effect of using beta-blockers drug to treat hypertension.

[IMPORTANT]

Answer 56

• Beta-blocker slows the heart down
• This leads to a reduction in the arterial pressure and an increase in venous pressure
• However, as the arterial pressure drops, so does the loss of fluid in the kidneys (this is how the kidneys work)
• Therefore, it is only a matter of time before intake of fluid exceeds loss, so that the circulation slowly fills back up to the previous pressure and the hypertension is renewed.
• HOWEVER, some beta-blockers also cause (1) afferent vasodilation of the arterioles supplying the kidney or (2) reduced salt reabsorption in the kidney. This therefore allows the loss of salt to be maintained at a lower MAP.

(Note: This might be a controversial view)

Question 57

What is the key to treating hypertension?

Answer 57

• You must alter blood volume chronically, not just modify vasodilation and heart action.
• With drugs like beta-blockers and vasodilators, by reducing the mean arterial pressure, you are also reducing renal perfusion such that salt and water excretion is reduced. This renews the hypertension.
• Therefore, successful anti-hypertensive drugs (including some beta-blockers and vasodilators) have their useful action on the ‘final common pathway’ of the kidney. This includes:
  
  • Increasing renal perfusion via afferent vasodilation
  • Reducing salt reabsorption in the kidneys
• Their effects elsewhere in the vasculature and on the heart are not the key to treating the hypertension

(CHECK ALL THIS and note that it might be controversial)

Question 58

What is a Guyton curve and why is it useful?

[IMPORTANT]

Answer 58

• It is a graph of cardiac output against venous pressure, with a Frank-Starling curve superimposed on it
• The gradient of the venous line is equal to -(1 + C_v/C_a)/R
• The point where the lines cross is the flow in the system (since flow is conserved)
• Therefore, this graph is useful since by changing one of the variables, such as cardiac output, compliance, resistance or pressure, we can predict the effects that this will have on the system (by looking at the intersect of the lines)

Question 59

Read your essay on Guyton curves.

Answer 59

Do it.

Question 60

How can the arterial line be added onto a Guyton diagram?

Answer 60

Question 61

What is the gradient of the arterial and venous lines on a Guyton curve?

Answer 61

• Venous: -(1 + C_v/C_a)/R
• Arterial: (1 + Ca/Cv)/R

Question 62

Draw and explain pressure-natriuresis graphs for:

• Normal hypertensive state
• Treatment with diuretics
• Treatment with ACE inhibitors
• Treatment with vasodilators

Answer 62

• In the normal hypertensive state, the higher the sodium intake, the higher the MAP (and conversely the higher the sodium excretion).
• The diuretics, ACE inhibitors and vasodilators act to lower the MAP at ever salt intake there is.
• Diuretics are most effective at high salt intakes.
• ACE inhibitors are most effective at low salt intakes.
• Vasodilators are equally effective at all salt intakes.

Question 63

How does renal perfusion affect natiuresis?

Answer 63

Higher perfusion leads to higher salt excretion.

Question 64

What is the principle of effective anti-hypertensive drugs?

Answer 64

They make the kidneys work at a lower arterial pressure.

(Note: This might be a controversial view)

Question 65

In patients with hypertension, how does the pressure graph along the length of the kidney vasculature change?

Answer 65

(Gomez, 1951):

• There is a 5 times higher resistance of the afferent arterioles, such that the MAP is increased and glomerular capillaries are decreased
• This leads to decreased glomerular filtration rate

Question 66

Classify anti-hypertensive drugs into 3 main categories.

Answer 66

• Afferent vasodilators -> These dilate the afferent arterioles supplying the kidney, so that perfusion is maintained as MAP drops
• Inhibitors of Na⁺ reabsorption in the kidney -> These increase salt excretion, so that more water is lost via the kidneys as MAP drops
• Afferent vasodilators + Inhibitors of Na⁺ reabsorption in the kidney -> These work by both mechanisms

Most of these drugs also have an effect on heart action or systemic vasodilation, so they reduce MAP.

(Check this is consistent with the later lecture)

Question 67

Give some examples of afferent vasodilators and how they affect the pressure graph along the length of the renal vasculature.

Answer 67

Question 68

Give some examples of inhibitors of Na⁺ reabsorption in the kidney and how they affect the pressure graph along the length of the renal vasculature.

Answer 68

Question 69

Give some examples of afferent vasodilators AND inhibitors of Na⁺ reabsorption in the kidney and how they affect the pressure graph along the length of the renal vasculature.

Answer 69

Question 70

Give a piece of experiment evidence for the importance of kidney function in developing and treating hypertension.

[EXTRA but VERY USEFUL]

Answer 70

(Crowley, 2006) produced 4 sets of mice and then infused them with a vasoconstriction, angiotensin II. The observed results:

• Wild-type -> The MAP increased and remained high the whole time.
• Knockout of all angiotensin receptors except renal -> The MAP increased gradually.
• Knockout of only renal angiotensin receptors -> The MAP increased acutely, but then it slowly decreased.
• Total knockout -> The MAP was relatively unaffected.

This showed that, while systemic vasoconstriction can contribute to blood pressure in the short term, it is renal blood flow that ultimately controls blood pressure in the long-term.

Question 71

Describe the causes of hypertension.

Answer 71

There are a number of causes that might act together and there may be more than this:

• Increased sympathetic activity
• Abnormal renal sodium handling
• “Metabolic Syndrome” (a syndrome of uncertain cause that includes obesity, type 2 diabetes mellitus and hypertension)
• Abnormal renin-angiotensin ratio -> A variant mild form of Conn’s syndrome (primary hyperaldosteronism)
• Increased salt intake

Keith Dorrington makes the case that any cause of chronic hypertension must somehow cause dysfunction of water excretion by the kidneys. This is because the kidneys are the organs that are ultimately responsible for blood volume control, and any changes in vasoconstriction, etc. should in theory be counteracted by changes in blood volume. (Check whether this is controversial or not!)

Question 72

How does blood pressure change with age?

[IMPORTANT]

Answer 72

A reasonable approximation is:

• Healthy systolic pressure increases linearly with age
• Healthy diastolic pressure rises between the age of 20 and 50 and then progressively declines.

Question 73

What is white coat hypertension and how can it be reduced?

Answer 73

• White coat hypertension is the slightly elevated blood pressure seen in some patients when measured in a clinical setting, due to stress or similar reasons
• It can be reduced by taking three measurements of the blood pressure at different times and averaging them

Question 74

When multiple readings are taken for the blood pressure of a patient, what should be done with these values?

Answer 74

• It is usually argued that the values should be averaged
• However, there is also an argument in some quarters that the damage done by hypertension is related to the volatility of the blood pressure more than the absolute level. If this hypothesis turns out to be true, then we ought not to be averaging the three measurements but rather we should be observing the variation in blood pressure over time. Portable monitors, which the patient can wear without discomfort and which are now fairly freely available, should help to resolve this question.

Question 75

Is blood pressure normally distributed?

Answer 75

• There isn’t a normal distribution
• The population’s blood pressure is skewed, with a thick and long tail at the upper end

Question 76

What classifies as hypertension?

[IMPORTANT]

Answer 76

According to NICE, hypertension is confirmed when a patient has:

• Clinic blood pressure of 140/90 mmHg or higher and
• ABPM daytime average or HBPM average of 135/85 mmHg or higher (these are measures of blood pressure throughout the day)

Question 77

What are the benefits and disadvantages of treating hypertension?

Answer 77

The benefits of treatment are due to the fact that hypertension is associated with other diseases:

• Stroke (both haemorrhagic and embolic)
• Heart attack
• Heart failure
• Renal disease
• Retinal disease

The disadvantages are that hypertension itself is usually asymptomatic and treatment often has side effects.

Question 78

Describe the changes in the cardiovascular system that lead to hypertension.

Answer 78

• Remember: BP = SVR x CO
• It has been observed that patients with pre-hypertension typically have a high cardiac output but normal systemic resistance
• However, in patients with hypertension, there is usually normal cardiac output but increased systemic resistance
• Thus, it has been suggested that the first event in the pathophysiology is usually an increase in cardiac output
• This results in an increased ratio of wall : lumen in systemic blood vessels, to combat the change in wall stress
• This leads to an increase in systemic vascular resistance

(Note: This might be controversial)

Question 79

What are some risk factors for hypertension?

[IMPORTANT]

Answer 79

• Obesity
• High salt intake
• Sedentary lifestyle
• Alcohol and coffee consumption
• Smoke
• Lack of sleep
• Age over 65
• Have a relative with high blood pressure
• Black African or black Caribbean descent
• Live in a deprived area

Question 80

What are some possible consequences of hypertension?

Answer 80

Hypertension can affect:

• Left ventricle
• Arteries
• Risk of stroke and TIA
• Kidney and retina

Question 81

How is the left ventricle affected in hypertension?

Answer 81

• The left ventricle has a thick wall, and so it is dependent on the coronary arteries and their transmural branches for its oxygen supply.
• The blood flow in these vessels is at its greatest during diastole, when the ventricular wall is relaxed and not compressing the coronary arteries.
• In hypertension, the left ventricle hypertrophies to overcome the increased resistance.
• This increases the risk of myocardial ischaemia for two reasons:
  
  • Decreased perfusion of the left ventricle since the wall compresses the coronary arteries
  • Increased metabolic demand of the heart to overcome the systemic resistance

(Note that this ventricular hypertrophy is not the same as ventricular dilation, which occurs when the ventricle cannot clear all of its blood in systole, so that it remains partly filled. If the ventricular hypertrophy leads to ischaemia, both may occur simultaneously.)

Question 82

How are arteries affected in hypertension?

Answer 82

• There is a bidirectional causal relationship between hypertension and atherosclerosis:
  
  • Hypertension increases the risk of atherosclerosis (due to increased turbulence of blood flow)
  • Atherosclerosis increases the risk of hypertension (due to reduced elasticity of the wall)
• There is a similar bidirectional relationship between hypertension and arterial wall thickening, where the muscular arterial wall thickens to sustain the increased pressure, which in turn leads to increased blood pressure due to reduced elasticity

Question 83

What is the main argument for early treatment of hypertension?

Answer 83

It is a self-exacerbating process, so early treatment is required to stop it spiralling out of control.

Question 84

How is the risk of strokes and TIAs affected in hypertension?

Answer 84

• Hypertension is associated with atherosclerosis, which can lead to embolic strokes, where a thrombus detaches from (usually) an atherosclerotic plaque on an arterial wall and is carried in the circulation to the brain, where it blocks an artery
• Hypertension also encourages the formation of aneurysms in cerebral, which occur at points of weakness in the wall and can result in haemorrhagic stroke
• Thus, the risk of stroke is reduced by lowering the blood pressure.

Question 85

How is the kidney affected in hypertension?

Answer 85

• The thickening of arterial walls already noted in the context of systemic arteries is conspicuous in the kidney
• Some smaller arterioles seem to become almost obstructed by the changes, leading to slow flow in some areas.
• Associated with these changes is a process that looks like chronic inflammation, with deposition of fibrous tissue and amyloid, and the progressive loss of functional nephrons.
• In addition, glomerular damage is usually evident after years of elevated blood pressure -> Proteinuria is the usual first indicator of this

Question 86

How is the retina affected in hypertension?

Answer 86

The mechanisms that cause kidney damage in hypertensive patients also damage the retina over a long period: haemorrhages and exudates from retinal vessels may compromise the function of the eye, usually over a period of one or more decades.

Question 87

How can the arterial pathology seen in hypertension be treated?

Answer 87

• Statins -> For prevention of atherosclerosis
• Exercise and dietary planning are often useful alternatives to drugs in the drive to lower blood pressure, and both of these interventions can also reduce serum lipid levels.

Question 88

How can the left ventricular ischaemia seen in hypertension be treated?

Answer 88

• Beta-blockers
• RAA antagonists can reduced the degree of left ventricular hypertrophy

Question 89

Is hypertension a disease?

[EXTRA]

Answer 89

• A persistent theme in discussions about hypertension and anti-hypertensive therapy has been that hypertension is not a disease in itself but is simply an indication of an underlying disease.
• This argument points to a reason for the continuing difficulty in identifying an ideal anti-hypertensive drug that works in all situations: we cannot use a single drug to treat several different diseases.
• This is also important because drugs that treat the underlying cause of symptoms tend to have fewer side effects than drugs that treat symptoms.

