renology and urology - wk 3 Flashcards
(118 cards)
1
Q
functions of the kidney
A
o Filtration of blood o Detoxification o Regulating blood pressure o Regulating blood ph o Regulating haematopoiesis o Making vitamin D
2
Q
what are the 2 things the kidney needs to filter molecules - and brief explanation of each
A
1- A pump
- Aka the heart
- Uses blood pressure from the heart to drive fluid through the filter
- Regulates the pressure by dictating how much of the output pressure of the heart is directed to this job
2- A filter
- “Design” problems
o Need a very fine filter (cut off c. 4nm = 40A, free flow below 18A)
o We need the filter not to clog
o We need to be able to filter lots of fluid in a small-ish space
3
Q
whats the very fine filter in the kidneys called
- whats its structure
A
The slit diaphragm
o Podocytes (in the pic to the right) – meaning foot cells
o Lie over the blood capillary
o Long finger like processes
o At molecular level this is made of nephron proteins
These stick out and stick together to make a large adhesive structure in the middle
o There are pores between nephron molecules
These pores are the spaces through which vv small molecules can go
o Only 3% of the slit diaphragm is actually slit (the hole itself)
o So it’s a major source of resistance to fluid flow
o So need enormous areas of it to get enough flow of proteins through it
o Also need pressure to push fluid through the filter
4
Q
how does kidney restrict blood supply and drain
A
Restrict afferent arteriole
- Blood pressure in capillaries drops
- Filtrate rate drops
Restrict efferent arteriole
- Blood pressure in glomerular capillaries rises
- Filtration rate rises
5
Q
how not to clog the filter
A
Pinocytosis of trapped proteins
- Proteins can become trapped in the pores of the filter
- This can be fixed via pinocytosis
- Similar to phagocytosis but smaller…
o Vesicles of membrane with receptors for proteins
o Grab the proteins and take them into the cell
o Exporting them or degrading them via lysosomes and reusing the protein products
6
Q
what are the layers before the slit diaphragm in the kidney
A
Endothelial cell – Course filter on outside – keeps cells out but let’s proteins in
Cleaned by blood flow and phagocytes
Glomeruli Basement Membrane (GBM) – Finer filter that stops bigger complexes going through and jamming the diaphragm
Renewed by mesangial cells
Then slit diaphragm with pinocytosis to help clean it up
7
Q
describe a renal corpuscle and its purpose
A
- Called a renal corpuscle
o Afferent arteriole carrying blood in
o Then lots of capillaries – glomerular capillaries
o Then unite again in efferent arteriole
Whole thing covered in Bowman’s capsule which captures the filtrate and roots it into a tube
- Massive surface area in a small space
- allows filtration of lots of fluid in a small space
8
Q
how many renal corpuscles are within a kidney and what can alter this amount
A
- Have lots of renal corpuscles in one kidney
- Humans – 50,000 – 1,000,000
- Same variation if nutrient starved during development in the womb
9
Q
typical values of blood an plasma flow and glomerular filtration rate, also how much plasma is removed as filtrate
A
- Blood flow to kidneys – 1,2L / min
- Plasma flow to kidneys – 0.66L/min (assuming normal haematocrit of 0.45)
- Rate of filtration through glomeruli (summed across all) = 0.13L/ min
- > 20% of plasma is removed as filtrate
- Amount of filtration will decline in people with renal problems
10
Q
how to determine the glomerular filtration rate
A
- Creatinine is filtered into the urine and not recovered
o Measure creatinine conc. In blood and urine
o Measure flow rate of urine by measuring the urine production of patient within set number of hours then calculating flow rate per minute
actual amount of creatinine in urine = urine conc. Of creatinine x flow rate of urine
amount of creatinine that got into the urinary space = plasma conc. Of creatine x glomerular filtration rate (GFR)
GFR x plasma conc = urine flow rate x urine conc.
