Renal Flashcards
At the most basic level, what are the kidneys responsible for
Why is this important
Urine production
By regulating urine composition, integrated with the CV system, the kidneys control the composition and volume of the body fluids
What kind of organs are the kidneys
Regulatory rather than excretory
Give 4 functions of the kidneys that are not studied in detail in these lectures
Excretion of metabolic waste, inactivated hormones, and foreign substances
Regulation of RBC production by producing erythropoietin
Activation of vitamin D3 to 1,25-dihydroxycholecalciferol as part of Ca2+ homeostasis
Gluconeogenesis in prolonged fasting
3 things that the kidneys regulate in bodily fluids
Osmolarity
Volume
Composition
How is the composition of body fluids maintained
Matching output to intake
Name 4 processes that the kidneys work in conjunction with
Regulation of ingestion (hunger etc)
Other excretory routes (CO2 excretion by lungs etc)
Regulation of metabolic processes
Control of absorption (eg Zn absorption is controlled by intestinal epithelium)
What is the extracellular compartment divided into
Give the volume of each
Blood plasma (within vasculature) ~3L
Interstitial fluid (around cells) ~13L
Trans cellular fluid (eg CSF) ~1L
How much intracellular fluid is there
~25L
Which bodily fluid compartment is the largest
ICF
Which compartment of fluid can the kidneys directly affect
Plasma
How much of the blood is plasma
What is the percentage make up of blood plasma
55%
91% water
7% protein
2% electrolyte, hormones, nutrients
How much osmotic pressure do ions eg K Ca and Cl exert across the capillary wall
NONE
their concentrations are similar either side as they freely cross the membrane
What is oncotic pressure
Colloid osmotic pressure
The osmotic pressure of proteins in blood
It pulls water into the blood
What resists oncotic pressure
Hydrostatic pressure (forces water out of capillaries)
Give the simplified renal version of Starling’s equation for Starling forces
Jv = Kf(Pc - σπc) Jv = volume flow Kf = filtration coefficient σ = protein reflection coefficient (usually close to 1)
Why can Pif and πif be removed from the starling equation in renal
They are v small and vary v little
What is the filtration coefficient
The product of surface area and hydraulic conductivity this varying greatly between different capillaries
How does Pc (capillary hydrostatic pressure) vary across a capillary length? Why?
What about πc
Decreases linearly along the capillary
Due to resistance
No change
What is the net flux like from a capillary at the arteriolar and venous ends?
Net filtration at arteriolar (inward)
Net reabsorption at venous end (outward)
If there is a small net outward flux at the end of a capillary, why do we not swell
It is removed my lymphatics
If outward flux exceeds lymphatic removal, oedema ensues
What is autotransfusion
When capillary pressures are low (eg after blood loss), starling forces may favour movement from IF into capillary
What clinically happens to Starling forces in capillaries in cardiac failure
Hydrostatic pressure increases due to increased atrial pressure
What happens to capillaries in septicaemia
Capillaries become leaky to plasma proteins reducing σ (colloid reflection coefficient)
What happens in Kwashiorkor
What other syndrome would have a similar effect
Protein intake is low so plasma protein levels drop and πc falls
Nephrotic syndrome
Is oedema always life threatening?
No sometimes it is purely aesthetic
However, increased IF volume increases diffusion distance which can produce ulceration in the peripheries and pulmonary oedema is DEADLY
What is extravasation? When would it occur and what can it cause?
Movement out of blood vessels
Septicaemia
Circulatory collapse
What is the hydrostatic pressure like between the interstitial and intracellular spaces?
THERE IS NONE
Therefore only osmotic water movement is considered
Compare movement of fluid between the interstitial and intracellular spaces vs between plasma and interstitium
No hydrostatic pressure between first 2
Small ions cannot freely cross cell membranes do exert some osmotic pressure
True or false?
The osmolarity if the intracellular and interstitial fluid is equal at steady state
Why is this
True
If the osmolarity if IF changes water will flow across the cell membrane until equilibrium is reached
What is the major extracellular cation
Na+
(Makes up nearly 1/2 of total extracellular osmolarity)
It is membrane impermeable apart from Na/K pump
What are the major extracellular anions
What excludes them from cells
Cl- and HCO3-
The membrane potential
What are the 2 ways to change the osmolarity of a solution
How is it primarily done in the body
Change amount of solute
Change volume of solvent
Regulating amount of water in the body
Which phase is most important to osmoregularity
Water follows salt 🧂
Give an example of what can happen to cells if they swell
Ion channels open, disrupting membrane potential and cell signalling
Which organ is most vulnerable to damage by swelling
The brain as it is encased in the rigid skull
What is the normal range of osmolarity
268-290 mOsm.kg-1
What are the units used for osmolarity
mOsm.kg-1
How do each of the following affect cells:
a) hypertonic
b) hypotonic
c) isotonic
a) causes cell to shrink
b) causes cell to swell
c) does not affect cell
Is there a link between osmo and volume regulation
Yes
A Change in Na content translates to a change in ECF volume
Give an example of water intoxication
Girl in 1995 collapsed after drinking too much after taking Ecstasy
Occurs when someone drinks >7 litres in a short time, diluting the blood. Her plasma Na level had dropped to 252 mOsm.kg-1
Water was sucked into her brain under osmotic pressure swelling the brain
The increased pressure on the brain resulted in coma and death
Does all water enter the body through the digestive tract
No
Most does but some is produced by cellular metabolism
What is the net daily intake of water
2.5L
+700 from food
+1600 from drink
+0.2L from cellular respiration
What is insensible loss of water
Loss we are unaware of eg exhalation and sweat
How much water is lost by the kidney daily
1400ml
