Renal Week 2 Flashcards
Describe the anatomy of the bladder:
- 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
What are the ureters made of?
smooth muscle
Describe the anatomy of the urinary sphincters:
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
Describe the nerve supply to the bladder:
- 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.
How does micturition take place?
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.
Describe the higher control over micturition involving the brain:
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.
How does the RAAS system work?
- 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
What is hydronephrosis and how does it arise?
- 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)
How is hydronephrosis treated?
- 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
What are the effects of back pressure on the kidneys?
- 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
Name pre-renal causes of chronic kidney disease:
- hypovolaemia
- reduced vascular filling
- heart failure and reduced renal perfusion
Name renal causes of chronic kidney disease:
- acute tubular necrosis due to drugs, stones etc.
Name post-renal causes of chronic kidney disease:
- ureter or urethral obstruction
What biochemical changes occur in the blood when there is reduced glomerular function?
- 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)
How is acid base balance normally controlled?
- 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
What happens chemically in acidosis at kidney level?
- 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
What happens chemically in alkalosis at kidney level?
- 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
Describe the biochemical status of respiratory/metabolic alkalosis and acidosis:
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
Describe what happens in respiratory alkalosis:
- 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
Describe what happens in metabolic acidosis:
- 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
Describe what happens in metabolic alkalosis:
- 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
How would you identify the cause of chronic kidney disease?
- 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
Describe how the kidney handles drugs and what can go wrong:
- 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
What is gentamycin and how can it damage the kidney?
- an antibiotic
- nearly all renally excreted
- main site of toxicity in the PCT
- can cause AKI
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
What are diuretics and why are they used?
Drugs that increase water and salt removal from the body - therefore they lower BP
What are the 5 main classes of diuretics?
1 - Loop diuretics 2 - Thiazides 3 - Aldosterone antagonists 4 - Other K-sparing diuretics 5 - Osmotic diuretics
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
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
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)
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
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
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
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
Name some drugs that are excreted in the urine that are largely unchanged by the kidneys:
- loop diuretics (furosemide, bumetanide)
- penicillins
- digoxin
- lithium
Name two acidic drugs:
loop diuretics
penicillins
