Week 3 RNU Lectures Flashcards
1
Q
Why is generation of CO2 a threat to homeostasis?
A
CO2 acts as an acid
2
Q
What amino acids create an acid load when metabolised?
A
Lusine, arginine, methionine, cysteine
3
Q
What amino acids create an alkali load when metabolised?
A
Glutamate, aspartate
4
Q
Is a protein rich diet acid or alkali?
A
It is acid load
5
Q
Is a vegetarian diet acid or alkali?
A
Alkali load
6
Q
Why is incomplete respiration (anaerobic respiration) a threat to homeostasis?
A
Keto-acids and lactic acid can be produced
7
Q
Why can vomiting be a threat to homeostasis?
A
Loss of acid
8
Q
What are the 3 main components of acid-base regulation?
A
- Buffering
- Ventilation
- Renal regulation
9
Q
How does renal regulation control acid-base conc.?
A
Regulation of HCO3 and H+ secretion and reabsorption
10
Q
How is ventilation involved in regulating acid-base balance?
A
Control of CO2
11
Q
What does acidotic mean?
A
Low bicarbonate
12
Q
What is acidaemia?
A
High H+
13
Q
What does alkalotic mean?
A
Low H+
14
Q
What is alkalaemia?
A
High bicarbonate
15
Q
How could H+ concentration be normal in the presence of an acid-base disturbance?
A
At the expense of other blood chemistry (HCO3 conc. or pCO2)
16
Q
What are buffers?
A
Weak acids that are partially dissociated in solution
17
Q
What is the Bronsted Lowry theory?
A
An acid is a substance capable of donating a H+ ion
The conjugate base is the substance that accepts it
18
Q
What are the defences against acidosis?
A
- Immediate - consumption of HCO3 - buffering
- Rapid - increase in ventilation
- Slow - renal adjustment to HCO3 concentration
19
Q
What is the principle physiological buffer?
A
CO2-HCO3 system
20
Q
Why is [CO2] held constant?
A
CO2 is highly diffusible and [CO2] is regulated and controlled by respiration
21
Q
What is respiratory acidosis?
A
Not breathing
22
Q
What is metabolic acidosis?
A
Addition of H+ ions
23
Q
What can HCO3 not buffer?
A
Respiratory acid
24
Q
What is another important physiological buffer? (not HCO3)
A
Plasma protein especially Hb which buffers CO2 in blood
25
What does increasing respiratory rate do?
Lowers pCO2
26
How do the kidneys regulate acid-base balance?
- Reabsorb filtered HCO3
- Secrete "fixed" acids
• Titrate non- HCO3 buffer in urine - primarily PO4
• Secrete NH4 into urine
27
How are the regulatory functions of the kidneys in acid base balance achieved?
Using selective permeability of the luminal and basolateral cell membranes to match the transport of H+ and HCO3 in opposite directions
28
Where does most HCO3 reabsorption take place?
It is an active process that takes place largely in the proximal tubule with small contributions from the ascending loop of Henley and the distal convoluted tubule
29
What can the inability to reabsorb filtered HCO3 cause?
metabolic acidosis
30
What is a major mechanism for H+ entering tubule?
Na/H anti-porter
31
How many Na ions are reabsorbed with each HCO3 ion?
1
32
What is the net change in H+ or HCO3 in reabsorption of filtered HCO3?
There is no net change
33
How much "fixed acid" is required to be eliminated daily?
About 70mmol/day
34
What is the excretion of an H+ ion matched with?
The generation of a new HCO3 which is absorbed
35
What are the two components of excretion of fixed acid?
- Excretion of titratable acid (mostly phosphate)
| - Excretion of NH4+
36
What is more common acidotic (abnormal HCO3) or acidaemic (decreased pH)?
More patients will be acidotic
37
What is [HCO3] like in metabolic acidosis?
Decreased [HCO3] --> decreased pH
38
What is pH like in metabolic alkalosis?
increased
39
What is [CO2] like in respiratory acidosis?