THEREFORE…
GFR = (urine conc. X urine flow rate) / plasma conc. Of creatinine
11
Q
dialysis machine mechanism
A
- Essentially work in the same way as a real kidney
- Contain
o A membrane which is a fine filter
o Blood on one side of the membrane returning to the patient
o Other side of the membrane have a dialysate
A liquid identical to plasma aka full of small molecules but without the toxins
So overall net flow of toxins from blood to dialysate which is then passed away and fresh dialysate is brought in
12
Q
how often do patients need dialysis and whats the prognosis
A
Patients who have renal failure need dialysis every 2-3 days
- Either as above with their blood
- Or with different body fluids and some of the patients own membranes as the filter
Dialysis works but it’s not good long-term usually
- Median life on dialysis <5 years
- This is less than average life expectancy with cancer
13
Q
what makes up a nephron
A
- Renal corpuscle
- Proximal tubule
- Henles loop
- Distal tubule
14
Q
what do the proximal tubules have that the distal tubules don’t and what is unusual about these
A
microvili
In proximal tubules…
- Tight junctions of the epithelial cells are much leakier than other areas of the body
- Allows ions to get past them
15
Q
epithelial structure
A
- Basement membrane around edge
- Single layer of epithelial cells
o Anchored to epithelial membrane
o Polarised - Cell adhesion complexes where lateral and apical domain meet
o Tight and adheren junction - Membrane on the apical side (full of microvilli in the proximal tubules)
16
Q
what molecules do the nephron epithelia have to recover
A
Na+ K+ Ca2+ Mg2+ Cl- HCO3- PO4 2- H2O amino acids glucose proteins
17
Q
what are the general types of transporters/ channels in the proximal tubule to recover things
A
Primary active transporters
- (Na/K ATPase and H ATPase are the only common ones in the plasma membrane)
Solute Carrier Family (SLC) proteins
- ~300 many are co-transporters powered by established conc gradient (eg Na)
- ‘secondary active transport’
Aquaporins (water channels)
Ion Channels
Protein endocytosis receptors
18
Q
how do we change the equilibrium between filtrate and plasma
A
The filtrate and the plasma will be around equilibrium (in context of small molecule/ions we want to recover)
- To move things from filtrate to plasma need to move from equilibrium
- Need to do work (ie move a lot of food towards equilibrium to move solute away from it – 2nd law)
- Need to burn up ATP
o Kidneys are vv highly packed with mitochondria
19
Q
explain primary active transport
A
- Located on basal side of the cell
- Main one is Na/K ATPase
- Inports 2 K and exports 3 Na using ATP
- This activity generates a membrane voltage – basis of electrochemistry in membrane
- Since sodium wants to move back into the cell
o There’s a strong gradient
o This can be used to power the recovery of other things using co-transporters
20
Q
sodium recovery - what transporters are involved
A
Sodium Proton Exchanger – SLC
- For one Na coming back into the cell one proton/H+ is transported out
(distal tubules)
Sodium chloride co-transporter – SLC
- For one Na coming back in one chloride is brought into the cell
(loop of Henle)
Na-K Cl transporter – SLC
- For one Na coming in, 2Cl and one K are brought in
- Electrically neutral
ROMK (renal outer medullary K channel)
- Allow potassium that’s came into the cell back out
- Regulated to allow leakage
21
Q
amino acid recovery
A
- Eg. Na comes in and so does 2Cl and neutral amino acids
- Lots of different variations of these channels to recover all diff. amino acid
22
Q
glucose recovery
A
Mostly SLC5A2 - Na:glucose = 1:1 uptake ratio SLC5A1 - 2:1 ratio This is rate limited! - Because if there’s an excessive amount of glucose in the blood there will be excess amount of glucose in primary filtrate - So cells can’t recover all the glucose - Normally there’s no glucose in urine - when high levels of glucose in blood there’s high level of glucose in urine (it tastes sweet) eg in diabetes mellitus
23
Q
what are the 3 types of organic cation and anion transporters
A
- organic anion transporters (OATs)
- Organic Cation transporters (OCTs)
- Organic cation/ carnitine transporters (OCNTs)
24
Q
- Organic Cation transporters (OCTs)
A
- Usual Na/K ATPase
- For price of sodium coming in a proton goes out = proton gradient
- Antiporter channel uses proton gradient – 1 proton coming in, 1 organic cation goes out
Also active transporter of organic cations
- Such as one that transports chemotherapy out of cell protecting cancer cells = BAD
- Uses ATP
Also passive cation channels
- Organic cations for extracellular fluid equilibrate into the cytoplasm
- Then the active ones kick the cations out of the cytoplasm and into the urine (apical side)
25
- organic anion transporters (OATs)
- Currency exchange
- Na/k ATPase
- On basal side of cell – 1 sodium comes in, 1 alpha-ketoglutarate also comes into the cell
- Antiporter – 1 alpha-ketoglutarate comes out pulling 1 anion into the cell
- Passive channels allow anions to drift out
Dangerous because…
- System pumps anions in but lets them drift out
- So if anion has a low out drift rate then import channels can create a build-up of anion in cell
- Leads to the cell becoming toxic = damage
- Many drugs in clinical use damage kidney cells via this mechanism
26
example of anions transported
- Methotrexate
o antitumour
- Furosemide
o Acts on kidney
- Penicillin
o Penicillin is quickly expelled through kidney
o Probenecid treatment stops kidneys from expelling penicillin