What mechanisms is water balance mostly controlled by
Water loss by ADH and water intake by thirst
What is the hypophysis
The pituitary gland (beneath hypothalamus)
Where is the pituitary gland found
How big is it
Below the hypothalamus in a skull depression called the sella turcica
Size and shape of a chickpea
Give a brief description of the pituitary
Divided into anterior and posterior
Hypothalamus is connected to anterior via short axons which innervate hypophyseal portal system
Give an example of neuroendocrinology
Hypothalamus releases factors into the hypophyseal portal system which stimulate the anterior pituitary. The anterior pituitary then releases long range endocrine signals
Name 3 endocrine hormones secreted by the anterior pituitary
TSH
FSH
ACTH
What is the adenohypophysis
Anterior pituitary
What is the other name for the posterior pituitary
What is its connection to the hypothalamus
Neurohypophysis
Neural only
What hormones does the posterior pituitary produced
Only 2
Oxytocin and ADH (vasopressin)
What is similar about the hormones produced by the posterior pituitary
Both constrictors of smooth muscle
How does vasopressin cause vasoconstriction
Binds to V1 receptors
Name some differences between vasopressin and ADH
there are none! They are the same hormone
Where does ADH act in the nephron
On the V2 receptors in All parts of the collecting duct? Including cortical collecting duct
Increases water reabsorption
How else does ADH increase the antidiuretic effect, other than increasing water reabsorption
Increasing urea permeability of inner medullary collecting duct
Compare affinity of ADH to V1 vs V2
Much higher affinity to V2
Why is ADH synthesised
In the neuroendocrine cells in the SON and PVN of the hypothalamus
What does SON and PVN stand for
Supraoptic nuclei
Paraventricular nuclei
How is newly synthesised ADH transported
ADH is packaged into granules and transported down neuron axon to be stored at terminal in posterior pituitary
Following an AP, ADH is secreted into systemic circulation by exocytosis
What dictates the amount of ADH released
Frequency of APs arriving at the SON
2 systems controlling ADH
Major physiological stimulus controlling ADH
Osmoregulatory system
Circulatory
ECF osmolarity
What detects ECF osmolarity
Hypothalamic osmoreceptors located near the SON and the OVLT
What is the OVLT
Organum vasculosum of the lamina terminalis
It is a circumventricular organ (acts outside blood brain barrier)
How does the OVLT detect a need for ADH
High [Na+] draws water out of OVLT, causing it to shrink and increase firing rate to SON/ PVN …
How Do changes in osmolarity affect the gut and ADH
How does this effect systemic ADH
What does this do ultimately
Reflexes in the gut and liver inhibit ADH release during drinking and water absorption respectively
Water absorption will dilute the plasma and promote a fall in ECF osmolarity which is detected by hypothalamic osmoreceptors. This results in a inhibition of ADH synthesis
Promotes water loss
How does the circulation detect changes in water content
An increase in blood volume leads to an increase in ABP which is detected by arterial baroreceptors
Where are the arterial baroreceptors
At the bifurcation of the common carotid in the carotid sinus
Aortic group are in the aorta
What happens when arterial baroreceptors sense an increase in BP
Signal to brainstem to increase frequency of discharge in afferent pathways. Brainstem interacts with hypothalamus to inhibit ADH synthesis and release
Where else (other than arterial baroreceptors) are blood volume sensors?
In the atria and great veins
These stretch and interact with hypothalamus to inhibit ADH secretion
This is part of the veno-atrial baroreflex
What is diuresis
Urine flow rate
Who did experiments on diuresis control
Verney
Describe the set up of Verney’s experiments
Water was administered to dogs by a stomach tube
Warm water was administered to stomach as high urine flow rate makes anti diuresis easier to measure
Diuresis measured using a catheter
Carotid arteries exteriorised to form carotid loops for introduction of fluid into carotid circulation and delivery to brain
What did Verney find
Intracarotid infusions of hypertonic NaCl reduced flow rate
However, isotonic infusions of NaCl and hypertonic infusions in malleolar vein had no effect
Antidiuretic effect also found when pituitary extract was injected into carotid loop
How sensitive are the osmoreceptors
Verney’s experiments showed antidiuresis with changes in osmotic pressure of carotid blood of 1.8% (very sensitive)
What did Verney find after performing a hypophysectomy
Hypertonic injections into the carotid were without effect but pituitary extract still caused diuresis
Which substances that were injecting hypertonically caused an effect
Which didnt
NaCl, fructose, sucrose, and sodium sulphate all caused diuresis
Urea did not cause an effect
Why does an increase in NaCl cause anti diuresis but not urea
Increased NaCl forces water out of the cell, making it shrink and triggering a signal
An increase in urea (which can freely enter the cell) is without effect on the volume of water inside the cell. There is no change in cell size and no signal is triggered
What does the graph of [ADH] secreted vs plasma osmolarity look like
Why is this
Very steep
So the system can be v sensitive
What the set point of ADH osmolarity and what happens here
282-290 mOsm.kg-1 H20
This is the value where ADH secretion begins
How would a fall in blood volume affect [ADH] in the blood
Why
Increase
BP would fall and dis-inhibit ADH release from the neurohypophysis via the baroreflex
How sensitive is the baroreceptor system compared to the osmoreceptor system
When can this be seen
What will this fall also do
Baroreceptor is much lower
A 5-10% drop in blood volume is required for an increase in plasma ADH
It will sensitise the relationship between plasma osmolarity and plasma ADH
Describe the cellular mechanisms underlying the antidiuretic effect of ADH
ADH binds to V2 receptors on the basolateral membrane of the collecting duct cells in the kidney
This results in activation of adenylyl cyclase, forming cAMP, which activates PKA.
