Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

YEAR 2 - Applied Physiology & Pharmacology > 51. Electrolytes and Fluid Balance > Flashcards

51. Electrolytes and Fluid Balance Flashcards

1
Q

What is mEq?

A

An milliequivalent:

  • An equivalent is the amount of a substance that will react with a certain number of hydrogen ions.
  • A milliequivalent is one-thousandth of an equivalent.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is 1mEq of potassium equal to in mmol?

A

1mmol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the typical daily intake of potassium for an average 70kg man?

A

Around 70-100mEq (a.k.a. 70-100mmol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the different routes of excretion of potassium and how much is excreted by each per day?

A
  • Urine -> 88%
  • Stool -> 11%
  • Skin -> 1%
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the total amount of potassium in a 70kg body?

A

About 3500mEq

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Draw a diagram to show potassium homeostasis.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the dietary balance of potassium.

A
  • Around 100mEq are taken in per day
  • Around 90mEq are excreted in the urine
  • Around 10mEq are excreted in the stool
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the distribution of potassium in the body. [IMPORTANT]

A
  • 98% stored intracellularly:
    • 80% in muscle -> 2700mEq
    • Liver -> 250mEq
    • Bone -> 300mEq
    • Erythrocytes -> 250mEq
  • 2% stored extracellularly -> 70mEq
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the biggest intracellular store of potassium? How much does it typically store?

A
  • Muscle
  • Stores about 80% of total potassium -> 2700mEq
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the extracellular concentration of potassium at rest?

A

4mmol/L

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the normal range for plasma potassium concentration?

A

3.5 - 5.5mmol/L

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the size of the potassium gradient between intracellular and extracellular fluid? What maintains this?

A
  • It is about 30 times greater intracellularly
  • This is maintained by a Na+/K+-ATPase on the cell membrane
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is responsible for short and long-term regulation of plasma potassium?

A
  • Short term -> Na+/K+-ATPase in cell membrane
  • Long term -> Kidneys
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What things can cause low and high plasma potassium? (hypokalemia and hyperkalemia) [IMPORTANT]

A
  • Hypokalemia -> Diuretics + Diarrhoea
  • Hyperkalemia -> Kidney failure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Draw the relationship between total body potassium levels and plasma potassium levels. How is this affected by diuretics and renal failure?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the effects of hypokalemia and hyperkalemia on the ECG? [EXTRA]

A
  • The T wave is most affected, since it is dependent on potassium currents (taller in hyperkalemia)
  • The QT interval is also affected (shorter in hyperkalemia), since low potassium inactivaes inward rectifier channels (IK1), lengthening the action potential
  • Hypokalemia induces a U wave.

In hyperkalemia, the T wave is very tall, and the action potential is very short with a short QT, leading to the potential of ventricular fibrillation, which is often fatal.

In hypokalemia, the T wave is very flat, and the action potential is long with a long QT. There is also a U wave. The long length means that there is lots of calcium entry during the AP, so the heart needs to work to get it out via the NCX. This leads to mass entry of sodium into the cells, depolarising the cell. This means that the heart is hyperexcitable and predisoposed to arrhythmias. [CHECK THIS]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the main consequences of hyperkalemia and hypokalemia?

A
  • Muscle weakness
  • Cardiac dysrhythmias
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Draw the effect of potassium on an cardiac action potential.

A
  • When there is high external potassium, the potassium activates inward rectifier potassium channels, so repolarisation happens faster. The action potential is therefore shorter.
  • The potassium also depolarises the cell membrane, so the resting membrane potential is higher.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Explain the effects of hyperkalemia and hypokalemia on inotropy of the heart.

A
  • Hyperkalemia leads to a shorter action potential due to faster repolarisation. Therefore, although the heart can contract more quickly in theory, there is less time for calcium entry, so it is negatively inotropic.
  • Hypokalemia is the opposite.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the two main mechanisms for controlling plasma potassium?

A
  • Hormone-mediated control of Na+/K+-ATPase activity
  • Renal excretion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Draw a graph to show how an intake of potassium is handled by the main mechanisms.

A
  • Hormone-mediated potassium intake into cells is rapid and is due to an increase in Na+/K+-ATPase activity
  • Kidney excretion is much slower
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Why is it important to maintain potassium homeostasis (for example by moving extracellular potassium into cells)?

A
  • Marked changes in the ratio of extracellular/intracellular K+ can affect the excitability of cells.
  • This is particularly the case with cardiac myocytes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is the Nernst equation for potassium?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Compare the effects of hyperkalemia on the heart and smooth muscle (e.g. vasculature).

A

In the heart:

  • It causes DEPOLARISATION
  • This is logical as predicted by the Nernst equation -> Increasing the extracellular potassium decreases the potassium gradient and thus the equilibrium potential is shifted
  • This makes the heart hyperexcitable

In smooth muscle:

  • It causes HYPERPOLARISATION
  • This is counter-intuitive but it can be explained by the high extracellular potassium causing:
    • Increased opening of inward rectifier K+ channels and decrease in intracellular inhibition caused by Mg2+ and polyamines
    • Activation of the Na+/K+-ATPase
  • This explains why hyperkalemia causes vasodilation (e.g. in exercise)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What things can affect the extracellular concentration of potassium, [K+]o by changing the action of the cell-surface Na+/K+-ATPase?

A
  • Insulin
  • Catecholamines
  • Acid-base status
  • Hypoxia
  • Exercise
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What effect do these have on extracellular potassium concentration:

  • Insulin
  • Catecholamines
  • Acid-base status
  • Hypoxia
  • Exercise

[IMPORTANT]

A
  • Insulin -> Decreases
  • Catecholamines -> Increase/Decrease (depending on whether they are alpha or beta agonists)
  • Acid-base status -> Increase/Decrease (acid leads to hyperkalemia)
  • Hypoxia -> Increase
  • Exercise -> Increase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Aside from the kidneys, which organs respond to high plasma potassium?

A
  • Pancreas -> Secretes insulin
  • Adrenal glands -> Secrete adrenaline and aldosterone
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How is insulin involved in potassium homeostasis?

A

It decreases plasma potassium by moving potassium into cells:

  • When there is increased extracellular potassium, there is increased insulin secretion from beta cells of the pancreas
  • Stimulates Na+/K+-ATPase on cell membrane
  • This is due to second messenger which is not agreed upon, but it is probably a protein kinase that phosphorylates the ATPase
  • It also has an effect via stimulating Na+-glucose co-transport into the cell, which drives the ATPase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Compare the effects of α and β2 agonists on plasma potassium.

A
  • α agonists increase plasma potassium
  • β2 agonists decrease plasma potassium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the effect of β2 agonists (e.g. salbutamol) on plasma potassium?

A

It decreases plasma potassium by moving potassium into cells:

  • Stimulates Na+/K+-ATPase on cell membrane
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is the effect of aldosterone on the plasma potassium?

A

It decreases plasma potassium by moving potassium into cells:

  • Stimulates Na+/K+-ATPase on cell membrane
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Draw a summary of the main hormones that affect the Na+/K+-ATPase on the surface of cells so as to reduce plasma potassium.

[IMPORTANT]

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What is the effect of adrenaline on plasma potassium levels?

A

Causes a transient hyperkalemia followed by hypokalemia:

  • This is due to the fact that it is a non-selective adrenergic agonist
  • The hyperkalemia is due to it acting on alpha receptors
  • The hypokalemia is due to it acting on beta-2 receptors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is some clinical relevance of salbutamol in potassium homeostasis? [EXTRA]

A

In asthmatics who use salbutamol, overdose of salbutamol can result in hypokalemia.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Give some ways in which hyperkalemia may be treated clinically.

A
  • Insulin (+ Dextrose) -> Slower
  • Beta-2 agonist (e.g. salbutamol) -> Faster
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What are the effects of metabolic acidosis on plasma potassium?

A
  • Metabolic acidosis leads to hyperkalemia
  • However, this is only the case with mineral acid (HCl) and not organic acid (lactic)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

For a 0.1 drop in pH due to these acids, what is the effect on plasma potassium:

  • Mineral acid (e.g. HCl)
  • Organic acid (e.g. lactic acid)
A
  • Mineral acid (e.g. HCl) -> Increase by 0.7mM
  • Organic acid (e.g. lactic acid) -> No change
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Exercise leads to hyperkalemia. Is this due to metabolic acidosis? What is the evidence for this?

A

No, because it produces lactic acid, but lactic acid does not lead to hyperkalemia (like HCl does) since it is an organic acid. Therefore, it must be by a different mechanism.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Draw the mechanism for how plasma acidosis leads to hyperkalemia.

[EXTRA?]

A
  • The acid responsible is HCl (not lactic acid).
  • H+ ions produced in cells are pumped into the blood in exchange for sodium.
  • High extracellular H+ decreases the gradient for this to happen.
  • This results in decreased intracellular sodium, so there less exchanged for potassium by the ATPase.
  • This leads to hyperkalemia.

(In the diagram, consider everything outside of the cell to be blood.)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What is the effect of respiratory acidosis on plasma potassium per 0.1 drop in pH?

A

For every 0.1 drop in pH, potassium increases by 0.1mM. This is caused by hypercapnia causing the pH to drop.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What is the effect of alkalosis (both metabolic and respiratory) on plasma potassium per 0.1 increase in pH?

A
  • It leads to hypokalemia.
  • In respiratory alkalosis, potassium drops by around 0.3mM.
  • In metabolic alkalosis, potassium drops by around 0.2mM.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What is the effect of hypoxia on plasma potassium?

A

Hypoxia causes hyperkalemia.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Explain the relationship between hypoxia and potassium.

A
  • Hypoxia leads to hyperkalemia
  • This is thought be due to low oxygen causing a drop in ATP levels, which leads to KATP channels remaining open, so that potassium can flow out of the cell.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Draw a graph of extracellular potassium against arterial oxygen.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What is the effect of exercise on plasma potassium? What is the mechanism for this?

A

Exercise leads to hyperkalemia:

  • Potassium is lost from cells through delayed rectifier channels
  • Incomplete reuptake of the potassium by the Na+/K+-ATPase leads to hyperkalemia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Exercise results in hyperkalemia. What things help the body recover from that?

A

Insulin and catecholamines increase the rate of potassium reuptake by the Na+/K+-ATPase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Draw a graph of plasma potassium against time during exercise. Explain it.

A
  • The initial rise is due to potassium expelled from cells during muscle contraction
  • The drop afterwards is due to catecholamines, which stimulate the Na+/K+-pump by the beta-2 pathway
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

What is the effect of administering propranolol after exercise?

A

It enhances the hyperkalemia caused by exercise. This is because propranolol is a β antagonist, so it promotes hyperkalemia since it slows down the Na+/K+-ATPase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What is some experimental evidence that lactic acid does not cause hyperkalemia?

A
  • In McArdle’s disease, the patient is unable to produce lactic acid from glucose
  • However, if these patients exercise, there is still a normal rise in plasma potassium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What are some of the functional consequences of hyperkalemia?

[IMPORTANT]

A
  • Skeletal muscle fatigue
  • Skeletal muscle hyperaemia (excess of blood in vessels supplying the muscle)
  • Blood pressure regulation
  • Hyperpnoea (increased breathing rate)
  • Myocardial stability
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

Describe the two consequences of hyperkalemia/hypokalemia that are mentioned in the spec.

