1
Q
Describe the anatomy of the bladder:
A
- embryologically derived from hindgut
- separated from pelvic bones by the fatty retropubic space
- all bladder is extraperitoneal except neck
- ligaments hold the bladder neck in place:
1) pubovesicle ligament (bladder neck -> posterior surface of the pubis bone)
2) median umbilical ligament (bladder -> umbilicus)
3) puboprostatic ligament (in males, from prostate to posterior surface of pubis bone) - temporarily stores urine and has rugae allowing it to expand and hold up to 600ml
- the musculature and sphincters help in urine expulsion
- urine enters bladder via L/R ureters and exits via urethra
- the three orifices mark the trigone region on the fundus of the bladder where there is no rugae
- the three orifices are surrounded by rings of detrussor muscle and tighten when bladder contracts to prevent urine backflow
- Bladder wall has 3 smooth muscle layers running in different directions to provide strength
-> outer adventitial coat
-> outer longitudinal layer
-> outer circular layer
-> inner longitudinal layer (spiral layer) - inner lining of bladder is transitional epithelium
- epithelium is stratified and can have 3-6 cell layers depending on distension
- there are umbrella/dome cells on epithelium surface allowing the epithelium to remain impermeable to urine when fully stretched and also prevents fluid entering the bladder when it is hypotonic
BLOOD SUPPLY: - internal iliac artery mainly and also obturator and inferior gluteal arteries
-> additionally in females = uterine and vaginal arteries
-> additionally in males = interior vesicle artery - internal iliac veins
LYMPH: drains into common iliac lymph nodes
2
Q
What are the ureters made of?
A
smooth muscle
3
Q
Describe the anatomy of the urinary sphincters:
A
Internal urethral sphincter - smooth muscle
External urethral sphincter - skeletal muscle
-> has intramural striated muscle and periurethral striated muscle fibres
-> intramural fibres are slow twitch, periurethral fibres are a mix of slow and fast twitch fibres
4
Q
Describe the nerve supply to the bladder:
A
- afferent fibres are found in bladder wall and send signals to the CNS via PELVIC NERVE when the bladder is full and urination is required
- efferent fibres arriving the bladder are complex:
- hypogastric nerve (releases NA) provides sympathetic supply and binds to B3 receptors on detrusor relaxing it, and to a1 receptors on internal sphincter contracting it. For pain, touch and temperature
- pudendal nerve supplies somatic innervation to the bladder and releases ACh binding to the nicotinic receptors on the external sphincter causing it to contract.
- pelvic nerve releases ACh and binds to M3 receptor on detrusor causing it to contract.
5
Q
How does micturition take place?
A
150-250ml = first desire to urinate, 300-350ml = greater urgency and pressure increases more intensely from here.
FILLING:
- Afferent pelvic nerve fibres sends info about bladder stretch to the sacral region of spinal cord (slow impulses sent)
- Hypogastric nerve stimulated -> releases NA -> B3 - detrusor relaxes, alpha 1 - internal sphincter contracts
- Pudendal nerve stimulated -> releases ACh -> nicotinic receptor - external sphincter contracts
FULL BLADDER:
- Afferent pelvic nerve sends faster signals to sacral region of spinal cord.
- Pelvic nerve stimulated -> releases ACh -> M3 - detrusor contracts
- Hypogastric nerve inhibited -> no NA -> detrusor contracts and internal sphincter relaxes
- Pudendal nerve inhibited -> no ACh -> external sphincter relaxes.
6
Q
Describe the higher control over micturition involving the brain:
A
Micturition is a spinal reflex but there is higher control over the process from the brain.
Signals sent to the sacral region are detected by the pontine micturition centre in the brain, and then the pons sends signals down to the ONUF’s nucleus in the sacral region via axons.
ONUF’s nucleus allows stimulation of the nerves in the sacral region when it is socially convenient to urinate.
7
Q
How does the RAAS system work?
A
- Renin is made in kidney and stored in cytoplasmic granules in cells of JGA.