PKA phosphorylates certain proteins, triggering the fusion of vesicles and exposing aquaporins on the apical membrane
What does the recruitment of aquaporins (AQPs) do
How much does ADH affect AQP content on the membrane
Transfers AQP2 to the membrane increasing its water permeability
Up to 6-fold (Neilson et al)
What is the water permeability like in the basolateral membrane
It is always high due to the constitutive presence of AQP3 and AQP4
The rate limiting step is at the apical membrane
How does ADH affect urea permeability
ADH stimulates the insertion of VRUT into the apical membrane of the inner medullary collecting duct
There are a number of urea transporters (UTs)
It is thought UTA is the one regulated by ADH
When do you feel thirsty (3)
Which is the most important stimulus
Hypertonicity (when body fluid osmolarity increases) this is the most important
Hypotension
Hypovolaemia (when blood volume decreases)
How much must plasma osmolarity change to produce thirst
What kind of thirst is this
2-3%
Osmotic thirst
How much must blood volume or pressure change to produce thirst
What kind of thirst is this
10-15% decrease
Hypovolaemic thirst
Where are the neural mechanisms controlling water intake located
The thirst centre of the hypothalamus near the OVLT
What does OVLT stand for
Organum vasculosum of the lamina terminalis
What do thirst centre cells respond to
An increase in osmotic pressure as a result of cellular shrinkage
What is thought to inhibit thirst receptors
How would a fall in blood volume affect thirst
Circulatory stretch receptors present in arterial baroreceptors, the atria, and the great veins
A fall in volume would dis-inhibit the influence of stretch receptors on the thirst centre, and the individual would perceive thirst
Where are the neural mechanisms controlling water intake located
The thirst centre of the hypothalamus near the OVLT
What does OVLT stand for
Organum vasculosum of the lamina terminalis
What do thirst centre cells respond to
An increase in osmotic pressure as a result of cellular shrinkage
What is thought to inhibit thirst receptors
How would a fall in blood volume affect thirst
Circulatory stretch receptors present in arterial baroreceptors, the atria, and the great veins
A fall in volume would dis-inhibit the influence of stretch receptors on the thirst centre, and the individual would perceive thirst
What is a dipsogen and who coined this term
A molecule that stimulates thirst
Prof James Fitzsimons in the Downing Site, Cambridge
Name a powerful dipsogen
Angiotensin II
How did Fitzsimons show that Angiotensin II is a dipsogen
What is AII mediated by
When injected into the OVLT, it causes an immediate increase in water intake
AT1 receptors
What kind of thirst do Angiotensin II injections cause
Highly motivated, vigorous drinking
The water drank within 15 minutes of the injection exceeds that which the animal would normally drink in a 24 hour period
What is diabetes insipidus
Characterised by the production of large volumes of dilute insipid urine
Can be caused by failed ADH production or secondary to a head trauma, brain tumour or congenital absence or a failure of the kidneys to respond to ADH
What is neurogenic diabetes insipidus
Diabetes insipidus caused by congenital absence Leading to reduced/ insufficient production of ADH
Eg inherited mutation of the AVP-NPII gene or Wolfram Syndrome
What is nephrogenic diabetes insipidus
DI caused by a failure of the kidneys to respond to ADH
Usually acquired, eg: from kidney disorders (eg poly cystic kidney disease) or lithium toxicity
How Can Diabetes insipidus be treated
Administering a synthetic ADH analogue via a nasal spray
Name an ADH analogue
Desmopressin acetate
Is DI usually fatal
No as thirst mechanisms are usually functional and plenty of water is available
Polydipsia (excessive drinking) gives rise to polyuria (excessive urine production)
Why is ECF volume related to the Frank Starling Law
It is related to plasma volume which is related to MSFP and in turn related to venous return. According to the Frank Starling mechanism, increased venous return increases cardiac output.
This therefore means that ECF volume impacts blood pressure
What is the main cation in the ECF
Na+
What is the volume of ECF primarily determined by
Why
Na+ content as Na+ is excluded from the cells due to the low membrane permeability and Na pump activity
How fast is ECF volume control
What does ECF volume reflect
V slow (from hours to days)
Short term changes ranging from -10 to 20%
Is osmoregulation subordinate to ECF volume control
What does this mean
No ECF volume is subordinate to osmoregulation
Changes in osmotic pressure will drive changes in ECF volume which will in turn change ABP
What is hypernatraemia and what does it lead to
Increased blood [Na+]
It promotes hypertension
How is ECF volume mainly achieved
By varying the loss of Na+ lost in urine
There is also a little control via “sodium appetite”
What are the 4 factors affecting sodium balance
Physical
Neural
Endocrine
Behavioural
What do the physical factors affect Na balance
Net filtration pressure in the glomerulus
Starling forces across the peritubular capillaries
Why can baroreceptors not work in the long term
They minimised short term blood pressure changes but sustained changes in blood pressure for over 24 hours causes the baroreceptors to adapt and reset
What does sustained ABP lead to
What is this called
Increased GFR leading to increased Na+ loss
The loss of Na due to raised ABP is called pressure natriuresis
What is the response to pressure natriuresis ?
The response is two fold:
Increase filtration and decrease reabsorption
Discuss the filtration response to pressure natriuresis
Increased ABP will increase glomerular capillary hydrostatic pressure (Pc).
This increases net filtration pressure and increases GFR
This all results in a promotion of Na+ excretion in the collecting duct
Describe the decreases reabsorption side of the response to pressure natriuresis
Increased ABP leads to increased peritubular capillary hydrostatic pressure
This reduces movement of fluid into these capillaries, raising renal interstitial hydrostatic pressure (RIHP), thus reducing fluid reabsorption in proximal tubule
This will increase tubular hydrostatic pressure, reinforcing natriuresis
Back leakage in tubule increases due to leaky proximal tubule
Why do we think other factors affect the response to pressure natriuresis
The effect of pressure changes in vivo is greater than in perfused kidneys (in vitro)
How does ECF affect colloid osmotic pressure (COP)
An increase in ECF volume leads to a decrease in COP due to [plasma proteins] being lower as volume has increased
What is the dual mechanism that alter Na excretion when there is a change in COP
A decrease in glomerulus capillary COP will favour Na excretion
Decreased peritubular capillary COP will reduce movement of fluid into these capillaries, raising RIHP, which reduces fluid reabsorption from the tubule
This increases tubular hydrostatic pressure and reinforces natriuresis
What are the main nerve fibres comprising the renal nerves
Sympathetic post ganglionic fibres from the coeliac plexus and the inferior splanchnic nerves
Where do the renal nerves enter the kidney
What is their course
At the hilum
Follows the tributaries of the renal arteries to reach individual nephrons
What modulates renal sympathetic nerve activity
Altered inputs to the CNS from cardiopulmonary receptors (atria and great veins) and arterial baroreceptors
How does a fall in ABP affect renal sympathetic nerves
increased ABP elicits a dose dependant increase in the frequency of renal sympathetic nerve activity
Where can the measure of the baroreflex sensitivity be seen
The linear part of a MAP vs RSNA graph
The baroreflex set point is the midpoint of this graph
What are the 3 main effects of RSNA
Directly stimulates Na+ reabsorption (mainly via the proximal tubule) via α1 adrenoreceptors. It promotes Na+/H+ exchange
Constriction of both afferent and efferent glomerular arterioles
Promotion of the secretion of renin, resulting in increased production of Na+ retaining hormones and therefore interacting with endocrine factors affecting Na+ balance
Does RSNA constricting glomerular arterioles affect GFR?