A
  • Muscle weakness
  • Cardiac dysrythmias
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

What is responsible for muscle pain and fatigue during exercise?

A
  • It has been proposed to be lactic acid, but this is controversial
  • Hydrogen ions (acid) are known to be negatively inotropic in muscle
  • Potassium can also cause depolarisation of nociceptive nerve fibres, leading to the feeling of burning
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

What is the normal plasma potassium range at rest and how is it affected by exercise?

A
  • At rest: 3.5-5.5mmol/L
  • During exercise there is an acute increase in potassium. [CHECK the normal range for exercise]
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

How high can blood potassium get during exercise? [IMPORTANT]

A

8mM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

How does hyperkalemia during exercise affect blood flow? What is some evidence for this?

A
  • Potassium released by muscles during exercise leads to hyperpolarisation of arterial muscle, so that blood flow to that muscle increases (hyperaemia)
  • (Knochel, 1972):
    • Blood flow through a muscle was correlated with the potassium released during exercise
    • Causation was shown by depletion of potassium from the system, which resulted in no change in blood flow
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

Draw how the hyperkalemia produced by this exercising muscle leads to the body’s response to exercise.

A
  • The potassium released by the muscle during exercise causing depolarisation and therefore activation of the C-type pain fibres in the muscle
  • This triggers the muscle-pressor reflex, mediated by the brain:
    • Vasoconstriction in non-exercising vascular beds
    • Sympathetic activation of the heart
  • Hyperkalemia is detected by arterial chemoreceptors, particularly in the carotid body
  • The carotid body feeds back to the cardiorespiratory integrating centre via the glossopharyngeal nerve (IX)
  • The response triggered involves stimulation of the diaphragm and intercostal muscles, so that the breathing rate is increased
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

Draw the position of the carotid bodies and how they link to the nervous system.

A

This allows them to detect hyperkalemia and respond to it.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

At rest, the blood potassium levels that are reached during exercise would cause cardiac arrest. Why does this not happen during exercise?

A

The catecholamines and potassium cancel out each others deleterious effects (mutual antagonism). The angiotensin pathway is also involved.

The increased calcium entry due to catecholamines and angiotensin cancels out the negative inotropic effect of potassium.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

Summarise the symptoms of hyperkalemia.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

Summarise the symptoms of hypokalemia.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What are dangerously high levels of plasma potassium endogenously antagonised by?

A

Ca2+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

How is hyperkalemia treated clinically?

A
  • Insulin, dextrose and beta-2 agonists are used.
  • In renal failure, dialysis is used.
  • If a very fast response is required, calcium injection can antagonise the negative inotropic effect of hyperkalemia -> Allows time for clinical intervention
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

What is some experimental evidence for hyperkalemia activating faster breathing?

A
  • (Band, 1985)
  • Injection of potassium chloride into a cat caused the ventilation to increase
  • When the carotid chemoreceptor nerves were cut, this effect was lost
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

Does potassium stimulate central chemoreceptors?

A

No, only peripheral ones, because it cannot cross the blood-brain barrier easily.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

What are some common causes of hypokalemia and hyperkalemia?

[IMPORTANT]

A
  • Hypokalemia -> Vomiting + Diarrhoea
  • Hyperkalemia -> Renal failure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

Compare intracellular and extracellular calcium levels.

A

Intracellular calcium levels are 10,000 fold lower than extracellular levels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

State the extracellular and intracellular calcium concentration.

[IMPORTANT]

A
  • Extracellular -> 2.4mM
  • Intracellular -> 0.1 micromolar
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

What is the plasma calcium level?

[IMPORTANT]

A

2.4mM, but only half of this (1.2mM) is free calcium:

  • 50% = Free, biologically active
  • 40% = Reversibly bound to protein
  • 10% = Bound to citrate or phosphate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

What are some examples of the intracellular roles of calcium?

A
  • Cell division (mitotic spindle)
  • Muscle contraction (cross bridge cycling)
  • Cell motility
  • Membrane trafficking
  • Exocytosis via Ca2+ dependent activation of SNARE proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

Do changes in extracellular calcium affect the intracellular processes mediated by calcium?

A

No, because there is a calcium pump that maintains the concentration gradient.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

What level of calcium does the body try to maintain?

A

It tries to maintain free plasma calcium at 1.2mM, because this is the biologically active form.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

How much calcium does the body store and where?

A
  • 1kg (25 moles)
  • 99% of this is in bones as hydroxyapatite, 1% is in the ECF
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

Describe how calcium is stored in bone.

A
  • 1% is freely exchangeable
  • 99% is hydroxyapatite bound to collagen (slowly-exchangeable)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

What are some roles of extracellular calcium?

A
  • Important effects on excitable tissues and blood clotting
  • Essential component of bone

There is, therefore, a conflict between ensuring that plasma calcium does not fall, and conserving calcium in the bone. In normal physiology the demands of plasma calcium are stronger, and the bones contains huge reserves of calcium that can be drawn on for some time before there is any appreciable weakening of the bones.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

Is hypocalcaemia or hypercalcaemia more dangerous acutely?

A

Hypocalcaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

What are the consequences of hypocalcaemia?

[IMPORTANT]

A
  • Changes to the electrical activity of the heart, including a long QT and heart failure
  • Muscle spasms -> Closure of vocal cords can occur, leading to asphyxiation
  • In chronic hypocalcaemia, some of the symptoms are explained by the underlying problems that are causing the low calcium, including kidney disease, hypoparathyroidism and sepsis:
    • Calcification of parts of the brain and seizures are seen with hypoparathyroidism.
    • Epidermal changes are common, as are changes in muscle function, such as an abnormal gait.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

How can hypocalcaemia result in muscle hyperexcitability?

A

Partial depolarisation of the membrane due to the charge of the calcium and also increases in sodium permeability (via action on the sodium channels) of the neuron membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

What are some causes of hypocalcaemia?

A

Acute:

  • Secondary hypocalcaemia can rapidly occur following hyperventilation, where the pH increases, meaning that proteins bind calcium and so free ionised calcium falls

Chronic:

  • Kidney disease
  • Hypoparathyroidism
  • Sepsis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

What are some diagnostic signs of hypocalcaemia?

[EXTRA]

A
  • Chvostek and Trousseau signs are indicators of hypocalcaemia.
  • The tests involve tapping the facial nerve (Chvostek) and constriction of the brachial artery (Trosseau), which induces tetany in the facial muscles and hand/wrist muscles respectively.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

How is hypocalcaemia treated?

A

Acutely:

  • Intravenous calcium

Chronic:

  • Treating the underlying cause, such as vitamin D supplementation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

What are the consequences of hypercalcaemia?

[IMPORTANT]

A
  • Decreased muscle excitability -> Hyperpolarisation due to calcium decreasing voltage-gated sodium channel activity
  • Short QT on ECG
  • Kidney stone formation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

What are some causes of hypercalcaemia?

A

For example, primary hyperthyroidism resulting from multiple endocrine neoplasia.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

How does the body attempt to deal with hypercalcaemia?

A

Polyuria helps rid the body of the excess calcium, but it also concentrates the plasma, renewing the problem.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

What are some diagnostic signs of hypercalcaemia?

[EXTRA]

A

Limbus sign in the eyes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

How is hypercalcaemia treated?

A

Treatment involves hydration and forced diuresis to remove excess calcium, along with treatment of the underlying cause, such as calcitonin supplements.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

What is it important to be aware of when diagnosing hypo/hypercalcaemia?

A

It is important to factor in for abnormal albumin levels which may affect the fraction of free calcium.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

Give examples of conditions where protein imbalances can result in hypercalcaemia or hypocalcaemia.

A
  • Hypercalcaemia -> Multiple myeloma (tumour of the plasma cells in bone marrow) reduces free calcium by binding it to immunoglobulins
  • Hypocalcaemia -> Nephrotic syndrome results in protein leaking into the urine, so that blood protein is low and therefore free calcium is high
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

Describe the effect of pH on calcium balance.

A
  • Alkalosis -> Increases negative charge on plasma proteins -> More calcium binds to proteins -> Hypocalcaemia
  • Acidosis -> Decreases negative charge on plasma proteins -> Less calcium binds to proteins -> Hypercalcaemia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

Summarise the main fluxes of calcium through the body.

[IMPORTANT]

A

In general, net intake (diet - faeces) equals the excretion in the urine. Most of the calcium that reaches the kidney is reabsorbed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

What is the net intake and loss in urine of calcium?

A
  • Net intake (diet minus faeces) = 3-5 mmol/day
  • Loss in urine = 3-5 mmol/day
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

What are some special considerations for calcium fluxes?

A
  • Children, pregnant women and lactating women -> Have a net accumulation of 3 mmoles of calcium per day
  • During pubertal growth spurt -> Accumulation of 5-7 mmoles of calcium per day
  • Post-menopausal women and ageing males -> Lose Ca2+ and undergo osteoporosis, so need increased intake
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

Is all calcium filtered at the kidney?

A

No, protein-bound calcium is not filtered.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

Draw a summary of all calcium homeostasis.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

What are the main hormones involved in calcium homeostasis?

A
  • Vitamin D (active form a.k.a. calcitriol)
  • Parathyroid hormone (PTH)
  • Calcitonin

FGF-23 is technically involved in phopshate homeostasis, but it also regulated vitamin D and PTH levels, so it also impacts calcium.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

In what form is calcium stored in bone?

A
  • Mostly as hydroxyapatite, Ca10(PO4)6OH2, which is not exchangeable
  • But also as exchangeable, non-crystalline salts and as calcium bone fluid, which protect against hypocalcaemia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

How is bone remodelling controlled so that there is no net gain or loss of bone?

A
  • Osteoblasts are activated by PTH, which leads to RANKL presentation on the osteoblast surface
  • Osteoclasts’ RANK receptors bind this RANKL to get activated
  • This means that bone breakdown cannot occur without bone being laid down, which allows balance
  • OPG (osteoprotegerin) is a naturally occuring RANKL decoy, decreasing activation of RANK receptors -> PTH downregulates this
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

Summarise bone remodelling.

[EXTRA?]

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

Why does osteoporosis often occur in post-menopausal women?

A
  • Oestrogen and testosterone stimulate osteoblasts and precursors
  • Therefore, deficits lead to osteoporosis, especially in post-menopausal women.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
99
Q

Summarise the more in-depth mechanism of coupling between bone resorption and formation.

A
  • Need for bone remodelling is somehow sensed by osteocytes trapped in the bone
  • They secrete soluble RANKL, which along with RANKL on osteoblasts, binds to RANK receptors on osteoclast surface
  • This leads to activation of the osteoclasts
  • In turns, osteoclastic activity leads to release of TGF-β1 and IGF-1 from the bone matrix, which lead to the maturation of osteoblast progenitors
  • Osteoclasts also release sema4D, which prevents excessive activation of osteoblasts
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
100
Q

What is an interesting way of treating osteoporosis?

[EXTRA]

A

Sema4D antagonists can be used, which decreases the inhibition of osteoblast activation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

Summarise the main roles of the different hormones involved in calcium homeostasis.