Question 90

What are some non-drug treatments of hypertension?

Answer 90

• Exercise
• Low salt intake
• Increased potassium intake (potentially)

Question 91

Should we treat hypertension early or late?

[EXTRA]

Answer 91

There is debate surrounding this because:

• Most “anti-hypertensive” treatment is not unambiguously targeted at an underlying disease: “anti-hypertensive” drugs are really “hypotensive drugs” – that is, drugs that lower blood pressure by means that are not necessarily related to the cause of the hypertension (which is often unknown)
• Hypertension is usually asymptomatic for many years before it starts to cause obvious problems, whereas most drugs cause symptomatic side-effects, so the patient feels less well with the drug than without it; this problem is likely to have arisen because we are not often treating the cause of the hypertension, but are arguably imposing a hypotensive influence (the drugs) upon an unknown disease which has hypertension as one of its effects.

However, we usually treat hypertension early because it is a self-exacerbating problem and therefore treating it early produces better results.

Question 92

What ethnic groups have the highest incidence of hypertension?

[IMPORTANT]

Answer 92

Black, non-Hispanics

Question 93

What kind of hypertension is most common in the elderly and why?

[IMPORTANT]

Answer 93

• Isolated systolic hypertension -> This is where the systolic pressure is classed as high, but diastolic is normal or even low.
• This is commonly seen among the elderly as there is increased deposition of calcium and collagen to the arterial wall, which reduces the compliance of the arterial vessels, decreased lumen-to-wall ratio, and increased thickening and fibrotic remodeling of the vascular intima and media.

Question 94

When the body wants to change blood flow to a certain tissue, does the ABP change?

[IMPORTANT]

Answer 94

No, it remains relatively constant. It can be seen as a reservoir of driving force, which can be distributed locally to different tissues by local regulation.

Question 95

What are the two main types of hypertension?

[IMPORTANT]

Answer 95

• Primary hypertension (a.k.a. ‘essential hypertension’) -> Hypertension with an unknown underlying cause
• Secondary hypertension -> Hypertension with a known disease causing it

Question 96

Give some factors that the spec says are associated with long-term increases in blood pressure.

[IMPORTANT}

Answer 96

• ‘Essential hypertension’ -> Unknown cause
• Renal disease
• Phaeochromocytoma -> Rare tumor of adrenal gland tissue. It results in the release of too much epinephrine and norepinephrine.

Question 97

What is the relationship between the radius of a blood vessel and its resistance?

Answer 97

R ∝ 1/r⁴

Question 98

Draw the process of excitation-contraction coupling in smooth muscles.

Answer 98

Question 99

What are the targets of anti-hypertensive drugs?

Answer 99

To achieve:

• Diastolic pressure of <90mmHg
• Systolic pressure of <140mmHg

Question 100

What was the first anti-hypertensive drug?

Answer 100

Question 101

What are the main drug classes used in the treatment of hypertension?

[IMPORTANT]

Answer 101

Diuretics:

• Thiazide, loop and potassium-sparing diuretics

Vasodilators:

• Alpha-adrenoceptor antagonists
• ACE inhibitors
• Angiotensin receptor blockers
• Ganglionic blockers
• Nitic oxide donors
• Ion channel modulators: Ca²⁺-channel blockers and K⁺-channel openers.
• Renin inhibitors

Cardio-inhibitory drugs:

• Beta-blockers.
• Ca²⁺-channel blockers.

Centrally acting sympatholytic drugs.

Question 102

What are the main classes of drugs currently used to treat hypertension?

Answer 102

• Drugs that modify the RAA axis (A)
• Calcium antagonists (C)
• Thiazide diuretics (D)
• Beta blockers (B)

Remember:

A (ACE Inhibitors), B (Beta blockers), C (Calcium antagonists), D (Diuretics)

Question 103

Summarise the main order of treatment for hypertension.

Answer 103

Note how beta-blockers are only used here after everything else has failed.

Question 104

What type of treatment do young patients with hypertension tend to respond best to?

Answer 104

Drugs that modulate the RAA axis (such as ACE inhibitors)

Question 105

What type of treatment do older patients and black patients with hypertension tend to respond best to?

Answer 105

Calcium channel blockers or diuretics

Question 106

What are the two proposed mechanistic classes of hypertension?

Answer 106

(Brown, 2006) proposes…

Type 1:

• More common in young people
• ‘Vasoconstrictor hypertension’ due to increased renin
• Best treated with RAA axis modulators and beta blockers

Type 2:

• More common in older people
• ‘Volume hypertension’ due to high sodium intake and volume retention
• Best treated with diuretics and calcium channel blockers

This difference in ages is seen because renin secretion decreases with age.

Question 107

Why does the black population tend to display a certain type of hypertension?

Answer 107

• Black patients with hypertension tend to have low-renin hypertension (type 2), which means they are usually first treated with diuretics and calcium channel blockers
• This is for two proposed reasons:
  
  • Commonly have a threonine to methionine substitution in the ENaC of the kidney -> This is a gainer mutation, so the function of the channel is increased and there is more salt retention
  • Lower nephron mass

Question 108

Where is renin secreted from?

Answer 108

Juxtaglomerular cells (which surround the afferent arteriole)

Question 109

Describe how the juxtaglomerular apparatus is involved in the RAA axis.

Answer 109

• The macula densa are the specialised Na⁺-sensing cells in the distal tubule that come into close contact with the afferent arteriole
• Renin is secreted by the juxtaglomerular cells that surround the afferent arteriole
• They receive input from the macula densa (via the mesangial cells) and sympathetic innervation, as well as pressure in the afferent arteriole and angiotensin II negative feedback

Question 110

Juxtaglomerular cells are modified … cells.

Answer 110

Smooth muscle

Question 111

Explain the recruitment of renin-secreting cells.

Answer 111

Smooth muscle cells that surround the afferent arteriole can be recruited to become renin-secreting juxtaglomerular cells when there is, for example, there is renal hypoperfusion.

Question 112

Describe the mechanism of renin secretion.

Answer 112

This is unusual because the calcium is an inhibitor of release.

Question 113

State the different factors that control renin secretion.

Answer 113

Question 114

How does the macula densa influence renin secretion from the juxtaglomerular cells?

Answer 114

• When there is reduced sodium detected by the macula densa, renin secretion is stimulated.
• Prostaglandins are used to stimulate release
• Adenosine is used to inhibit release

Question 115

What are the three main classes of anti-hypertensive drugs that modulate the RAA axis that you need to know about?

Answer 115

• ACE inhibitors
• Angiotensin receptor blockers
• Renin inhibitors

Question 116

What are some examples of ACE inhibitors?

Answer 116

• Captopril was the first
• Lisinopril, ramapril, enalapril, benazepril, cilazapril, fosinopril all have a slower onset of action that captopril
• Some are pro-drugs converted in the body: ramipril to ramiprilat, enalapril to enalaprilat

Question 117

How do ACE inhibitors work?

Answer 117

• Block conversion of angiotensin I to angiotensin II (so that aldosterone is also not secreted)
• This reduce peripheral resistance (passive dilatation) and sodium retention.
• No direct effect on the heart.

Question 118

Aside from hypertension, when are ACE inhibitors used?

Answer 118

They can also be used to treat congestive heart failure.

Question 119

What are some examples of angiotensin receptor blockers?

Answer 119

Losortan

Question 120

How do angiotensin receptor blockers work?

Answer 120

• They block the AT₁ receptors that bind angiotensin II.
• Angiotensin II usually causes vasoconstriction and aldosterone release (which leads to salt retention).

Question 121

What are some examples of renin inhibitors?

Answer 121

Aliskerin

Question 122

How do renin inhibitors work?

Answer 122

• They block the enzymatic activity of renin in converting angiotensinogen to angiotensin I.
• Thus, they reduce peripheral resistance (passive dilatation) and sodium retention (thus reduce blood volume).

Question 123

What are the main classes of calcium-channel blocker?

Answer 123

Question 124

What are some examples of calcium channel blockers used to treat hypertension?

Answer 124

• Dihydropyridine calcium channel blockers, a group that includes amlodipine, felodipine and lacidipine, are a common choice for treatment.
• Verapamil (more cardiac-specific tbf)

Question 125

How do calcium channel blockers work as antihypertensive drugs?

Answer 125

• Block calcium entry into cells
• This prevent contraction of smooth muscles, which leads to vasodilation
• They also inhibit cardiac contraction, which lowers cardiac ouput
• In the kidney, the afferent arteriole appears to be more affected than the efferent, so that GFR is maintained despite the falling blood pressure

Question 126

What is the most common class of diuretics used to treat diuretics?

Answer 126

Thiazides

Question 127

How do thiazide diuretics work?

Answer 127

• Inhibit the Na⁺-Cl^- co-transporter in the distal convoluted tubule.
• This leads to greater excretion of salt and therefore less water retention, lowering blood pressure.

Question 128

What are some examples of thiazide diuretics?

Answer 128

• Bendroflumethiazide
• Chlorothiazide
• Structurally unrelated drugs e.g. metolazone

Question 129

Is the diuresis produced by thiazide diuretics strong?

Answer 129

It is weaker than with loop diuretics, but this is usually sufficient for treatment.

Question 130

How do loop diuretics work?

Answer 130

Inhibit the NKCC (Na/K/2Cl transporter) in the thick ascending limb of the loop of Henle.

Additional effects include that they are vasodilators of:

• Systemic resistance arterioles -> Useful in lowering arterial pressure in hypertension and in reducing peripheral resistance in cardiac failure
• Renal resistance arterioles -> Useful in increasing GFR and so potentially increasing diuresis
• Vasa recta of the renal medulla -> Resulting in a “washout” of the accumulated osmotically active substances of the medullary interstitium, and so further reducing the osmotic potential there and increasing the potency of the diuresis

Question 131

Give some examples of loop diuretics.

Answer 131

Furosemide

Question 132

Compare the effects of loop and thiazide diuretics in terms of their effects on calcium.

Answer 132

• Loop diuretics increase calcium excretion
• Thiazide diuretics reduce calcium excretion -> This can be used in treatment of conditions such as stone formation in the urinary tract

Question 133

What are some side effects of thiazide and loop diuretics?

Answer 133

• Metabolic alkalosis and hypokalemia
• Hypovolemia
• Hypercalcaemia (thiazides) or hypocalcaemia (loop)

Question 134

How do potassium-sparing diuretics work?

Answer 134

There are two main classes:

• Aldosterone antagonists
• Inhibitors of the epithelial Na+ channel in the collecting duct

Question 135

What are some examples of potassium-sparing diuretics?

Answer 135

• Aldosterone antagonists -> Spironolactone
• Inhibitors of the epithelial Na+ channel in the collecting duct -> Amiloride

Question 136

When are potassium-sparing diuretics used?

Answer 136

They are used when:

• Aldosterone levels are too high in disease, such as:
  
  • Cardiac failure
  • Hypertension
• Aldosterone levels are too high as a natural response to diuretic therapy (sinc aldosterone conserves water indirectly by conserving salt)

Question 137

Why may aldosterone levels be raised in diuretic therapy?

Answer 137

• Diuresis activates the juxtaglomerular apparatus, which releases renin and causes the production of aldosterone.
• Potassium-sparing diuretics may be used in these cases.

Question 138

Describe how the kidney adapts to diuretics.

Answer 138

During diuretic action:

• Downstream nephron segments increase NaCl reabsorption as delivered NaCl load increases.

Post-diuretic NaCl retention (short term):

• As diuretic concentrations in the tubule decline, Na+ retention increases until the next dose of diuretic is administered.

Chronic increase in Na+ retention (the ‘braking phenomenon’):

• Ability to increase renal NaCl excretion declines over time. Due to both depletion of the extracellular fluid volume and structural (hyperplasia, hypertrophy) and functional (include increase in Na/K ATPase in basolateral membrane) changes in the kidney tubules.

Question 139

How do beta-blockers work in treating hypertension?