No tubulo- glomerular feedback maintains GFR
Only under intense RSNA (eg in haemorrhage) does renal blood flow fall low enough to significantly decrease GFR, minimising Na+ excretion
Are both efferent and afferent arterioles affected by RSNA equally
No there is evidence of a greater density of α1 receptors in the afferent for greater constriction of afferent arteriole
What are the 3 main hormones influencing Na+ excretion
Give their abbreviations
Angiotensin II (AII) Aldosterone (Aldo) Atrial Natriuretic Peptide (ANP)
Where is renin secreted
By modified smooth muscle in the wall of the afferent arteriole of the nephron - (part of the juxta glomerular apparatus)
What is the juxta glomerular apparatus
The relationship between the juxtaglomerular cells of the afferent arteriole and the macula Densa in the ascending loop of Henle
What does the macula densa do, simply?
Detects changes in tubular fluid composition
What does renin do to angiotensin
Renin catalysed the production of Angiotensin I from the precursor plasma globulin, angiotensin
What is the structure of angiotensin I
A decapeptide
How is angiotensin I converted to AII
It is cleaved into a octapeptide (AII) by angiotensin converting enzyme (ACE)
Where is ACE found
In lung capillaries
What is the normal circulating Level of AII
How may this change in severe Na+ depletion
500-600 pMolar
Ten fold
What are the 3 main factors for renin release
1) afferent arteriole acts as intrarenal baroreceptor. A fall in P here promotes renin secretion
2) renal sympathetic nerves release noradrenaline that can stimulate renin secretion via β2 adrenoreceptors
3) change in composition/ flow rate of fluid at the macula densa
What regulates sympathetic nerve stimulation of renal β1 receptors
Atrial/ great vein volume receptors and arterial baroreceptors
How will GFR affect renin release
What does this result in
A fall in GFR will Lowe the Na load at the macula densa, stimulating renin
Increased renin will promote Na reabsorption at proximal tubule, further decreasing Na load at macula densa
This creates a positive feedback loop
Once AII is synthesised it has 3 distinct effects. What are these
Vasopressor effects
Sodium retention effects
Stimulation of aldosterone secretion
Discuss the vasopressor effects of AII
It can directly and powerfully cause vasoconstriction via its Action on AT1 receptors
This raises TPR as arterioles constrict and thereby ABP
after volume depletion, AII contributes to the general increase in vascular tone
Discuss the Na retention effects of AII
Mimics effects of sympathetic stimulation on the kidney:
Na reabsorption at proximal tubule
Increases Na+/H+ exchange
Increased Na+ reabsorption increases water reabsorption, increasing blood volume
Constricts renal arterioles (but efferent more than afferent unlike RSNA)
What does AII induced efferent arteriole constriction do
What is the short term and long term effect of this
Promotes an increase in the filtration fraction
Short term: favours Na+ excretion
Long term: the opposite- assists An+ reabsorption
How does AII induced efferent arteriole constriction promote Na reabsorption
Increased GFR drags water with it, increasing COP downstream of peritubular capillaries
This increases fluid reabsorption from renal interstitial space into blood vessel
A more concentrated interstitial will drag more fluid out of the proximal tubule, reducing renal hydrostatic pressure.
This reduced pressure will reduce speed of urinary Na loss and increase time for Na reabsorption in the collecting duct
Discuss the aldosterone secreting property of AII
AII stimulates aldosterone synthesis and secretion by the adrenal glands via AII action on AT2 receptors
How big are the suprarenal glands and what shape are they
Drawn as a triangle
Size of a walnut
Discuss the structure of the suprarenal glands
2 zones: inner adrenal medulla and outer adrenal cortex
Cortex is divided into 3 layers: zona glomerulosa; zona fasciculata; and zona reticulartis (from out inward)
Remember with acronym (GFR)
Where is adrenaline secreted
Adrenal medulla
What are the 2 families of hormones
What distinguishes each
Peptides and steroids
Peptides are water soluble
Steroids are fat soluble
What does the different solubility of peptides vs steroids mean for their action
Peptides have to act on membrane receptors
Steroids can diffuse through the cell’s lipid membrane and act directly inside the cell
What are the 3 kinds of steroid hormones
Mineralcorticoids
Glucocorticoids
Sex hormones
What are the 3 types of sex hormone
Oestrogens
Progesterones
Androgens
Where are mineralcorticoids secreted and give an example of one
The zona glomerulosa
Aldosterone
What does the zona fasciculata synthesise
Give an example
Glucocorticoids
Cortisol
Where are androgens made
Give an example of an androgen
Zona reticularis
DHEAS
Where does aldosterone act
On the distal parts of the renal tubule, mainly the cortical collecting duct
May also act on thick ascending loop of Henle
What does aldosterone do
What is its main regulatory role
Promotes:
Na+ reabsorption
K+ secretion
H+ secretion
K+ excretion
Where does aldosterone act primarily
The distal nephron in principal cells
What does aldosterone do on a cellular level?