A
  • Parathyroid hormone (PTH) -> Responds to low extracellular calcium in the short-term by mobilisation of Ca2+ from stores in the bone
  • Calcitriol -> Responds to a chronic lack of calcium in the plasma, leading to an increase in net uptake of calcium.
  • This allows rapid maintenance of a constant plasma calcium, while simultaneously ensuring that there is a net maintenance of calcium stores for structural functions.
  • Calcitonin -> Responds to high extracellular calcium.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

When is PTH released and what is its function?

A
  • PTH is produced in the parathyroid glands and is the major hormone acting in response to low plasma calcium.
  • Low calcium is detected via calcium-sensing receptors (CaSR), which are GPCRs that act via Gq and Gi actions.
  • When calcium is low, IP3 is low and cAMP is increased, leading to release of PTH.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
103
Q

Give some experimental evidence relating to the calcium-sensing receptor in the parathyroid gland.

A

(Brown, 1993):

  • The parathyroid CaSR was cloned to produce BoPCaR, which had similar properties and helped determine that other divalent ions have a similar effect as calcium on the receptor
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

Describe the main functions of PTH.

A
  • In bone:
    • PTH acts on PTH1R, found on osteoblasts.
    • This in turn triggers RANKL release, which binds to RANK receptors on osteoclasts, completing their differentiation and activation.
    • PTH also inhibits osteoprotegerin, which is a decoy receptor for RANKL.
    • Chronically raised PTH leads to bone breakdown, thus increasing extracellular calcium.
    • Also stimulates the PTH calcium pump in bone, quickly mobilising calcium.
  • In the kidney proximal tubule:
    • PTH binds to PTH1R
    • Stimulates production (in the proximal tubule) and action of 1 alpha-hydroxylase, which catalyses the production of calcitriol (an active form of vitamin D) by hydroxylation of vitamin D
  • In the kidney distal tubule:
    • PTH binds to PTH1R
    • Stimulates active calcium reabsorption from the distal tubule and collecting duct [CHECK IF THIS IS AN INDIRECT EFFECT VIA CALCITRIOL]
    • It also decreases phosphate reabsorption from the proximal tubule, which is significant because phosphate usually forms insoluble salts with calcium, reducing free ionized calcium in the blood.

Summary: Stimulates osteoclasts, calcium efflux from bone, kidney calcium reabsorption, and vitamin D activation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
105
Q

What are some pathologies relating to PTH?

A
  • Deficiency of PTH (hypoparathyroidism) -> Leads to low plasma Ca2+ and tetany
  • Pseudohypoparathyroidism -> Resistance to PTH due to receptor defect.
  • Excess hyperparathyroidism (tumours, such as MEN-1) -> Leads to raised plasma Ca2+, bone destruction, urinary stones and sluggish CNS.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
106
Q

What receptors does PTH bind to?

A

PTH1R and PTH2R

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
107
Q

Describe the action of PTH in bone, acutely and chronically.

A
  • PTH acts on PTH1R, found on osteoblasts.
  • This in turn triggers RANKL release, which binds to RANK receptors on osteoclasts, completing their differentiation and activation.
  • PTH also inhibits osteoprotegerin, which is a decoy receptor for RANKL.
  • Also stimulates the PTH calcium pump in bone, quickly mobilising calcium.
  • Chronically raised PTH leads to net bone breakdown, thus increasing extracellular calcium.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
108
Q

Where is most calcium reabsorbed in the kidney?

A

Proximal tubule

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
109
Q

Compare which diuretics increase and decrease calcium reabsorption in the kidney.

A
  • Diuretics that work on the thick ascending limb such as furosemide (loop diuretic) decrease calcium absorption.
  • Diuretics acting on the distal tubule such as amiloride & thiazides increase calcium uptake.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
110
Q

What is the overall role of vitamin D?

A

It increases whole body calcium, via stimulating uptake.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
111
Q

Describe the metabolism of vitamin D.

A
  • In the skin, UV light converts a cholesterol derivative to cholecalciferol (pre-vitamin D3)
  • In the liver, this is hydroxylated at the 25th position, leading to an inactive form.
  • In the kidney, this is hydroxylated at the 1st position, which activates the vitamin D. This is under the control of PTH.

There is also some dietary intake of D3.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
112
Q

What is another name for the activated form of vitamin D?

A

Calcitriol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
113
Q

What is vitamin D activated by?

A

PTH, which occurs most when PTH is raised chronically. This suggests that PTH responds to acute drops in calcium, while chronically low calcium levels are responded to by calcitriol.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
114
Q

Compare the structures of PTH and calcitriol.

A

PTH is a peptide hormone, while calcitriol is a steroid hormone, meaning that PTH has a shorter duration of action than calcitriol.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
115
Q

Describe the receptors for calcitriol.

A

They are intracellular receptors, since calcitriol is a steroid hormone.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
116
Q

What are the actions of calcitriol?

A
  • In the intestine:
    • Increases transcellular calcium uptake from the diet
    • By synthesis of calbindin, an intracellular Ca2+-binding protein, as well as stimulating paracellular uptake.
  • In the kidney:
    • Reduces excretion of calcium and phosphate
  • In bone:
    • Supports the action of PTH
    • Inhibits synthesis of collagen by osteoblasts and increases osteoclast action

In other words, it supports the action of PTH along with stimulating uptake of calcium from the diet.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
117
Q

What are some examples of pathologies relating to vitamin D (calcitriol)?

A
  • Rickets (in children)
  • Osteomalacia (adults) [IMPORTANT]
  • Vitamin D poisoning
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
118
Q

What is rickets and how does it occur?

A
  • Rickets is a condition that results in weak/soft bones in children
  • This is due to vitamin D deficiency or mutations in the calcitriol receptor
  • This may be counter-intuitive since calcitriol is involved in breakdown of bone to mobilise calcium, but the reason why this happens is because low levels of vitamin D (calcitriol) lead to increased secretion of PTH that breakdown bone and also because vitamin D is required for absorption of calcium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
119
Q

What is osteomalacia and how does it occur?

[IMPORTANT]

A
  • Osteomalacia is a condition that results in weak/soft bones in adults
  • This is usually due to vitamin D deficiency
  • This may be counter-intuitive since calcitriol is involved in breakdown of bone to mobilise calcium, but the reason why this happens is because low levels of vitamin D (calcitriol) lead to increased secretion of PTH that breakdown bone and also because vitamin D is required for absorption of calcium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
120
Q

How do pathologies of vitamin D affect blood calcium?

A

Pathologies of vitamin D are not usually marked by abnormal extracellular calcium, which demonstrates its role is primarily in controlling net flux of calcium through the body, rather than plasma calcium homeostasis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
121
Q

Describe the relationship between PTH and vitamin D (calcitriol).

A
  • PTH, involved in acute response to hypocalcaemia, is required for activation of vitamin D (when PTH is chronically activated)
  • Vitamin D inhibits PTH (negative feedback)
  • This demonstrates how PTH is mostly involved in acute control, while vitamin D is involved in chronic control
  • It also explains why vitamin D deficiency leads to rickets (since there is decreased inhibition of PTH)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
122
Q

How can you remember the difference between calcitriol and calcitonin?

A

Calcitriol ends in ‘ol’ so it is a steroid (cholesterol) hormone, which means it is the activated form of vitamin D. Calcitonin is calcitonin.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
123
Q

How does the parathyroid gland know when to release PTH?

A

It has a calcium-sensing receptor (CaSR) that detects low plasma calcium.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
124
Q

Where is the calcium-sensing receptor found and what is its function in these places?

[EXTRA]

A
  • Parathyroid gland -> Controls release of PTH
  • Renal tubules of the kidney -> Controls reabsorption of calcium
  • Brain
  • Gut enterocytes
  • Osteoblasts
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
125
Q

Describe how the CaSR in the parathyroid works.

[EXTRA]

A
  • Low calcium is detected via calcium-sensing receptors (CaSR), which are GPCRs that act via Gq and Gi actions.
  • When calcium is low, IP3 is low and cAMP is increased, leading to release of PTH.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
126
Q

Give some clinical relevance related to the CaSR.

[EXTRA]

A
  • Calcimimetics are drugs that mimic or sensitise the stimulation of CaSR by calcium.
  • Therefore, they lead to lower release of PTH.
  • Thus, they can be used to treat hyperthyroidism.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
127
Q

What is the role of calcitonin?

A

It is the only hormone that actively decreases plasma calcium levels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
128
Q

What is the hormone class of calcitonin?

A

Peptide (so it has a short duration of action)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
129
Q

Where is calcitonin secreted from?

A

C cells in the thyroid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
130
Q

Describe the main functions of calcitonin.

A
  • In bone:
    • Inhibits osteoclasts activity, most of all in children.
  • In the intestines:
    • Helps control uptake of calcium after a meal by inhibiting uptake
  • In the kidney:
    • Pharmacological doses affect calcium fluxes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
131
Q

What sort of receptors does calcitonin bind to?

A

Gs-coupled

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
132
Q

Draw a graph showing the interplay between PTH and calcitonin.

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
133
Q

What hormone is especially important in pregnancy and lactation?

A

During pregnancy and the lactation period, calcitonin is increased, which primarily acts to ensure that sufficient calcium is preserved for the mother (since it promotes storage in bone).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
134
Q

Draw a diagram to show the main hormones involved in calcium control during pregnancy and lactation.

[EXTRA]

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
135
Q

Describe pathologies relating to calcitonin.

A
  • Deficiency -> Compensation by changes in PTH.
  • Excess -> Uncontrolled secretion from ‘medullary’ carcinoma of thyroid.

In both these situations, serum calcium is maintained at approximately normal levels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
136
Q

What is the relationship between calcium and phosphate levels?

A

They have an inverse relationship.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
137
Q

What hormone is involved in phosphate homeostasis, when is it released and how does it affect calcium homeostasis?

[EXTRA?]

A

FGF23:

  • Released by osteocytes when they sense high phosphate levels
  • FGF23 has these effects:
    • Promotes phosphate and calcium excretion
    • Downregulates PTH formation
    • Downregulates vitamin D activation
  • Therefore, calcium levels and phosphate levels drop
138
Q

Compare PTH and calcitriol in terms of their effects on phosphate.

A
  • PTH and calcitriol overlap to a large degree but keep in mind that the primary function of these two hormones are very different.
  • The main role of active calcitriol is to promote mineralization of new bone (mainly through indirect mechanisms) and as a result, increase the absorption of both calcium and phosphate.
  • On the contrary, PTH acts as guardian against hypocalcaemia and therefore this hormone therefore promotes the loss of phopshate (in addition to the increased absorption of calcium) in order to increase free plasma calcium.
139
Q

Summarise the response to low plasma calcium, including FGF23.

A
140
Q

What is hyperparathyroidism, and what is the difference between primary and secondary hyperparathyroidism?

