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1

What is the normal range of plasma pH?

7.38 - 7.42

2

What are the major clinical effects of Alkalaemia?

Lowers free Ca2+ in serum:

Increases excitability of nerves

If greater than 7.45:

Parasthesia (tingling)

Tetany (Involuntary muscle contraction, danger to breathing)

 

3

What are the mortality rates of Alkalaemia at pH 7.55 and 7.65?

45% at 7.55

80% at 7.65

4

What are the major clinical effects of Acidaemia?

Increase plasma potassium

Affects enzymes:

Reduced cardiac and skeletal muscle contractility

Reduced glycolysis in many tissues

Reduced hepatic function

Effects sever below 7.1 and life threatening below 7.0

5

How is plasma pH determined? What systems are involved?

Dependent on pCO2 to [HCO3-] ratio

pCO2 determined by respiration

[HCO3-] determined by kidney

6

What causes respiratory acidaemia and alkalaemia?

Resipiratory Acidaemia:

Hypoventilation leads to hypercapnia, causing plasma pH to fall

Repiratory Akalaemia:

Hyperventilation leads to hypocapnia causing plasma pH to rise

7

Explain briefly the role of chemoreceptors in pH balance

Central:

Keeps pCO2 within tight limits

Corrects disturbances in pH with respiratory changes

Peripheral:

Enable changes in respiaration driven by changes in plasma pH

8

Explain the role of the kidneys in correcting respiratory driven pH changes

Kindey control [HCO3-] and hence can conpensate for change in pCO2 with change in [HCO3-]

Respiratory acidaemia can be compensated by increase in [HCO3-] (Compensated respiratory acidaemia)

Respiratory alkalaemia can be compensated by decrease in [HCO3-] (Compensated respiratory alkalaemia)

9

Describe metabolic acidaemia and it's compensation

Metabolic acidaemia:

Tissues produce acid (E.g. H+) that reacts with HCO3-

This leads to a fall in plasma pH

Also produces an anion which can replace HCO3-

Compensation via change in ventilation:

Peripheral chemoreceptors

Increased ventilation lowers pCO2

Restores normal pH (ideally)

10

Describe metabolic alkalaemia and its compensation

Metabolic alkalaemia:

Plasma [HCO3-] rises (E.g. post-vomiting)

Leads to rise in plasma pH

Compensation via ventilation change:

Decrease in ventilation can only partially compensate

11

Briefly describe renal control of [HCO3-]

Large quantities filtered per day (4500mmol)

Should be able to lose HCO3- very easily

To increase [HCO3-] must both recover all filtered and make new

12

How does the kidney produce HCO3-?

Normal metabolic activity:

CO2 + H2O = HCO3- + H+

HCO3- enters plasma

H+ excreted in urine

Additionally:

HCO3- can be produced from amino acids, this produces NH4- to enter urine

13

From where in the kidney tubule is HCO3- recovered?

80-90% in PCT

Rest in Tal of LoH

14

Describe the reabsorption of HCO3- from the kindey lumen

Basolateral Na+/K+ ATPase produces Na+ gradient across luminal membrane

Gradient allows Na+/H+ exchanger to pump H+ out of cell and Na+ in

H+ reacts with HCO3- in the lumen

HCO3- + H+ = H2O + CO2

H20 and CO2 are reabsorbed and react

H20 + CO2 = HCO3- + H+

HCO3- is reabsorped through basolateral membrane

H+ is recycled

15

How is HCO3- produced via the mechanism specific to the proximal tubule?

Glutamine is broken down to produce Alpha-Ketoglutarate and NH4-

Alpha-Ketoglutarate makes 2 HCO3-

HCO3- into ECF

NH4- into lumen

16

How does the kidney produce HCO3- via a mechanism specific to the DCT?

Intercalated cells:

Metabolic CO2 reacts with H20 to produce HCO3- and H+

HCO3- secreted into ECF

Na+ gradient insufficient to drive H+ secretion into lumen

Active secretion of H+ used instead

H+ in lumen buffered by filtered phosphate and excreted ammonia

 

17

What is the total acid excretion per day in the kidneys?

In what form is H+ found in the urine?

50-100mmol of H+

Some H+ buffered by phosphate, the rest attached to ammonia

18

How is H+ excretion controlled?

Probably by changes in tubular cell's intracellular pH

This pH change is the concequence of changing rates of [HCO3-] export

Therefore control of H+ is acheived through control of [HCO3-]

 

19

How might respiratory function lead to a change in H+ excretion?