Acts on DNA to increase mRNA in principal cell for 3 different proteins:
ENaC
SK
Na/K pump
What is ENaC
Epithelial Na+ channel found in the epithelial of the distal nephron
It increases in density and activity when aldosterone levels increase
What are SK channels
Small conductance K+ channels believed to be responsible for K+ secretion increase
They increase in density when Aldosterone levels rise
What do the extra channels formed by aldosterone action result in
Additional ENaC increase Na+ entry across apical membrane
The resulting increase in cytosolic [Na+] stimulates removal by Na/K pump across basolateral membrane - Na pumping capacity is increased
Increased SK channels favour K+ diffusion into the tubule lumen. This increases trans-epithelial potential
What is the effect of aldosterone on type A intercalated cells
Increase H+ secretion from these acid secreting cells
How does AII affect thirst
AII is a dipsogen and increases thirst, helping to maintain blood volume
What behaviour does AII stimulate
Thirst and sodium appetite
Discuss the effect of AII on sodium appetite
Give experimental evidence
Increases Na appetite
Increased Na increases the blood’s osmotic pressure. This leads to an increase in blood volume and thus ABP
Repeated injections of AII into rat brains stimulate drinking of NaCl solutions in preference to fresh water
Where is ANP made
Discuss the structure of ANP
Where is it present
Atrial myocytes contain granules of the precursor of ANP
It is a hormone made of 28αα
It is present in the plasma and it’s concentration increases when atrial stretch is increased
What is the overall aim of ANP
To promote natriuresis
When do ANP levels decrease
ANP’s overall aim is natriuresis and a loss of Na leads to a loss of water, reducing ECF volume MSFP falls VR falls Atrial stretch falls
Give the 5 actions of ANP
- Vasomotion of the glomerular arterioles
- Inhibition of renin secretion
- Inhibition of Na reabsorption in medullary collecting duct
- Inhibition of Na reabsorption in proximal tubule
- Inhibition of ADH secretion
Why does ANP inhibit ADH
To increase water loss, decreasing blood volume and pressure
How does ANP inhibit Na reabsorption in medullary and cortical collecting duct
Direct action by increasing intracellular cGMP
How does ANP Inhibit Na reabsorption in proximal tubule
Indirect action
ANP stimulates proximal tubule cells to secrete dopamine which inhibits Na reabsorption
What is the effect of ANP decreasing renin secretion
AII and aldosterone levels fall this reducing Na reabsorption
What is the effect of ANP on glomerular arterioles
Efferent remains the same or is constricted and afferent diameter increases
This raises GFR and thus the amount of Na filtered
What is Addison’s disease
Adrenal insufficiency
Both aldosterone and glucocorticoids are deficient
Loss of aldosterone leads to natriuresis and reduced ECF volume and eventually circulatory collapse
Extracellular [K+] control also fails
What does excess aldosterone result in
Increased ECF volume, hypertension, K depletion and metabolic alkalosis
Is the movement of fluid between the interstitial and intracellular spaces influenced by the same variables as between the plasma and interstitium?
No they are entirely different
There is no hydrostatic pressure
Small ions cannot move across membranes freely so exert osmotic effect
The osmolarity if the intracellular and interstitial fluid is equal. What happens if one changes
Water will flow across the membrane until equilibrium is attained
How can hyper hydration be treated
With mannitol
It is an unreactive sugar that can cross capillary membrane but not cell membranes, thereby drawing water out of cells by osmosis
Osmolarity =
Amount of solute
————————-
Amount of solution
How do kidneys regulate osmolarity
Changing water (the solvent)
What are the 5 things necessary for a material used to test ECF
Restricted to one compartment Evenly distributed Not change volume itself Not change over time (via excretion etc) Non toxic Easily measurable
How is total body water measured
Why
D2O
Volume distribution is very large cf it’s rate of excretion
How does the single injection method work
If there is a single injection, substance is not immediately equally distributed so you must wait until it is, but then some will be lost!
Therefore you extrapolate back to time of injection
What is used in single injection method to measure blood volume
Why
Albumin with Evan’s blue
Confined to plasma and lost slowly
When is constant infusion method used
What is it used to measure
What substance is used
If excretion is fast but lost by a single measurable route
Used to measure total ECF
Inulin- Something that can cross capillary membrane but not that of the cell
How does constant infusion method work
Infuse substance at a constant rate until measured plasma concentration is constant
Stop infusion and then measure amount of substance excreted from that time
How is ICF measured
Total body water-ECF
How much of the blood at resting CO do the kidneys receive
How much do they weigh
25%
2% of human body weight
What are the interlobular and arcuate arteries
Interlobular: in renal columns to renal cortex and Medulla
Arcuate: run along corticomedullary border and branch into interlobular arteries
Where is most of the filtrate reabsorbed
Peritubular capillaries which follow the efferent arteriole
What are the vasa recta
What do they do
Capillary loops that descend into the medulla before returning to the cortex
Maintenance of hyperosmotic environment within the medulla
How much of the plasma is filtered from the glomerular capillaries
20%
Give the basic function of the proximal tubule
Reabsorption of 70% of filtrate and all glucose and αα
Reabsorption is varied so proximal tubule is useful in volume regulation
Isotonic fluid reabsorption
Mention the histology of the proximal tubule cells
Large surface area and many mitochondria
Give the basic function of the loop of Henle
Separate reabsorption of solutes and water
Makes fluid leaving the loop hypo-osmotic to plasma and the inner medullary hyperosmotic
Therefore is central to concentration of urine
Give the basic function of the distal tubule
Control of K+ and pH
Water reabsorption occurs here in concentrating kidney
In the diluting kidney it is water impermeable
Give the basic function of the collecting duct
Allows water reabsorption into first the iso-osmotic cortex and then the hyper osmotic medulla
What are the 2 populations of nephrons
Cortical and juxta medullary (only these have loops of Henle that descend into the inner medulla)
Why can all nephrons use the hyperosmotic inner medulla to concentrate urine
All nephrons join collecting ducts that run in the inner medulla
What is filtration
Movement of water and dissolved solutes through a filter due to a pressure gradient
How does water pass from the glomerular capillaries into the Bowman’s capsule
Give detail
Through a 3 layer filter
3 layers: fenestrated capillary membrane, basal lamina, filtration skits between podocytes that line the capsule
What is the most restrictive part of the 3 layered filtration in Bowman’s capsule
The diaphragms bridging the floors of the podocytes
What is the role of the fenestrated capillary membrane
Large pores (~70nm) prevent passage of cells (~7μm) but allow passage of large proteins
What is the role of the basement membrane in the glomerular capillary
Negatively charged to repel large negative proteins eg albumin but is too large to interact with small ions
restricts passage of large solutes
What do the renal podocytes do
Most restrictive layer and carries a negative charge
How is GFR primarily regulated
Changing capillary hydrostatic pressure by varying resistance in arterioles
How does changing resistance in the glomerular arterioles change GFR
Increasing afferent resistance protects capillaries from high blood pressure and reduces Pc
Constructing efferent increases Pc
Why have 2 arterioles
Flow=ΔP/ R
Allows control of Pc and plasma flow separately
Dilating afferent increases Pc AND renal plasma flow
Dilating efferent decreases Pc and increases renal plasma flow
Equation for RBF (renal blood flow)
ΔP
———-
R(aff)+R(eff)
ΔP= arterial pressure - renal venous pressure
How does the GFR change with ABP
Changing ABP has little effect on GFR within the normal range
What are the mechanisms in place to keep GFR constant when ABP increases
Myogenic
Tubulo-glomerular feedback
Describe the myogenic mechanism to control GFR
Afferent arteriole constricts when stretched and relaxes when released from stretched
Describe tubulo glomerular feedback
Macula densa senses NaCl uptake