Increased [CO2] --> decreased pH
40
What is [CO2] like in respiratory alkalosis?
decreased [CO2] --> increased pH
41
What are potential causes of metabolic acidosis?
- Addition of extra acid
- failure to excrete acid
- Loss of HCO3
42
what is the primary abnormality in metabolic acidosis?
Fall in plasma HCO3
43
What is the compensatory response of the body to metabolic acidosis?
Fall in pCO2 due to respiratory drive
44
What are the metabolic symptoms of metabolic acidosis?
protein wasting, resorption of Ca from bone
45
What are the CVS symptoms of metabolic acidosis?
arrhythmias, decreased cardiac contractility
46
What are the respiratory symptoms of metabolic acidosis?
increased ventilation (Kussmaul's breathing)
47
What is a high anion gap due to?
The presence of an organic acid
48
What does hypoalbuminemia do to the anion gap?
Reduces it as albumin is a major plasmin anion
49
How is the anion gap calculated?
[Na] - [Cl + HCO3]
50
What is the normal range for the anion gap?
9-16
51
How much does decreased albumin affect the anion gap?
Every 10g/L fall in [albumin] reduces the anion gap by 2.5
52
How much should pCO2 fall for every 1mmol/L fall in bicarbonate?
(as compensation for metabolic acidosis)
0.125kPa
If this has not fallen sufficiently then there may be a co-existing respiratory acidosis
53
What happens in acidosis of chronic renal failure?
- As renal function declines, most patients become acidotic
- Initially this is a normal-AG acidosis due to reduced renal ammonium excretion
- Titratable acid excretion initially preserved due to ↑PO4 excretion and ↓ PO4 reabsorption in PCT
- Eventually patients may develop high AG as PO4 and other anions accumulate
54
What can cause lactic acidosis?
usually results from hypoperfusion and reduced hepatic clearance – major problem in sepsis
Drugs (metformin), Liver failure, Poisoning (cyanide, aspirin)
55
What is the primary abnormality in metabolic alkalosis?
Decreased H+ and increased HCO3
56
What is the compensatory response to metabolic alkalosis?
Hypoventilation --> increased pCO2
57
What is volume depleted type metabolic alkalosis usually caused by?
Gastric acid loss (vomiting)
58
What should the response to alkalosis be?
To excrete HCO3 (equivalent to retaining H+)
59
What is maintenance of alkalosis due to?
Failure to excrete HCO3 - occurs as HCO3 is reabsorbed with Na when there is a deficiency of Cl
60
How does chloride depletion contribute to metabolic alkalosis?
HCO3 reabsorption in DCT requires Cl secretion – if tubular CL reduced, gradient to reabsorb HCO3
61
How does potassium depletion contribute to metabolic alkalosis?
Not entirely clear probably a combination of factors
- e.g. distal tubule H secretion occurs with K transport in opposite direction – in trying to retain K, H will be excreted leading to alkalosis
62
What causes respiratory alkalosis?
Hyperventilation - thus decreased pCO2 with compensatory response to excrete HCO3
63
What causes respiratory acidosis?
Hypoventilation - thus increased PCO2 with compensatory response to retain HCO3
64
What does examination of the urine tell us?
- Shows how the kidney is reacting to changes in the extracellular fluid sensed volume and composition
- shows other metabolic processes in the body
- Shows if the glomerular filtration barrier is damaged
- Shows inflamed or neoplastic tissue in the lining of the urinary tract
- shows recent toxin ingestion
65
How is the urine examined?
- Inspection
- Dipstick testing
- Microscopy
- Urine biochemistry
66
What does visible (frank/gross) haematuria mean?
Blood can be seen with the naked eye
67
What does non-visible (microscopic) haematuria mean?
Blood would show on dipstick but can only be seen with a microscope
68
Where could the source of blood in the urine be?