o So penicillin lasts longer / you need less
27
phosphate recovery
- 1 Na comes in and 1 phosphate comes in via a co-transporter
28
bicarbonate recovery
- Proton exporter – 1 Na in, 1 H/ proton out
- Proton can combine with any bicarbonate in the filtrate to form carbonic acid
- Carbonic anhydrase hydrolyses this to make water and CO2
- CO2 can cross cell membrane without need for transporters
- Once across the membrane carbonic anhydrase turns it back into carbonic acid which naturally dissociates into proton/H and bicarbonate
- So proton is effectively coming round in a cycle and bicarbonate is taken back up into the body fluids from the urine
29
why bicarbonate recovery doesn't effect body ph and how it changes during acidosis
- This has no effect on the body Ph
- Because although H+ is being expelled, we are effectively regenerating it in the cell
- There’s no net loss of bicarbonate or protons/ H+
- If there’s remaining protons when all bicarbonates been taken up – ACIDOSIS
If this is the case a diff. reaction is used
o Hydrogen phosphate can pick up H+
o This new compound will leave the compound in urine
o This does effect acid base
o So if you’re in acidosis the H+ will be expelled from the body via this mechanism
o Ammonia can also take up protons and leave via the urine this also helps correct acidosis
30
intercalated cells
- Later on in the kidney before urine leave
- Alter Ph
TYPE A CELLS - expel protons
Proton ATPase
- Directly hydrolyses ATP to get the energy to expel protons
Proton potassium antiporter
- Expelling protons
TYPE B CELLS- retain protons
- Same ATPase but on the basal side instead of apical side
- Throws bicarbonate out into the urine
- Corrects for alkalosis
31
recovery of calcium
- Since tight junctions aren’t that tight calcium simply diffuses across
- Once water is being removed from urine the calcium tends to become more concentrated in body so runs down gradient into urine to equiblirate
32
recovery of water
- Recovered passively through aquaporins
o Not pumps only allow travel down gradients
- All above pumps pump ions out of lumen of kidney back into body so fluid in kidney lumen becomes more and more dilute therefore setting up an osmotic gradient that makes water want to move to follow the salt
- So there is passive recovery of water
33
whats an extra measure the proximal tubules have to recover proteins
- Proximal tubules cells have special vv large proteins like megalin
- Good at binding to other proteins driving receptor mediated endocytosis
- Allows proximal tubule cells to take proteins up and bring cells back from urine
34
in summary what does the proximal tubule recovered
- Recovery of 65% of sodium, chloride, phosphate, calcium etc
- Recovery of some water
- But hasn’t concentrated the urine
- Hasn’t controlled acid/base
35
how do we concentrate the urine and draw out maximum amount of water
o Na/K ATPase
o SLCs and ion channels that can parasitize the Na+ gradient to move ions and small molecules about
o Osmosis will make water follow ions (only takes water form a dilute solution to a concentrated one)
In order to make concentrated urine we must get water out of the concentrated urine into the plasma of the body
So we must make a solution that’s even more concentrated than the urine
Kidney makes an area of it’s own tissue extremely concentrated with ions to draw the water out of the urine
36
explain the pulling of ions from the proximal tubule to the tissues and what this results in
- In proximal tubule water flows with ions into the plasma due to leaky tissues (tight junctions)
- These junctions are only a property of the proximal tubules
- If we don’t have these tight junctions and aqua porins leads to a diff. system…
o Ions get dragged back from the urinary space into a super concentrated area in the basal side
o This area will be super Hypertonic (super salty)
o So water will want to go here
o But won’t be able to travel here because there’s no aquaporins
37
the loop of henle - properties of each limb
Descending limb
- Permeable to water
- But doesn’t pump ions
- Impermeable to urea
Ascending limb
- Impermeable to water
- Permeable to ions
- Permeable to urea
38
explain the recovery of ions in the ascending limb of loop of henle
In ascending part there’s recovery of ions via the sodium pump
- This makes the surrounding extracellular fluid vv salty
o in the medulla of the kidney
- This fluid is vv close to the descending limb which allows water to travel into it through the water permeable descending limb
- Leaves urine more concentrated
- Since middle bit is salty makes it easier to get water out of the start of the system as it draws it out
- At the end there’s dilute urine as ions have been pumped out
39
how much sodium, chloride and water is recovered in the loop of henle
This system recovers ~25% of sodium and chloride and ~10% of filtered water
= running total of 90% NaCl including the proximal tubule
40
where are the renal corpuscles and henle in the kidney
o Renal corpuscles are in the cortex
| o Loops of henle come into the medulla
41
how are the blood vessels organised in the kidney to facilitate the medulla remaining salty ie not being flushed away
o Organisation of blood vessels
o Blood that leaves the glomerulus leaves in an efferent arteriole
o This arteriole goes down into the loop of henle
o As blood comes down it enters the hypertonic region
o Has water drawn out of it and ions going into it