Increased NaCl suggests extra NaCl is being filtered / flow rate is too high for NaCl to be reabsorbed
Macula densa releases ATP, which releases a paracrine hormone to constrict adjacent hormone
What are the most important mechanisms controlled GFR
Renin - Angiotensin system
RSNA
How does the filtration coefficient effect GFR
Kf is the product of glomerular capillary permeability and capillary area for filtration
Kf can drop if pores are blocked or mesangial cells contract
Why may a kidney stone impede filtration
Increases hydrostatic pressure in Bowman’s capsule
What can affect the reflection constant in the kidneys
An increase in glomerular protein permeability reduces its value
This is nephrotic syndrome
Protein loss here can cause oedema due to reduced COP
How does COP change in the glomerular capillaries
Increases along the capillary as fluid is filtered out
RBF therefore affects GFR because a high RBF reduces the rise in COP along the capillary so more filtration takes place at the end of the glomerular capillary
What is reabsorption in the proximal tubule primarily responsible for
What about the distal parts of the nephron
Conservation
Regulation
Clearance =
Rate of excretion
—————————
Plasma concentration
What are the units for clearance
ml/ min
ml of plasma per minute
If a substance in filtered freely, what is the equation for rate of filtration
Rate= GFR x plasma concentration
If the substance is neither reabsorbed nor secreted, what is the rate of excretion equal to
Rate of filtration
When does clearance= GFR
If a substance is freely filtered, not reabsorbed and not secreted
What requirements is there for a substance needed to measure GFR
Give an example of such a substance
Freely filtered Not reabsorbed Not secreted Not metabolised/ synthesised Not toxic No influence of GFR
Inulin
What method is used to measure GFR using inulin
Constant perfusion
What else can GFR be calculated using
How is its clearance calculated
Creatine
Using rate of excretion and plasma concentration
What does estimation using creatine require
Why
Adjusting for weight height etc
It is produced by muscle and so proportional to muscle mass
Clearance ratio of X =
Clearance of X
————————-
Clearance of inulin
What does a clearance ratio greater than 1 suggest
What about less than 1
CR>1 implies secretion
CR<1 implies reabsorption/ incomplete filtration
What can be used to estimate renal plasma flow
Why
By how much does this underestimate
Para-aminohippurate (PAH)
Freely filtered and secreted by kidney so almost completely cleared by the kidney
Almost all PAH entering the kidney ends up in the urine
By ~10%
Why does using PAH to measure renal plasma flow underestimate by 10%
PAH is only secreted from cortical peritubular capillaries and 10% of blood travels through the medullary capillaries
What is a more accurate way to use PAH to estimate renal plasma flow
Fick Principle
Flow x (Δ[PAH])
3 forms of passive reabsorption mechanisms
Simple diffusion
Facilitated diffusion
Solvent drag
What is facilitated diffusion
Movement of a substance across a membrane via a channel or transporter
What is solvent drag
Para cellular flow of water carries dissolved substances with it
3 forms of active transport
Primary
Secondary
Endocytosis
What is primary active transport
Transmembrane transport directly coupled to ATP by a transport protein
What is secondary active transport
Transmembrane transport of a substance coupled to the electrochemically favourable movement of another substance
2 types of secondary active transport
Symport- substances travel in same direction
Antiport- travel in opposite directions
Difference between channels and transporters
Channels are simply pores whereas transporters require an active change
Carrier proteins therefore have a transport maxima
Where can transport maxima be seen in the kidneys
Diabetic patient
Glucose is freely filtered but actively reabsorbed so reaches a maximum rate and cannot keep up with filtration
Why does Na concentration remain constant in the proximal tubule despite being reabsorbed
Reabsorption is isotonic and water follows the solute
Give the concentration of glucose and αα after the proximal tubule
0
What are the 2 glucose transporters in the nephron
Where are they and why are they different
SGLT-2 = early proximal tubule SGLT-1 = late
SGLT-1 transports 2 Na for each glucose as glucose is in lower concentrations later
Give experimental evidence of isotonic reabsorption in the PCT
Simple micropuncture:
Samples from early and late reveal same osmotic pressure
Injected inulin increases in concentration is found and as it is not secreted or reabsorbed it must be caused by fluid reabsorption
Describe stopped flow perfusion / split oil drop method to show isotonic reabsorption in the PCT
Inject mineral ion into Bowman’s so some enters PCT
Isotonic NaCl is injected to split oil drip such that solution between droplets is known
Droplets move towards each other, indicating reabsorption of fluid
Name 4 organic anions secreted into the PCT
Prostaglandins
cAMP and cGMP
Bile salts
Drugs eg penicillin
Name 4 organic cations that are secreted in the PCT
Creatine
Adrenaline and NA
dopamine
Drugs eg morphine
2 things worth considering about reabsorption
What does this mean for drug administration
Transport maxima for these transporters is low
Different anions or cations May compete for the same transporter
Co-administering 2 drugs that are excreted by the same transporter can raise concentrations of both
What is the ratio of K+ in the ECF compared to in the cells
98% inside to 2% in ECF
What is the physiological role of K+
Membrane potential
It is thus important for cell functions including volume and pH regulations as well as excitability
What is normal extra and intracellular [K+]
Extracellular: ~4mmol
Intracellular: 125mmol
Why do changes in amount of K+ in extracellular space have a bigger effect on membrane potential than changes inside the cell
Extracellular space is smaller than intracellular and [K+]i»[K+]e
How much K+ might you take in during 1 meal
How much would [K+] increase if all this entered the extracellular space (16L) at once
Why is this relevant? ( the numbers are massively important to remember, just understand the gist)
33mmol
33mmol/16L =2mmol-1
This would increase membrane potential of K by +10mV whereas if K+ was quickly taken into cells, intracellular [K+] would only change by 1.4mmol-1 so Ek would differ by -0.3mV
Hence, by moving K+ into cells the change in membrane potential is decreased 30 fold
True or false:
Intracellular K+ is more tightly controlled than extracellular K+
False
Normal functioning of cells requires tight control over extracellular K+ whereas intracellular can vary considerably without affecting membrane potential too much
How is extracellular [K+] regulated in
a) short term
b) long term
a) moving K+ between intracellular and extracellular compartments
b) controlling amount of K+ in the body
How much K+ is ingested each day
100mmoles
What are the insensible losses of K+
10mmol lost in faeces and sweat
What are the controlled losses of K+
Kidneys can excrete between 1% and 80% of filtered K+
Name 4 physiological or pathological factors causing intracellular to extracellular K+ shift
Action potentials
Dehydration
Cell lysis
Acidosis
How do action potentials change the distribution of K+
Where is this significant
Repolarisation shifts K+ out of the cell
In skeletal muscle
In what type of tissue is most of the body’s K+ stored
What proportion
Skeletal
70%
Why does dehydration change K+ distribution
An increase in plasma osmolarity causes cell shrinkage, increasing intracellular [K+]. Therefore the cell may lose K+
How does cell lysis change K+ distribution
When does this become a problem
Cell death releases K+ into extracellular space
When lots of cells die rapidly eg severe burns, trauma, when the blood supply is restored rapidly to an ischaemic limb or in tumour lysis syndrome
What is tumour lysis syndrome
Excessively rapid chemotherapy induced death of tumour cells
How does acidosis change K+ distribution
Movement of H+ into cells displaces K+
As cells are well buffered they can take up lots of H+
What factors can cause an extracellular to intracellular K+ shift
Why
Hyper hydration (cell swelling from decreased plasma osmolarity can cause cells to take up more K+)
Insulin (activates Na/K pump and increases Na+ entry via Na+/ glucose transport)
Adrenaline (activates Na/K pump
What does high and low [K+]e cause
High: hyperpolarisation
Low: depolarisation, can also reduce Na/K pump activity
Low [K+]e and digoxin is a bad combination. Why?
