Urinary 6 Flashcards
What is the normal range of plasma pH?
7.38 - 7.42
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)
What are the mortality rates of Alkalaemia at pH 7.55 and 7.65?
45% at 7.55
80% at 7.65
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
How is plasma pH determined? What systems are involved?
Dependent on pCO2 to [HCO3-] ratio
pCO2 determined by respiration
[HCO3-] determined by kidney
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
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
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)
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)
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
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
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
From where in the kidney tubule is HCO3- recovered?
80-90% in PCT
Rest in Tal of LoH
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
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
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
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
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-]
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
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
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
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-
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-
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
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
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
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
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
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
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
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
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
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
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
What maintains the difference between ICF and ECF [K+]?
Na+/K+ ATPase
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
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
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
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)
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)
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+]
How is Aldosterone involved in K+ homeostasis?
K+ in serum stimulates aldosterone secretion
Which in turn stimulates uptake of K+ via Na+/K+ ATPase
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+
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)
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)
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
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)
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
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%
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
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
What is the mechanism of K+ absorption via Intercalated cells in the DCT and CD:
Active process
Uptake via H+/K+ ATPase
Define hyperkalaemia
[K+] = >5.0mmol/l
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
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
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
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
What are the clinical features of hyperkalaemia?
Heart:
Altered excitability - Arrhythmias, heart block
GI:
Neuromuscular dysfunction - Paralytic ileus
Acidosis
Outline the ECG changes that occur as hyperkalaemia progressively worsens
Symptoms worsen as [K+] rises as demonstrated by incresing numbers below
- High T wave
- As above + Prolonged PR interval and depressed ST segment
- P wave absent and intraventricular block
- VFib
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
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
Define Hypokalaemia
[K+] = <3.5mmol/l
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)
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
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
outline the ECG changes that occur with worsening hypokalaemia
Worsening degree of hypokalaemia indicated by numbers below:
- Low T wave
- As above + High U wave
- As above + Low ST segment
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