- Renin released when there is decreased pressure in the afferent arteriole or if the macula densa detect low osmolarity in the DCT
- angiotensinogen is made in the liver and converted to AT1 by renin
- AT1 is inactive and is converted into AT2 by ACT which is found in vascular endothelium of lungs
- AT2 has various effects:
- > vasoconstriction of afferent arteriole
- > contraction of mesangial cells reducing filtration SA
- > aldosterone production
- aldosterone is produced by the zona glomerulosa of adrenal cortex and causes more Na and H2O retention
8
Q
What is hydronephrosis and how does it arise?
A
- condition where one/both kidneys become swollen and ureters stretched and renal pelvis dilated due to build up of urine inside them
- if left untreated in severe cases the kidneys can become scarred -> kidney failure
Causes:
- ureter blockage
- urine backflow from bladder -> kidneys
- blockage in urethra so urine cannot leave bladder
- Benign Prostatic Hyperplasia (BPH)
9
Q
How is hydronephrosis treated?
A
- use catheter to drain out the built-up urine
- is kidney stone is present remove
- treat enlarged prostate with medication or TURP
- is there is a cancer treat with radio/chemotherapy
- antibiotics used to treat UTI
- alpha blockers used for smooth muscle relaxation
10
Q
What are the effects of back pressure on the kidneys?
A
- reduced renal blood flow
- reduced GFR
- increased RAAS system activation
- renal tubules may undergo atrophy and fibrosis of interstitial spaces may occur as macrophages infiltrate = CKD eventually and then renal failure
11
Q
Name pre-renal causes of chronic kidney disease:
A
- hypovolaemia
- reduced vascular filling
- heart failure and reduced renal perfusion
12
Q
Name renal causes of chronic kidney disease:
A
- acute tubular necrosis due to drugs, stones etc.
13
Q
Name post-renal causes of chronic kidney disease:
A
- ureter or urethral obstruction
14
Q
What biochemical changes occur in the blood when there is reduced glomerular function?
A
- increased serum urea (kidneys cannot excrete the nitrogenous waste)
- increased serum creatinine (reduced GFR means reduced removal of creatinine from the body)
- hyponatraemia (reduced kidney function means Na cannot be reabsorbed out of the tubule and into the blood)
- hyperkalaemia (reduced kidney function means K cannot be excreted from the body in the urine and more remains in the blood)
- loss of HCO3- (as the tubular cells make HCO3 but this can not get reabsorbed back into the blood)
- increased H+ (as there is less HCO3 in the blood to neutralise it)
15
Q
How is acid base balance normally controlled?
A
- tubular epithelial cell makes H+ and HCO3-
- the HCO3- moves into the interstitium and then is absorbed into the blood
- the H+ is excreted into the tubule lumen and combined with filtered HCO3 and forming H2O and CO2
- there is not net change in [HCO3] in the plasma
16
Q
What happens chemically in acidosis at kidney level?
A
- not enough HCO3- in the kidney lumen to neutralise the H+ that is formed, so a non-bicarbonate buffer is used
1) PHOSPHATE - H+ and HCO3- are formed in the tubular cell and H+ released into tubule lumen
- combines with phosphate that has been filtered and forms H2PO4 which is then excreted in the urine
- there is still a HCO3- formed which is released into the interstitium and then into the blood, and so there is a net gain of a HCO3 and alkalinisation of the acidic plasma
2) AMMONIUM
- glutamine can be taken up by tubular epithelial cells and metabolised forming NH4+ and HCO3-
- the NH4+ is then excreted into tubule lumen and excreted out of the body in the urine
- the HCO3- is added to the blood and there is a net gain of a HCO3- and the plasma is alkalinised
17
Q
What happens chemically in alkalosis at kidney level?