Low [K+]e reduces Na/K pump activity and digoxin is a Na/K pump blocker so there is a potentiation effect
How do the effects of slight hyperkalaemia and extreme hyperkalaemia differ
What is the ultimate effect of both
Hyperkalaemia causes depolarisation, bringing excitable cells closer to the threshold but eventually causes inactivation of VG Na+ channels
Therefore small degrees of depolarisation causes increased excitability but greater depolarisation causes inexcitability
Both increase risk of cardiac arrest
What are the effects of hypokalaemia
Hyperpolarisation, reducing excitability thus causing muscle weakness or in extreme cases paralysis (including diaphragm paralysis) and cardiac arrhythmia
When is regulation of internal K+ balance particularly important in 2 physiological stresses
Eating (rapid intake into extracellular space)
Exercise (prolonged muscular activity causes a shift of K+ from within skeletal muscle into the extracellular space
What are the fees forward responses to eating and exercising to prevent severe hyperkalaemia
Eating: rise in blood glucose stimulates insulin release
Exercise: adrenaline release
Both insulin and adrenaline stimulate Na/K pumps driving K+ into cells in exchange for Na+
If the Na/K pump requires intracellular Na+, how can insulin effectively increase the pump’s activity?
It also stimulates the Na+_glucose transporter thereby bringing both Na+ and glucose into the cell from the blood after/ during a meal
Which hormone is important in feedback control of K+
How
Aldosterone
A rise in plasma [K+] is detected by aldosterone secreting cells in the adrenal cortex. Aldosterone controls K* excretion in kidneys and stimulates Na/K pump, driving K+ into cells
What are beta blockers
Temporary exercise induced what can occur in patients taking these
β2 adrenergic blockers taken for hypertension
Transient hyperkalaemia
What are the 5 stages K+ takes through the kidney
1) K+ is freely filtered
2) unregulated absorption of K+ in proximal tubule
3) unregulated reabsorption of K+ occurs in TAL of loop of Henle
4) some unregulated reabsorption in Type A Intercalated of distal tubules and collecting duct
5) regulated secretion from principal cells of distal tubule and collecting duct
How much of the filtered K+ is reabsorbed in the proximal tubules
67%
How much of the filtered K+ is reabsorbed in the thick ascending loop of Henle
20%
How much of the filtered K+ enters the distal tubule and collecting duct
~13%
How much of the filtered K+ is reabsorbed in the Type A cells of the distal tubule and in the collecting duct
Type A: (3%)
Collecting duct:9%
Where is regulated secretion of K+
In the principal cells of the distal tubule and in collecting duct
Where does all regulation of K+ excretion occur
Principal cells of the DCT and collecting duct
Usually does secretion or reabsorption of K+ dominate in the DCT and CCT
Secretion as K+ intake»insensible losses
3 ways to increase K+ secretion
High plasma [K+]
Aldosterone
High tubular flow rate
How does high plasma [K+] increase control of K+ secretion
It increases interstitial [K+] thus enhancing K+ transport into principal cells, increasing K+ gradient across luminal membrane
How does aldosterone increase control of K+ secretion
Where is it released from and when
How long does it take to work? Why?
Increases activity of SK, ENaC and Na/K pump
Released from adrenal cortex in response to raised plasma [K+]
At least an hour Cos it stimulates protein synthesis
Does aldo increase the channels themselves?
Possible but it might instead increase the number of activatory proteins
However the Na/K pump density does increase in the long term
How does high tubular flow rate increase control of K+ secretion
K+ secretion across luminal membrane is passive so will slow if K+ builds up in tubule. This is prevented by a high flow rate.
How can you show the the importance of [K+] plasma and aldosterone
Compare effects of variation in dietary K+ intake in normal animals vs without adrenal glands given constant aldosterone infusion
In hypovolaemia, how is K+ secretion decreased
Increased Na+ reabsorption in earlier segments reduces tubular flow rate reaching the distal tubule , so less K+ is secreted
Why is increased Na+ retention in hypovolaemia not associated with increased K+ loss, if aldosterone is released
Other Na+ retention mechanisms are also activated leading to a decreased flow rate in distal tubule
Does ADH have a big impact on K+ excretion
No
It actively avoids altering K+ excretion
Why does ADH have to enhance K+ secretion
ADH promotes water absorption, reducing flow in DCT and CCT. Therefore ADH must balance this (as decreased flow decreases K+ secretion) by stimulating luminal K+ conductance in principal cells
3 causes of hypokalaemia
Diuretic treatment
Diarrhoea, vomiting
Nil by mouth
3 causes of hyperkalaemia
Renal failure (glomerular filtration below 20% of normal prevents adequate K+ excretion despite normal diet)
Iatrogenic: IV cannot have too much K+
Acidosis: H+ enters from cells, displacing K+ so K+ shifts from ICF to ECF
H+ also increases K+ reabsorption in DCT and CCT so less lost in urine
Treatment for hypokalaemia
K+ supplement (must be gradual to avoid sudden changes in membrane potential)
Treatment for hyperkalaemia
Glucose and insulin administered
Ca2+ can stabilise membrane potential in short term to reduce chance of arrhythmia
K+ chelating agents can reduce K+ absorption from diet in patients with renal failure
Why is pH regulation important
Protein charges are pH dependent meaning enzyme and ion channel function are pH sensitive
Give the normal pH range in the average human cell
What about in plasma in extremes
- 35-7.45
6. 8-7.8 in plasma
What is the [H+] range in humans
Normal: 45 to 35nmol-1
Abnormal: 160 to 16 nmol-1 (a ten fold difference!!!)