Anywhere in the urinary tract from the glomerular basement membrane to the urethra
69
What does protein +/- blood in the urine indicate?
Glomerular disease
70
What is a cast in the urine?
In the tubules leakage of proteins and blood cells forms a cast the width and shape of the tubule
71
What are urine electrolytes and osmolality useful for?
* confirming kidneys responding to reduced sensed intravascular volume ([Na] <20mmol/L, osmolality much higher than plasma osmolality)
* Identifying if plasma electrolyte disturbance is due to kidney tubular dysfunction
* Working out the cause of some acid disorders
* Identifying a stone-forming tendency
72
How can we tell when the kidneys aren't working?
- Low eGFR - <60ml/min
| - Rise in serum creatinine within the eGFR>ml/mini range
73
How is kidney injury/disease defined?
Reduced eGFR and detection and quantification of urine protein +/- blood
74
How is the aetiology of kidney injury/disease identified?
a combination of history, examination and investigation
75
What is the difference between acute and chronic?
Acute is over a couple of weeks and chronic is over a long period of time
76
What are examples of causes of AKI or CKD?
- Ineffective blood supply (reduced effective plasma volume or narrowed renal arteries)
- Glomerular diseases
- Tubulo-interstitial diseases
- obstructive uropathy
77
What is a warning of impending acute tubular necrosis?
Oliguria (low urine output)
78
What is the classification scale of CKD?
Stage 1 - Kidney damage with normal or increased GFR
Stage 2 - kidney damage with mildly impaired GFR
Stage 3 - Moderately impaired GFR
Stage 4 - severely impaired GFR
Stage 5 - Established renal failure
79
What are the causes of AKI/CKD best thought of?
Pre-renal
Obstructive
Renal parenchymal
80
What is a key treatment in oliguria?
IV saline
81
What are patients with CKD at risk of?
- Progressive deterioration in kidney function
| - CV disease
82
What is X-ray good for imaging in terms of the kidney?
Useful for radio-opaque stones
83
What is ultrasound used for in terms of the kidney?
- kidney size
- Kidney shape
- Location and number
- Structure
- drainage/ obstruction
- renal blood flow
84
How thick should the cortex of the kidney be?
>1cm
85
Normally what is more echo bright the kidney or liver?
Liver
86
What is CT useful for in terms of the kidney?
Trauma, stones, tumours, infection
87
What is non-contrast CT used for in kidney imaging?
Information of renal stones - location +/- type
88
What is contrast CT used for in kidney imaging?
Information on arteries/ veins/ perfusion/ neighbouring structures/ excretion of contrast
89
What is MRI used for in kidney imaging?
Useful for soft tissue pathology: tumour, infection
May be used in the assessment of:
- renal structure (cysts/ tumours)
- Renal vasculature (MRA)
90
What is isotope scanning used for in kidney imaging?
- structure
- perfusion
- excretion
- differential renal function
91
What causes renal stones?
When there is a lot of solute (calcium, oxalate, urate, cysteine) to not enough solution (filtrate/ urine)
92
What is a kidney stone / renal calculus/ nephrolithiasis?
A solid concentration of crystal aggregation formed within the urinary space
93
How can kidney stones be classified?
By location or by composition
94
How are kidney stones classified by location?
Kidney/nephrolithiasis
Ureter/ ureterolithiasis
Bladder / cystolithiasis
95
How are kidney stones classified by composition?
Calcium - phosphate/ calcium oxalate
| Urate/cysteine/struvite etc.
96
What are the risk factors for kidney stones?
- Genetic factors
• Male
• 50% have genetic component
• Positive family history = RR 2.5
- Environmental factors – EPIC data n=65,000 UK)
• BMI >27 (RR 2.0) / immobile or sedentary/ dehydration/ UTI
• Vegetarian (RR 0.5)
• High fruit (RR 0.6)
• High fibre (RR 0.6)
- Rise in obesity + metabolic syndrome (DM/HBP) have cause an increase in uric acid stones
97
What are the different compositions of renal stones?