Answer 139

• Block of β₁-adrenergic receptors in the kidney, reducing renin release (remember that the juxtaglomerular cells receive sympathetic innervation)
• May also have a CNS effect to reduce sympathetic outflow to the heart and reduce cardiac output

Question 140

What are some examples of beta-blockers used to treat hypertension?

Answer 140

‘Cardioselective’ β blockers -> e.g. Atenolol

Question 141

How do alpha-blockers work in treating hypertension?

Answer 141

They block alpha-1 receptors in the vasculature, causing vasodilation.

Question 142

What is the limitation of using alpha-blockers in treating hypertension?

Answer 142

Sympathetic innervation of the vasculature is important in everyday life, such as when standing up.

Question 143

What are some examples of alpha-blockers?

Answer 143

• Prazosin
• Terazosin

Question 144

How do potassium channel opener drugs work in treating hypertension?

Answer 144

• They open K_ATP channels on smooth muscle cells in the arteries
• This leads to hyperpolarisation and therefore vasodilation of the vessels

Question 145

What are some examples of potassium channel opener drugs?

Answer 145

• Diazoxide
• Minoxidil
• Hydralazine (maybe)

Question 146

How do nitric oxide donors work in treating hypertension?

Answer 146

• They are drugs that lead to the production or release of NO
• This NO is responsible for the dilation of blood vessels, especially the venous system

Question 147

What are some example of nitric oxide donor drugs?

Answer 147

Nitroprusside

Question 148

How do ganglionic blockers work in treatment of hypertension?

Answer 148

• They lead to decreased activity of post-ganglionic nerves
• Therefore, in theory, they should reduce both sympathetic and parasympathetic activity
• However, since arteries receive only sympathetic innervation, this means that vasodilation is favoured

Question 149

What are some examples of ganglionic blockers used in treating hypertension?

Answer 149

Pentamethonium (C5) and hexamethonium (C6) found to be selective, non-depolarising ganglion blockers.

Question 150

What are two classes of anti-hypertensive drugs used primarily in acute hypertensive emergencies?

Answer 150

• Ganglionic blockers
• Nitric oxide donors

Question 151

What are sympatholytic drugs and what are the main types?

Answer 151

Drugs that block the sympathetic nervous system at different points:

• Peripheral sympatholytic drugs (e.g. alpha-adrenoceptor and beta-adrenoceptor antagonists) block the influence of noradrenaline at the effector organ
• Ganglionic blockers block impulse transmission at the sympathetic ganglia
• Centrally acting sympatholytic drugs block sympathetic activity within the brain

Question 152

How do centrally acting sympatholytic drugs work in treating hypertension?

Answer 152

• They are agonists of α₂-adrenoceptors primarily in the brainstem.
• This reduces sympathetic outflow to the heart and vasculature.

Question 153

What are some examples of centrally acting sympatholytic drugs?

Answer 153

• Clonidine
• Methyldopa

Question 154

Give a summary of anti-hypertensive drugs.

Answer 154

Question 155

What are some possible treatments for hypertension that does not respond to drug treatment?

[EXTRA]

Answer 155

Question 156

What is an alternative explanation for the efficacy of anti-hypertensive drugs?

[EXTRA]

Answer 156

• There is the argument that all anti-hypertensive drugs must also exert an effect on the kidney, making it filter salt and water out more quickly (as Keith Dorrington argues).
• This is because any systemic changes caused by anti-hypertensives, such as vasodilation, should in theory be counteracted by the decreased blood pressure reduced GFR, so that the volume of the system gradually increases again
• This is controversial though?

Question 158

What is cardiovascular shock?

Answer 158

A potentially fatal, pathophysiological disorder characterised by acute failure of the cardiovascular system to perfuse the tissues of the body adequately.

Question 159

What are the general signs of shock?

[IMPORTANT]

Answer 159

• Rapid and weak pulse (tachycardia with reduced stroke volume) -> Unless the cardiac failure is due to bradycardia
• Mean arterial pressure may be reduced or normal, but pulse pressure reduced
• Shallow and rapid breathing
• Reduced urine output is reduced
• Reduced mental awareness or confusion

Question 160

What are the four main types of cardiovascular shock?

Answer 160

• Hypovolaemic
• Cardiogenic
• Distributive (vasodilatory)
• Obstructive

Question 161

What is hypovolemic shock and what are the causes?

[IMPORTANT]

Answer 161

• Lack of perfusion of tissues caused by loss of fluid volume.
• Causes:
  
  • Hemorrhage
  • Diarrhoea/vomiting
  • Third space losses (pancreatitis, burns) -> Fluid losses into spaces that are not visible

Question 162

What is cardiogenic shock and what are the causes?

[IMPORTANT]

Answer 162

• Lack of perfusion of tissues caused by decreased effectiveness of heart pumping.
• Causes:
  
  • Reduced stroke volume in MI or myocarditis
  • Bradycardia
  • Tachyarrhythmias (when the heart rate is too fast for the heart to refill between strokes)
  • Acute valve rupture

Question 163

What is distributive shock and what are the causes?

[IMPORTANT]

Answer 163

• Lack of perfusion of tissues caused by systemic vasodilation.
• Causes:
  
  • Sepsis
  • Anaphylaxis
  • Neurogenic causes (epidural anaesthesia/spinal injury)

Question 164

What is obstructive shock and what are the causes?

[IMPORTANT]

Answer 164

• Lack of perfusion of tissues caused by mechanical obstruction of inflow or outflow from the heart.
• Causes:
  
  • Cardiac tamponade
  • Pulmonary embolism
  • IVC obstruction (e.g. thrombus)

Question 165

Describe simply how hypovolaemic shock affects the cardiovascular system.

Answer 165

There is an overall loss of fluid volume leading to decreased pressure, but the mechanism can also be understood in terms of Frank-Starling, where reduced filling of the heart leads to reduced cardiac output.

Question 166

For hypovolaemic shock, describe the main changes in physiological values and the compensatory responses.

Answer 166

• CVP and ABP both fall, although ABP may be maintained by compensatory mechanisms -> Pulse pressure is greatly reduced though
• Heart rate and TPR resistance increase due to increased sympathetic activity (via baroreflex) and increases in circulating catecholamines/RAA axis
• Limb blood flow is reduced and the limb volume is decreased as venoconstriction occurs -> There is also transfer of fluid from the interstitial fluid into the blood
• Blood pH drops and lactate levels increase due to anaerobic respiration in underperfused tissues

Question 167

Summarise the rapid reflex responses to hypovolaemic shock.

Answer 167

• The drop in blood pressure detects to decreased firing of arterial and cardiopulmonary baroreceptors -> This is the baroreflex
• There is also increased firing of arterial chemoreceptors due to metabolic acidosis
• These increase brainstem sympathetic stimulation of the vasculature and heart
• Arterial vasoconstriction and increased cardiac output lead to maintained blood pressure
• Venous vasconstriction increases cardiac filling pressure

Question 168

Summarise the neurohumoral responses to hypovolaemic shock.

Answer 168

Activation of the RAA axis:

• The RAA axis is activated by the decreased perfusion of kidney, decreased flow of NaCl and increased sympathetic stimulation
• Angiotensin leads to vasoconstriction, central effects (e.g. stimulating thirst) and aldosterone release
• The aldosterone leads to increased salt and water retention

ADH release:

• Severe water loss (10-15% loss of fluid volume) leads to a shift of the vassopressin-osmolarity release curves
• This means there is more ADH release
• This is due to baroreceptors and arterial receptors detecting the drop in blood pressure, which via the brainstem leads to stimulation of ADH release from the posterior pituitary
• This ADH leads to vasoconstriction (via V1 receptors) and antidiuresis (via V2 receptors)

Question 169

Describe the concept of internal fluid transfusion in hypovolaemic shock.

Answer 169

• In shock, the capillary pressure is decreased
• According to Starling forces, by the end of the capillary, there is a net inward force that causes fluid to enter the capillary from the interstitial fluid
• This helps maintain blood pressure
• It is observed at a time scale of minutes to hours

Question 170

Describe how internal fluid transfusion during hypovolaemic shock can be studied experimentally.

[EXTRA]

Answer 170

Landis-Michel red cell method:

• A capillary is blocked
• The capillary pressure is then changed
• The movement of red cells within the capillary is used to assess whether there is absorption or filtration occurring

Question 171

Summarise the long term responses to hypovolaemic shock.

Answer 171

On a time scale of hours to days:

• Reduction in GFR
• Thirst
• Red cell synthesis
• Hepatic alobumin synthesis -> This increases oncotic pressure, helping retain water

Question 172

Describe the symptoms of hypovolaemic shock on various organs.

Answer 172

• Type II Myocardial infarction -> Due to hypoperfusion, anaemia, increased coagulability and increased metabolic demand of the heart as it tries to compensate.
• Acute tubular necrosis
• Multi-organ failure

Shock is a downwards spiral since the effects and some compensatory mechanisms reinforce the problem of decreased oxygen delivery to tissues.

Question 173

What are the main stages of hypovolaemic shock?

[EXTRA}

Answer 173

Question 174

Summarise the general principles of treating shock.

Answer 174

• Identify early
• Rapidly stabilise the patient
• Treat the underlying cause
• ITU/CCU monitoring/support

Question 175

What is a system for classifying shock?

[EXTRA?]

Answer 175

National Early Warning Score (NEWS2) is a system used to assign a score to a patient based off several parameters.

Question 176

How is assessment done in cases of shock?

[EXTRA?]

Answer 176

• A: Airway
• B: Breathing
• C: Circulation
• D: Disability
• E: Exposure

Question 177

What determines the sort of fluid that is used for resuscitation during hypovolaemic shock?

Answer 177

• The way the fluid distributes within the body compartments determines how effective it is.
• 1L of glucose solution only increases plasma volume by 1/12L since it can enter intracellular compartments too
• 1L of saline solution increases plasma volume by 1/4L since it is distributed between all the extracellular compartments.
• 1L of blood will increase plasma volume by 1L due to the oncotic pressure it exerts
• Thus, blood is best, especially in stage 3 hypovolaemia and beyond
• Colloid (e.g. albumin) or crystalline (e.g. saline) solution are best used

Question 178

Give some experimental evidence for the use of colloid and crystalloid solutions in fluid resuscitation during hypovolaemic shock.

[EXTRA]

Answer 178

(Annane, 2013) CRISTAL trial:

• Found no significant difference in 28 day mortality in hypovolaemic patients between use of colloids or crystalloids
• 90 day mortality was lower in patients treated using colloids, but this is a tentative finding and it requires more research

Question 179

What are some difficulties with using blood for fluid resuscitation during hypovolaemic shock?

[EXTRA]

Answer 179

It is difficult to know how much blood to give the patient (i.e. do we bring them back to ‘normal’ or just to a safe point) -> This will vary on a case-by-case basis (e.g. a patient with poor cardiac function may struggle with pulmonary oedema if too much fluid is given)

Question 180

Summarise the main treatments for hypovolaemic shock.

[IMPORTANT]

Answer 180

• Treat underlying cause
• Fluid resuscitation
  
  • Colloid or crystalloid solution is usually sufficient if mild shock
  • Blood infusion required if severe shock
• Major haemorrhage protocols (used if more than 50% blood lost in 3 hours)
  
  • Guided administration of RBC, plasma and platelets in the correct ratio
• Bleeding control techniques

Question 181

What are some bleeding control techniques used to treat hypovolaemic shock?

Answer 181

• Drive clotting:
  
  • Account for underlying cause (e.g. supplement vitamin K if patient takes warfarin)
  • Anti-fibrinolytics: Tranexamic acid if within 3 hours
• Mechanical intervention
  
  • Tourniquets
  • Sengstaken–Blakemore tubes (device with a balloon that inflates to stop bleeding in the stomach and oesophagus)
• Cell salvage (recovery of blood that the patient has lost, such as during surgery)
• Endovascular repair
  
  • Embolization
  • Stents
• Surgical repair
  
  • Clamps
  • Suturing/ligation
  • Grafting
  • By-pass
• RAPTOR units -> Specialised units that use a combinations of all of the above

Question 182

What is the difficulty with surgical intervention for hypovolaemic shock?

Answer 182

• Surgery requires general anaesthesia, which tends to depress the cardiovascular system, exacerbating the shock.
• Therefore, the patient usually needs to be stabilised before surgical intervention.