A
  • Hyperplasia of the parathyroid gland in response to perceived low plasma calcium levels.
  • Primary hyperparathyroidism -> Usually due to tumours of the parathyroid gland. The phenotype shows an osteoporosis-like phenotype (due to excess osteoclast activity) along with HYPERcalcaemia.
  • Secondary hyperparathyroidism -> Usually due to kidney failure, which means that calcitriol cannot be produced. The phenotype shows an osteoporosis-like phenotype (due to excess osteoclast activity) along with HYPOcalcaemia, since there is insufficient calcitriol to promote calcium absorption from the diet.
141
Q

Compare osteoporosis, vitamin D deficiency, rickets and osteomalacia.

A

Green is normal bone, while yellow is actively exchanged bone.

142
Q

Summarise the main role of each of the hormones involved in calcium homeostasis.

A
  • PTH -> Increasing reabsorption of calcium from the kidney and osteoblast/osteoclast activity
  • Calcitriol -> Increasing dietary absorption of calcium
  • Calcitonin -> Decreasing osteoclast activity and aborption of dietary calcium, Increasing calcium excretion in urine
143
Q

What are the main axes involved in fluid balance?

A

Primary regulators:

  • RAA axis
  • ADH (vasopressin)
  • ANP / BNP (natriuretic factors)

Secondary regulators:

  • ACTH - cortisol axis
144
Q

How does infusion of fluid affect venous and arterial blood pressure?

A

The CVP increases first because of the high compliance of the venous system.

145
Q

What are the sensors involved in fluid balance?

A
  • Carotid and aortic baroreceptors -> High pressure, for arterial pressure
  • Renal baroreceptors -> Medium pressure, for renal perfusion
  • Atrial stretch receptors -> Low pressure baroreceptors, for blood volume and CVP

Also:

  • Left ventricular stretch receptors -> Related to secretion of BNP
  • Macula densa -> Flow detectors, related to distal convoluted tubule
146
Q
A
147
Q

Summarise the concepts of how plasma osmolarity and volume are regulated.

[IMPORTANT]

A
  • Osmolarity -> Alterations in water balance
  • Volume -> Alterations in Na+ balance.
148
Q

Summarise how the renin-angiotensin-aldosterone axis works.

A
  • Renin is released from juxtaglomerular cells surrounding the afferent arteriole due to:
    • Renal baroreceptors (low pressure) detecting drops in pressure
    • Macula densa detecting decreased salt or water flow
    • Sympathetic stimulation
    • (Release is also decreased by negative feedback of angiotensin II)
  • Renin cleaves angiotensinogen (made in the liver) to form angiotensin I
  • In the lungs, ACE cleaves angiotensin I to angiotensin II
  • Angiotensin II:
    • Stimulates sympathetic activity
    • Stimulates NaCl reabsorption in the proximal tubule
    • Stimulates arterial vasoconstriction (except renal afferent arterioles)
    • Stimulates ADH secretion
    • Stimulates aldosterone release from the adrenal cortex
  • Aldosterone:
    • Stimulates sodium and water retention in the distal tubule, with potassium and proton loss
149
Q

What are the actions of angiotensin II?

A
  • Causes vasoconstriction
  • Causes release of aldosterone

Other actions:

  • Stimulates sodium reabsorption at several renal tubular sites
  • Stimulates ADH release from the posterior pituitary
  • Stimulates thirst centers within the brain
  • Enhaces sympathetic activity
  • Stimulates cardiac hypertrophy and vascular hypertrophy
150
Q

How does angiotensin II increase sodium reabsorption at the renal tubule?

A
  • Stimulates Na+/H+ exchangers located on the apical membranes of cells in the proximal tubule and thick ascending limb of the loop of Henle
  • Stimulates apical Na+ channels in the collecting duct
151
Q

What is aldosterone release triggered by?

A

In approximate descending order of potency:

  • Plasma potassium concentration
  • Angiotensin II
  • Plasma acidosis
  • Low atrial pressure (detected by atrial baroreceptors)
  • ACTH
152
Q

What are the actions of aldosterone?

A
  • Increase the number of sodium channels (ENaC) in the luminal membrane
  • Increase the activity and number of Na+/K+-ATPase pumps on the basolateral membrane, increasing sodium reabsorption in exchange for K and H (principal cells)
  • Increase the activity and number of sodium-chloride symporters (NCC) in the distal convoluted tubule
  • Increase H+-ATPase pumps (intercalated cells), leading to further loss of protons
  • Increases sodium and water absorption from the gut, in exchange for K+ and H+.
153
Q

Draw and explain a diagram to show how water retention and sodium retention are linked.

A
  • When there is increased intake of sodium, there is increased concentration and osmolarity of body fluid
  • ADH increases water retention, so concentration falls but volume increases
  • ANP increases salt excretion (while angiotensin-aldosterone system increases sodium retention, so it is downregulated)
  • Increased salt excretion leads to lower osmolarity, so ADH is down-regulated and water is not retained
  • This means that the volume also falls back to normal

In this way, the two mechanisms allow maintenance of osmolarity and volume.

154
Q

What are the triggers for ADH release?

A

Mostly triggered by:

  • Rising plasma osmolarity
    • Detected by the hypothalamic osmoreceptors

And to a lesser extent:

  • Hypovolaemia
    • Detected as fall in CVP by the atrial baroreceptors (low-pressure)
    • Signal to the nucleus tractus solitarii and lead to ADH production in the hypothalamus
  • Hypotension
    • Detected by carotid and aortic arch baroreceptors
    • Leads to activation of the sympathetic nervous system, which triggers ADH synthesis and release
  • Angiotensin II
    • Acts directly on the hypothalamus.
155
Q

Summarise the actions of ADH.

A
  • Insertion of aquaporins II in collecting duct principle cells
  • Activation of NKCC in thick ascending loop of Henle
  • Activation of urea transporters in the inner medullary collecting duct principle cells
  • Slowing of the blood flow through the vasa recta

This is via binding of V2 receptors in the collecting duct. ADH also stimulates vasoconstriction and pituitary release of ACTH via V1 receptors.

156
Q

What are the two types of natriuretic peptide and where are they secreted from?

A
  • Atrial natriuretic peptide (ANP) -> From the atria
  • B-type natriuretic peptide (BNP) -> From the (left) ventricles
157
Q

What do the natriuretic peptides signal?

A

They signal blood volume expansion, since their release is triggered by stretch of the atria.

158
Q

What are the main functions of the natriuretic peptides?

A
  • Natriuretic and diuretic effects at the kidney
  • Vasodilation
  • Inhibition of the RAA axis
  • Inhibition of sympathetic nervous activity systemically, but especially to the kidney
159
Q

What is a useful way to think about ANP?

A

It is like the ‘brake’ to RAA axis, inhibiting it and counteracting it.

160
Q

Give some clinical relevance of natriuretic peptides.

A

BNP, and especially the “inactive” part of pro-BNP (known as NT-proBNP, for N-terminal pro-BNP), are widely used clinically as markers of cardiac failure. Blood concentrations of these compounds can provide an easy and relatively objective measure of the severity and progression of cardiac failure.

161
Q

Are glucocorticoids involved in fluid volume control?

A
  • They are not directly concerned with direct regulation of fluid volume in normal circumstances, but they can influence it, especially when secreted at high levels.
  • Cortisol at high levels, like aldosterone, causes sodium retention and potassium loss.
  • This effect is seen in Cushing’s disease, which involves high levels of cortisol secretion. Unlike aldosterone, cortisol excess usually produces a moderate degree of peripheral oedema. There is usually also a modest degree of arterial hypertension, though usually less than that seen with aldosterone excess.
162
Q

What are the 4 common disorders of fluid volume control?

A
  • Shock
  • Dehydration
  • Heart failure
  • Hypertension

Note: These will be discussed more in-depth in their respective lectures.

163
Q

What is shock and what are the main types?

A
  • The formal definition of shock is concerned with tissue hypoxia, which can include biochemical abnormalities (failure to utilize oxygen effectively) as well as cardiovascular problems.
  • But usually when people talk about shock they mean “distributive shock”, named after a failure of distribution of blood, which implies under-perfusion of tissues (i.e., tissue ischaemia because of a failure of the blood supply).
  • The three most common types:
    • Septic shock
    • Cardiogenic shock
    • Hypovolaemic shock
164
Q

What is septic shock?

A
  • When an infection results in a widespread systemic acute inflammatory response, causing widespread arteriolar dilation and an increase in the permeability of the post-capillary venules.
  • Thus there may be a reduction in absolute blood volume (because of loss of plasma into the tissues) as well as a significant increase in vascular volume (because of the vasodilation), meaning a substantial fall in arterial pressure.
165
Q

What are the physiological responses to shock?

A
  • Under-perfusion of the kidneys activates the RAA axis.
  • Sympathetic nervous system is activated by the fall in blood pressure, RAA axis and the inflammatory response directly.
  • ADH is released in response to the fall in blood pressure and the activation of the RAA axis.
  • Acidaemia, which is a characteristic feature of this type of shock (because the under-perfused tissues resort to anaerobic metabolism), further activates the RAA axis.
166
Q

How can shock be managed?

A
  • Fluids
  • Vasoconstriction
  • Treating the underlying cause
167
Q

Which other disorder in dehydration most closely related to?

A

Shock (it is just a more mild version)

168
Q

How does heart failure present in terms of fluid balance?

A

Most patients with heart failure present with oedema of some kind:

  • Pulmonary oedema -> In the case of left ventricular failure
  • Peripheral oedema (sacral or ankle) -> In the case of right ventricular failure

The oedema results from a combination of increased venous pressure from venous congestion behind the failing chamber, and dilution of plasma proteins by the kidney’s retention of water and sodium.

169
Q

Why is salt and water retained by the body in heart failure?

A
  • Retention is due to hypotension (because of the fall in output from the failing ventricle) and thus a fall in renal perfusion.
  • The hypotension also triggers the baroreceptor reflex and so the sympathetic nervous system is activated. Sympathetic innervation “primes” the kidney to increase secretion of renin.
  • Since no additional proteins are produced, the nlood is diluted and therefore water moves out of the blood, causing oedema.
170
Q

What is the role of natriuretic peptides in heart failure?

A
  • The stretch of the atria and ventricles in heart failure triggers ANP and BNP
  • You might think that this would counteract the retention of salt and water by inhibiting the RAA axis, but the RAA axis appears to predominate still
171
Q

How can the fluid balance problem in heart failure be treated?

A
  • Diuretics (risk of electrolyte disturbance and also of hypotension that can exacerbate the disease process)
  • RAA antagonists
  • Vaptans (ADH antagonisis, relatively weak action but perhaps useful as adjuncts to other therapies)

This is covered in more detail in another lecture.

172
Q

What are two disorders of the RAA axis that you need to know?

A
  • Conn’s syndrome (primary hyperaldosteronism)
  • Addison’s disease (hypoadrenalism) [EXTRA]
173
Q

What is Conn’s syndrome, what are the symptoms and how is it treated?

A
  • It is primary hyperaldosteronism, which means that there is a tumour (or other cause) in the zona glomerulosa of the adrenal cortex causing excess secretion of aldosterone
  • Symptoms:
    • Hypokalaemia
    • Increased systemic arterial blood pressure (due to sodium retention)
    • Potentially a metabolic alkalosis (but usually not significant)
  • In practice, patients usually complain of weakness and fatigue (because of the hypokalaemia) and intermittent throbbing headaches.
  • Treatment:
    • Aldosterone antagonist (e.g. spironolactone).
    • Remove the adenoma, if there is one
174
Q

What is Addison’s disease and what are the symptoms?