```
- Calcium containing (80%)
• Calcium oxalate
• Calcium phosphate
- Magnesium ammonium phosphate – struvite (5-10%)
- Uric acid (5-10%)
- Cystine (1-2%)
- Mixed stones
```
98
How is a patient with kidney stones evaluated?
- History
• Renal colic/ passage of stones/ haematuria/ infection
• Family history
• Diet
- Examination
• Flank tenderness/ signs of infection/ urinalysis
• Obesity/ hypertension/ gouty tophi
• Diabetes mellitus
- Investigations
• Imaging
• Serum and urine biochemistry
99
What is the treatment for stones in the kidney?
- < 2 cm – expectant management or offer extracorporeal shock wave lithotripsy
NB. asymptomatic stone >5mm in the healthy will cause symptoms in 77%
- > 2cm or multiple stones – expectant management or percutaneous ultrasonic lithotripsy
- Large branched stones “staghorn” may require percutaneous ultrasonic lithotripsy and extracorporeal shock wave lithotripsy .
- Cystine stones percutaneous ultrasonic lithotripsy or open nephrolithotomy
100
What is the treatment for stones in the ureter?
- Small ureteral stones with good chance of passage (<7 mms)
• allow time to pass (2-4 weeks)
• lower ureter- ureteroscopy stone removal
• mid-upper ureter extracorporeal shock wave lithotripsy
-Large ureteral stones (>7mms)
• extracorporeal shock wave lithotripsy
• ureteroscopic stone fragmentation
• open surgery
101
What are ureteral stents used to accomplish?
- drain obstructed kidney thereby alleviating pain
- dilate ureter perhaps facilitate passage of stone
- facilitate performance of extracorporeal shock wave lithotripsy and ureteroscopic procedures
102
What is the most important inhibitor of kidney stone formation?
Citrate - can be increased by low Na diet
103
What are the mechanisms of citrate in preventing kidney stone formation?
- Reduces urinary supersaturation of calcium salts by forming soluble complexes with calcium ions and by inhibiting crystal growth and aggregation.
- Increases the activity of some macromolecules in the urine (eg. Tamm-Horsfall protein) that inhibit CaOx aggregation.
- Alkalinising effect which inhibits urate and cystine stones.
104
What are the functions of the kidney?
- Removing metabolic waste from the extracellular fluid
- Controlling the volume of extracellular fluid
- Maintaining optimal concentrations of solutes in the extracellular fluid (Na, K, H, Ca, Mg, Cl, Phos)
- Production of calcitriol and erythropoietin
105
What are the three body fluid compartments?
- Intracellular space
- Interstitial space
- Intravascular space
106
What is the barrier between the intracellular and interstitial spaces?
The cell membrane
107
What is movement across the cell membrane determined by?
Osmotic (oncotic) forces
108
What is osmosis?
the diffusion of water through a semipermeable membrane down its concentration gradient
109
How many ions does the sodium potassium pump move?
3Na+ out 2K+ in
110
What does the action of the sodium potassium pump do?
Increases oncotic pressure outside the cell which is balanced by cell proteins which are more abundant inside the cell
111
What is the barrier between the intravascular space and the interstitial space?
The blood vessel endothelium
112
What is movement between the intravascular and interstitial spaces balanced by?
Hydrostatic and osmotic (oncotic) forces
113
What pushes fluid out of the intravascular spaces?
Hydrostatic forces
114
Which side (venous or arterial) are the hydrostatic forces greater?
Along the capillary the hydrostatic forces are greater on the arterial side
115
What happens to the forces as you move along a capillary to the venous side?
Hydrostatic force decreases and there is more of an osmotic force to drive fluid back in
116
What is the most abundant cation in the extracellular fluid?
Sodium
117
What is the most abundant anion in the extracellular fluid?
Chloride
118
What is the most abundant cation in the intracellular fluid?