o So blood getting more and more concentrated as it reaches the bottom as it comes back up it gives the ions back as it’s vv salty and it picks up some water
o SO water drawn out of blood as it descends and added back as it ascends, ion go into blood as it descends and out of blood as it ascends
42
whats the defect of the blood vessels moving through the loop of henle
- Oxygen difference is affected in same way as water is
- So oxygen descending tends to get short circuited to the ascending part
- Rather than remaining in the blood to go down to the bottom
43
whats a summary of the activity in the distal tubule
More recovery of ions no water transport
- Polarity in urine less than that in tissue so naturally water wants to go out
- Also, active ion pumping recovering more salt
- Leads to very dilute urine
44
whats considered the end of the nephron, and what comes after this
Due to developmental reasons the end of the distal tubule regarded as the end of the nephron
But in terms of plumbing, it leads straight onto a branched urine collecting system called the collecting duct
45
the collecting duct pathway and how much filtered water is removed in this area
- The collecting duct system leads from the cortex back through the hypertonic zone (medulla of kidney) to the pelvis
- Taking dilute urine back through vv salty zone means that water wants to go from vv dilute urine into the hypertonic zone
- So up to further 24% of filtered water removed here
46
whats the cumulative removal of water from urine in the nephron and collecting duct
~99%
47
when is the recovery fo water regulated and by what
- This is regulated bc sometime don’t want to recover all your water
- Eg if you are intaking lots of fluid
- Regulated via aquaporins (cells which allow passive transport of water)
o In these cells aquaporins can be in the plasma membrane (have effect) or taken into vesicles inside the cell to be stored (so have no effect)
o Depending on how much water you want to retain there are more or less in the membrane
o Controlled by AVP hormone
48
explain behaviour of urea in the collecting duct, what is the benefit of this?
In collecting duct cell there’s also passive transporters for urea
- Urea is vv concentrated at this point
- So if allowed back it’ll want to travel down the conc. Gradient aka leaving the urine and entering the medulla
- Small amount of Urea DOES leave
o This leads to increased hypertonicity
49
how is the function of the collecting duct facilitated by our anatomy
1- We need a separation between normal and hypertonic zones
2- We need the route to pass again through the hypertonic route
3- So it makes sense to have the normal zone on the outside of the organ and the hypertonic zone near the place that urine will collect
4- And, for big animals to group several of these units around a central urine collecting space
50
why is the kidney sensitive to ischaemia and what is the kidneys response to low renal oxygen
the long runs of parallel arteries and veins mean that there is counter current exchange of oxygen, so that much gets shunted from artery to vein before the blood enters capillaries
- Probably maladaptive and it means kidneys are particularly sensitive to ischaemia
Low renal oxygen -> erythropoietin release -> more red cells made on bone marrow
51
how is flow rate controlled in the kidneys
```
1- Blood flow to glomerulus
a. systemic blood pressure
b. constriction of afferent arterioles
c. constriction of efferent arterioles aka in diabetes
2- Na+ recovery
3- Urea recovery by CD
4- Water permeability of CD
5- Acid-base balance in CD
```
52
describe the kidneys ability to keep a constant flow rate
Within limits, kidneys hold a constant flow rate across a range of arterial pressures…
- Dead flat line means control of efferent and afferent arterioles manage to hold glomerular pressure steady despite changes in systemic blood pressure
- But if its too high or too low it’s affected as seen on each side of the line
___/------/~~~~
53
what are the 2 mechanisms of constricting arterioles
1- Direct pressure sensing in the afferent arterioles – the myogenic mechanism
o Stretch activated cation channels depolarise membrane causing smooth muscle to contract in response
2- Monitoring the performance of the nephron – tubuloglomerular feedback
o Kidney measure performance via salt conc. In distal tubule and feeding it back to control the afferent and efferent arterioles (and also some systemic effects)
54
how do we overcome the challenge of nephron-to-nephron specific control
Arrange a nephron so that the end of the distal tubule makes a ‘kissing contact’ with the glomerulus
- Forming an area called the macula densa
- These 2 objects develop together and never part
55
how does the macula densa work
- Elevated glomerular blood pressure leads to filtrate flowing faster, so there’s less time for solute recovery in proximal tubule and loop of henle.
- So there will be more sodium in the distal tubule. `The macula densa cells pump out more NaCl than they normally do, as there’s more available
- The juxtaglomerular cells sense this increase saltiness, and they secrete adenosine. Adenosine causes afferent arteriole to constrict, reducing glomerular blood pressure so the filtrate flow returns to normal etc etc
56
where do you find the macula densa
the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule,
- at the point where the thick ascending limb of the Loop of Henle meets the distal convoluted tubule.
- The macula densa is the thickening where the distal tubule touches the glomerulus.