Question 183

What is the mortality for acute heart failure (cardiogenic shock) and chronic heart failure?

Answer 183

• Acute = 40%
• Chronic mortality is higher at lower ejection fractions

Question 184

What is the body’s response to cardiogenic shock?

Answer 184

• The response is similar to in hypovolaemic shock, since the arterial baroreceptors detect the low pressure and there is the baroreflex
• The RAAS and sympathetic nervous system lead to vasoconstriction, fluid retention (at the kidneys) and cardiovascular remodelling in the long term
• This helps to increase cardiac output due to increased cardiac filling, but it causes the heart to have to work more against the increased fluid, which can exacerbate the problem
• However, natriuretic peptide release is triggered by stretch of the atria -> This leads to countering of the damaging effects of the shock

Question 185

What are the clinical signs of cardiogenic shock?

Answer 185

• Left sided -> Pulmonary oedema
• Right sided (or both sides) -> Jugular vein distension

Question 186

Summarise the approach to treating cardiogenic shock.

Answer 186

• Treat underlying cause (frequently a heart attack)
• Improve oxygenation
  
  • High flow O₂
  • Continuous positive airway pressure
  • Invasive ventilation via endotracheal tube
• Either:
  
  • Reduce fluid retention if the patient is ‘falling off’ the Frank-Starling curve -> Increases cardiac output
    
    • Loop diuretics (furosemide)
  • Infuse fluid if hypovolaemic -> Increases preload and therefore cardiac output
• Either:
  
  • Reduce afterload (if there is sufficient blood pressure to sacrifice) -> This increases cardiac output by shifting the Frank-Starling curve upwards
    
    • Nitrates (as blood pressure allows)
    • ACE inhibitors or angiotensin receptor blockers
  • Use vasoconstrictors (if hypotensive) -> This maintains pressure
• Improve cardiac contractility
  
  • Inotropes: Dobutamine, Milrinone, Levosimendan
• Mechanical haemodynamic support (i.e. mechanically supporting the heart)
  
  • Intra-aortic balloon pump use
  • Others: Impella, Tandem Heart, Extracorporeal membrane oxygenation (ECMO)

(CHECK when fluid infusion/retention and vasoconstriction/dilation are used)

Question 187

Summarise the contradictory treatments for cardiogenic shock. Explain why each may be used.

Answer 187

Fluid management:

• Fluid infusion
  
  • Most of the fluid enters the venous circulation and therefore increases preload
  • This increases cardiac output
• Reducing fluid retention (loop diuretics)
  
  • This is used if the patient is ‘falling off’ the Frank-Starling curve
  • In these situation, further increases in preload decrease cardiac output because the heart cannot mobilise all of the blood supplied to it

Vascular control:

• Vasodilation (nitrates, ACE inhibitors, ARBs)
  
  • Reduces afterload, which increases cardiac output by shifting the Frank-Starling curve upwards
  • This is useful, but can only be done if there is sufficient arterial blood pressure to sacrifice
• Vasoconstriction
  
  • Increases arterial blood pressure
  • But also increases afterload, which reduces cardiac output

Question 188

Summarise how you can think of the shock and its treatments using Guyton diagrams.

[CONCEPTUALLY USEFUL]

Answer 188

• Fluid infusion (which mostly enters the veins) or venous vasoconstriction (i.e. decreased capacitance) lead to a shift to the right of the Pmcf, which consequently shifts the venous and arterial lines
• Arterial vasoconstriction leads to increases in TPR, which decreases the gradient of the arterial and venous lines (no change in Pmcf though)
• When both happen at the same time (i.e. both arterial and venous vasoconstriction), the two effects are combined and so the lines shift to the right but the gradient decreases
• Decreased afterload (e.g. due to arterial vasodilation) shifts the Frank-Starling curve upwards

Question 189

Describe the diagnosis and treatment for distributive shock caused by sepsis.

Answer 189

Diagnosis:

• ABCDE
• Blood cultures

Treatments:

• Oxygen supply
• IV fluids
• Broad spectrum antibiotics
• Vasopressors
• Steroid -> Support vasoconstriction, but weaken the immune response against the infection
• Manage coagulation

Question 190

Describe the treatment for distributive shock caused by anaphylaxis.

Answer 190

• Remove trigger
• Lay down
• Adrenaline (“epipen”)
• Oxygen delivery
• IV fluids
• Chlorphenirame
• Hydrocortisone

Question 191

What are the symptoms of chronic ischaemic heart failure?

[IMPORTANT]

Answer 191

• Tiredness and lethargy (caused by reduced perfusion of tissues, and by acidaemia)
• Breathlessness, particularly on exertion and (in the case of left ventricular failure) on lying flat
• In the case of right ventricular failure, dependent oedema (i.e., usually ankle oedema)

Question 192

What are some clinical signs of heart failure?

[IMPORTANT]

Answer 192

• Reduced systemic arterial pressure
• Increased heart rate
• Apex beat displaced to the left (left ventricular dilation)
• Pulmonary oedema

And if there is right ventricular failure:

• Raised jugular venous pressure
• Dependent oedema (venous congestion in dependent areas, plus reduced oncotic pressure as resulting from fluid retention by the kidneys)

Question 193

Summarise in general what causes chronic ischaemic heart failure.

Answer 193

• Chronic ischaemic failure may occur in isolation, or may be an end point of other diseases, such as hypertension.
• When it apparently occurs in isolation, the underlying pathology is usually some form of obstruction to the blood supply of the myocardium.

Question 194

List some causes of chronic ischaemic heart failure.

[IMPORTANT]

Answer 194

• Coronary atherosclerosis
• Small vessel disease (occlusion of small and medium arteries supplying the myocardium)
• Ventricular hypertrophy (in response to hypertension or valve disease, but increasing metabolic demand)
• Atrial fibrillation (there is a correlation between atrial fibrillation an heart failure, but it is not certain which is the primary event)
• Anaemia (decreased oxygen delivery)

Question 195

Give some reasons why chronic ischaemic heart failure is an escalating disease that gets worse over time.

Answer 195

Physical:

• Ventricular dilation -> The failing ventricle does not clear the venous return that is presented to it and so begins to dilate. This is usually useful but it is a problem when the hump of the Frank-Starling curve is passed and cardiac contractility is decreased.

Neuroendocrine:

• Sympathetic activity -> Decreased cardiac output triggers the baroreflex, which leads to increased heart rate, but also increased the metabolic demand of the heart.
• RAA axis -> Triggered by decreased renal blood flow and sympathetic stimulation. Leads to increased fluid retention and vasoconstriction, increasing the work the heart must do.
• ADH -> Release triggered by angiotensin and sympathetic stimulation. Leads to increased fluid retention and vasoconstriction, increasing the work the heart must do.

Question 196

How are natriuretic peptides involved in heart failure?

Answer 196

• Atrial natriuretic peptide (ANP, released mainly from the atria) and B-type natriuretic peptide (BNP, released mainly from the ventricles) are released in response to myocardial stretch.
• Blood levels of both are elevated in chronic failure, and BNP is used clinically as a measure of the severity of the failure.
• Both are weak angiotensin antagonists so they should be capable of counteracting the progression of heart failure. It is a mystery why this effect is so small.

Question 197

What is the 5-year survival of chronic ischaemic failure and what is the cause of death?

Answer 197

• Around 40%
• The cause of death is usually cardiac dysrhythmia, probably from ischaemia and/or cellular uncoupling as a result of ventricular dilation.

Question 198

Describe the principles of treating chronic ischaemic heart failure.

Answer 198

• It is usually difficult to treat the underlying cause of chronic ischaemic heart failure.
• The exceptions are treating anaemia or surgical interventions (for valve disease or large-vessel coronary atherosclerosis)
• In the majority of cases the aim of medical therapy is to relive the symptoms and, where possible, to slow the progression of the disease.

Question 199

What are some targets of treatments for heart failure?

Answer 199

• Should increase cardiac contractility without increasing oxygen demand (or, alternatively, it should increase oxygen delivery through obstructed blood vessels)
• Should maintain systemic arterial pressure without increasing peripheral resistance
• Should reduce ventricular dilation without reducing arterial pressure and without reducing venous return too much
• Should reduce oedema without dehydrating the patient, and without triggering the RAA axis

However, these are all very difficult to achieve, so the drugs tend to have significant side effects.

Question 200

State the main classes of drugs used for treatment of heart failure.

[IMPORTANT]

Answer 200

• Diuretics
  
  • Thiazide
  • Loop
  • Potassium-sparing
• Vasodilators
  
  • ACE inhibitors
  • Angiotensin receptor blockers (ARBs)
  • Nitric oxide donors
  • Natriuretic peptides
  • Phosphodiesterase inhibitors
• Cardio-stimulatory (inotropic) drugs
  
  • Digitalis
  • Sympathomimetic drugs (beta agonists)
  • Phosphodiesterase inhibitors
• Cardio-inhibitory drugs
  
  • Beta blockers
  • Calcium channel blockers

Question 201

How can the RAA axis be targeted in the treatment of heart failure? What are the side effects?

Answer 201

ACE inhibitors or angiotensin receptor blockers:

• Reduces vasoconstriction, which reduces cardiac work and increases cardiac output
• Reduces the sodium-retaining effects of angiotensin and aldosterone, which reduces oedema and also slightly reduces the effective circulating volume, so reducing ventricular dilation
• Reduces the activation of the sympathetic nervous system (so reducing cardiac oxygen demand) and of ADH (so further reducing vasoconstriction and fluid retention)

Spironolactone:

• Reduces the sodium-retaining effects of aldosterone, which reduces oedema and also slightly reduces the effective circulating volume, so reducing ventricular dilation

Side effects:

• Postural hypotension (due to reduced vasoconstriction and plasma volume)
• Electrolyte disturbances (due to reduced renal perfusion)
• Cardiac problems (mostly related to the reduced volume and the electrolyte disturbances), including angina, palpitation and other rhythm disturbances

Question 202

In what patients may RAA axis inhibitors be unsuitable for the treatment of heart failure?

Answer 202

Not always suitable for patients with renal disease, which is an increasingly common problem in this age group.

Question 203

Give examples of an ACE inhibitor and angiotensin receptor blocker used in the treatment of heart failure.

Answer 203

• Ramipril (ACE inhibitor)
• Losartan (angiotensin-receptor blocker)

Question 204

How do beta blockers work in the treatment of heart failure? What are the side effects?

Answer 204

Beta blockers work by:

• Reducing vasocontriction, which reduces the workload on the heart, but also reduces blood pressure
• Reducing cardiac contractility, which reduces the metabolic demand on the heart, but also reduces cardiac output
• Reducing the release of renin and ADH

Side effects:

• Postural hypotension
• Others

Note that calcium channel blockers have similar effects to beta blockers.

Question 205

What type of diuretic appears best for treatment of heart failure?

Answer 205

• Spironolactone (aldosterone antagonist) produces much better results than other diuretics and also the other RAA axis antagonists.
• Aldosterone is elevated in heart failure, which may explain why this is so effective, but it does raise the question about whether the spironolactone is acting by a different mechanism too.

Question 206

How do positive inotropes work in the treatment of heart failure?

Answer 206

Their use is relatively limited:

• Sympathomimetics (beta agonists) -> Increase contractility but also increase oxygen demand, so they are not widely used in chronic heart failure, only cardiogenic shock.
• Glycosides (Na⁺/K⁺-ATPase inhibitors) -> Increase contractility with little effect on oxygen demand, but they are highly toxic and clinical trials have shown mixed results.
• Calcium sensitizers -> None are used clinically yet but they show promise. Levosimendan is the drug closest to clinical use.
• Phosphodiesterase inhibitors -> Analogous to sympathomimetics.

Question 207

Give an example of cardiac glycosides used in treatment of heart failure. How does it work?

Answer 207

• Digitalis
• Works by inhibiting the Na⁺/K⁺-ATPase, which leads to increased intracellular sodium and thus increased extrusion in exchange for calcium. This leads to increased contractility.

Question 208

How do diuretics work in the treatment of heart failure? What are the side effects?