Potassium
119
What is osmolality?
osmolarity expressed in kg
120
What happens if water was added into the intravascular space?
it would immediately go into the blood (high osmolality compared to water which has no osmolality) and cause haemolysis
121
What happens when we add water with glucose to the intravascular space?
The glucose will be rapidly metabolised so it is basically the same as adding water without the consequences of adding water
122
What does the isotonic addition of salt and water lead to?
The expansion of the intravascular and interstitial spaces but no change in the intracellular space
123
What factors affect the composition of extracellular fluid?
- Salt intake
- water intake
- salt and water losses
124
What makes up the nephron?
Glomerulus, PCT, loop of Henle, DCT, collecting duct
125
What are the three basic processes that the nephron carries out?
1. glomerular filtration
2. tubular reabsorption
3. Tubular secretion
126
What is glomerular filtration?
filtering of blood into the tubule forming the primitive urine (glomerular filtrate)
127
What is tubular reabsorption?
selective absorption of substances from the tubule back into the blood
128
What is tubular secretion?
secretion of substances from the blood into the tubular fluid
129
What are the three key features of the glomerular filtration barrier?
1. Specialised capillary endothelium
2. Glomerular basement membrane (collagen based)
3. Podocyte foot processes
130
What is specialised about the endothelium in the glomerulus?
It is fenestrated to allow filtration
131
What is the significance of podocytes in the glomerulus?
between each of the foot processes is a specialised protein barrier that the filtrate has to pass through to get into Bowman’s space and into the tubule
132
What can be filtered through the glomerulus?
The glomerular filtration barrier has got sieve properties and is size selective
Only water and small molecules she get through
133
What can't pass through the glomerular filtration barrier?
Albumin and red blood cells
134
What is the normal glomerular filtration rate?
roughly 100ml/min
| this is about 144l/day
135
What lines the PCT?
Tubular cells
136
Where does whatever comes out of the tubule go?
Into the capillary
137
What do the tubular cells of the PCT have on their basal side?
A sodium potassium pump
138
What does the sodium potassium pump on the basal side of the PCT create?
A negative charge within the cell and a concentration gradient where sodium outside the cell is high and sodium inside the cell is low
139
What is found on the luminal side of the tubular cells of the PCT?
Sodium and anion transporters
140
What happens when the Sodium and anion transporters on the luminal side of the tubular cells of the PCT open?
```
Sodium moves into the cell due to the concentration gradient and the negative charge.
An anion (usually chloride) also enters the cell to maintain neutrality
```
141
What happens to sodium after it enters the PCT?
It is driven out by the sodium potassium pump and because it is moving this creates an osmotic gradient and water follows sodium
142
What is the presence and activity of membrane channels in the PCT controlled by?
Systemic and local mediators e.g. angiotensin II, anti-diuretic hormone (ADH), aldosterone and parathyroid hormone (PTH)
143
What cells are present in the DCT?
Intercalated and principle cells
144
What channels are present in the DCT?
Channels that allow the control of potassium and acid in the body
145
What happens when the epithelial sodium channel in the DCT opens up?
Allows the movement of sodium down the concentration gradient creating a negative charge inside the lumen and allows the movement of potassium/hydrogen into the lumen (depending on which of these channels is more open)
146
What happens in the thick ascending loop of Henle?
Filtrate containing sodium, chloride, potassium etc moves upwards.
As the fluid moves up it meets a K2Cl channel
147
What happens when the K2Cl channel is open in the thick ascending loop of Henle?
there is a gradient created by the sodium potassium pump and sodium, chloride and potassium all move into the cell.
Potassium then leaks back down a concentration gradient if the potassium channel is open which creates a positive gradient that means the calcium and magnesium can move between the cells down the concentration gradient back into circulation
148
How much of all sodium and chloride ions are reabsorbed in the PCT?
Roughly 70%
149
Where are nearly all amino acids and glucose reabsorbed?