57
what are the 2 types of UTIs
Upper urinary tract – pyelonephritis
- Infection of the kidney
Lower urinary tract – cystitis
- Infection of the bladder
58
risk factors for uncomplicated UTIs
```
Risk Factors…
- Females
- Previous UTI
- Sex
- Vaginal infections
- Diabetes
- Obesity
- Genetic susceptibility
- Older age
o Oestrogen deficiency
o Cognitive impairment
```
59
risk factors for complicated UTIs
- Urinary obstructions
- Urinary retention caused by neurological disease
- Immunosuppression
- Renal failure
- Renal transplantation
- Pregnancy
- Presence of foreign bodies eg catheters or drainage devices
- Cathers assoc. urinary infections are 2nd most common cause of bloodstream infections – high cause of mortality
60
what are the main organisms that cause UTIs
- E.coli
o 75% in uncomplicated, and 65% in complicated
- K. pneumoniae
o Gram negative organism usually resistant to many antibiotics
- S. saprophyticus
o In young women who are sexually active
61
what are the steps in UTI development
1- Contamination of urethral area
2- Colonisation of urethra
3- Organisation swims upstream and colonises bladder wall
a. Due to pili and adhesions
4- Infiltration of neutrophils and multiply within the cytoplasm of bladder wall
5- Cause epithelial damage and inflammation = pain
6- Bacteria can ascend up into kidneys and multiply here
7- Since kidneys are highly vascularised bacteria can move into the bloodstream and cause bloodstream infection
62
why do catheters increase risk of UTI
Catheter gets coated in fibrinogen which is a substance that bacteria likes to grow on
63
how do bacteria invade the bladder wall and what does this lead to
Invades bladder cell wall using type I pili
- Multiplication to form intracellular bacterial communities (IBC)
- These exfoliate
OR
- Form quiescent bacterial reservoirs (QIR)
64
bacteria virulence factors
```
Adherence
- Pili
- Adhesins
Toxins
- Eg haemolysins
Immune evasion
- Eg capsule
Iron acquisition
Other
- Flagella
```
65
host defences
Antibacterial defences
- Urine
o Extremes of osmolarity, low pH and high urea concentration inhibit bacteria growth
- Urine flow and micturition
- Urinary tract mucosa (bactericidal activity, cytokines)
- Urinary inhibitors of bacterial adherence
o Tamm-Horsfall protein
- Inflammatory response
66
where in males additionally can you get a UTI
- Urethritis
- Prostatis
- Epididymo-orchitis
- Cystitis
- Pyelonephritis
67
clinical presentation of pyelonephritis and cystitis
```
Pyelonephritis
- Loin pain/ flank tenderness
- Fever/ rigors
- Sepsis
Cystitis
- Dysuria
- Frequency
- Urgency
- Suprapubic tenderness
```
```
In infants (<2yrs) – vomiting/ fever
In elderly – less localised symptoms – confusion/falls
```
68
urinary dipstick flaws and usage
- Only to be used in patients <65
o Asymptomatic bacteuria
o Bc ~50% of older people have harmless bacteria in urine
o Long-term catheter = 100% of people
- Good for diagnosing blood in urine
- Only helpful in presence of clinical UTI symptoms
o Presence of nitrates indicate a UTI is a possible diagnosis
o As low as 75% sensitivity
69
urine cultures - what different types exist and at what level are they significant
- Types of samples
o Midstream urine
Pee a bit then keep next section of urine and not the last bit of urine
To stop picking up periurethral bacteria and only get bacteria in bladder
o Clean catch urine
Urine form start to end
o Catheter sample urine CSU – from port not bag
o Other – urostomy/ cystoscopy/ pad
- Most laboratories will only detect > 10^4 – 10^5 CFU/mL
- Generally significant if >10^5 CFU/mL
70
what are some important definitions for UTI
Bacteriuria
- Bacteria in urine
Significant bacteriuria
- Indicates that the number of bacteria in the voided urine exceeds the number epeded from contamination from the anterior urethra
Asymptomatic bacteriuria
- Significant bacteriuria in a patient without symptoms
- Only ever treated in pregnant women
Symptomatic bacteriuria – UTI
Culture results support the clinical diagnosis only
71
what are the issues with UTI diagnosis and what is a solution available
- Samples take 48 hours in the lab to come back
- O,Neill AMR report in antimicrobial resistance – in 2020 all antibacterial treatment should be prescribed via a diagnostic test to prove bacteria is present
Solutions…
- Flexicult – for primary care – culture at bedside in 24 hr
- Rapid detection using molecular marker…
o Presence in bacteria
o Presence of inflammation
o Presence of antimicrobial resistance genes
- Challenge of phenotypic vs genotypic resistance
72
management of cystitis
MANAGEMENT OF LOWER UTI/CYSTITIS
- Duration – women 3 days, men 7 days
- If no RFs for trimethoprim resistance = trimethoprim 200mg every 12 hrs
- RFs for trimethoprim resistance = nitrofurantoin M/R 100mg every 12 hrs
73
why should we be avoiding antibiotics for cystitis
Cystitis is self-limiting so it can get better by itself
- Antibiotics are for amelioration and shortening of symptom duration in cystitis
o RCT - trim decreased symptom duration by 4 days
- What subgroup of patients could be managed without antibiotics?