[EXTRA]

A
  • It is hypoadrenalism, which is the deficiency of steroid secretion from the adrenal cortex, including both aldosterone and the glucocorticoids such as cortisol.
  • Most often due to an autoimmune reaction but sometimes secondary to infection
  • Symptoms include a failure to maintain an adequate arterial blood pressure (because of the lack of aldosterone) and metabolic disturbances (because of the lack of glucocorticoids).
175
Q

What are some disorders of ADH?

[EXTRA]

A
  • Neurogenic diabetes insipidus -> Failure of secretion of ADH, usually following injury to pituitary stalk (e.g., whiplash). Supplement ADH.
  • Nephrogenic diabetes insipidus -> Autoimmune attack on renal ADH receptors. Give immune suppression.
  • SIADH -> Excess ADH secretion due to tumours, etc. Give ADH antagonists if the primary condition is not treatable.
176
Q

Give the equation for pH in relation to H+ ions.

A

pH = -log10[H+]

177
Q

Describe the relationship between [H+] and [OH-] in the body.

[EXTRA?]

A
178
Q

In the body, why must [H+] be kept within a very narrow range?

A

The structure and function of many large organic molecules is very sensitive to [H+].

179
Q

Give a summary of the main physiological responses that occur as pH deviates from 7.4 in order to correct the pH.

A
180
Q

Give a summary of the main pathological consequences of body pH away from 7.4

A
181
Q

Describe the traditional approach towards understanding acid-base balance in the human body.

[EXTRA?]

A
  • Acids (symbolised AH) are taken in from the diet
  • These are buffered and taken out of solution by buffers (symbolised B-) in the body, such as proteins and bicarbonate

The problem with this is that substances such as water make defining acids, bases, buffers, etc. very difficult. For example, water is in theory an endless supply of H+.

182
Q

Describe the newer approach towards understanding acid-base balance in the human body.

[EXTRA?]

A
  • It accounts for the intake and excretion of ALL substances that affect [H+] in the body, rather than just the intake and excretion of H+
  • This allows us to identify independent variables that determine body pH

The problem with this is that the equations become way too complicated and there is no true independent variables, just a mess of inter-dependent variables.

183
Q

Summarise Stewart’s (1983) way of looking at what things control [H+] of body fluids.

[IMPORTANT? + USEFUL]

A
  • H+ participates in 4 main reactions:
    • Reactions with proteins and other ‘weak acids’
    • Reactions with OH-
    • Reactions with HCO3- (leading to CO2 formation)
    • Reactions with CO32-
  • These can be represented in a cross diagram
  • The strong ion difference (SID) is the difference between the sum of the charges of all of the main positive ions minus the sum of the charges of all of the main negative ions -> It is equal to around +40mM/L
  • Then, assuming the charges need to be balanced:
  • [H+] + SID = [OH-] + [Protein-] + 2[CO32-] + [HCO3-]
  • Thus, by rearranging the equation, we find the [H+] is dependent on:
    • SID (controlled by the kidneys)
    • CO2 (controlled by the lungs) -> Since it affects bicarbonate and carbonate
    • Total protein
184
Q

Write equilibrium constant equations for each of the determinants of extracellular [H+]. Which of these is particularly important?

A

The final of these can be rearranged to give the Henderson-Hasselbalch equation.

185
Q

What are Stewart diagrams and how are they useful?

A
  • They are graphs produced by Stewart combining the 3 main determinants of [H+], which are SID, CO2 and protein
  • They show how [H+] varies with PCO2 and either SID or protein (the other is kept constant)
  • These allow us to see the effects of changing each of these variables to produce acidosis or alkalosis
186
Q

Describe how different types of acidosis and alkalosis are shown on Stewart diagrams.

A
  • Metabolic acidosis/alkalosis is shown by a vertical change due to changes in SID or protein
  • Respiratory acidosis/alkalosis is shown by a change along the lines of the diagram due to changes in ventilation
187
Q

What is the plasma Gamlegram and what is it used for?

A
  • It is a diagram used to understand the different factors that determine [H+]
  • It uses the assumption that positive and negative charges are balanced
  • The SID is the difference between the strong ions at the bottom of each column, which do not change much
  • Protein, HCO3- and H+ are the variables that ensure that charges are balanced
  • A large SID means that there is not a lot of H+ required to balance out the protein and HCO3- and keep reactions in equilibirum, since the strong negative ions are doing part of the job
  • A large amount of protein means that there is a lot of H+ required to balance out the protein and keep reactions in equilibirum
188
Q

Where in the body is there an unusual SID?

A
  • In gastric acid, the SID is very negative, which is unusual
  • This means there is no protein or bicarbonate, but there are very high amounts of H+
189
Q

Which reaction is traditionally considered in acid-base balance (out of the 4 main determinants of [H+])?

A
190
Q

Derive the Henderson-Hasselbalch equation.

[EXTRA]

A
191
Q

Write the Henderson-Hasselbalch equation for blood pH.

A
192
Q

Fill in the Henderson-Hasselbalch equation with normal values.

A
193
Q

What are Davenport diagrams?

A
  • Plots of [HCO3-] against pH at different PCO2 values
  • They allow us to see the effects of different metabolic disturbances
194
Q

What should you think of bicarbonate in Davenport diagrams as?

A

Think of it as a product of CO2 reacting with water. It is the dependent variable.

195
Q

What is the importance of proteins in Davenport diagrams?

[USEFUL]

A
  • Proteins act as non-bicarbonate buffers
  • As PCO2 is increased, the magnitude of the resulting change in pH (i.e. the gradient of the red line) is dependent on the buffering power of the non-bicarbonate buffers present in the solution.
  • If protein is present, then it will quickly absorb the vast majority of protons released by the formation of bicarbonate, and pH will change very little for a given rise in bicarbonate concentration -> This will present as a steep slope.
  • If no protein is present, then a much larger change in pH will be observed for a given change in bicarbonate concentration -> This will present as a shallow line.

Think of it this way: If there is protein present then, as bicarbonate is produced, the H+ is quickly mopped up by the protein, leading to small changes in pH per unit bicarbonate produced.

196
Q

Draw a Davenport diagram for a solution containing no protein. If relevant, give an equation for the gradient of the red line.

A
197
Q

Draw a Davenport diagram for a solution containing protein. If relevant, give an equation for the gradient of the red line.

A
198
Q

Draw Davenport diagrams for blood with different concentrations of haemoglobin.

A

The higher the haemoglobin concentration, the steeper the gradient, due to the buffering power of the protein.

199
Q

How do each type of acidosis and alkalosis appear on a Davenport diagram?

A
200
Q

Show on a Davenport diagram how each type of acidosis and alkalosis is corrected. How fast does this happen?

A
  • Metabolic disturbances are corrected by respiratory changes -> This is FAST
  • Respiratory disturbances are corrected by metabolic changes -> This is SLOW
201
Q

What are some causes of metabolic acidosis?

A
202
Q

How does renal failure lead to metabolic acidosis?

A

It leads to the retention of chloride, which reduces the SID (strong ion difference).

203
Q

How does acetazolamide lead to metabolic acidosis?

A

It is carbonic anhydrase inhibitor so it reduces retention of bicarbonate.

204
Q

What are some causes of metabolic alkalosis?

A
205
Q

How does aldosteronism lead to metabolic alkalosis?

A

It increases excretion of chloride, increasing the strong ion difference (SID).

206
Q

How does diuretic therapy lead to metabolic alkalosis?

A

It leads to an increase in the SID (strong ion difference).

207
Q

What are some causes of respiratory acidosis?

A
208
Q

What are some causes of respiratory alkalosis?

A
209
Q

In what pH range do the kidneys maintain the plasma?

A

7.36-7.44

210
Q

What ion is involved in buffering blood pH?

A

Bicarbonate (HCO3-)

211
Q

How is the bicarbonate buffer system an open buffer system?

A
  • When H+ and HCO3- produce H2CO3, it can dissociate into H2O and CO2.
  • This CO2 can then be lost via the lungs, so it is an open system.
212
Q

What is the bicarbonate ion concentration in plasma?

A

25mmol/L

213
Q

How many moles of bicarbonate are filtered out into the tubular fluid by the kidneys each day?

A
  • 5mol
  • This is a very large amount compared to the 25mmol/L concentration of bicarbonate in the blood, implying that the kidneys must be reabsorbing a large amount of bicarbonate back into the blood.
214
Q

What are the roles of the kidney in acid-base homeostasis of the blood?

A

The kidneys regulate HCO3- concentration by:

  1. Reabsorption of filtered HCO3- (back from the tubular fluid)
  2. Generation of new HCO3- (that has been used in buffering non-volatile acids)
  3. Distal tubular secretion of HCO3-
215
Q

The kidneys are involved in reabsorption of HCO3- from the tubular fluid and in generation of new HCO3-. What process do these processes rely on?

A

H+ secretion into the tubular fluid

216
Q

Where does each of the kidney’s three processes involved in maintaining acid-base homeostasis occur?

A
  • Reabsorption of filtered HCO3- -> Proximal tubule + Loop of Henle
  • Generation of new HCO3- -> Distal tubule + Collecting duct
  • Distal tubular secretion of HCO3- -> Distal tubule
217
Q

What type of acids does HCO3- buffer?

A

Non-volatile acids (NVAs)

218
Q

What are volatile acids? What are they produced by?

A

Volatile acids:

  • Carbon dioxide
  • Carried in blood as the potential acid H2CO3
  • Volatile means it can be excreted via the lungs
  • Produced by the metabolism of carbohydrates and fats
219
Q

What are non-volatile acids? What are they produced by?

A
  • Acids produced by metabolism of amino acids and phopshate
  • They are essentially the blood acids that are not produced by CO2
220
Q

What are non-volatile acids produced by and what is their production offset by?

A

Produced by the metabolism of:

  • Amino acids -> Cationic and sulphur containing
  • Phosphate

Offset by HCO3- production by the metabolism of:

  • Amino acids -> Anionic
  • Organic ions
221
Q

What type of non-volatile acid is produced by the metabolism of:

  • Sulphur-containing amino acids
  • Cationic amino acids
  • Phosphate
A
  • Sulphur-containing amino acids -> H2SO4
  • Cationic amino acids -> HCl
  • Phosphate -> H2PO4-
222
Q

Compare how metabolism of anionic and cationic amino acids affects non-volatile acid production.

A
  • Cationic -> Produce non-volatile acids
  • Anionic -> Produce HCO3- (offsetting non-volatile acid production)
223
Q

After accounting for non-volatile acid formation and its offset by HCO3- production, what is the net non-volatile acid production?

A

70mmol/day (or mEq/day -> Milliequivalents)

224
Q

What must happen to NVAs and why?

A
  • They must be buffered and then excreted
  • This is done by reacting them with HCO3-
225
Q

What is produced when a HCO3- reacts with an NVA?

A
  • Salt
  • Carbon dioxide
  • Water

For example:

HCl + NaHCO3 -> NaCl + CO2 + H2O

226
Q

What two organs is the blood pH controlled by? How?