Answer 208

• Diuretics used to be routinely used to treat chronic ischaemic heart failure, since they provided fast relief of symptoms, especially the breathlessness that follows left ventricular failure
• They work by reducing the circulating volume, but many vasdilators also have a secondary effect as vasodilators -> Evidence for this comes from the fact that furosemide provides rapid relief of breathlessness after a myocardial infarction before diuresis has had time to occur
• Thus, they reduce left ventricular dilation, which is beneficial
• However, the reduction is fluid volume also leads to:
  
  • Sympathetic stimulation (via the baroreflex)
  • Activation of RAA system
  • Increase myocardial oxygen demand (due to sympathetic stimulation)
  • Electrolyte disturbances that increase the risk of dysrhythmia.
• So now diuretics are not normally used as first-line treatment for new patients with failure where there is a reduced ejection fraction.

Question 209

Which is more effective in treating heart failure: diuretics or RAA axis inhibitors?

Answer 209

• RAA inhibitors are more effective because they also act as diuretics and vasodilators (via their inhibition of angiotensin and aldosterone), just like diuretics, but they have fewer side effects
• This is because they inhibit sympathetic tone (unlike the compensatory sympathetic stimulation in diuretic use), so they tend to reduce metabolic demand of the heart, rather than increase it
• However, RAA antagonists leave the kidney relatively under-perfused and can lead to electrolyte disturbances

Question 210

How do NICE guidelines distinguish between different types of heart failure?

[EXTRA]

Answer 210

Based on the ejection fraction:

• In classical heart failure, the LVEF is below 40%
• In a normal heart, the LVEF is 50-70%

It is possible to have symptoms of heart failure with a normal LVEF, which can occur when the left ventricle is stiff during diastole and thus the reduced stroke volume does not affect the LVEF. It is typical in cases of hypertension or diabetes.

Question 211

Give the NICE guidelines for treating a heart failure patient with preserved and reduced ejection fraction.

[EXTRA]

Answer 211

Reduced ejection fraction:

• First use RAA antagonist or beta-blocker -> Combine the two as the heart failure worsens. The RAA antagonists currently recommended are ACE inhibitors, switching to angiotensin-receptor blockers (ARBs) if ACE-inhibitors are not well tolerated.
• If symptoms worsen, use spironolactone.
• Closely monitor renal function.

Normal ejection fraction:

• Use furosemide (loop diuretic) for symptomatic relief.

Question 212

Aside from ACE inhibitors and ARBs, name some vasodilator classes that can be used in the treatment of chronic ischaemic heart failure.

Answer 212

• Nitric oxide donors
• Natriuretic peptides
• Phosphodiesterase inhibitors

Question 213

Describe how natriuretic peptides can be used in the treatment of chronic ischaemic heart failure.

Answer 213

• One of the puzzles about the endocrine network in cardiac failure is the apparent silence of the ANP/BNP natriuretic peptides.
• Blood levels of BNP are certainly elevated in cardiac failure, but they seem to be ineffective. By contrast, ANP levels are not elevated to the same extent, despite the common rise in central venous pressure.
• Analogues of ANP are unsuccesful therapeutically, but attempts to inhibit the degradation of natriuretic peptides via inhibition of the enzyme neprilysin. The drug most commonly used for this now is called neprilysin.
• Initial clinical trials suggested only a weak effect for secubitril, but combination with valsartan (an ARB) shows more promising results and is being used clinically.

Question 214

What are some new drugs being used in the treatment of chronic ischaemic heart failure?

[EXTRA]

Answer 214

Ivabradine:

• Inhibits the funny current, reducing the activity of the pacemaker current.

Vaptans:

• ADH inhibitors used to releive oedema.

Omecamtiv:

• Modifies myosin, increasing contractility. Similar to calcium sensitizers.
• Not yet in clinical use.

Question 215

Give some speculative information about endogenous glycosides in chronic ischaemic heart failure.

[EXTRA]

Answer 215

• Cardiac glycosides (purified from foxgloves) have historically been a major part of treatment of cardiac failure.
• It has been found that these drugs act at remarkable low concentration relative to their effects, which has led to the idea that these glycosides may influence an endogenous regulator that leads to more profound effects.
• Since glycosides tend to take 3-6 hours to work, this suggests the regulator they control may influence transcription. This is supported by their steroid structure.
• Attempts to identify the endogenous regulator led to the discovery of some pregesterone-derived steroids that were present in the urine of hypertensive patients. It appears that these steroids can increase cardiac output and increase arterial blood pressure.
• One suggestion is that heart failure might result from the failure of synthesis of these endogenous glycosides.
• If this is the case, then replacement of these glycosidfes would be the best therapy for heart failure. This would involve discovery of a less-toxic version of digoxin.

Question 217

Summarise the kidney filtration system using a simple diagram.

Answer 217

• Fraction of the filtered load is reabsorbed
• This fraction is different for different solutes and varies with regulation
• Secretory processes also present to augment excretion of solutes (e.g. organic anions or acid)
• Combination of both of the above allows maintainence of the body’s fluid composition

Question 218

How much of the blood volume do the kidneys filter each minute?

Answer 218

1/5th of the blood volume per minute

Question 219

What are the endocrine functions of the kidney?

Answer 219

• Endocrine target (e.g. for aldosterone or renin)
• Endocrine sensor/organ for:
  
  • Fluids/minerals
  • Flow and blood pressure
  • O2 and blood composition

Question 220

What are the endocrine agents acting on the kidney?

Answer 220

• Angiotensin II (both secreted by and acting on)
• Aldosterone
• Natriuretic peptides
• ADH
• Calcitriol and PTH

Question 221

What are the endocrine agents secreted by the kidney?

Answer 221

• Angiotensin II (both secreted by and acts on)
• Calcitriol (Vit D3)
• Erythropoietin (EPO)

Question 222

What protein facilitates the truncation of pre-prorenin into its active form?

Answer 222

• Peptidase: kallikrein
• This protein itself is generated from a pre-protein synthesised in connecting tubule cells of the kidney

Question 223

Where is renin released from and what is the cascade that follows its activation?

Answer 223

• Released from granular cells of the afferent arteriole wall (part of the juxtaglomerular apparatus) in response to signals from the macula dense
• Catalyses the truncation of angiotensinogen (synth. in the liver) to yield angiotensin I
  
  • This is further truncated by ACE in the pulmonary circulation to produce angiotensin II
  • ACE expression and angiotensinogen synthesis has also been noted within the kidneys itself (therefore Ang II can be considered a hormone secreted by the kidneys, acting on the kidneys)

Question 224

What are the triggers for renin release?

Answer 224

A drop blood pressure and fluid volume causes granular cells in the afferent arteriole walls in the kidney to release renin.

Question 225

What is a local signal for renin release?

Answer 225

• The macula densa detects NaCl levels in the glomerular filtrate at the beginning of the distal tubule
• Most significant trigger for the release of renin is a decrease in the delivery of NaCl to the macula densa
  
  • This occurs due to a decrease in GFR, as a result of decrease in BP/effective circulating volume

Question 226

What is the ultimate goal of the renin-angiotensin-aldosterone axis?

Answer 226

• Increase Na+ (and therefore H2O) retention and cause vasoconstriction
• This aims to maintain blood pressure and restore effective circulating volume (ECV)

Question 227

Label this diagram.

Answer 227

Question 228

What is the process of tubuloglomerular feedback? What effects does it have?

Answer 228

• ↑ Cl- efflux (through apical NKCC, anion channel on basolateral surface for efflux) -> depolarisation -> Ca2+ influx (via VGCCs)
• ↑ [Ca2+] activates an anion channel
  
  • This allows ATP efflux
• ATP release, adenosine production (by an ectoenzyme/extracellular nucleotidase)
• ATP/adenosine increases [Ca2+]
  
  • In granular cells: inhibition of renin release
  • In afferent arteriole smooth muscle: contraction
  • The above effects cause a reduction in GFR

Question 229

What is the juxtaglomerular apparatus?

Answer 229

• Afferent arteriole
• Efferent arteriole
• Macula densa
• Extraglomerular mesangial cells

Question 230

Give some experimental feedback on the topic of tubuloglomerular feedback.

[EXTRA]

Answer 230

• Bell et al, 2003
• Demonstrations of ATP release from macula densa cells
• PC12 is a cell line that expresses P_2X ATP receptors
  
  • These cells are being used as a bioassay system to check for ATP release, and are not part of the JGA
  • PC12 cells are attached to a patch pipette and are brought close to the macula densa
• B shows the effect of increased NaCl delivery to macula densa cells through changes in current across PC12 cell membranes
  
  • Can see that current is seen after increase of NaCl
  • This indicates ATP release by macula densa cells and its subsequent binding to P_2X receptors on the PC12 cells, causing the opening of Ca2+ channels
• D shows the use of a calcium-sensitive fluorescent dye to measure intracellular Ca2+ levels
  
  • These readings confirm that Ca2+ influx occurs as a result of P_2X activation by ATP as it occurs after NaCl delivery to the macula densa has occurred

Question 231

How is ATP converted into adenosine during tubuloglomerular signalling?

Answer 231

• Adenosine is generated from ATP using an enzyme/nucleotidase on the cell membrane of macula densa cells
• ATP released via basolateral anion channels from macula densa cells
• Adenosine acts at granular cells to suppress renin release and smooth muscle cells to induce vasoconstriction

Question 232

How can the influx of calcium throughout the JGA be visualised?

[EXTRA]

Answer 232

• Use Ca2+ sensitive fluorescent dye
• In diagram, warm colours = high concentration, cold colours = low concentration
• Using this method, we can see a wave of elevated Ca2+
• Peti-Peterdi et al, 2006

Question 233

What is seen in A1AR (A1 adenosine receptor) KO mice?

[EXTRA]

Answer 233

• These mice lack tubuloglomerular feedback (TGF)
• These experiments confirm that it is adenosine (and not ATP) that controls TGF
• Can indicate this using the stop-flow perfusion technique
  
  • Collection pipette placed in PCT
  • Pressure applied to stop flow of fluid out of the tubule/into the pipette
    
    • This stop-flow pressure is roughly equivalent to the hydrostatic pressure in the glomerular capillary driving filtration and fluid flowing along the PT
  • As afferent arteriole diameter changes, the hydrostatic pressure in the capillary does not change (?)
  • Pressure used to stop flow down and out of the tubule by the pipette will change
    
    • This provides a means of assessing SMC tone in afferent arteriole wall
  • Distal to the collection pipette, a 2nd pipette is inserted into the tubule to control the rate of perfusion of fluid past macula densa cells, therefore manipulating TGF
  • Increased perfusion resulted in subsequent reduced stop-flow pressure, indicated that the macula densa signalled to arteriolar SMCs to contract
  • In A1AR KO mice, there was no change in stop-flow pressure when perfusion was modified, indicating that the signal required was adenosine

Question 234

Through which receptors do catecholamines act to stimulate renin release?

Answer 234

Beta-1 adrenoceptors

Question 235

What are some inhibitors of renin release?

Answer 235

• Angiotensin II
• ADH
• Stretch of granular cells

Question 236

What is needed for renin release in terms of tubuloglomerular feedback?

Answer 236

• Tubuloglomerular feedback needs to be attenuated for renin secretion to occur
• When NaCl delivery to the macula densa is reduced (reflecting a contraction of the ECV and reduction in GFR), ATP release/adenosine production is attentuated
  
  • This causes the inhibition on renin secretion to be relieved

Question 237

Describe/draw the RAAS.

Answer 237

• Angiotensin II acts mostly on the proximal tubule
• Aldosterone acts mostly on the collecting duct
• The aims of angiotensin are:
  
  • Increase effective circulating volume
  • Increase blood pressure
• ADH acts mostly on principal cells, causing AQP2 insertion

Question 238

Fill in the blanks.

Answer 238

Question 239

What is angiotensin II and where does it predominantly act in the kidney?

Answer 239

• Peptide hormone indirectly generated by the kidney
• Acts on the kidney to promote sodium reabsorption
• Predominantly acts on the proximal tubule

Question 240

How does angiotensin II achieve its actions on the kidney?