o Ibuprofen trial
- Antimicrobial use can increase risk of recurrent UTI
- Antimicrobial use increases antimicrobial resistance
74
how do we decide whether oral or Iv antibiotics are used for UTI
o Are there any signs of SIRS or sepsis?
| o Some MDR organisms only have IV choices available
75
why is it very important to take blood cultures before giving antibiotics
TAKE BLOOD CULTURES BEFORE GIVING IV ANTIBIOTICS – BECAUSE THEN YOU CAN STRUGGLE TO FIND SOURCE OF ACTUAL INFECTION IF PERSON DOESN’T HAVE A UTI
76
management of pyelonephitis
Duration – 7 days
- Gentamicin
o Consider adding amoxicillin where enterococcus has been isolated or source of infection unclear or patient has signs of severe sepsis
- Whenever you prescribe IV antibiotics you review patient every 48-72 hours and decide whether they can change from IV to oral
77
management of catheter associated UTI
- Never use dipstick to diagnose this
- Is temp above 38, is there signs of symptoms elsewhere
- Take blood cultures and urine samples
- Change the catheter
- Some people only require single dose of gentamicin
- If patient in primary care treat as cystitis
- Always ask if patient needs to have a catheter rn
78
management of UTI in specific patient groups - men, pregnant women, children
```
Men
- Is prostate involved
o Requires longer treatment and specific Abx to penetrate prostate
Pregnant women
- Avoid contra-indicated Abx
- Treatment of asymptomatic bacteria
Children
- All children with confirmed UTI need investigation and consideration of vesico-ureteric reflux
```
79
recurrent UTI management
- Occur in 1 in 4 women
- Antimicrobial exposure is a risk factor
- Often MDR organisms
- Managed by GPs, urogynae, urologists and infection specialists
80
renin release in the macula densa cycle
- Renin released by juxtaglomerular cells
- Unless the macula densa cells are pumping out large amounts of sodium chloride (because this would mean BP is already too high)
- If vv little NaCl in distal tubule = blood flow too slow = BP too low therefore macula densa cells don’t inhibit juxtaglomerular cells from making renin
If glomerular BP is high…
- More NaCl than normal in distal tubule
- Macula densa cells do inhibit renin release
81
what are the general actions of renin in the renin-angiotensin system
- Renin converts angiotensinogen (made by liver) into angiotensin 1
- Angiotensin 1 converted by ACE (angiotensin converting enzyme) in lungs to angiotensin 2
82
what are the general effects of Angiotensin 2
- Direct arterial vasoconstriction
- Increase in BP in arterials
- Increase in sympathetic activity
- Increase in sodium chloride reabsorption
83
angiotensin effect on the kidneys
- Work on angiotensin receptors in cells to increase activity of Na/H antiporter
o This increases sodium uptake in these cells
o Increase proton export
84
angiotensin 2 effect on the adrenal gland
o Makes cells on cortex of adrenal gland secrete aldosterone
o Also signals to the kidney (as well as other places in body)
o Aldosterone acts on gene transcription of proton export system – proton ATPase
o Increases export of protons
o Works on transcription of ASC
ASC in cells of collecting duct
So allows sodium to come into cell from apical domain of urease
Then kicked out as usual by ATPase into plasma
So amount of sodium recovery in last part of renal system depends highly on amount of aldosterone in system.