PCT
150
What would happen if there was no system for concentrating urine relative to plasma?
There would be no way of dealing with salt/water depletion
151
What would happen if there was no system for diluting urine relative to plasma?
There would be no way of dealing with water excess
152
What is responsible for varying the concentration of urine?
The kidneys - they are therefore responsible for keeping plasma osmolality within homeostatic limits
153
Where does concentration of urine occur?
The loop of Henle
154
What happens if the body senses reduced volume of urine, increased serum osmolality or a high stress situation?
ADH is released from the hypothalamus
155
What does ADH do?
- Increases water reabsorption
- Causes vasoconstriction
- increases thirst
156
How does ADH exert its effects?
aquaporins are present on the collecting duct and are opened up so that water can move down the concentration gradient so that the urine will be more concentrated relative to the plasma (water and salt concentration)
157
What is the thick ascending loop of Henle impermeable to?
Water
158
What does the thick ascending loop of Henle transport?
Actively transports sodium, potassium and chloride
159
What is the descending limb of the loop of Henle permeable to?
Freely permeable to salt and water
160
What are baroreceptors?
Pressure receptors that are present in the carotid sinus, aortic arch and cardiac chambers
161
What do baroreceptors detect?
Changes in volume or pressure and relay them to the brainstem
162
What happens if baroreceptors detect reduced sensed volume?
They react by increasing sympathetic stimulation
163
What is the macula densa?
a group of specialised cells (part of the juxtaglomerular apparatus) that detect reduced tubular flow
164
What happens if the macula densa detect increased tubular flow?
They can produce adenosine which causes local constriction of the afferent arterioles
165
What happens if the macula densa detect reduced tubular flow?
The granular cells produce renin which activates the RAA system which results in production of angiotensin II
166
What are the effects of angiotensin II?
- Increased sodium reabsorption in the PCT
- Constriction of the efferent arteriole
- Acts on the adrenal gland to produce aldosterone which acts on the DCT to increase sodium reabsorption in exchange for potassium which conserves fluid
167
What is pressure natriuresis?
A way of resolving increased volume.
Baroreceptors detect changes and respond by causing the sympathetic nervous system to relax alongside release of natriuretic peptides (incl. atrial natriuretic peptide and brain natriuretic peptide)
These respond to increased sensed volume with the opposite effects of Angiotensin II
168
How is extracellular fluid calcium concentration maintained?
Interaction between:
- Sensing tissue (parathyroid gland) - have calcium sensing receptors
- Calciotropic hormones - PTH, hydroxylated vitamin D
- Effector tissues - kidney, intestine, bone
169
What is the consequence of the failure of the kidney to excrete small solute?
Increased plasma concentration of these (e.g. urea, creatinine)
170
What is the consequence of the kidney failing to excrete drugs?
drug toxicity
171
What is the consequence of the kidney failing to manage salt and water balance?
Extracellular fluid overload or depletion
172
What is the consequence of the kidney failing to manage blood pressure?
Hypertension
173
What is the consequence of the kidney failing to manage electrolyte balance?
Hyperkalaemia, hypokalaemia etc.
174
What is the consequence of the kidney failing to manage acid base balance?
Metabolic acidosis
175
What is the consequence of the kidney failing to produce erythropoietin?
Anaemia
176
What is the consequence of the kidney failing to manage vitamin D activation?
Hypocalcaemia and secondary hyperparathyroidism
177
What is the unit measure of kidney function?
Total glomerular filtration rate (GFR)
178
What is clearance?
Clearance = number of particles urine ÷ [particles] plasma
179
What is the gold standard for measuring GFR?
Inulin (not insulin)
180
Why is inulin the gold standard for measuring GFR?
It is freely filtered by the glomerulus and neither re-absorbed nor secreted by the tubule.
181
What is creatinine?
A normal product of muscle metabolism with constant daily production.
182
What is the plasma concentration of creatinine dependent on?