A
  • Kidneys -> Vary the HCO3- concentration
  • Lungs -> Excrete CO2 from the system

Since both HCO3- and CO2 are in the Henderson-Hasselbalch equation for the HCO3-/CO2 buffer system, these two organs control the blood pH.

227
Q

What is the result of HCO3- reacting with NVAs and what is the response to this?

A
  • The blood becomes less acidic
  • But the HCO3- is gradually used up because the CO2 produced can be lost at the lungs
  • Therefore, the kidneys need to regenerate HCO3-
228
Q

What is the total amount of H+ that must be secreted into the tubular fluid per day by the kidneys?

A
  • 4320mEq/day is needed to recovered filtered HCO3-
  • 70mEq/day is needed to regenerate HCO3- that was used in buffering NVAs

So the total is 4390mEq/day (equal to 4390mmol/day).

229
Q

Summarise the principle of the kidneys excreting acids.

A
  • The body produces both volatile acids (H2CO3) through the metabolism of carbohydrates and fats, and non-volatile acids through the metabolism of cationic and sulphur-containing amino acids
  • The volatile acids can be dealt with by breathing out CO2 in the lungs
  • The non-volatile acids must be buffered using HCO3-
  • The net amount of NVA that must be neutralised by HCO3- (after accounting for anionic acid metabolism, which offsets this) is 70mEq per day
  • Thus, the kidney needs to recover 4320mEq/day of HCO3- that is filtered by the kidney and it needs to regenerate 70mEq/day that was used in buffering NVAs
  • Since recovery and regeneration require H+ secretion into the renal tubule, this is how much H+ must be secreted
230
Q

Where does H+ secretion into the tubular fluid occur? [IMPORTANT]

A

All along the renal tubule.

231
Q

What are the roles of the different segments of the nephron in acid-base homeostasis? [IMPORTANT]

A
  • Glomerulus
    • Involved in filtering out almost all HCO3- from the blood
  • Proximal tubule
    • Involved in 80% of HCO3- reabsorption into the blood
    • Not really involved in HCO3- regeneration
    • Ammoniagenesis (ammonia is used as a urinary buffer)
  • Loop of Henle
    • Involved in 15% of HCO3- reabsorption into the blood
  • Distal tubule and collecting duct
    • Residual HCO3- recovery
    • Involved in HCO3- regeneration
232
Q

Draw the model for how H+ secretion into the renal tubule occurs.

A
  • CO2 and H2O react in epithelial cells, which is catalysed by carbonic anhydrase
  • HCO3- -> Pass across basolateral membrane into interstitial fluid and then blood
  • H+ -> Pass across apical membrane into the lumen

Depending on conditions in the renal tubule, this model can be used to both reabsorb bicarbonate ions, and to regenerate bicarbonate ions and excrete H+ in the urine.

233
Q

How does the polarity of the cells in the nephron allow for acid-base balance?

A

There are transporters on each membrane that move H+ or HCO3-.

234
Q

What determines the fate of H+ when it is secreted into the renal tubule?

A
  • If the H+ reacts with filtered HCO3-, the bicarbonate is reabsorbed (4.3mol day-1)
  • If the H+ reacts with a urinary buffer, it is excreted. This is used in regenerating bicarbonate. (70mmol day-1)
235
Q

What is a need that conflicts with the need for acid-base balance in the renal tubule?

A

Individual cells along the renal tubule need to maintain their own pH too, so they have transporters on their membranes that pump H+ and HCO3- in the opposite direction to what is expected (H+ out across the basolateral membrane or HCO3- across the apical membrane).

236
Q

Name some transporters in the renal tubule that are involved in the maintenance of the individual cells’ pH. These transporters pump H+ and HCO3- in the opposite direction to what is expected (H+ out across the basolateral membrane or HCO3- across the apical membrane).

A

On basolateral membrane:

  • NHE (sodium-hydrogen exchange)
  • NDAE (sodium-dependent anion exchange)
  • NBC (sodium-bicarbonate co-transporter)
  • AE (anion exchanger)
237
Q

Summarise the main channels on the apical and basolateral membranes of renal tubule cells. Categorise them into those involved in acid-base homeostasis, cell pH regulation and K+ homeostasis.

A

Apical membrane:

  • NHE3 -> In proximal tubule
  • V H+-ATPase -> In type A intercalated cells of the collecting duct
  • P H+/K+-ATPase -> In collecting duct cells

Basolateral membrane:

  • NBC -> In proximal tubule
  • AE -> Type A intercalated cells of the collecting duct
  • NHE1 -> Cell pH regulation
  • NDAE (4 ion) -> Cell pH regulation
238
Q

Compare the membranes that NHE1 and NHE3 are found on.

A
  • NHE3 -> On apical membrane in proximal tubule
  • NHE1 -> On basolateral membrane
239
Q

Draw the model for how H+ secretion into the renal tubule occurs.

A
  • CO2 and H2O react in epithelial cells, which is catalysed by carbonic anhydrase
  • HCO3- -> Pass across basolateral membrane into interstitial fluid and then blood
  • H+ -> Pass across apical membrane into the lumen

Depending on conditions in the renal tubule, this model can be used to both reabsorb bicarbonate ions, and to regenerate bicarbonate ions and excrete H+ in the urine.

240
Q

Describe where reabsorption HCO3- from the renal tubule occurs and the mechanism by which this happens.

A

In the proximal tubule mostly and loop of Henle (and somewhat in the distal tubule and collecting duct):

  • H+ ions are secreted into the tubular fluid by Na+/H+ exchange (due to large sodium gradient) and H+-ATPase
  • The H+ ions combine with HCO3- in the lumen to form carbonic acid
  • Carbonic acid (H2CO3) can dissociate into carbon dioxide and water under the action of carbonic anhydrase on the apical membrane
  • The CO2 can diffuse into the cell and react with water to reform H2CO3
  • Cytosolic carbonic anhydrase can reform HCO3- and H+
  • H+ can be returned to the lumen, restarting the process
  • HCO3- can move across the basolateral membrane into the interstitial fluid by:
    • HCO3-/Cl- exchanger
    • Na+/3HCO3- symporter (more important)
241
Q

How is HCO3- moved across the basolateral membrane of epithelial cells in the renal tubule? What is usual about this?

A
  • HCO3-/Cl- exchanger
  • Na+/3HCO3- symporter (more important)

This is unusual because the symporter is moving sodium ions against their concentration gradient, which is why 3 bicarbonate ions are required per sodium.

242
Q

Describe where HCO3- is regenerated in the renal tubule and the mechanism by which this happens.

A

This happens mostly in the collecting duct and distal tubule. The mechanism is essentially the same as for HCO3- reabsorption, except no HCO3- is reabsorbed and there is no sodium-dependent processes:

  • H+ is secreted into the tubule by a H+-ATPase (with no help from the Na+/H+ exchanger since no sodium reabsorption is occuring at this point in the tubule)
  • In this case, however, H+ does not combine with HCO3-, since very little is present at this late point in the renal tubule
  • Instead, H+ is buffered by PO43- or by NH3 (or it acidifies the tubule fluid)
  • Inside the intercalated epithelial cells, cytosolic carbonic anhydrase forms HCO3- and H+ from water and CO2
  • This newly generated HCO3- can move across the basolateral membrane into the interstitial fluid by an HCO3-/Cl- exchanger
  • Na+/3HCO3- symporter is not involved because no sodium reabsorption is occuring at this point in the renal tubule

Note: The hydrogen isn’t really doing anything here, it is just being buffered.

243
Q

By what transporters is H+ secreted into the renal tubule?

A
  • Mostly by the Na+/H+ exchanger, driven by a sodium gradient
  • Also by a H+-ATPase
244
Q

What causes reabsorption of HCO3- in the early renal tubule and regeneration of HCO3- in the late renal tubule?

A
  • Firstly, HCO3- is all reabsorbed in the early renal tubule, so there is none left in the late tubule
  • Secondly, there is no sodium gradient across the epithelium in the late distal tubule (which is because there is no reabsorption of sodium here) and so the sodium-dependent processes do not occur.

Note: Ignore the middle part of the diagram.

245
Q

How much CO2 is used in HCO3- regeneration?

A

The same amount as was formed by the original reaction of the HCO3- with an NVA.

246
Q

In which cells does HCO3- regeneration take place?

A

Type A intercalated cells of the collecting duct (and distal tubule?)

247
Q

What can mutations in transport proteins involved in the reabsorption and regeneration of HCO3- in the tubule, as well as in carbonic anhydrase, result in?

A

Renal tubular acidosis -> This is acidosis of the plasma, NOT the tubular fluid

248
Q

How much H+ is generated in the regeneration of HCO3- in type A intercalated cells of the collecting duct and distal tubule?

A

Equivalent to the amount of NVA buffered by HCO3- in the plasma.

249
Q

Describe the location and mechanism for ammoniagenesis. [IMPORTANT]

A

Occurs in the cells of the proximal tubule:

  • Glutamine is converted to glutamic acid by glutaminase
  • Glutamic acid is converted to α-ketoglutaric acid by glutamate dehydrogenase
  • Both of these steps yield: 1 NH3 and 1 HCO3-
250
Q

What are urinary buffers?

A
  • Buffers other than HCO3- that are found in the renal tubule
  • They react with the H+ that is secreted into the renal tubule lumen at the collecting duct and distal tubule
  • They are used to allow large amounts of free H+ secretion into the tubular fluid without unsustainable drops in urinary pH
251
Q

What are the main urinary buffers?

A
  • Phosphate
  • Ammonia
252
Q

Where does phosphate buffer come from, how much of it is available and how does it work as a urinary buffer?

A
  • Dietary in origin
  • So amount available is amount filtered minus that reabsorbed earlier in the tubule
  • Work by a two-step process:
    • H+ + PO43- -> HPO42-
    • H+ + HPO42- -> H2PO4-
253
Q

Where does ammonia buffer come from, how much of it is available and how does it work as a urinary buffer?

A
  • Synthesised within tubular cells from glutamine
  • Synthesis altered to reflect acid-base status: one of the main ways kidney responds to an acid load
  • H+ + NH3 -> NH4+
254
Q

Describe how ammoniagenesis is involved in acid-base balance. Where does it occur? [IMPORTANT]

A
  • Ammoniagenesis is upregulated when plasma pH is acidic
  • It occurs in proximal tubule cells
255
Q

Describe the concept of diffusion trapping in the nephron.

A
  • After NH3 is synthesised in the epithelial cells of the proximal tubule, it diffuses into the lumen
  • The NH3 is converted to charged NH4+ using secreted H+
  • The pK is around 9, so at physiological pH the reaction is strongly to the right and there is lots of NH4+
  • This traps the ammonium in the lumen
  • As the luminal pH falls along the nephron, NH4+ is increasingly trapped

Some other points:

  • NH4+ may be generated from NH3 and H+ WITHIN tubule cells, then secreted by the Na+/H+ exchanger
256
Q

Why are the kidneys not always able to reabsorb all of the bicarbonate from the tubular filtrate? What is the name for this?