85
angiotensin 2 effect on the posterior lobe of pituitary gland
- Secretes arginine vasopressin (AVP)
- AVP is a hormone that cause aquaporins to be moved from storage vesicles to plasma membrane (in collecting duct)
- Causes more fluid retention from the urine
- Increasing the amount of fluid in the body / decreasing fluid excretion
- This can help raise blood pressure
86
angiotensin 2 sympathetic response
- Renal nerves cause secretion of nor-adrenaline
- Secretes both vessels conserving to glomerulus which reduces the flow
- Also, effects renin release
87
what happens if blood pressure gets too high as a result of the renin-angiotensin system
- ANP in the heart responds if pressure is too high
- This ANP blocks the Na+ re-uptake channel in collecting ducts and causes more sodium loss
- Which acts against this system if pressure is too high and heart feels strain
- ANP system isn’t strong enough to bring BP down to safe levels if renal system strongly activated
88
control of calcium ion in the bloods
Monitored by parathyroid glands
- If there is low calcium parathyroid gland signals using parathyroid hormone
- Parathyroid hormone has receptors on renal cells
89
what are the 2 major effects of parathyroid hormone on the kidneys
1- Increases uptake channel to bring calcium in from the urine in the distal tubule
- Calcium shovelled across cell bonded to calbindin
- Export channel increased in activity by PTH
- The export channel and the calbindin both need vitamin D for synthesis
- So vit D shortage = lack of work = restriction of calcium uptake = low free calcium in blood
2- Blocks activity of sodium and phosphate in the proximal tubule
- This is because of general titration in the body between ca and phosphate
- In that if you want lots of calcium in the blood you don’t want phosphate around to mop it up = making insoluble calcium phosphate
90
whats the simple mechanism of controlling acid-base in the kidneys
If pH inside the cell falls apical Na+/H+ exchanges are more active leading to more H+ excreted in the urine
91
potassium - natural reabsorption, what 2 cells in the collecting ducts facilitate this
- For lots of substances reabsorption for urine happens naturally always and is not regulated – 90% of reabsorption is constant
- Regulation happens in the remaining 10%
o Late in kidney – distal tubule/ collecting duct
1- Intercalated cells
- Less common
- Constantly reabsorb K+
- Antiporter moving protons out and bringing potassium in
2- Principle cells
- Regulated excretion of potassium
- K+ being excreted is being pumped into basal side by ATPase
92
what happens if there's high tissue potassium
- Lot to flow into the cells and bounce out
- So automatic regulation
- If animals given low k+ diet the K+ excretion channel is removed from membrane = reduction in calcium loss, high K+ diet has opposite effect
There’s a consequence of this related to body pH…
93
whats the acid-base consequence of the bodies automatic mechanism to high potassium in tissues
During alkalosis
- In cells that export proton and import K+…
- If cell in alkalosis there won’t be many protons to export
- So, this export takes place slowly and there’s less overall potassium recovery
- Therefore, body goes into hypokalaemia
Also…
- Other channel (for export of K+) is increased in alkalosis
- This causes more K+ loss
During acidosis
- many protons to pump out therefore strong reuptake of K+
- and less export of potassium
- = hyperkalaemia
- But in chronic acidosis the sodium pump becomes less effective in proximal tubule and this means the urine helps to flush extra potassium away
94
why do we carry out clinical intervention in renal functions
- Control of hypertension
- Control of oedema
- Control of ion imbalance
- Control of acid-base disturbances
95
diuretics - generel description,
Diuresis – through/ of urine
- Increasing the amount of water (+ salts) lost from the body
- Primary purpose is control of blood pressure
o Doesn’t just work by simple loss of water
96
loop diuretics - how/ where do they work, and what are some disadvantages
WORK ON CELLS IN THE THICK ASCENDING LIMB OF LOOP OF HENLE
- These cells do salt recovery to produce salty region in medulla of the kidney
- If we block activity of uptake channels for sodium, potassium and chloride then slat isn’t recovered there
o Direct effect on salt recovery and also has effect on water recovery
o Therefore, if you take drugs to block this channel = loss in salt and water
o Since these drugs work on loop of Henle, they are called loop diuretics
disadvantages
- They are powerful
- Destroy salty area of medulla – up to 20% of filtrate to bladder – usually around 0.4%
- = loss in ions because of failure to recover in the TAL of LoH
- They can result in hypocalcaemia
o less Ca recovery – more Ca in urine = kidney stones
- More Na+ getting to collecting duct as not recovered in loop of henle
o So lots of sodium inflow at this area and more K+ loss
97
what is the main reason loop diuretics lower BP
- Main effect on BP is NOT due to fluid loss (the patient will detect this and drink more water)
- It is effect of urine being unusually salty at distal tubule (specifically at macula densa)
- Changes tubular glomerular feedback in the macula densa
o Leads to more NaCl being pumped out
o This leads to inhibition of renin production
o This leads to vasodilation and lowers BP
98
distal tubule diuretics - thiazide
- Operate on distal tubule
o Part of the kidney which is recovering less salt
o Leads to more subtle effect
o Blocks Na/Cl co-transport in distal tubule cells
99
potassium-sparing diuretics - amiloride etc
- Operate on collecting duct cells
- Particularly on amiloride sensitive channels