Respiratory acidaemia/alkalaemia will affect intercellular pH in the renal tubule due to changes in CO2 diffusing in as pCO2 is altered

This will produce an increase/decrease in HCO3- export to plasma and hence increase/decrease H+ excretion

 

20

How does [K+] affect pH of plasma?

[K+] affects HCO3- reabsorption and ammonia excretion

E.g. [K+] rise leads to decreased capacity of the kidney to reabsorb and create HCO3-

Hypokalaemia can therefore lead to metabolic alkalosis

Hyperkalaemia can lead to metabolic acidosis

21

Outline the renal cellular responses to acidosis

Enhanced H+/Na+ exchange (Fully recover filtered HCO3-)

Increase NH4- production in PCT

Increased H+ ATPase in DCT

All lead to an increased capacity for the renal cells to produce and export HCO3- and correct acidosis

22

Explain the Anion Gap

Difference between ([Na+] + [K+]) and ([Cl-] + [HCO3-])

Indicates whether HCO3- has been replaced with something other than Cl- (ie. unaccounted ions) 

Normally 10-15mmol.l-1

Increased if anions from metabolic acids have replaced plasma HCO3-

Sometimes renal problems can reduce [HCO3-] and not increase the anion gap as the HCO3- has been replaced with Cl-

23

Describe the kidney response to metabolic alkalosis

When might problems arise with correction?

[HCO3-] increases after persistent vomitting

HCO3- infusions can be corrected extremely rapidly as rise in intracellula pH in the renal tubule leads to decreased H+ secretion and hence HCO3- recovery

But:

If there is also volume depletion, Na+ conservation is prioritised

High rates of Na+ reabsorption raise H+ excretion, favouring HCO3- recovery

This limits our ability to excrete HCO3-

24

Describe the kidney's response to respiratory alkalosis

Rise in tubular pH due to lower pCO2 induce less HCO3- export by reducing H+ secretion into lumen (hence reduing HCO3- recovery from lumen)

HCO3- is therefore excreted and [HCO3-] falls to correct the [HCO3-]/pCO2 ratio

25

Give the reference ranges for:

pH

pCO2

[HCO3-]

pO2

pH = 7.38 - 7.42/7.46

pCO2 = 4.2 - 6.0 kPa

[HCO3-] = 22 - 29 mmol.l-1

pO2 = 9.8 - 14.0 kPa

26

What are the would you expect an increase or decrease in the values given below in uncompensated metabolic acidosis?

pH

pCO2

[HCO3-]

pO2

Decrease

Normal

Decrease

Normal

27

What are the would you expect an increase or decrease in the values given below in compensated metabolic acidosis?

pH

pCO2

[HCO3-]

pO2

Normal or Low

Low

Low

Normal

28

What are the would you expect the values given below to be low, high or normal in uncompensated metabolic alkalosis?

pH

pCO2

[HCO3-]

pO2

High

Normal

High

Normal

29

What are the would you expect the values given below to be low, high or normal in compensated metabolic alkalosis?

pH

pCO2

[HCO3-]

pO2

High/Normal

High

High

Low

30

What are the would you expect the values given below to be low, high or normal in uncompensated respiratory acidosis?

pH

pCO2

[HCO3-]

pO2

Low

High

Normal

Low

31

What are the would you expect the values given below to be low, high or normal in compensated respiratory acidosis?

pH

pCO2

[HCO3-]

pO2

Low/Normal

High

High

Low

32

What are the would you expect the values given below to be low, high or normal in uncompensated respiratory alkalosis?

pH

pCO2

[HCO3-]

pO2

High

Low

Normal

Normal/High

33

What are the would you expect the values given below to be low, high or normal in compensated respiratory alkalosis?

pH

pCO2

[HCO3-]

pO2

High/Normal

Low

Low

High/Normal

34

What is the total body K+?

How is it distributed?

Total:

3500mmol

ICF

98%

120-150mmol/l

Mainly in skeletal muscle cells, liver, RBCs and bone

ECF:

2%

3.5-5mmol/l

35

What maintains the difference between ICF and ECF [K+]?

Na+/K+ ATPase

36

Why is tight regulation of [K+] critical?