A
  • Because the reabsorption is a carrier mediated process, meaning that there is a maximum rate of reabsorption possible
  • The maximum rate of reabsorption is the transport maxmimum (Tm)
257
Q

How is H+ secretion into the lumen of the renal tubule (and therefore bicarbonate reabsorption) regulated?

A

H+ secretion is stimulated by:

  • Decreased plasma pH
  • Increased blood PCO2

This is due to:

  • In proximal tubule and TALH -> Upregulation of Na+/H+ exchanger
  • In collecting duct -> Insertion of H+-ATPase from vesicles

The result is that the Tm is changed and full reabsorption of bicarbonate is possible over a wider range of bicarbonate concentrations.

258
Q

Describe where and how secretion of bicarbonate into the renal tubule lumen occurs.

A

In the Type B intercalated cells of the collecting duct:

  • The same system is used as for regeneration of bicarbonate, except that the membrane proteins are reversed
  • The HCO3-/Cl- exchanger is on the apical membrane, while the H+-ATPase is on the basolateral membrane
  • Carbonic anhydrase converts water and CO2 into HCO3- and H+
  • However, this time the HCO3- moves into the tubule lumen, while H+ goes into the interstitial fluid (this is due to reversal of the membrane proteins)
259
Q

Where does bicarbonate secretion into the renal tubule lumen happen?

A

Type B intercalated cells of the colleting duct

260
Q

Compare the location and reason for each of these processes occurring where they do:

  • Bicarbonate reabsorption
  • Bicarbonate regeneration
  • Bicarbonate secretion
A

Bicarbonate reabsorption:

  • Occurs most in the earliest part of the tubule -> PT, LOH
  • This is because there is enough bicarbonate in the lumen for this to happen, although the amount decreases along the tubule

Bicarbonate regeneration:

  • Occurs in the late parts of the tubule -> DT, CD
  • In type A intercalated cells
  • This happens because there is no bicarbonate left in the lumen, so it has to be generated by carbonic anhydrase in the epithelial cell
  • Allows response to acidosis

Bicarbonate regeneration:

  • Occurs in the late parts of the tubule -> DT, CD
  • In type B intercalated cells
  • This happens by the same process as bicarbonate regeneration, BUT the membrane proteins are on the opposite membranes, so bicarbonate is secreted into the tubule instead of the interstitial fluid
  • Allows response to alkalosis
261
Q

Describe how you can remember the difference between type A and type B intercalated cells of the collecting duct.

A

You can think of it as the side on which the H+-ATPase (the driving force behind acid-base balance) is found:

  • Type A -> On the Apical side
  • Type B -> On the Basolateral side
262
Q

How does hyperkalemia lead to acidosis?

A

Hyperkalemia inhibits NH3 production, and so H+ excretion (since it is a urinary buffer that increases H+ excretion).

263
Q

Give some experimental evidence for how you can study type A and B intercalated cells in the collecting duct.

A
  • They can be identified using differently coloured fluorescently-labelled antibodies for the apical and basolateral H+-ATPase
  • The outer medullary collecting duct has only type A cells (with the apical ATPase), while the inner medullary collecting duct has both type A (with the apical ATPase) and type B cells (with the basolateral ATPase).

(Brown, 1992)

264
Q

Are there only type A and type B intercalated cells in the collecting duct?

A

No, there may also be intermediate cells which are yet to differentiate based on acid-base balance, so they express the H+-ATPase on both the apical and basolateral membranes.

265
Q

Renal tubule cells may have an H+-ATPase and H+/K+-ATPase on their apical membrane. What is the role of each and what is the evidence for this?

A
  • H+-ATPase -> Acid-base balance
  • H+/K+-ATPase -> Potassium balance

The evidence for this is done via acidification of a test model and then inhibiting one of the two ATPase types. H+-ATPase inhibition leads to slow recovery from acidosis, while H+/K+-ATPase inhibition leads to only slightly impaired recovery from acidosis (Schwartz, 1995).

266
Q

How does the renal tubule respond to acidosis?

A
  • Acidosis leads to insertion of H+-ATPase into the apical membrane of the renal tubule cells, leading to increased H+secretion into the tubule.
  • This is done by cytoskeletal-driven fusion of subapical vesicles.
267
Q

Give some experimental evidence for the insertion of H+-ATPase into the apical membrane of renal tubule cells during acidosis.

A

ATPase activity in the apical membrane was markedly reduced by colchicine, which is a cytoskeletal disrupted (so it prevents fusion of ATPase-containing vesicles with the apical membrane).

(Brown, 1992)

268
Q

Compare how the Stewart model and Henderson-Hasselbalch consider acidosis and alkalosis.

A

Stewart model:

  • pH is controlled by SID, PCO2 and weak acid (Atot)
  • Increases in the SID lead to falls in [H+], leading to alkalinsation
  • Argues that it is the movement of strong ions ASSOCIATED with the action of transporters that move H+ and HCO3- that controls pH. The movement of H+ and HCO3- is simply coincidental.

Henderson-Hasselbalch model:

  • pH is controlled by PCO2 and actions of the kidneys on HCO3- and H+
  • Increased H+ secretion into the renal tubule leads to increased HCO3- regeneration and alkalinisation.
  • Argues that it is this movement of H+ and HCO3- that determines pH.
269
Q

Explain how the Stewart model and traditional Henderson-Hasselbalch model of acid-base balance may explain acidosis resulting from carbonic anhydrase II mutation (intracellular enzyme in the proximal tubule).

A

Henderson-Hasselbalch:

  • Decreased production and secretion of H+ into the lumen of the tubule
  • This leads to impairment of H+ and HCO3- reacting in the lumen, so that reabsorption of HCO3- is decreased
  • This causes acidosis

Stewart model:

  • Decreased production of H+ and HCO3- in the cell, which are substrates for the NBC and NHE transporters
  • This means there is decreased reabsorption of sodium
  • This decreases the SID
  • This causes acidosis
270
Q

Describe and explain the relationship between potassium levels and pH.

A
  • Hyperkalaemia leads to acidosis
  • Acidosis also leads to hyperkalaemia
271
Q

Why does acidosis lead to hyperkalaemia?

A
  • Raised [H+] inhibits the basolateral Na+/K+-ATPase in the collecting duct and the apical membrane permeability to K+
  • This in turn reduces K+ secretion in the collecting duct
272
Q

Why does hyperkalaemia lead to acidosis?

A

Hyperkalaemia inhibits NH3 production and therefore H+ excretion (since NH3 is a urinary buffer that stops the urine becoming too acidic - CHECK THIS)

273
Q

What are the 3 lines of defence against alkalosis/acidosis?

A
  • Buffers
  • Ventilatory mechanisms
  • Renal mechanisms
274
Q

What is the biological importance of iron? Why?

A
  • Haemoproteins
  • Iron-sulphur proteins
  • Co-factor for enzymes

This is due to it redox properties, since it can exist in the ferrous (Fe2+) and ferric (Fe3+) forms.

275
Q

What is the ferric state of iron?

A

Fe3+

276
Q

What is the ferrous state of iron?

A

Fe2+

277
Q

How can iron be harmful?

A

It can be very toxic in excess, since it participates in intracellular ‘Fenton reactions’ (e.g. Fe2+ + H2O2 -> Fe3+ + OH· + OH-) that can generate harmful free-radicals compounds.

278
Q

What is the need for homeostatic mechanisms for iron?

A

Homeostatic mechanisms must balance the requirement of the body for sufficient iron against the risk of cellular iron overload.

279
Q

How much iron is stored in the body?

A

Around 4000mg

280
Q

Summarise the main stores of iron in the body.

A
  • RBCs -> 1800mg
  • Liver -> 1000mg
  • Reticuloendothelial macrophages -> 600mg
  • Bone marrow -> 300mg
  • Other tissues -> 400mg
  • Blood -> 3mg
281
Q

Summarise the main iron fluxes in the body.

A
282
Q

How much iron is in the blood (not in RBCs) and what is it bound to?

A
  • 3mg
  • Transferrin
283
Q

Where is most of the body’s iron contained?

A

In the erythropoietic pathway

284
Q

Draw the erythropoietic pathway and show where iron is stored.

[IMPORTANT]

A
  • Blood contains iron bound to tranferrin (3mg iron)
  • Iron is taken up from the blood into the bone marrow (300mg iron)
  • Iron is incorporated into RBCs (1800mg iron)
  • Senescent RBCs are broken down by reticuloendothelial macrophages (600mg iron) and released back into the blood
285
Q

How is iron taken up by the body? How much per day?

A
  • Enters via the duodenum
  • 1-2mg/day
286
Q

What is notable about the size of daily uptake of iron?

A
  • Only 1-2mg are taken up per day, which is a very small amount compared to body stores.
  • Therefore, it is very easy to become anaemic if there is blood loss.
  • So if there is a patient with anaemia, it is very important to make sure there is not any unnoticed bleeding, such as in small amounts in the bowels.
287
Q

How does iron loss from the body happen and how is it regulated?

A
  • It happens via shedding of skin cells and gut cells, etc.
  • This is unregulated, which means that all regulation of body iron must be via intake of iron
288
Q

What are some important dietary sources of iron?

A
  • Meat and fish -> Contain haem iron.
  • Green vegetables, tofu, beans and pulses -> Contain non-haem iron.
289
Q

In which oxidation state is most dietary iron?

A

Most dietary iron found as Fe(III), but converted to Fe(II) in the gut.

290
Q

What promotes absorption of non-haem iron in the gut?

A

It is promoted by vitamin C.

291
Q

Describe the mechanism for iron absorption in the duodenum.

A
  • Fe2+ crosses the apical membrane by the divalent cation transporter DCT1 (dependent on the H+ gradient generated by the acidity of the duodenum lumen)
  • Any Fe3+ in the lumen is reduced to Fe2+ by iron reductase on the apical membrane, so it can be taken up by DCT1
  • Haem can also be taken up by a haem transporter on the apical membrane, after which it is converted to Fe2+ by haem oxidase
  • Fe2+ can now enter one of two pathways:
    • Absorptive pathway
      • A complex of two proteins (hephaestin and ferroportin) transports the Fe2+ into the blood -> The hephaestin converts the Fe2+ into Fe3+
      • In the blood, the Fe3+ is bound to transferrin for transport
    • Storage pathway
      • Fe2+ binds to ferritin in the cytoplasm, where it is stored
      • When needed, the Fe2+ can be mobilised and taken to the hephaestin/ferroportin complex for transport into the blood
292
Q

What is the purpose of storing iron using ferritin in enterocytes?

A

It means that it has not yet technically been absorbed, which is advantageous because it means that this iron can either be fully absorbed or shed with the enterocytes (depending on the iron levels in the body).

293
Q

What transporter is used to take up Fe2+ from the duodenum lumen?

A

DCT1 (divalent cation transporter 1)

294
Q

How is any Fe3+ in the duodenum lumen absorbed?

A
  • It is reduced to Fe2+ by iron reductase on the apical membrane
  • Then it is taken up by DCT1
295
Q

How is haem in the duodenum lumen absorbed?

A
  • It is taken up by a haem transporter on the apical membrane
  • Then it is converted to Fe2+ by haem oxidase.
296
Q

What transporter moves iron from enterocytes into the blood?

A

A complex of two proteins (hephaestin and ferroportin).