o Act on uptake channel on collecting duct cells that are the same cells that export potassium
o By blocking import Na channels Na/K ATPase acts slowly
o So potassium doesn’t get pumped in from plasma and there’s not much potassium loss
100
drugs that have an indirect effect on kidney function - spironolactone
- Interferes with ability of aldosterone to signal to cells
- Aldosterone acts to increase production of amiloride sensitive channels
- If action of aldosterone broken, then this gene isn’t transcribed
- So cells are incapable of taking up much sodium
- Similar to effects of amiloride
o Except for side effect of being an antiandrogen = production of female-like breasts
101
carbonic anhydrase inhibitors
- Result in more bicarbonate in the lumen
| - Has osmotic effect of resisting export in the proximal tubule (in leaky type junctions)
102
osmotic agents egv Mannitol
- Stay in lumen and resist water export
- Not used clinically
- Vv high glucose has this effect
o If so much glucose that it can’t be recovered in the proximal tubule
o Means less water recovery
o One reason diabetes mellitus = lots of urine flow
A reason for thirstiness in diabetics
103
barters syndrome
BARTTER’S SYNDROME (TYPE 1) – IMPAIRED SLC12A2
- Transporter that picks up chloride, potassium and sodium to make the medulla salty
Effects
- Loss of Na+, K+, H2O, hypercalciuria (high Ca+)
- Same effect as loop diuretics
104
Gitelman's syndrome
GITELMAN’S SYNDROME – IMPAIRED SLC12A3
- Effects transporter in distal tubule that uptakes Na+ and CL-
Effects
- Loss of Na+, K+, modest loss H2O
- like a thiazide diuretic
105
Liddle's syndrome
LIDDLE’S SYNDROME – HYPERACTICE ASC
- hyperactivating ASC leading to inc. Na+ importation
Effects
- volume expansion (body), hypertension
- can still treat with amiloride
106
pseudohypoaldosteronism
PSEUDOHYPOALDOSTERONISM – inactive ASC
- aldosterone usually triggers the transcription of ASC
- too little aldosterone = too little ASC
Effects
- Na+ loss, K+ retention, high aldosterone
107
inactivating mutations of aquaporins
INACTIVATING MUTATIONS OF AQUAPORINS
- So aquaporins in the collecting duct is inactivated
- Less water recovery of remaining ~24% of water normally recovered in collecting duct
Effects
- Diabetes insipidus (polyuria, polydipsia)
o HIGHLY DILUTE URINE, unlike diabetes mellitus which is sweet urine bc of glucose
- This is “nephrogenic” diabetes insipidus
108
addisons disease
ADDISONS DISEASE
- Destruction of the adrenal glands
Effects
- Loss of Na+, hyperkalaemia and hypovolaemia
- Less aldosterone
- Same effect as treatment with spironolactone
109
psychogenic polydipsia
PSYCHOGENIC POLYDIPSIA
- Someone who keep son drinking water that seems unconnected to body physiology
Effects
- Whole body osmolarity
110
in development where do the collecting duct system and nephron develop from
Collecting duct system comes from nephric duct
Rest of the nephron comes from the mesenchyme
- This is why we consider the nephron stopping at the distal tubule
111
development of the bladder
- Starts to form from where the nephric duct and the ureter bud diverge as they come into the cloaca
- Bladder starts to form and nephric duct, and early ureter flow into the bladder
o These cells end up separating these pipes
o So ureter at the top end of bladder
o And pipe from testis (in male) coming into bottom of bladder to form prostate
o In females this duct is destroyed
112
development of prostate gland
- Where this junction is – below the bladder
| - Seminal vesicle and vas deferens develop
113
components of semen
- Testis – sperm
- Prostate – citric acid, enzymes, acidic proteins
- Sem. Ves. – fructose, basic proteins
These all need to form for fertility
- Each gland releases at a specific time during ejaculation
114
renal agenesis
```
- Bilateral – no kidneys form
o Rare, fatal after birth
o Lack of amniotic fluid cause Potter’s Facies
o Amniotic fluid is mostly foetal urine
- Unilateral
o One kidney missing
o Common 1/500
o Often no clinical consequences unless surgical removal of other one
```
115
polycystic kidney disease
```
- Bilateral – no kidneys form
o Rare, fatal after birth
o Lack of amniotic fluid cause Potter’s Facies
o Amniotic fluid is mostly foetal urine
- Unilateral
o One kidney missing
o Common 1/500
o Often no clinical consequences unless surgical removal of other one
```
116
supernumerary ureter
- Supposed to only be one ureteric bud and one collecting duct system per kidney
- Sometimes nephric duct gives rise to 2 branches = 2 ureters going into kidney
- This leads to no consequence if both ducts go into the bladder properly
- BUT sometimes one of the ducts ends up not going into bladder instead going underneath the bladder
o leading to urine constantly dribbling out of urethra as it’s not stored
o also leads to infections more likely to travel up as there’s defensive store of urea in bladder
o in females where UTIs more common this = vv high risk of renal infection
117
pelvic kidney
- kidney forms normally but ends up in wrong place
- kidney remains in pelvic region as doesn’t move up properly
- not usually a problem in males
- problem in pregnant females
o bc kidney in same place as expanding uterus
o puts kidney under lots of pressure
HORSHOE KIDNEY
118
congenital abnormalities of cloacal development
Cloaca is common exit in embryo between the gut, the urinary system and reproductive system
In normal development these get separated by folds in tissue
- Failure of correct positioning of Rathke and Tourneaux folds results in…
o Rectovaginal fissure
o Rectoprostatic fissure
o Rectoclocal canal (rectum, vagina, urethra unite inside body)
- In males, incomplete migration of the urethral groove from the base of the penis to its tip results in hypospadias