Answer 240

• Predominantly at the PT
• Direct effects are through AngII-mediated activation of PLC and generation of IP3
  
  • This stimulates the release of calcium from intracellular stores
• Ca2+ release causes activation of kinases, which phosphorylate Na+/H+ exchangers in the apical membrane
  
  • These are involved in the reabsorption of Na+, HCO3- and Cl- ions
• This action augments the NaCl absorbing capacity of the proximal tubule

Question 241

What are the renal actions of AngII other than those on the PT?

Answer 241

• Induces efferent arteriole constriction
  
  • Preserves GFR (despite fall in ECV)
  • Reduces medullary blood flow
    
    • Reduces flow through the vasa recta
    • This augments urinary concentration as it prevents ‘wasahout’ of the hypertonic interstitium
  • Alters renal interstitial hydrostating pressure
    
    • Changing the balance of Starling forces dictates the movement of fluid between interstitium and peritubular capillaries
    • Therefore alters backflux/reabsorption of fluid back into renal tubule
    • Inhibits synthesis of PGE2, which normally inhibits Na+ pumps and so removes this inhibition
• Potentiates TGF
  
  • Therefore greater effects of changes in flow on GFR and renin release

Question 242

What is aldosterone and where/how does it act?

Answer 242

• Steroid hormone secreted by the adrenal cortex (zona glomerulosa)
• Acts on the kidney through:
  
  • Classical steroidal pathway
    
    • Aldosterone binds to a cytoplasmic receptor which is then translocated to the nucleus for the transcription of proteins involved with Na+ reabsorption, including: ENaC, Na+/K+ ATPase, metabolic enzymes to generate more ATP to fuel the pump
  • Non steroidal pathway
    
    • Receptor activates PKC and PKD through increasing [Ca+] intracellularly, which increases the activity of a variety of transport proteins within epithelial cells
• Aldosterone acts to promote Na+ retention (and therefore also K+ excretion)

Question 243

How does adenosine interact with extraglomerular mesangial cells?

Answer 243

• EMCs express adenosine A1 receptors
  
  • This induce increased intracellular [Ca2+] after binding to adenosine
• These cells are coupled to other mesangial cells by gap junctions
  
  • These are ultimately connected to other vascular smooth muscle cells and granular cells
  • In this way, the wave of increased [Ca2+] passes from the EMCs to effector cells (SMCs and granular cells)

Question 244

What is the non-steroidal pathway of action for aldosterone?

Answer 244

• This pathway increases activity of a variety of transporters within minutes
• Non-steroidal actions are mediated by PKC and PKD, which are induced by elevation of [Ca2+] intracellularly as a result of epithelial cell exposure to aldosterone

Question 245

How can we show that calcium mediates the non-steroidal effects of aldosterone?

[EXTRA]

Answer 245

• Through using calcium-sensitive fluorescent dyes, you can measure waves of calcium/intracellular calcium through observing fluorescence
• Within 1 minute of exposure to aldosterone, significant increases in [Ca2+] are apparent
  
  • This can lead to altered activity of protein kinases and phosphorylation of pre-existing transport proteins in the apical and basolateral membranes to increase their activity

Question 246

When are natriuretic peptides released?

Answer 246

During volume expansion

Question 247

What are the natriuretic peptides?

Answer 247

• ANP
  
  • Main peptide hormone (17aa)
• BNP
• CNP

Question 248

Where are the natriuretic peptides released from?

Answer 248

The heart and the brain

Question 249

What are the ANP receptors and what is their general action?

Answer 249

• ANPR-A
• ANPR-B
• These act on the kidney to promote natriuresis

Question 250

What are the specific mechanisms and effects of natriuretic peptides?

Answer 250

• Act through cGMP and PKG
• PKG (serine/threonine kinase) phosphorylates target proteins to result in the following effects
  
  • Tubular effects:
    
    • Inhibits renin release via macula densa mechanism
    • Inhibits transport of Na+ (through inhibition of a number of transport proteins in the renal tubule)
  • Haemodynamic effects: vasodilation
    
    • ​Increased GFR
    • Increased flow to medulla - this washes out the hypertonic interstitium and alters the renal interstitial hydrostatic pressure, causing balance of Starling forces to be tilted back towards backflux of fluid reabsorption across the epithelial cells and into the renal tubule

Question 251

What is the general function of ADH/vasopressin?

Answer 251

Involved in homeostasis of osmotic potential of body fluids

Question 252

What type of hormone is ADH/vasopressin and where is it released from?

Answer 252

• Peptide hormone (9aa)
• Released from the posterior pituitary

Question 253

What are the triggers for ADH/vasopressin release?

Answer 253

• Increased osmolarity
• Decreased blood pressure

Question 254

What potentiates ADH/vasopressin release?

Answer 254

• Angiotensin II
• This is in keeping with the increased H20 requirements when Na+ retention is increased (as is seen during action of AngII and aldosterone)

Question 255

Where does ADH/vasopressin act and through which mechanisms?

Answer 255

• Acts on the kidney to promote urinary concentration
• Inserts AQPII into the apical membrane of principal cells in the collecting duct
• Stimulates NKCC in the TALH
  
  • This potentiates the single effect that creates medullary hypertonicity, by which water is extracted from the collecting duct via aquaporins
• Activates urea transporter A (UT_A) ​
  
  • This occurs in the inner medullary collecting duct and allows for urea efflux from the renal tubule into the interstitium
  • This potentiates the interstitial hypertonicity that allows for H20 reabsorption
• Vasoconstriction
  
  • Reduces blood flow to the inner medulla, therefore minimising washout of the hypertonic interstiitium

Question 256

Fill in the blanks.

Answer 256

Question 257

Describe calcium homeostasis and its involvement with the kidneys.

Answer 257

• Calcium homeostasis requires the coordinated regulation of:
  
  • Assimilation of calcium into or the liberation of calcium from bone
  • Regulation of absorption by the GI tract
  • Regulation of fractional excretion of calcium excretion by the kidney
• The kidney is the site of the final hydroxylation of vitamin D3, one of the essential hormones in calcium homeostasis

Question 258

What are the hormones involved in calcium homeostasis and what are their general aims?

Answer 258

• Parathyroid hormone (PTH)
• Calcitriol (Vitamin D3)
  
  • These two aim to elevate calcium levels when they are too low
• Calcitonin
  
  • This hormone aims to reduce calcium plasma levels when elevated, but only really has physiological importance in children and breastfeeding mothers

Question 259

What are the actions of calcitriol?

Answer 259

Question 260

What is the active hormone in the vitamin D3 pathway?

Answer 260

• 1,25-dihydroxycholecalciferol
  
  • aka 1,25(OH)₂D₃ or calcitriol
• This is a derivative of D3

Question 261

What happens to vitamin D3 in the kidneys if PTH is not present?

Answer 261

• In absence of PTH, 25(OH)D3 is hydroxylated at the 24th postition at the kidneys
• This produces an inactive molecule

Question 262

What is the classical steroid pathway of action for aldosterone?

Answer 262

• Aldosterone binds to a cytoplasmic receptor which is then translocated to the nucleus for the transcription of proteins involved with Na+ reabsorption
• This includes the transcription of:
  
  • ENaC (apical protein)
  • Na+/K+ ATPase (basolateral protein)
  • Metabolic enzymes to generate more ATP to fuel the pump
• This pathway takes hours to have a noticeable effect

Question 263

What are the epithelial effects of PTH and calcitriol in the gastrointestinal tract?

Answer 263

• Calcitriol aims to increase Ca2+ reabsorption
• This is achieved in a similar fashion to what is seen in the renal tubule

Question 264

What are the epithelial effects of PTH and calcitriol in the kidneys?

Answer 264

• Act to increase Ca2+ reabsorption through:
  
  • Increasing activity and/or number of transport proteins involved in Ca2+ reabsorption, including:
    
    • ECaC
    • Na2+/Ca2+ exchanger
    • Ca2+ ATPase
• PTH also inhibits Pi reabsorption
  
  • NaPi cotransporter in the PT is inhibited
  • This elevates plasma calcium levels as calcium phosphate concentration is reduced

Question 265

What is the general function and trigger for erythropoietin (EPO)?

Answer 265

• General function is to induce transcription of regulators of RBC growth and maturation
• This hormone is released from the kidneys in response to hypoxia

Question 266

What type of hormone is EPO?

Answer 266

• Peptide hormone (165aa)
• 34kDa, glycosylated

Question 267

What is the mechanism of action for EPO?

Answer 267

• Actions are achieved through tyrosine-kinase associated receptors (dimers)
• EPO binding initiates Jak (Janus kinase) autophosphorylation
  
  • This is the cytoplasmic component of the receptor
• Following this there is subsequent activation of MAP/Akt kinases
  
  • This proteins induce changes in gene transcription through interactions with transcription factors for regulators of RBC growth and maturation

Question 268

What cell type synthesises EPO?

Answer 268

Type 1 interstitial cells in the renal cortex and outer medulla

Question 269

What factors increase EPO levels?

Answer 269

• High altitude
  
  • Due to associated fall in PaO2
• Pulmonary disease, e.g. emphysema
  
  • Compromised gas exchange at lungs, therefore hypoxia and EPO release
• Right to left shunts, e.g. in the heart
  
  • Causes blood to bypass the alveoli in the pulmonary circulation, therefore are not oxygenated
• Alkalosis
  
  • Affects affinity of Hb for O2
• Renal tumours
  
  • If secretory can increase production of EPO
• Professional cycling lmao
  
  • Associated with elevated EPO levels

Question 270

How is HIF involved with EPO synthesis? How is expression of HIF controlled?

Answer 270

• Low local O2 triggers EPO synthesis through HIF signalling
• HIF = hypoxia inducible factor, which translocates to the nucleus to promote transcription of the EPO gene in type 1 interstitial cells when present
• Translocation of HIF to the nucleus in normoxic conditions is prevented by the enzyme prolylhydroxylase
  
  • In presence of O2 and Fe, this enzyme hydroxylates HIF, causing it to adopt a conformation that can then be bound by 2 proteins:
    
    • Von Hippel-Lindau protein (VHL)
    • Ubiquitin
    • Together, these proteins chaperone HIF for destruction/proteosome degredation

Question 271

How much ultrafiltrate is produced at the glomeruli each day? What molecules does this initial ultrafiltrate contain?

Answer 271

• 150 litres per day
• Useful molecules such as: glucose, amino acids, water, bicarbonate
• Waste products such as: urea, ammonium, creatinine

Question 272

Where is the ultrafiltrate modified?

Answer 272

• In the tubules (majority in the proximal tubule, balancing and smaller modifications are achieved in the tighter epithelium of the distal tubule and collecting duct)
• Useful products are reclaimed and waste products are also secreted to increase their excretion

Question 273

What is the function of the glomerular filtration barrier?

Answer 273

• Blocks the entry of proteins and other large structures into the ultrafiltrate/Bowman’s space

Question 274

Label this diagram.

Answer 274

Question 275

What is defined as a failure of the glomerular filtration barrier?

Answer 275

• Presence of proteins from the blood in the ultrafiltrate
• This is nephrotic syndrome

Question 276

Describe 3 ways in which failure of the glomerular filtration barrier/nephrotic syndrome can occur.

Answer 276

• Idiopathic (unknown cause/spontaneously)
• Immunological
  
  • Abs binding to components of the barrier, or immune complexes formed elsewhere end up deposited within the barrier
  • How the latter process results in loss of the barrier is not yet completely clear
• Structural/genetic
  
  • See diagram for the proteins involved in this barrier
  • Particular mutations that can result in nephrotic syndrome include podocin and nephrin

Question 277

What is a way to define nephrotic syndrome? What are some other associated features?

[EXTRA]

Answer 277

As a triad of:

• Proteinuria (>3.5 g/day)
• Hypoalbuminaemia (<30g/dL)
• Oedema

Other associated features:

• Hyperlipidaemia
• Hypercoagulability
• Various histopathologies
  
  • Often perform renal biopsy to elucidate cause, wide variety of histopathologies can be seen but all result in the same pathophysiological response

Question 278

Describe a typical history in a case study of a patient with ‘minimal change’ nephrotic syndrome.

[EXTRA]

Answer 278

• Patient shows acute onset
• Frothy urine is due to the increased protein content of the urine - this causes bubbles to form

Question 279

Explain the progression of nephrotic syndrome (as would be presented in a textbook).