(Ferroportin is the one mentioned in the spec, while hephaestin is responsible for converting Fe2+ into Fe3+)

297
Q

What are two important iron binding proteins/glycoproteins and what is the function of each?

A
  • Ferritin -> Storage of iron in enterocytes
  • Tranferrin -> Transport of iron in the blood around the body
298
Q

What is the only transport protein that allows iron to exit cells (enterocytes and macrophages)?

A

Ferroportin

299
Q

What is the chemical class of tranferrin?

A

Glycoprotein

300
Q

What oxidation state of iron does tranferrin bind and how many irons does it bind?

A
  • Fe3+
  • It binds two irons
301
Q

How does serum tranferrin change in response to iron deficiency?

A

Serum transferrin concentration rises in response to iron deficiency, and is often quantified as ‘total iron-binding capacity’.

302
Q

What is usually a good measure of iron availability?

A

Transferrin saturation (serum iron/TIBC x 100) is usually around 20-30%, and is often used as index of iron availability.

303
Q

How is iron taken up into cells from the blood?

A
  • Target cells (e.g. erythroid cells) express the cell surface transferrin receptors TfR1
  • These bind the Fe3+-transferrin complex and lead to the formation of a clathrin-coated pit.
  • An endosome is then formed, which is acidified to release the iron.
  • The iron is stored using ferritin or converted into haemoglobin
304
Q

How is iron availability in the blood sensed?

A
  • Liver cells also express TfR2 (tranferrin receptor 2).
  • This allows the liver to regulate iron homeostasis via hepcidin.
305
Q

What chemical class is ferritin?

A

Protein

306
Q

How does ferritin store iron?

A

Ferritin is a capsule that stores iron in the centre.

307
Q

How is ferritin clinically useful?

A
  • Plasma ferritin levels are an indicator of total body stores of iron (even though we don’t know why it finds its way into the plasma).
  • However, it is also an acute phase protein, so its levels rise with inflammation or infection.
308
Q

What is the main hormone regulating iron in the body?

A

Hepcidin

309
Q

What is the chemical class of hepcidin?

A

Peptide

310
Q

Where is hepcidin produced?

A

Liver

311
Q

When is hepcidin produced and what are the main actions?

A
  • Hepcidin is produced when the liver senses elevated iron levels (via sensing transferrin-iron complexes)
  • It opposes the release of iron from macrophages and enterocytes

(You can think of hepcidin as an equivalent of insulin, but for iron)

312
Q

What is the mechanism of action of hepcidin?

A
  • Hepcidin inactivates ferroportin by binding to it, so that it is internalised and degraded by lysosomes.
  • Thus, it prevents the release of iron from macrophages and enterocytes.
313
Q

Aside from iron levels, what other things affect hepcidin release?

A
  • Erythropoiesis [EXTRA] -> Reduces hepcidin production. This can cause problems in patients with excessive but ineffective erythrocytosis (e.g. thalassaemia), in whom profound hepcidin suppression can produce tissue iron overload.
  • Hypoxia [IMPORTANT] -> Reduces hepcidin production. This is partly by stimulating erythropoiesis and causing iron deficiency, but also directly via HIF.
  • Inflammation [EXTRA] -> Inflammatory cytokines (esp. IL-6) stimulate hepcidin production. This may reflect a desire to deprive invading microbes of iron.
314
Q

How does hypoxia affect hepcidin secretion?

[IMPORTANT]

A
  • It reduces hepcidin secretion
  • This is partly by stimulating erythropoiesis and causing iron deficiency, but also directly via HIF.
315
Q

Summarise the regulation of hepcidin release.

A
316
Q

What proteins are responsible for INTRACELLULAR iron homeostasis?

A

IRPs (iron-regulatory proteins)

317
Q

How do IRPs (iron regulatory protein) work when intracellular iron levels drops?

A

When cellular iron levels are low, IRPs:

  • Inhibit translation of ferritin
  • Stabilise transferrin receptor mRNA

Thus, they encourage iron uptake.

318
Q

How do IRPs (iron regulatory protein) work when intracellular iron levels rise?

A

When cellular iron levels are high, IRPs are degraded, so that:

  • Ferritin translation is no longer inhibited
  • Transferrin receptor mRNA is no longer stabilised, so it is degraded

Thus, they inhibit iron uptake.

319
Q

What are the main indicators of iron status?

A
  • Haemoglobin and mean cell volume
  • Serum ferritin
  • Serum iron and transferrin
  • Serum transferrin saturation
  • Soluble transferrin receptor
320
Q

What type of anaemia is a hallmark of iron deficiency anaemia?

A

Hypochromic microcytic anaemia

(Hypochromic = Lacking colour, Microcytic = Small RBCs)

321
Q

What are some causes of iron deficiency?

A
  • Inadequate dietary intake
  • Malabsorption (e.g. coeliac disease)
  • Excessive use of iron (e.g. pregnancy, growth)
  • Hookworm infection (common worldwide)
  • Blood loss:
    • Blood donation
    • Menstrual loss in young women
    • Gastrointestinal bleeding
322
Q

What are some causes of iron overload?

A
  • Primary genetic disease (haemochromatosis)
  • Alcoholic cirrhosis
  • Excessive oral intake of iron
  • Repeated blood transfusions
  • Excessive (ineffective) erythropoiesis
323
Q

What is hereditary haemochromatosis?

[EXTRA]

A
  • Relatively common group of genetic diseases characterised by excessive dietary iron absorption or cellular iron retention.
  • Most are due to inadequate hepcidin expression.
324
Q

What are the symptoms of hereditary haemochromatosis?

[EXTRA]

A

Due to iron deposition in parenchymal tissues:

  • Liver (cirrhosis)
  • Pituitary (hypogonadism)
  • Pancreas (diabetes)
  • Joints (arthropathy)
  • Heart (cardiomyopathy)
  • Skin (hyperpigmentation)
325
Q

How is hereditary haemochromatosis diagnosed and treated?

[EXTRA]

A
  • Diagnosis involves blood tests (e.g. transferrin saturation and ferritin), genetic testing and sometimes liver biopsy
  • Treatment may include therapeutic phlebotomy or iron chelation
326
Q

Why does hyperkalemia lead to muscle weakness?

A

It depolarises skeletal muscle, causing it to become refractory since the sodium channels remain in an inactivated state.

327
Q

Give the normal values for arterial and venous blood for these:

  • pH
  • PCO2
  • PO2
  • HCO3-
  • Base excess
A
328
Q

Describe how you can interpret blood gases to identify the various types of alkalosis and acidosis.

A
  1. Check the pH to see if it is acidosis or alkalosis
  2. Check to see if this can be explained by the pCO2 level
    • If yes, then it is respiratory acidosis/alkalosis
    • If not, then it is metabolic acidosis/alkalosis
329
Q

Why might PCO2 be low when the pH is low?

A

If there is metabolic acidosis, then there is likely to be compensatory hyperventilation.

330
Q

What is base excess and why is it important?

[IMPORTANT]

A
  • There may be situations where there is both a respiratory acidosis AND metabolic acidosis simultaneously
  • In these situations, the metabolic acidosis will only be revealed once the respiratory acidosis is corrected
  • In these situations, the base excess is a way of identifying this right at the start
  • How it is done:
    • “Ventilate” a sample of blood
    • Titrate to assess the acidity
    • Base excess is a measure of this
331
Q

Do we ever look at bicarbonate in blood analysis?

A

Not really, because there are very many complications in its interpretation.

332
Q

What is an advanced clinical graph used to understand acid base balance?

[EXTRA]

A

Siggaard-Andersen Acid-Base Chart

333
Q

Compare the Henderson-Hasselbalch and Stewart models way of looking at acid-base balance.

[EXTRA]

A
  • The Stewart model is like a more complicated version of the Henderson Hasselbalch equation
  • It explains acid-base balance using a wider range of causes.
  • For example, it explains the mechanism of oddities like saline-induced acidosis.
  • Note that Henderson-Hasselbalch also MEASURES this saline-induced acidosis, it just cannot explain it mechanistically.
  • Thus, there have been discussions about which is more clinically useful and accurate.
  • A major advantage of Henderson-Hasselbalch is simply that it is easier to understand and arguably more intuitive.
334
Q

What are the consequences of chronic acidosis and alkalosis?

[IMPORTANT]

A

Chronic acidosis:

  • Loss of bone density -> Due to acid buffering
  • Muscle wastage -> Due to increased protein catabolism Acid buffering leads to loss of bone density, resulting in an increased risk of bone fractures

Chronic alkalosis:

  • Neuromuscular irritability + Tetany
  • Abnormal heart rhythms (usually due to accompanying electrolyte abnormalities such as low levels of potassium in the blood)
335
Q

How does renal handling of potassium work?

A
  • Potassium is freely filtered by the glomerulus.
  • In the proximal tubule:
    • K+ reabsorption is mostly passive via the paracellular route. It is proportional to Na+ absorption since water follows the sodium and carries potassium with it (solvent drag).
  • In the thick ascending loop of Henle:
    • K+ reabsorption in the thick ascending limb of Henle occurs through both transcellular (via NKCC) and paracellular pathways.
  • In distal convoluted tubule and collecting duct:
    • Principal cells (in the collecting duct):
      • Actively secrete K+ using K+ transporters and K+/Cl− cotransporters on the apical membrane
    • Type A intercalated cells
      • Can insert H+/K+-ATPase into the apical membrane to increase K+ reabsorption
336
Q

Where along the renal tubule does most regulation of potassium happen?

A

In the distal nephron.

Delivery to the distal nephron is approximately constant, but secretion of potassium into the renal tubule (by principal cells and type A intercalated cells) varies according to physiological needs.

337
Q

What determines the rate of secretion of potassium into the renal tubule at the distal nephron?

A

The main determinants of secretion of potassium in the principal cells include:

  • Intracellular K+ concentration
  • Luminal K+ concentration
  • Potential difference across the luminal membrane (i.e. electronegativity of the lumen)
  • Permeability of the luminal membrane for K+

Thus, the two main determinants are:

  • Mineralocorticois
  • Distal delivery of Na+ and water
338
Q

Which ion are K+ fluxes in the kidney related to?

[IMPORTANT]

A
  • There is reciprocity between K+ and H+ fluxes.
  • This is due to the H+/K+-ATPase on principal cells of the collecting duct.
339
Q

How does aldosterone affect renal handling of potassium?

A
  • Increases the activity and number of Na+/K+-ATPase pumps on the basolateral membrane of principal cells -> This increases intracellular potassium concentration, meaning more is secreted via the H+/K+-ATPase
  • Increases sodium absorption by increasing the activity and number of sodium-chloride symporters (NCC) in the distal convoluted tubule as well as ENaC channels -> This increases luminal electronegativity, so more potassium is secreted into the lumen
  • Increase apical membrane permeability to potassium
340
Q

How does distal delivery of sodium and water affect renal handling of potassium?

A
  • Increased distal delivery of Na+ stimulates distal Na+ absorption, which will make the luminal potential more negative -> This increases K+ secretion
  • Increased flow rates also increase K+ secretion by diluting the lumen and thus maintaining potassium gradients

YEAR 2 - Applied Physiology & Pharmacology (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions