Week 8

Question 1

Renal pelvis and ureter

Answer 1

Urine flows from each of the renal calyces into a funnel-shaped dilation of the upper ureter called the renal pelvis
In the renal pelvis, peristaltic waves can be initiated from ‘atypical smooth muscle cells’ and slowly propagate down the ureter helping to encourage the flow of urine down the ureter into the bladder
Obstruction to the flow of urine in a ureter, commonly by ‘kidney stones’ (nephrolithiasis or ureterolithiasis; due to precipitation of barely-soluble constituents of urine) can painfully obstruct this flow. Treatments: percutaneous nephrostomy or extracorporeal shock wave lithotripsy.

Question 2

The urinary bladder

Answer 2

Can expand enormously in size, from an empty volume of <100ml (usually much less than this) to typical maximum volumes of 500-1000ml (or more)
Once in the lower urinary tract urine is excreted essentially unchanged (apart from some signalling molecules and cells originating from the urothelium
Wall consists of:
-urothelium
-lamina propria
-detrusor smooth muscle
-Serosa

Question 3

Urothelium

Answer 3

High resistance tight junction between the cells greatly reduce permeability through the wall
The urine facing surface has specialised cells called ‘umbrella cells’
Once thought of as a passive barrier, there is now much research focusing on signalling from the urothelial cells to the underlying lamina propria and detrusor sensing the contents of the store urine and affecting the urinary frequency

Question 4

Lamina propria

Answer 4

Contains blood vessels, lymphatics, nerves and interstitial cells (of cajal) in a connective tissue mesh
Many nerve terminals in this area are sensory and involved in detecting chemical and mechanical stimuli (filling state of bladder)
Interstitial cells are an area of active research; while they have unknown function (in the bladder) it may be that they mediate signalling between the urothelium and detrusor smooth muscle without involving nerves

Question 5

Detrusor

Answer 5

Smooth muscle cells run in bundles; these bundles are arranged in an irregular ‘basket weave’ pattern, rather than being arranged in regular longitudinal and circular muscle cells layers
Muscle bundles are innervated by autonomic nerves
Parasympathetic nerves represent the dominant innervation and their main neurotransmitter is acetylcholine (ACh) acting on M3 muscarinic receptors to cause contraction
Sympathetic nerves release NAd onto beta3-adrenoceptors to cause relaxation

Question 6

Continence and voiding

Answer 6

Continence: low pressure reservoir for storage of waste products, continually active sphincter to prevent leakage
Voiding: relaxation of sphincters, increase pressure in reservoir
What do you need:
-sensory mechanism to inform about filling
-higher control centres for voluntary voiding
-reflex pathways to generate voiding
-the right muscles to do it

Question 7

Continence

Answer 7

Somatic systems active
Keeps striated sphincter contracted
Sympathetic system active
Constricts smooth muscle sphincters
Keeps storage element relaxed
Parasympathetic system inactive

Question 8

Voiding

Answer 8

Somatic system and sympathetic system switched off
Sphincters relax
Parasympathetic system activated
Storage element walls contract

Question 9

When is urinary continence a problem

Answer 9

Urinary tract infection: chemical stimuli increase bladder activity and hence urge to void
Spinal cord disorder:
-spinal cord injury
-multiple sclerosis
Stroke
Pelvic floor injury (eg following childbirth)
Detrusor overactivity (leading to overactive bladder syndrome): very common with age. May be associated with outflow obstruction
Atonic bladder: may be secondary to autonomic neuropathy

Question 10

Treatments for stress incontinence

Answer 10

If stress incontinence is the predominant symptom in mixed UI, discuss with the woman the benefit of conservative management including OAB drugs before offering surgery
When offering a surgical procedure discuss with the women the risks and benefits of the different treatment options for SUI using the information to facilitate discussion of risks and benefits of treatments for women with stress urinary incontinence
If conservative management for SUI has failed offer:
-synthetic mid-urethral tape
-open colposuspension
-autologous rectus fascial sling

Question 11

Pharmacological management of overactive bladder

Answer 11

Antimuscarinic drugs (oxybutynin) useful in short to medium term but show tolerance
Botulinum toxin: very useful but difficult to use and requires repeated/ongoing treatment
B3 adrenoceptor agonists (mirabegron; NICE recommended as of June 2013)
Others: resiniferatoxin and capsaicin (targeting sensory nerves)
Experimental drugs:
-phosphodiesterase type 5 inhibitors, K+ channel activators

Question 12

OAB management in women

Answer 12

Offer one of the following choices first to women with OAB or mixed UI:
-oxybutynin (immediate release)
-tolterodine (immediate release)
-darifenacin (once daily preparation)
If the first treatment for OAB or mixed UI is not effective or well tolerated offer the drug with the lowest acquisition cost
Offer a transdermal OAB drug to women unable to tolerate oral medication
Migabegron for treating symptoms of overactive bladder
-mirabegron is recommended as an option for treating the symptoms of overactive bladder only for people whom antimuscarinic drugs are contraindicated or clinically ineffective or have unacceptable side effects

Question 13

Urinary outflow obstruction

Answer 13

Causes: prostatomegaly (most commonly benign prostatic hyperplasia BPH), urethral stricture
Incidence: “for a symptom- free man of 46 years, the risk to develop LUTS/BPH over the coming 30 years, if he survives, is 45%”
Treatment:
-surgical: transurethral resection of the prostate TURP
-medical: alpha-adrenoceptor antagonists (terazosin, tamsulosin) partly through relaxation of the smooth muscle of the prostate
-5alpha-reductase inhibitors (eg finasteride); reduce hypertrophy