A
- rate of H+ secretion into the kidney tubule lumen is insufficient to neutralise all the HCO3- released, so HCO3- is lost in the urine and HCO3- made by the tubular epithelial cell keeps getting added to the blood
- to compensate:
- > little/no excretion of non-bicarbonate buffers e.g. PO4-
- > glutamine and ammonium metabolism is decreased
18
Q
Describe the biochemical status of respiratory/metabolic alkalosis and acidosis:
A
R. alkalosis: low H, low HCO3, low CO2
R. acidosis: high H, high HCO3, high CO2
M. alkalosis: low H, high HCO3, high CO2
M. acidosis: high H, low HCO3 and low CO2
19
Q
Describe what happens in respiratory alkalosis:
A
- low H in plasma
- your body wants to increase H levels and so the kidneys which are working fine produce LESS HCO3 so that less H is neutralised and H levels in the body increase
- your body wants you to keep more air in the body so that there is more acidic CO2 gas to increase the H+ plasma concentration, but you have a respiratory issue and cannot and so you hyperventilate and CO2 is lost
20
Q
Describe what happens in metabolic acidosis:
A
- H levels are high
- lungs are working fine so they get rid of acidic CO2 from the body by hyperventilation
- your kidneys are not functioning properly and they want to increase HCO3 to neutralise the H but they cannot and so HCO3 decreases
21
Q
Describe what happens in metabolic alkalosis:
A
- H levels are low
- lungs are working fine so they keep more acidic CO2 in the body by hypoventilation
- your kidneys are not functioning properly and they want to decrease HCO3 production to prevent H getting neutralised but they cannot and so HCO3 increases worsening the alkalosis
22
Q
How would you identify the cause of chronic kidney disease?
A
- serum creatinine raised
- urinalysis (proteinuria and haematuria)
- US to look at size of kidney, any obvious blockages
- eGFR < 60ml/min/1.73m2
- renal biopsy
- X-rays
- CT
- MRI’s
23
Q
Describe how the kidney handles drugs and what can go wrong:
A
- drugs are excreted by glomerular filtration and only drugs that are unbound are removed
- no many lipid soluble drugs are excreted as they are passively reabsorbed by diffusion across the tubule into the blood
- impaired renal function = altered pharmacokinetics, drug effect may be weakened or strengthened, altered half-life of drugs can be damaging
24
Q
What is gentamycin and how can it damage the kidney?
A
- an antibiotic
- nearly all renally excreted
- main site of toxicity in the PCT
- can cause AKI
25
What are the ideal drug characteristics of a drug to prevent kidney damage?
- mainly hepatic and biliary handling
- not renally excreted
- no active metabolites
- wide therapeutic margin
- protein and fluid balance changes should not alter the drug deposition
26
What are diuretics and why are they used?
Drugs that increase water and salt removal from the body - therefore they lower BP
27
What are the 5 main classes of diuretics?
```
1 - Loop diuretics
2 - Thiazides
3 - Aldosterone antagonists
4 - Other K-sparing diuretics
5 - Osmotic diuretics
```
28
How do loop diuretics work and give an example?
Furosemide, bumetanide
- are the most powerful causing excretion of 15-25% of filtered Na
- they act on thick ascending limb
- combine with Cl binding site of NKCC2 pump and lower its activity
- increase Na delivery to the distal nephron so more Na is lost is urine and therefore more water is also lost
29
How do thiazides work and give an example?
Bendroflumethiazide
- are less powerful than loop diuretics
- act in DCT on ENaC channels by binding to the Cl binding site and inhibiting the action of the channel
- more Na loss and therefore more H2O loss
- also reduce Ca excretion so are beneficial for people with osteoporosis
- as Na is lost, RAAS system is activated and aldosterone is released
- used clinically for hypertension, mild heart failure, oedema
- UNWANTED EFFECTS: increased urinary frequency, erectile dysfunction, impaired glucose tolerance due to activation of K-ATP channels in pancreatic B cells and inhibition of insulin secretion
30
How do aldosterone antagonists work and give an example?
Spironolactone
- acts on the Na-K exchange ATP pump in the DCT
- limited action as only 2% of Na reabsorbed here
- competes with aldosterone for its binding site and inhibits distal Na retention (as aldosterone normally increases the activity of the Na-K ATP pumps to cause more Na retention in the body so that more water is retained and BP increases)
31
How do K-sparing (other than aldosterone antagonists) work and give an example?
Amiloride
- block luminal Na channels in the collecting ducts and tubules preventing Na reabsorption so Na and water are lost
- again, like spironolactone, they have limited diuretic efficacy
32
How do osmotic diuretics work and give an example?