High ICF and low ECF [K+] contributes to the resting membrane potential and allows for action potentials

An increase in ECF [K+] would depolarise cells

A decrease in ECF [K+] would hyperpolarise cells

These changes would have profound effects on excitability of cardiac and nuromuscular tissues:

Problems with cardiac conduction and pacemaker automaticity

Alter neuronal function, skeletal and smooth muscle function

Arrhhythmias, cardiac arrest, muscle paralysis

37

What events follow a meal containing K+?

Intestine and colon absorb K+

Substatial amounts of K+ therefore enter the ECF (Danger!)

Kidney's cannot excrete this K+ fast enough

4/5 of ingested K+ moves into ICF/cells within minutes

After a slight delay K+ is released from ICF slowly as Kidney's begin to excrete K+

Excretion takes 6-12h

38

What 2 processes are responsible for K+ homeostasis?

External balance:

Adjustment of renal K+ to match intake

Responsible for longer term control of total K+

Internal balance:

Moves K+ between ICF and ECF to correct ECF levels of K+ should they rise or fall

Effect is immediate (within minutes of imbalance)

Responsible for moment to moment control

39

Internal K+ balance is a result of 2 processes, what are they?

Movement of K+ into ICF via Na+/K+ ATPase

Movement of K+ out of ICF into ECF via K+ channels (E.g. ROMK)

40

What are the factors promoting uptake of K+ into ICF?

Hormones (acting on Na+/K+ ATPase):

Insulin
Aldosterone
Catecholamines

Increased [K+] in ECF

Alkalosis:

Low ECF [H+]  causes H+ to move out of cells and correct imbalance causing a reciprocal shift  of K+ into cells (maintains electrochemical balance)

41

Why is insulin used as an emergency therapy for hyerkalaemia?

K+ in plasma stimulates insulin release under normal physiological conditions

This leads to increased K+ uptake by muscle and liver via an increase in Na+/K+ ATPase channels

Administration of insulin boosts this process and lowers ECF [K+]

42

How is Aldosterone involved in K+ homeostasis?

K+ in serum stimulates aldosterone secretion

Which in turn stimulates uptake of K+ via Na+/K+ ATPase

43

How are Catecholamines involved in K+ homeostasis?

Acts via B2 adrenoceptors which in turn stimulate Na+/K+ ATPase

This increases the cells uptake of K+

44

What are the factors promoting K+ shift into ECF

Low ECF [K+]

Exercise

Cell lysis (K+ leaks through ruptured membrane)

Increase in ECF osmolarity

Acidosis (Increase in ECF [H+]:

Shift of H+ into cells and reciprocal K+ shift out (to preserve electrochemical gradient)

45

How does exercise affect K+ homeostasis?

Skeletal muscle contraction leads to a net loss in K+ during recovery phase of action potential

Damage to muscle also releases K+

Increases are proportional to intensity of exercise

Uptake of K+ into non-contracting cells + Exercise stimulation of catecholamines prevents dangerous rise

Cessation of exercise leads to rapid fall in ECF [K+] (often <3mmol/l)

46

How is cell lysis involved in K+ homeostasis?

Give examples where this effect is significant

K+ leaks through ruptured membranes

Rhabdomyolysis:

Trauma to skeletal muscle resulting in muscle cell necrosis

Intravascular haemolysis:

Breakdown of RBC in vascular system

E.g. Incompatible blood transfusion

Cancer chemotherapy

47

How can a rise in plasma/ECF tonicity lead to K+ movement into the ECF?

Water moves out of cells into ECF to correct osmolarity

Increase in [K+] in ICF

Net movement of K+ into ECF via concentration gradient (despite action of Na+/K+ ATPase)

48

How do [K+] balance disturbances affect ECF pH?

K+ movement in and out of a cell causes H+ to move in opposite direction

Significant K+ movement (Hypo/hyperkalaemia) can therefore lead to acidosis or alkalosis

49

Describe renal handling of K+ under physiological conditions

K+ freely filtered at glomerulus

PCT:

Uptake via paracellular diffusion

67% of filtered load reabsorbed

Thick al of LoH:

Uptake is active (Driven by basolateral Na+/K+ ATPase and Na+/K+/2Cl- transporter in apical membrane

20% reabsorbed

Principal cells of DCT and Cortical CD:

Substantial secretion of K+ in a normal or high K+ diet

Little secretion in a low K+ diet

Intercalated cells of DCT and CD:

Reabsorb 10-12%

 

50

Outline the mechanism of K+ secretion from principal cells in the DCT and Cortical CD

Na+/K+ activity on BLM

High intracellular K+ creates chemical gradient across luminal membrane

Luminal ENaC allows Na+ to move down chemical gradient, producing an electrical gradient

Favourable electrochemical gradient allows K+ secretion via K+ luminal channels

51

What factors influence the K+ secretion from principal cells of the DCT and Cortical CD?