Question 14

Intracellular space as a K+ reservoir

Answer 14

Extracellular space (14L): 4mM
Intracellular space (28L): 140mM

Question 15

Nernst equilibrium for K+

Answer 15

Ek+= -RT/F ln([K+]i)/[K+]o
This means that cellular equilibrium will be reached when:
[K+]i/[K+]o is constant now initially this ratio is 140/4

Question 16

New equilibrium position

Answer 16

Suppose x mmol move intracellularly the new internal concentration of K+ would be 140+(x/28) if there now remains (56-x) mmol of extra K+ ions in the extracellular space, the concentration there is 4+((56-x)/14). To find x we have to find the value when the ratio of K+ concentrations across the membrane is the same as the start

Question 17

K+ equilibrium

Answer 17

This means that the equilibrium will re-establish when 55.2mmol of the K+ has moved intracellularly and only 0.8mmol extra remains extracellularly. This ratio reflect the large size of the intracellular space and the high normal K+ concentration
However this equilibrium takes time to develop and so for acute loads K+ remains in the extracellular space

Question 18

Clinical problems of K+ dysregulation

Answer 18

Hyperkalaemia:
-causes: end stage renal failure, crush injuries, blood transfusion, cytotoxic drugs, insulin deficiency, over-use of k+ sparing diuretics
-consequences: (cardiac) dysrhythmias
-treatments: treat the cause, K+ restricted diet (if chronic), insulin+ glucose (or just glucose in those without diabetes)
Hypokalaemia:
-causes: diarrhoea, furosemide, insulin overdose
-consequences: (cardiac) dysrhythmias
-treatments: treat the cause, give K+ IV (if acute) or orally (if chronic)

Question 19

Sites of renal K+ exchange

Answer 19

Proximal tubules: reabsorption; passively and paracellularly with the water
Thick ascending limb: through the NKCC cotransporter, but much of the K+ cycles back into the filtrate here
Distal tubule through to collecting duct in the “principal cells”
-apical membrane K+ channel (ROMK), under the control of aldosterone
-a Ca2+ activated K channel (flow rate dependent)
Most diuretics increase the distal K+ secretions by both increasing distal Na+delivery and by increasing the amount of water in the filtrate (dropping the K+ concentration)

Question 20

Aldosterone

Answer 20

It’s important in volume regulation (as part of the renin-angiotensin response) but its secretion is also very sensitive to K+
Is the main hormone regulating K+ concentration in the body

Question 21

Fate of filtered calcium

Answer 21

20% of plasma free Ca2+ is filtered in the glomerulus which means that only 10% of total Ca2+ is filtered
Proximal tubule: moves transcellularly (channels on apical;active on basolateral) proportional to water movement
Thick ascending limb: absorption, driven by the positive potential in the lumen of the TAL driving the above mechanism

Question 22

Erythropoietin EPO

Answer 22

A glycoprotein hormone; 166 amino acids, normal concentration 10pM
Synthesised mainly from peritubular fibroblasts (sometimes call mesangial cells) in the renal cortex
Production and release is stimulated by hypoxia (eg for adaptation to altitude) mediated by the release of prostaglandins
The transcription is stimulus is via hypoxia-inducible factors (particularly HIF-2)
HIF-alpha degradation is enhance by Fe2+ as it is a cofactor in HIF-a deoxygenases. Hence low iron leads to increased EPO production
HIF-2 is a transcription factor that stimulates the EPO enhancer
There is also a B-adrenoceptor and AT-II mediated increase in EPO in the kidneys

Question 23

Actions of EPO

Answer 23

Also an anti-apoptotic agent for erythrocytic progenitors
In the bone marrow EPO then binds to the EPO receptor increases production of proerythroblasts which then become erythrocytes
The receptor EPOR activates JAK2 (Janus kinase) tyrosine kinase which then activates different intracellular pathways including: Ras/MAP kinase, phosphatidylinositol-3-kinase and STAT transcription factors
The EPOR receptor clears the EPO by binding and internalisation so low EPOR expression leads to a higher EPO concentration and longer half life

Question 24

Erythropoietin in renal failure

Answer 24

EPO production falls in most causes of renal failure leading to anaemia
One exception is renal failure associated with polycystic kidney disease in sufficient renal parenchyma is present to prevent the loss of EPO production
Treatment for the anaemia of renal failure may include giving EPO analogues
Note that dialysis does not treat the anaemia

Question 25

How common is anaemia in renal failure

Answer 25

Very
The anaemia is normochromic normocytic

Question 26

Synthetic EPO

Answer 26

EPO analogues are produced by cell cultures: several companies sell similar forms of EPO alpha such as “darbepoetin alfa”
The complex gylcosylation patterns of human EPO are difficult to reproduce in cultured cells. Several of the mutations in the EPO alpha have been places in order to increase glycosylation

Question 27

EPO abuse

Answer 27

EPO analogues have been used in sport to increase endurance
The dangers of such use include an increased risk of thrombosis
If the haematocrit is increased too much then viscosity increases and flow decreases
At 34kDa some of the protein can be found in the urine

Question 28

Vitamin D metabolism

Answer 28

Vitamin D cholecalciferol from the diet or skin is converted to 25-hydroxycholecalciferol in the liver then to 1,25-dihydrocholecalciferol in the kidney
Production of 1,25-vitD is under control of PTH stimulates and calcitonin inhibits
It’s actions are to:
-increase Ca2+ and phosphate absorption from small intestine
-decrease Ca2+ and phosphate excretion
Patients with renal failure also have low 25-VitD perhaps due to dietary restrictions the presence of some extra renal 1-a hydroxylase activity in target tissues led to trails investigating 25-VitD supplementation