Muscle mass and kidney function (and recent protein intake)
183
How is creatinine clearance measured?
```
Timed (usually 24hr) urine collection.
Creatinine clearance (GFR) = (urine volume x [creat]urine ÷ [creat]plasma) /1440
```
184
When is creatinine clearance/GFR an accurate measure?
Only accurate as an estimate of kidney function in 'steady state'
185
What is eGFR?
Can be thought of as an estimate of GFR assuming average muscle mass for age, sex and race
186
When is eGFR not accurate?
- >60ml/min
| - under 18 years of age (paediatricians use different formula)
187
What is normal GFR?
approximately 100ml/min/1.73m2
188
Why is creatinine clearance a good estimate of GFR?
Because creatinine is produced at a constant rate, is (almost) fully filtered at the glomerulus and is neither reabsorbed or secreted (a wee bit) in the tubule
189
What does eGFR of <60ml/min/1.73m2 mean?
Reduced kidney function (adults)
190
What is the definition of transplant?
Transfer of living tissue or organ to another part of the body or to another body
191
What is Autologous transplant?
The donor and recipient are the same individual
192
What is allogenic transplant?
donor and recipient are not genetically identical but are from the same species (related and unrelated donors)
193
What is Syngeneic transplant?
donor and recipient are genetically identical twins
194
What is xenogeneic transplant?
Donor and recipient are from different species
195
In allogenic transplant what can be given by living donors?
- Haematopoietic stem cells
- Kidney
- Liver lobe
- lung lobe
196
In allogenic transplant what can be given by deceased donors?
- Kidney
- Liver
- Pancreas
- Heart
- Lung
- Cornea
- Other tissues
197
Why are there no graft survival rates for heart, lung and liver?
Because if these fail then the patient will die
198
What are taken into account when deciding who should get an organ for transplantation?
Clinical need, waiting time and compatibility
199
Why is it harder for patients who are blood group O to find organs?
They can only receive from other O people
200
What are the compatible donors for patients in blood group A?
A and O
201
What are the compatible donors for patients in blood group B?
B and O
202
What are the compatible donors for patients in blood group AB?
O, A, B, AB
203
What are the compatible donors for patients in blood group O?
O
204
What is hyper acute rejection of a transplanted organ?
Occurs immediately after connection of the blood vessels
205
How can hyper acute rejection of a transplanted organ be overcome?
It can be prospectively overcome using immunoadsorption, plasma exchange, immunosuppression (limited to living donors- as it can be planned in advance)
206
What is the major histocompatibility complex?
Defined as group of genes present in vertebrate species which are associated with the acceptance and rejection of transplanted material from genetically different donors.
207
Which chromosome is Human Major Histocompatibility Complex (MHC) located on?
Chromosome 6
208
What do HLA class I proteins do?
Bind peptides that are derived from intracellular proteins including peptides derived from viruses
209
How are HLA class I proteins made?
1. Peptides are derived from proteolytic degradation by the immunoproteasome
2. Peptides are transported via the transporter associated with antigen processing (TAP) heterodimer from the cytoplasm to the lumen of the endoplastic reticulum (ER).
3. The MHC molecule is associated with TAP on the luminal side of the ER by accessory molecules including tapasin.
4. Once the MHC peptide complex is assembles it is transported via the golgi to the cell surface where it can interact with receptors on the surface of CD8+ T-cells.
210
How are HLA class II proteins made?
1. HLA Class II proteins are assembled partially within the ER. The α and β chains join together in association with the invariant chain which stabilises the class II molecule and stops peptides from binding to the peptide binding grove while the molecule is in the ER.
2. The HLA class II protein is then transported via the golgi to MIIC vesicles where HLA-DM aids association of antigenic peptides
3. derived from proteolytic degradation of extracellular proteins, to the class II molecule.