Answer 279

• Protein loss at kidneys (proteinuria and catabolism) leads to
• Reduced oncotic pressure in the blood, and so this causes a reduced oncotic gradient leading to
• Oedema formation and (as fluid is leaving the blood) reduced circulating volume, leading to
• Activation of the RAAS (IMPORTANT), leading to
• Sodium and water retention (this refills the intravascular space but supplies more water and salt for oedema formation)

Question 280

In the textbook description of nephrotic syndrome, what are the predictions? How often are these seen in reality?

[EXTRA]

Answer 280

Predictions in nephrotic syndrome:

• Plasma oncotic pressure will fall
• Circulating volume will be reduced
• Renin levels will rise/RAAS activation will occur

Reality:

• Literature from the 70s suggests that the oncotic pressure does not really show much change, ECV is neither always reduced nor always raised, renin levels can be medium, low or high
• This therefore provides some uncertainty over what the actual underlying pathology of nephrotic syndrome is

Question 281

Take a look at these sources for another explaination of pathophysiology of nephrotic syndrome

[VERY EXTRA]

Answer 281

Question 282

How can you test for glycosuria?

Answer 282

• Dip test
• Dip a tes stick into a urine sample to analyse it and estimate a value for glucose levels
• In health, urine should contain no glucose, but may do so in pathology
• This test is not quantitative

Question 283

Describe this graph.

Answer 283

• Glucose is taken up from the renal tubule via transporters (GLUT transporters), which can therefore become saturated
• If filtered load exceeds the concentration at which the transporters become saturated, then glucose will start appearing in the urine
  
  • As filtered load increases from this point, so will the concentration of glucose in the urine
  • Below the concentration at which saturation occurs, there should be no glucose in the urine, making glycosuria an indication of potential pathology

Question 284

What might cause glycosuria to occur?

[EXTRA]

Answer 284

• Excess glucose in blood
  
  • E.g. in diabetes mellitus
  • Black line on graph
• Excess glucose filtered
  
  • E.g. during pregnancy
  • Increased BP results in increased GFR, therefore even at normal blood glucose levels, filtered load can reach concentrations that exceed the tubular filtration maximum and so glucose is seen in the urine
  • Blue line on graph
• Failure of tubular reabsorption
  
  • E.g. after tubular damage
    
    • For example after extended periods of hypotension
    • Until the tubule recovers, there will transiently be a period where there is a reduced maximum capacity for glucose reabsorption in the tubule
  • E..g SGLT2 inhibitor treatment
    
    • These drugs were used (initially) to treat diabetes but are now also used to generally improve kidney function
    • This reduces tubular maximum for glucose reabsorption and therefore glycosuria occurs at ‘normal’ blood levels

Question 285

What can occur as a consequence of excessive tubular glucose?

[EXTRA]

Answer 285

• Osmotic diuresis
• This is a common presentation of diabetes, as results in polyuria and excessive thirst

Question 286

How can you calculate concentration of glucose?

Answer 286

Question 287

Describe the acid-base status of the patient in this case study.

[EXTRA]

Answer 287

• Arterial blood gases frequently taken upon arrival if patient presents as unwell
• pH: low
• pCO2: low
• pO2: adequate
• HCO3: low
• Therefore acid-base status is:
  
  • Acidotic (low pH)
  • Metabolic acidosis (therefore driver for low pH is the absence of alkali)
  • Low pCO2 due to sensing of acidaemia by carotic bodies and subsequent increase in respiratory drive/hyperventilation (respiratory compensation)
    
    • These are common findings in diabetic patients with ketoacidosis
      *

Question 288

Describe the relationship between pH and pCO2 in various disorders.

Answer 288

• Reaching chronic respiratory acidosis or alkalosis is through the action of/compensation by the kidneys (cause the shift)
• In metabolic acidosis, respiratory compensation occurs almost immediately, therefore it is very rare that metabolic acidosis occurs without some change in pCO2, unless the patient has very severe lung disease

Question 289

In the case of an individual with metabolic acidosis in the absence of any other (renal) pathology, what would you expect the urinary pH to be? In what conditions might this normal response not be seen?

[EXTRA]

Answer 289

• Low urinary pH
  
  • Normal function of the kidneys, therefore urinary pH will mirror that of the blood pH (increased [H+], lower pH)
• This normal response might not be seen in renal tubular acidoses (this is where kidneys fail to secrete protons into the urine, so the blood remains too acidic)

Question 290

What is the mechanism for proximal renal tubular acidosis?

[EXTRA]

Answer 290

• Reduced bicarbonate reabsorption in PCT delivers a high amount of bicarbonate to DCT
  
  • DCT has a limited ability to reabsorb bicarbonate
  • Leads to massive bicarbonate loss in urine, causing acidosis due to the massive alkali loss
  • This causes a decrease in bicarbonate concentration
    
    • Therefore glomerular filtrate bicarbonate concentration falls
• This cycle continues until filtered bicarbonate concentration falls low enough for full bicarbonate reabsorption in the DCT (limits the extent of bicarbonate loss)
• Acid urine CAN then be excreted, meaning that severe acidosis does not occur

Question 291

What are some causes for proximal renal tubular acidosis?

[EXTRA]

Answer 291

• Can be associated with isolated effects, e.g. mutation in one of the proteins involved in H+ excretion or HCO3- reabsorption in the PCT
• Sometimes associated with a more generalised PCT disorder, however, e.g. Faconi’s syndrome

Question 292

Which condition is usually more severe: proximal or distal renal tubular acidosis?

[EXTRA]

Answer 292

Distal renal tubular acidosis

Question 293

What is Fanconi’s syndrome?

[EXTRA]

Answer 293

• Renal tubular acidosis + generalised proximal tubular dysfunction
• Associated features:
  
  • Aminoaciduria
  • Glycosuria
  • Phosphaturia
  • Impaired vitamin D activation
  • Raised urinary calcium and citrate levels
  • Uricosuria (uric acid in the urine)
  • Hypokalaemia
• Can be caused by some toxins causing generalised damage to the proximal tubule (also some antibiotics), but can also be due to genetic defects
  
  • Genetic defects have recently been found to include molecules involved in the energetics of the tubule, as the PCT has a high ATP demand
  • Condition can also occur as a result of kidney transplant

Question 294

What are the features of distal renal tubular acidosis?

[EXTRA]

Answer 294

• H+ excretion impaired in the DCT and CD
• Typically causes more severe metabolic acidosis than proximal RTA
• Diagnosis made by failure to produce acidic urine even in response to acid load with NH4CL
• Associated features:
  
  • Acidosis mobilises bone calcium:
    
    • Osteomalacia (thinning of bones)
    • Nephrocalcinosis
    • Renal stones
    • Above two are due to increased deposition of calcium in the kidneys, and will increase in prevalence
  • Hypokalaemia

Question 295

How does the kidney control body water?

Answer 295

• Osmotic gradient is generated in the renal medulla by the countercurrent mechanism
• Urinary filtrate in the collecting ducts runs through this osmotic gradient
  
  • In the presence of ADH/vasopressin (from the hypothalamus/posterior pituitary), AQPs are inserted to allow the movement of water out of the filtrate, resulting in the concentration of and a reduced volume of urine

Question 296

Describe the action of ADH/vasopressin at the kidneys.

Answer 296

• Specific receptor is a V2 receptor (also V1(a) and V3(or 1b) receptors elsewhere in the body)
• AQP4 is constitutively present on the basolateral membrane
• Insertion of AQP2 apically increases permeability to H2O
• Receptors are coupled to Gs proteins

Question 297

In the principal cells of the collecting duct, which AQP channels are constitutively active and which are inserted in response to ADH signalling?

Answer 297

• AQP4 is constitutively active (basolateral)
• AQP2 is inserted in response to ADH (apical)

Question 298

Which conditions can present as:

• Excessive thirst
• Excessive drinking
• Excessive urine output

Answer 298

• Compulsion to drink
• Failure of ADH production from the hypothalamus/posterior pituitary
• Failure of kidneys to respond to ADH

Question 299

Discuss these results. What would be the next step?

[EXTRA]

Answer 299

• Plasma osmolarity is normal, but urine is dilute (for urine) with no real change
  
  • Plasma osmolarity rises, indicating concentration of the plasma and therefore should have triggered ADH release and stimulated the concentration of urine by up to ~1000
• Weighing allows the clinician to know whether H2O intake is being restricted as instructed
  
  • Can see that the patient has dropped 2.6kg over the time period due to polyuria
• These results indicate a failure of the renal response to hyperosmolar blood
  
  • Next step is to determine whether this is a renal or pituitary issue
  • Administer synthetic ADH (DDAVP) - if a normal response is then seen/urine concentrated, then the issue is in the pituitary, whereas if the same response is observed then the issue can be localised to the kidneys

Question 300

Discuss these results. What is the diagnosis?

[EXTRA]

Answer 300

• Increase in weight is due to free access to water
• Should have seen an increase in urine osmolarity in response to DDAVP, but as this is not seen then the issue can be located to the kidneys
• The diagnosis is therefore: nephrogenic diabetes insipidus (kidney cannot respond to ADH)

Question 301

Why might the nephrogenic diabetes insipidus occur?

Answer 301

• Osmotic diuretic causes the osmotic gradient to be less/the lumen to not be as hypoosmolar
• Tolvaptan is a V2R antagonist
  
  • Can also have failure of ADH action at V2R via mutation
• Inflammation in the kidneys stops the tubules from functioning normally, therefore can result in a hopefully transient form of diabetes insipidus

Question 302

What can be seen in this histology slide?

[EXTRA]

Answer 302

• Interstitial nephritis
• Can see eosinophils and other inflammatory cells amongst the tubule cells
  
  • This prevents/limits normal tubular function
  • This causes failure of normal urinary concentration mechanisms and presents initially as thirst and polyuria

Question 303

What conditions can provoke interstitial nephritis? How does the condition present and develop?

[EXTRA]

Answer 303

• Drugs (idiosyncratic)
  
  • Penicillins
  • Proton pump inhibitors
  • NSAIDs
• Autoimmunity
  
  • Sarcoid and Sjogren’s commonly present with interstitial nephritis
• Injections
  
  • CMV
  • EBV
  • Toxoplasmosis
• Initially present with thirst and polyuria but if they get dehydrated or inflammation is not reversed then the condition can progress to kidney failure

Question 304

What are the sensors for the RAAS?

Answer 304

• Macula densa signalling (needs to be attentuated for renin secretion, this occurs when NaCl load is decreased)
• SNS innervation

Question 305

Describe RAAS.

Answer 305

• NB as less NaCl is filtered (indicating decreased delivery/GFR) PCT reabsorption is able to take up more of the NaCl, causing the decreased load to the macula densa
• NB Angiotensin II acts as a vasoconstrictor

Question 306

Discuss the results from this case study. What would you consider if ACE inhibitors caused no change in blood pressure?

[EXTRA]

Answer 306

• Sodium - normal
• Potassium - low
• Bicarb - slightly alkalotic/high
• ACE inhibitors are not affecting blood pressure indicating that the cause of hypertension lies downstream in RAAS
  
  • One of the more common causes of this is increased aldosterone secretion
  • See diagram

Question 307

What are some causes of excess renin secretion, and some of the associated risk factors?

[EXTRA]

Answer 307

• Renal hypoperfusion, e.g. due to renal artery stenosis (atheromatous change in the artery causing it to be narrowed)
  
  • Risk factors: older, smoker, male
• Fibromuscular hyperplasia (change in the muscle of the renal artery, causing a characteristic series of stenoses along the length of the artery)
  
  • Risk factors: Young/middle aged females
  • Not a common diagnosis, but should be considered in those presenting with hypokalaemia, hypertension and alkalosis
• Treatment of stenoses can be achieved through performing angioplasty to open up the vessel and improve renal blood supply (which should also decrease renin secretion)
• Top image: renal artery stenosis
• Bottom image: Fibromuscular hyperplasia

Question 308

Discuss the results from this case study. What would you consider if ACE inhibitors caused no change in blood pressure?