Mannitol
- act indirectly by modifying the content of glomerular filtrate
- they are filtered at the glomerulus and are not reabsorbed by the nephron
- they cause diuresis by increasing the osmolarity of tubular fluid and so water is kept in the tubule lumen
- they work on the parts of the nephron that are freely-permeable to water (PCT, descending LOH and CD in presence of ADH)
- as there is a non-reabsorpable solute in the lumen it means more H2O is excreted from the body with only a small Na loss
33
What mechanisms are involved in excretion of drugs at different areas of the kidney tubule?
- the bowman's capsule filters all drugs of low molecular weight into the tubule but drugs that have a large MW or are bound to proteins may not get through
- in the PCT tubular secretion may occur
- in the LOH there is concentration of urine
- in the CD water soluble drugs may be reabsorbed into the blood
34
What happens in an aspirin overdose and what do you do to treat it?
- after aspirin overdose there is too much salicylic acid in the body
- by adding HCO3 to the body the urine will become more alkaline and therefore H+ ions will be used up to neutralise the HCO3
- this will result in less salicylic acid being in the body
35
Name some drugs that are excreted in the urine that are largely unchanged by the kidneys:
- loop diuretics (furosemide, bumetanide)
- penicillins
- digoxin
- lithium
36
Name two acidic drugs:
loop diuretics
| penicillins
37
Name two basic drugs:
amiloride
| ethambutol (an antibiotic)
38
How can impaired kidney function alter drug metabolism and clearance?
- impaired absorption and elimination can alter the pharmacokinetics
- drug affect worsened or weakened
- enhanced adverse effects
- increased tissue sensitivity
- altered half life of drug alters its potency and may be damaging
39
What dose adjustments are necessary in patients with compromised kidneys?
1) modify the drug dose
2) alter the loading dose
3) monitor drug concentrations closely
4) always consider when prescribing drugs if the patient has compromised renal function/kidney disease/dysfunction
40
What is the cockcroft gault (CG) formula?
Used to calculate creatinine clearance from serum creatinine levels
41
What is nephrotoxicity?
Can be described as uraemia = urea in the blood due to kidney dysfunction.
It can lead to altered pharmacokinetics due to increased urea in the blood which can cause vomiting (altering absorption), altered metabolism, and altered protein binding and altered drug distribution.
42
Why is the kidney vulnerable to the toxic effects of drugs?
- large blood flow
- drugs and metabolites concentrate in the renal medulla
- drugs are concentrated within tubular cells
43
Where is the internal sphincter found in males?
- it is pre-prostatic and and found at the bladder neck
44
What is the gaiting theory of bladder control?
The post-ganglionic parasympathetic pelvic nerves are 'protected' from afferent input until a threshold is reached when the bladder is full and you need to urinate.
- pelvic afferent fibres are constantly signalling to the pelvic spinal cord region (S2-4) but only when a high enough rate of firing occurs is the bladder made to contract
45
Describe anatomy of the pontine micturition centre:
- also called Barrington's nucleus
- in dorsolateral region of pons
- receives projections from the cerebrum, cerebellum and brainstem
- sends axons down in lateral columns to the sacral micturition centre and once urine storage is at a critical level the PMC triggers the urge to urinate
46
What is the physiology behind detrusor smooth muscle contraction?
- involves a neuromuscular junction
- ACh is released and binds to G-protein coupled receptor
- membrane depolarises and Ca influx occurs as voltage gated Ca channels open
47
What neurological conditions can affect bladder function?
- spinal cord injury
- multiple sclerosis
- neuropathic detrusor hyper-reflexia (e.g. in patients with spina bifida)
- Parkinson's disease
48
What is detrusor hyper-reflexia and how is it treated?
- bladder overactivity in a patient with an underlying neurological condition like MS or Parkinson's where the detrusor muscle is contracted all the time.
- treat with anticholinergics (pelvic nerve cannot release ACh onto M3 receptor on detrusor wall causing it to contract)
49
What is autonomic dysreflexia?
- spinal cord injury to T6 or above
- exaggerated sympathetic activity in response to as stimulus below the level of the spinal cord injury
- increased BP, HR and sweating
- redness above lesion and paleness below the lesion
50
What is spinal shock?