4. The Class II protein is transported to the cell surface when an optimum peptide has bound to the peptide binding groove where it can be recognised by receptors on CD4+ T-cells
211
What do HLA class II proteins bind?
peptides derived from extracellular and cell surface proteins including peptides derived from bacteria
212
What do HLA class I proteins bind?
peptides derived from intracellular proteins including peptides derived from viruses
213
What are the different class I HLA molecules?
HLA - A, - B, - C
214
Where are class I HLA molecules expressed?
Virtually all cells including platelets
215
What are the different class II HLA molecules?
HLA-DR, - DQ, -DP
216
Where are class II HLA molecules expressed?
more restricted expression than class I :
- surfaces of antigen presenting cells (dendritic cells, B-cells, macrophages)
- activated T-cells
- other activated / disturbed cells (marker of when they are activated
217
Why are there multiple different types of class I and class II molecules?
- Structural differences affecting peptide binding
- May be other (more specialised) roles for these molecules
- Increases chances that an individual will possess an HLA molecule that will allow initiation of an immune response against a pathogen
218
Why is HLA polymorphism an advantage to the species?
for protection against different pathogens
219
Why is HLA polymorphism a disadvantage?
for transplantation of tissue and organs between HLA incompatible individuals
220
How can mismatches be used for transplantation?
Using immunosuppression
221
What matching takes place for kidney transplantation?
Aim to match HLA-A,B, DR low resolution (to maximise use of available organs)
Avoid transplant in the presence of 'donor specific antibody'
222
What matching takes place for liver transplantation?
HLA matching is not performed as the liver doesn't seem to suffer from acute rejection (immunoprivileged
223
What matching takes place for cardiothoracic transplantation?
HLA matching recognized as important but not performed due to logistics
Avoid transplant in presence of ‘donor specific antibody’
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Which routes can patients make antibodies against non-self HLA via?
- Pregnancy
- Blood transfusion
- Previous transplant
- Viral infection
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What happens if an incompatible organ is transplanted?
Pre-formed allo-reactive antibodies target and attack the transplanted organ and blood vessels resulting in rejection
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When does hyper acute rejection happen?
Minutes/ hours after surgery - it should not happen as it means Patient has pre-formed complement fixing donor reactive antibodies.
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What does hyper acute rejection result in?
Prevention of vascularisation of the graft - irreversible damage from ischaemia
228
What causes acute rejection?
Immune mediated: T-cells (cellular) and B-cells (antibodies)
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How is acute rejection treated?
With modulation of immunosuppression
230
What does acute rejection provide a risk of?
Chronic allograft nephropathy
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What is chronic allograft nephropathy?
Indolent but progressive form of primarily immunological injury to graft, more slowly compromises organ function than acute rejection
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What does the current organ allocation system aim to match?
Aims to match graft life expectancy with patient life expectancy
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What puts patients on tier A for receiving an organ?
- Patients with a matchability score of 10 OR
- Patients with 100% calculated reaction frequency OR
- Patients who have accrued 7 years of waiting time
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What patients are on tier B for receiving an organ?
All patients that aren't on tier A
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What is matchability in terms of organ transplantation?
how easy it will be to find a HLA matched donor (1-10 easy-hard) – patients with a score of 10, if a organ comes through that is suitable they are much more likely to get this organ
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What is reaction frequency in terms of organ transplantation?
Defines presence of HLA antibodies in patient 0% = none, 100% = antibodies present that react with multiple HLA mismatches
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How are people ranked/ prioritised in tier B for organ transplantation?
According to a points based system based on 8 elements:
- Waiting time from earliest of start of dialysis or activation on the list
- Donor-recipient risk index combinations
- HLA match and age combined
- Location of patient relative to donor
- Matchability
- Donor-recipient age difference
- Total HLA mismatch
- Blood group match
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What are important tests to perform prior to transplant?
- HLA type patient
- HLA type donor
- Screen patient for presence of preformed HLA alloantibodies (evert three months when patient is on transplant list)
- Crossmatch patient and donor prior to transplant to ensure negative result