ECF [K+]:

Stimulates Na+/K+ ATPase

Increases permeability of apical K+ channels

Stimulates aldosterone secretion

Aldosterone:

Increases transcription of Na+/K+ ATPase, K+ channels and ENaC

Acid/Base:

Acidosis decreases K+ channel permeability, inhibits Na+/K+ ATPase (hence decreasing K+ secretion)

Alkalosis increases K+ secretion through stimulation of Na+/K+ ATPase and K+ channels

Luminal factors:

Distal tubular flow rate washes away luminal K+ hence increasing K+ secretion

Increased Na+ in DCT, more Na+ absorbed hence more K+ loss

52

What is the mechanism of K+ absorption via Intercalated cells in the DCT and CD:

Active process

Uptake via H+/K+ ATPase

53

Define hyperkalaemia

[K+] = >5.0mmol/l

54

What problems with internal K+ balance might cause hyperkalaemia?

Problems with external balance

Increased intake:

Only causes problem when there's renal impairment

Unless there has been an inappropriate dose given IV

Inadequate renal excretion

55

What might be the causes for inadequate renal excretion of K+?

AKI

Chronic kidney injury

Reduced aldosterone (with normal kidneys):

Adrenal insufficiency

Aldosterone blockers (secretion or action)

K+ sparing diuretics

ACE Inhibitors

56

What might be the cause of hpyerkalaemia due to problems with internal K+ balance?

Diabetic ketoacidosis:

No insulin reduces K+ intake into ICF

Plasma hypertonicity (Causes shift of K+ into ECF)

Metabolic acidosis causes reciprocal shift of K+ into ECF as H+ moves into ICF

Other causes of metabolic acidosis

Cell lysis

Exercise

57

What is the effect hyperkalaemia on the resting membrane potential?

What is the direct concequence of this to cardiac tissue?

Raises the resting membrane potential (depolarisation)

Cardiac:

More Fast Na+ channels remain inactive and the heart is less excitable

58

What are the clinical features of hyperkalaemia?

Heart:

Altered excitability - Arrhythmias, heart block

GI:

Neuromuscular dysfunction - Paralytic ileus

Acidosis

59

Outline the ECG changes that occur as hyperkalaemia progressively worsens

Symptoms worsen as [K+] rises as demonstrated by incresing numbers below

  1. High T wave
  2.  As above + Prolonged PR interval and depressed ST segment
  3. P wave absent and intraventricular block
  4. VFib

60

What is the emergency treatment method for hyperkalaemia?

Reduce K+ effect on heart:

IV calcium gluconate

Shift K+ into ICF:

Glucose + IV insulin

Nebulised B agonists (salbutamol)

Remove excess K+:

Dialysis

61

What are the long term treatment steps for Hyperkalaemia?

Treat cause

Reduce intake

Measures to remove excess K+:

Dialysis

Oral K+ binding resins to bind K+ in gut

62

Define Hypokalaemia

[K+] = <3.5mmol/l

63

What might cause hypokalaemia?

Problems of external balance:

Excess GI loss (bulimia/vomiting)

Excess renal loss (Diuretics, Osmotic diuresis - Diabetes, High Aldosterone)

Problems with internal balance:

Shift of K+ into ICF (Metabolic alkalosis)

64

What is the effect of hypokalaemia on the resting membrane potential?

What is the direct concequence of this in cardiac muscle?

Hyperpolarisation

More fast Na+ channels active in cardiac muscle

Cardiac muscle is more excitable

65

What are the clinical feature of hypokalaemia?

Heart:

Altered excitability - Arrhythmias

GI:

Neuromuscular dysfunction - Paralytic Ileus

Skeletal muscle:

Neuromuscular dysfunction - Muscle weakeness

Renal:

Dysfunction of CD cells - Unresponsive to ADH causing nephrogenic diabetes insipidus

66

outline the ECG changes that occur with worsening hypokalaemia

Worsening degree of hypokalaemia indicated by numbers below:

  1. Low T wave
  2. As above + High U wave
  3. As above + Low ST segment

67

Outline treatment of hypokalaemia

Treat cause

Potassium replacement (IV/Oral)

If due to increase mineralocorticoid activity:

Potassium sparing diuretics which block action of aldosterone on principal cells