- period of low muscle excitability below the area of the spinal cord injury
- absent reflexes and flaccid muscles that are paralysed
- bladder is not controlled and so overfills and patient is incontinent
- patient must be catheterised
51
Describe chronic urine retention and its categories:
- permanent holding of urine in the bladder that is not removed
- if retention is ~300ml then retention is painless
- chronic retention can be:
- > high pressure (HPCR) where the residual volume remains at a higher pressure than the intra-abdominal pressure after micturition
- > low pressure (LPCR) where the residual volume is not at higher pressure than abdominal cavity but is associated with hydronephrosis
52
What is post-obstructive diuresis?
- when someone has had a urinary obstruction and you catheterise them, and then they start to produce dilute urine due to the sudden relief
- it can take up to 3 months for the kidneys to normalise
- ANP (atrial natriuretic peptide) is thought to be increased which causes afferent arteriole dilation and increases Na excretion and decreases renin levels so that you RETAIN WATER
53
What is a transplant?
The transfer of living tissue or an organ to another part of the body or to another body
54
What is an autologous transplant?
Donor and recipient are the same individual
55
What is a syngeneic transplant?
When donor and recipient are genetically identical e.g. identical twins, triplets etc.
56
What is an allogenic transplant?
When donor and recipient are from the same species but are not genetically identical
57
What is a xenogenic transplant?
When the donor and recipient are from different species
58
How are decisions about who receives a transplant made?
- NHS blood and transplant system is used
- ensures equity of access irrelevant of geographical access
- clinical need, waiting time and compatibility are all taken into account
59
How are blood groups used to determine compatibility?
Blood groups can be A, B, AB or O
- If a recipient is O they can only receive a donation from someone of blood group O
- If the donor is blood group O, they can donate to ANY INDIVIDUAL
- NHS have a rule that only O recipients receive O donors to prevent O recipients being disadvantaged
60
What is a hyper-acute rejection and how can it be overcome?
Immune system of recipient quickly rejects the donor tissue that has been put in
- antibodies target and attack transplanted organ and its blood vessels
- in hyperacute reaction the organ is transplanted immediately
- these reactions happen VERY RARELY
- the antibodies that cause the rejection are usually PREFORMED and to avoid this reaction a lot of screening and planning occur
To overcome:
- > immunoadsorption (blood purification technique to eliminate pathogenic antibodies)
- > plasma exchange (blood transfusion)
- > immunosuppression (only carried out with recipients of living donors)
61
What is the major histocompatibility complex?
- The MHC contains our HLA genes
- A group of genes present in vertebrate species that are associated with the acceptance / rejection of transplanted material from genetically different donors
- the MHC group of genes are found on short arm of chromosome 6 and contain our HLA genes
62
What are the 6 HLA genes that are important in transplantation?
HLA - A, B C
| HLA - DR, DQ, DP
63
Describe the class 1 HLA genes:
- HLA A, B or C
- HLA class 1 molecules consist of a single polypeptide chain (an alpha chain) that interacts with a beta 2 microglobulin
64
What is an exon?
A gene that codes for the production of an RNA molecule
65
Describe the class 2 HLA genes:
- HLA DR, DQ, DP
- consist of two single polypeptide chains that cross the cell surface membrane
- one of the chains is an alpha chain and the other is a beta chain
66
How are class 1 HLA genes derived?
- intracellular proteins are degraded by proteolytic degradation by the immunoproteaome which is in dendritic cells (APC cells)
- proteins are actively transported into the lumen of ER of APC
- proteins become associated with HLA type 1 proteins
- class 1 protein complex is then formed which is carried to APC surface and exposed to circulating T cells
- the T cells are helper cells (CD8) and react to the class 1 protein molecules
67
How are class 2 HLA genes derived?
- just like the HLA class 1 proteins, intracellular proteins are degraded by the immunoproteaome in APC cells and then proteins are then actively transported into the lumen of the ER of the APC
- this time the proteins become associated with HLA type 2 proteins
- the class 2 protein complex is then transported out of the APC in MHC2 vesicles
- the MHC2 vesicles are transported to the surface of T cells and there they are recognised by CD4 T cytotoxic killer cells
68
Describe the expression of HLA molecules:
- class 1 are expressed on virtually all cells including platelets and expression levels vary between tissues
- class 2 molecules have more restricted expression and are found on:
- > APC
- > activated T cells
- > other activated cells
- the surface of an APC has many different HLA molecules expressed on its cell surface and as most humans are heterozygous we will get a mix of HLA types from each parent
69
What is the benefit of having a large variety of HLA molecules being expressed on our APC cells? (i.e. the benefit of HLA polymorphism)
We can mount immune responses to a variety of different pathogens
It is highly unlikely that two individuals will have exactly the same HLA type unless they are identical twins
70
What is the disadvantage of HLA polymorphism?