[EXTRA]

Answer 308

• Sodium - normal
• Potassium - low
• Bicarb - slightly alkalotic/high
• ACE inhibitors are not affecting blood pressure indicating that the cause of hypertension lies downstream in RAAS
  
  • One of the more common causes of this is increased aldosterone secretion
  • See diagram

Question 309

What investigations would be carried out if high blood pressure is not responding to ACE inhibitors?

[EXTRA]

Answer 309

• Measure renin and aldosterone levels
  
  • If aldosterone is high (and renin is suppressed, as would be expected due to the negative feedback loop), try to identify where the source of secretion is
  • This presentation indicates a source of excess aldosterone production, for example:
    
    • Benign adrenal adenomas (these can sometimes have high secretion despite small size)
• Could identify this through imaging - indication would be an enlarged adrenal gland
  
  • This can occur for a number of reasons, however, so first would use radiology to insert catheters into the adrenal veins on both sides and confirm from which gland the elevated blood aldosterone levels were coming from

Question 310

Discuss the following case study. Assuming that the change is not due to trancellular shifts (e.g. movement of ions into cells from the blood), what diagnostic possibilities should be considered?

[EXTRA]

Answer 310

• Underweight and young age raises concerns over accompanying psychiactric disorders (e.g. eating disorder)
• Potassium levels are very low
• Potential causes of hypokalaemia:
  
  • Diarrhoea
    
    • Including purgative abuse and malabsorption
  • Renal artery stenosis
  • Conn’s syndrome (hyperaldosteronism, on spec)
  • Liddle’s syndrome
    
    • Autosomal dominant condition, gain of function mutation in ENaC
  • Renal tubular acidosis
  • Diuretic (ab)use
  • Bartter’s syndrome
  • Gitelman’s syndrome
    
    • The two syndromes above are rare genetic conditions, resulting in abnormal K+, Na+ or Cl- handling in the renal tubule

Question 311

What are some potential causes of hypokalaemia?

Answer 311

• Potential causes of hypokalaemia:
  
  • Diarrhoea
    
    • Including purgative abuse and malabsorption
  • Renal artery stenosis
  • Conn’s syndrome (hyperaldosteronism, on spec)
  • Liddle’s syndrome
    
    • Autosomal dominant condition, gain of function mutation in ENaC
  • Renal tubular acidosis
  • Diuretic (ab)use
  • Bartter’s syndrome
  • Gitelman’s syndrome
    
    • The two syndromes above are rare genetic conditions, resulting in abnormal K+, Na+ or Cl- handling in the renal tubule

Question 312

Describe how to tell that GI losses are causing hypokalaemia as opposed to issues with renal function.

Answer 312

• If urinary potassium conc is low, can discern that the issue is not likely to be within the kidneys so can then investigate GI causes such as diarrhoea
• If GI issue, normal kidney responses should be seen, so in hypokalaemia the normal response is to retain as much potassium as possible
  
  • This results in low K+ losses in the urine

Question 313

How can it be indentified that hormonal imbalances are the cause of hypokalaemia?

Answer 313

• High [K+] in urine indicates that the hypokalaemia is caused by renal losses in some form
  
  • This could either be intrinsic within the kidney or driven by hormonal mechanisms
• If the latter is true, imbalances in renin or aldosterone will be seen in the blood, and this could be for a number of reasons
  
  • There is also likely to be hypertension if RAAS is the reason for potassium imbalance

Question 314

What should be considered if [K+] is high in urine but the patient is not hypertensive?

[EXTRA]

Answer 314

• Next step is to check plasma bicarbonate levels
• If low, this could be due to renal tubular acidosis and so further tests are required to check whether this is distal or proximal
• If high, need to check urinary concentration of Cl-
  
  • If alkalotic, high plasma bicarbonate and high urinary Cl-, we consider:​
    
    • Gitelman syndrome
    • Bartter syndrome
    • Magnesium deficiency
    • Diuretic (ab)use
  • If urinary concentration of Cl- is low, we condsider:
    
    • Gastric loss: vomiting (loss of HCl from stomach, kidneys compensate for this loss by reabsorbing as much Cl- as poss. at the expense of K+)
    • Nonreabsorbable ion

Question 315

Label diagram to show genetic disorders of tubular function.

[EXTRA]

Answer 315

Question 316

What is Bartter’s syndrome (BS)?

[EXTRA]

Answer 316

• Caused by loss of function in the thick ascending limb of the loop of Henle
• Can compare mechanism with the action of furosemide (targets NKCC), but as action of the channels in the TALH are all integrated, genetic mutations in any of the channels can all alter uptake of NaCl
  
  • Bartter syndrome can be caused by mutations in at least five genes.
    
    • Mutations in the SLC12A1 gene cause type I.
    • Type II results from mutations in the KCNJ1 gene.
    • Mutations in the CLCNKB gene are responsible for type III.
    • Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes.
  • Presentation can occur either as a neonate or at a slightly older age (classical presentation)
• Symptoms:
  
  • Autosomal recessive
  • Salt and water wasting
  • Hypokalaemia
  • Alkalosis
  • Increased renin and aldosterone

Question 317

What is Gitelman’s syndrome?

[EXTRA]

Answer 317

• Caused by loss of function mutations in the thiazide sensitive channel (NCCT) in the distal convoluted tubule
  
  • Can be compared to thiazide usage
  • Less commonly seen is a causative mutation in the CLC-Kb channel, occurs due to the integration of channels in epithelia
• Later presentation – often in adulthood
  
  • This is due to the milder presentation of this syndrome (much less severe than Bartter’s) so is only picked up fairly late
• Autosomal recessive
• Symptoms
  
  • Normotensive, muscle cramps / weakness
  • No polyuria
  • Hypokalaemia
  • Hypocalciuria
  • Hypomagnesmia
  • Metabolic alkalosis

Question 318

What is Liddle’s syndrome?

[EXTRA]

Answer 318

• Very rare
• Due to GAIN of function mutations in ENaC resulting in hypertension
• Can be treated with amiloride

Question 319

What is the progression of renal failure?

Answer 319

• EARLY EFFECTS may relate to site of damage
  
  • E.g. Nephrotic syndrome
  • Glomerulonephritis
  • Tubulo-interstitial nephritis
• END RESULT is nephron loss with consequent loss of
  
  • EXCRETORY FUNCTION
  • CONTROL OF BODY WATER
  • CONTROL OF BLOOD PRESSURE
    
    • Many patients become hypertensive, which can then lead to further kidney damage
  • CONTROL OF pH
  • CONTROL OF HAEMATOCRIT
    
    • Patients can become anaemic
  • CONTROL OF BONE METABOLISM
    
    • This is due to the role of the kidney in phosphate excretion and VitD3 activation

Question 320

Explain the causation of the blood results in the following case study.

Answer 320

• Patient has chronic kidney disease
• Creatinine levels show significant elevation due to decreased GFR and therefore a failure to properly excrete waste products
• Corrected calcium (e.g. corrected for proteins) are low due to increased phosphate concentrations in the blood and decreased production of VitD3 in the kidney
• Phosphate is significantly incresaed due to lack of phosphate excretion/over secretion of PTH
• Alkaline phosphatase is elevated due to increased bone turnover as the body attempts to correct the altered biochemistry/lack of calcium
  
  • Also driven by increase in PTH levels, which is increased in response to hypocalcaemia
• Patients become anaemic in chronic renal failure (decreased EPO secretion)

Question 321

Show how renal failure leads to calcium, phosphate and bone imbalances.

[EXTRA]

Answer 321

• Renal failure means that VitD3 cannot be activated, and a decreased GFR also occurs therefore limiting Pi excretion
• Decreased plasma calcium concentration (due to inactivity of VitD3) is sensed in the parathyroid gland, causing increased secretion of PTH
  
  • This leads to increased bone breakdown, which in turn increases alkaline phosphatase and release of Ca and Pi
• As ingestion of Pi continues as normal and excretion is impaired, plasma Pi rapidly rises
  
  • This exacerbates the decreased Ca2+ levels as Ca3(PO4)2 is insoluble
  • Therefore, if Pi increases, Ca2+ decreases, and if Ca2+ decreases, Pi again increases
  • Decreased Ca2+ will also cause PTH release and breakdown of bone, releasing more Pi alongside Ca2+
• This means that PTH contributions to restore plasma Ca2+ through bone breakdown can never fully restore blood calcium levels, partly due to its interactions with Pi
• Calcium also moves into tissues, meaning that patients have a lot of calcification (particularly in blood vessels)

Question 322

How can we intervene with the management of calcium, phosphate and bone during chronic kidney disease?

[EXTRA]

Answer 322

• Can replace active Vitamin D3 with drugs such as ergocalciferol
• Reducing intake and absorption of phosphate can be done through changing the diet or through giving phosphate-binding drugs so that not all of the Pi in the diet is absorbed
• Calcimimetics sensitise Ca2+ sensing receptors on parathyroid gland, making them more sensitive than usual
  
  • This suppresses PTH secretion (as CaSR activation inhibits release of PTH)
• If the above treatments fail, hyperparathyroidism will occur in which the best treatment is some form of surgical excision

Question 323

What is the relationship between the kidneys and the haematocrit?

Answer 323

• In health, kidneys are the main source of EPO
• EPO acts as a survival factor for RBC precursors in the bone marrow
  
  • If EPO levels increase, so do the survival rates of RBC precursors, increasing RBC production which in turn improves/increases the haematocrit
  • This should ideally increase the oxygen-carrying capacity of the blood, therefore turning off the hypoxic signal for EPO release

Question 324

Describe this graph.

Answer 324

• Upper/diagonal bar is normal physiology
• Lower bar is renal failure
• In anaemia, plasma levels of EPO increase massively
  
  • As long as Fe is available and the bone marrow is functioning, more RBCs are produced to restore blood [Hb] and O2 saturation
  • Patients with chronic kidney disease can normally not secrete EPO, so as Hb falls an adequate response cannot be mounted
  • This causes them to equilibrate at a lower [Hb]
    
    • In untreated patients, [Hb] = as low as ~6-8g/L
• In health, as haemoglobin levels fall erythropoietin is produced by renal interstitial fibroblasts in response to elevated levels and activity of HIF-2alpha resulting from oxygen-regulated inhibition of HIF-hydroxylase activity.

Question 325

What are some methods of treatment for end-stage renal failure?

[EXTRA]

Answer 325

• Haemodialysis
  
  • Allows clearance of waste products from the blood
  • Often needed fairly frequently (3x a week)
• CAPD/APD
  
  • Continuous ambulatory peritoneal dialysis, replace kidney function through using the fine capillaries in the peritoneum, put a certain amount of fluid in the peritoneal space and drain/replace frequently to continue dialysis
  • Automated peritoneal dialysis (APD) is similar to CAPD, except a machine is used to control the exchange of fluid during sleep - bag is attached (filled with dialysate fluid) and connected to the APD machine before going to bed. During sleep, the machine automatically performs a number of fluid exchanges.
• Transplantation
• Palliative care (especially in older patients with comorbidities)
• Diet and fluid restriction
• Drugs to treat complications
  
  • Blood pressure
  • Anaemia
  • Mineral bone disease

Question 326

What are the effects of aldosterone on:

• Renal function
• Vascular tone
• Circulating volume

Answer 326

• Renal function -> Increases sodium reabsorption and potassium excretion
• Vascular tone -> Increases vascular tone due to endothelial dysfunction and enhances the pressor response to catecholamines and up‐regulation of angiotensin II receptors
• Circulating volume -> Increases circulating volume

Question 327

What are the effects of cortisol on:

• Renal function
• Vascular tone
• Circulating volume

Answer 327

• Renal function -> Increases GFR by increasing glomerular blood flow and increases phosphate excretion by decreasing its reabsorption in the proximal tubules. In excess, cortisol has aldosterone-like effects in the kidney causing salt and water retention.
• Vascular tone -> Increases vascular tone
• Circulating volume -> Increases circulating volume

[CHECK THESE]

Question 328

What are the effects of adrenaline on:

• Renal function
• Vascular tone
• Circulating volume

Answer 328

• Renal function -> Decreases flow to kidneys by increasing the resistance in all renal vascular segments, leading to antidiuresis
• Vascular tone -> Decreases vascular tone
• Circulating volume -> Increases circulating volume

[CHECK THESE]