Hard for transplantation to find compatibility between individuals as HLA types must match to prevent rejection
71
How does an abberent immune response arise in transplantation?
- host T cells interact with donor APC cells leading to T cell activation and an abberent immune response
72
What is alloreactivity?
When an immune response occurs against a transplanted allograft
73
What is involved in making sure a transplant is not rejected?
- HLA types of donor and recipient must be matched as closely as possible
- immunosuppression must be carried out as well as HLA matching
- the liver is immunoprivileged and is not rejected like other organs so HLA matching doesn't need to be carried out
74
How can donor-specific antibodies arise?
- a patient can make antibodies against non-self HLA via
- > pregnancy
- > blood transfusions
- > previous transplant
- > in viral infection
75
How is HLA sensitisation carried out?
- HLA status of recipient is determined prior to transplant
| - serum from patient tested against proteins to see if they have made antibodies against HLA types of prospective donor
76
What is an acute rejection?
When the organ is rejected but more slowly than a hyperacute rejection reaction
77
Describe the cellular stages of a hyperacute rejection reaction:
- activation of complement
- MAC activated (membrane attack complex)
- endothelial damage
- release of pro-inflammatory mediators
- platelet aggregation
- thrombosis
- blood cannot flow from recipient into the donor organ
- IRREVERSIBLE PROCESS
78
What factors are considered when allocating transplants to patients?
1 - paediatrics who are more difficult to find an appropriate transplant for as they are HLA sensitised are given priority (based on waiting times)
2 - other paediatric patients who are not HLA sensitised are then given priority
3 - then adults who are HLA sensitised
4 - then adults who are not HLA sensitised
5 - all other eligible patients
A score is given to rate the patients in categories 3-5 based on waiting time, age, location, blood group, HLA match etc.
79
What are de-novo antibodies?
Antibodies that do not pre-exist in a recipient but that develop following donation and are directed against the foreign graft HLA
80
When testing urine for acidosis, what is special about vegetarians?
Their urine is more alkaline as they eat more foods containing carboxylic acids (a weak base)
81
What does presence of glucose in urine test suggest?
Diabetes
| Renal disease
82
What does presence of bilirubin in urine test suggest?
Liver disease
83
What does presence of ketones in urine test suggest?
Diabetes, body has lack of glucose or poor ability to utilise glucose
84
What does presence of specific gravity in urine test suggest?
- The higher the specific gravity the more dehydrated you are
- It is a measure of how much solute is in the urine
85
What does presence of blood in urine test suggest?
- renal disease
| - menstruation
86
What does presence of acidic pH in urine test suggest?
renal stone
87
What does presence of alkaline pH in urine test suggest?
infection
88
What does presence of protein in urine test suggest?
hypertension, diabetes, liver disease
89
What does presence of urobilinogen in urine test suggest?
liver disease
90
What does presence of nitrite in urine test suggest?
bacterial infection
91
What does presence of leukocyte esterase in urine test suggest?
- esterase is a enzyme made by leukocytes thats presence suggests infection/WBC present in urine
Year 2
flashcards
Decks in class (22)
# Cards
-
Endocrine Week 157
-
Endocrine Week 278
-
Endocrine Week 359
-
Endocrine Week 438
-
Gastrointestinal Week 162
-
Gastrointestinal Week 298
-
Gastrointestinal Week 3101
-
Gastrointestinal Week 472
-
Reproduction Week 1100
-
Renal Week 291
-
Reproduction Week 278
-
Renal Week 182
-
HNN Week 1170
-
HNN Week 2149
-
HNN Week 397
-
HNN Week 4100
-
HNN Week 586
-
HNN Week 646
-
VS - Professionalism13
-
People and illness Week 181
-
People and illness Week 268
-
VS - Right thing to do27