How much metabolic CO2 is produced each day by a human
15-20 moles (NOT nmol)
Why does a normal diet make the blood acidic
Food contains both acids and bases but bases are usually lost in faeces
Name 3 static buffer systems for blood plasma pH
Inorganic phosphate
Plasma proteins
Haemoglobin
Give the buffer equation for inorganic Phosphate
H2PO4- ↔️ H+ + HPO4 2-
Give the equation for plasma proteins as a buffer
Protein - + H+↔️protein-H
True or false
The bicarbonate system is a powerful static buffer system
False
The bicarbonate buffer system is dynamically controlled by the respiratory and renal systems
How is non volatile acid buffered
By HCO3- and it is excreted as CO2
Give the buffer equation involving non volatile acids
Metabolic acids + NaHCO3 —> CO2 + H2O + Na*salt of the acid
According to which equation does the state of the bicarbonate system determine plasma pH
The Henderson Hasselbalch equation:
6.1 + log([HCO3-]/0.03PCO2)
How is the concentration of CO2 given in the Henderson Hasselbalch equation
As 0.03PCO2
This is the solubility of CO2 multiplied by its partial pressure (Henry’s Law)
What is important to consider when calculating the influence on pH of addition of a non volatile acid
The acid reduces [HCO3-] by an equimolar amount and does not influence PCO2
Do the kidneys usually net produce or excrete HCO3-
Produce
But can do both
4 steps required for production of HCO3- by the kidneys
1) reabsorption of filtered HCO3-
2) production of HCO3- and H+ in proximal tubule …
3) … allowing secretion of H+ and the return of HCO3- to the plasma
4) buffering of tubule H+ to allow further secretion
How is HCO3- produced in proximal tubule
How does it enter the tubule
From glutamine
It is freely filtered and can be secreted by Type B intercalated cells in collecting duct
How is H+ buffered in the urine
As H2PO4- and NH4+
How is HCO3- reabsorbed in all parts of the tubule
Secretion of H+, acidifying the tubule
This pushes HCO3- + H+↔️CO2+H2O to the right
Neutral CO2 diffuses into the cell
The cell is more alkaline due to secretion of H+ so equation is pushed to the left producing HCO3- and H+
HCO3- is transported across the basolateral membrane and H+ is secreted
This is catalysed by carbonic anhydrase
Does HCO3- reabsorption replace the HCO3- lost to buffer metabolic H+
No some must be produced
What is the problem with the kidneys’ production of HCO3-
How do we fix this
The associated H+ must be excreted BUT
the minimum urine pH 4.5
At pH 4.5, [H+]= 30μm but daily intake is 50-100mmol so we would either have to produce 3300L of urine a day at pH 4.5 or produce pH 1 wee
Buffering pH in urine
Why can’t we use HCO3- to buffer urine
We can not afford to lose it
Why can’t we use inorganic phosphate to buffer urine
What is employed instead
There is not enough to buffer all H+ to be excreted
Ammoniagenesis
What is the net effect of ammoniagenesis
What is the buffer
What else is produced
H+ is excreted as NH4+
NH3
2 HCO3-
How is glutamine found for ammoniagenesis
What is this an alternative to
Produced from waste amino acids in the liver by trans animation
Deamination into urea
Where is NH4+ excreted
The proximal tubule
What happens to NH4+ from glutamine one proximal tubule cells
It dissociates into NH3 and H+
NH3 freely diffuses across the membrane into the tubule
The lumen is acidic due to Na/H exchange and H+ ATPase so NH4+ is formed and is trapped in the tubule
What is the path of NH4+ throigh the nephron
After entering as NH4+ in the proximal tubule, it is reabsorbed in the TAL, substituting for K+ in the Na/K/2Cl- co-transporter
NH4+ builds up in the medullary interstitium and the NH3 formed diffuses through collecting duct cells to be protonated in the tubule. Here it is finally trapped in the tubule as NH4+ to be excreted
What is the key control point in the journey of NH4+ through the kidney
The ammonium trapping stage
Ammonium is trapped in the tubule if pH is low. What happens if pH is high
Much of the NH4+ is instead converted to urea in the liver
How much of NH4- and HCO3- is produced from the catabolism of glutamine each day
1 mole of ESV
What is the equation in the urea cycle to remove NH4+ and HCO3- and form urea
What pathway is instead Up regulated in metabolic acidosis
2 ammonium + 2 bicarbonate —> H2N-CO-NH2 + 3H2O + CO2
2 ammonium + α-ketoglutarate —> glutamine
Describe the intrinsic control of HCO3- absorption and acid secretion in the kidneys
H+ is required for HCO3- reabsorption and H+ secretion is enhanced by low pH and reduced by high pH
Increased PCO2 enters tubules, lowering pH thus enhancing H+ secretion and HCO3- absorption
Expression and activity of transporters increases in low pH (possibly due to autocrine and paracrine effects of endothelin
Name 4 hormones that respond to pH change
Cortisol
PTH
AII
Aldosterone
How does cortisol react to low pH
Cortisol levels increase and it increases transcription of NHE and NBC in proximal tubule
How does PTH react to low pH
In prolonged acidosis, PTH promotes acid secretion in the TAL and DCT
PTH also reduces inorganic phosphate reabsorption in PCT, increasing buffering in tubule
How does AII react to low pH
Stimulates Na/H exchanger in proximal tubule
What does aldo do in low pH
Stimulates K/H ATPase in Type A cells, increasing H+ secretion and K+ reabsorption
Why may respiratory acidosis occur
Chronic obstructive pulmonary disease
Why may respiratory alkalosis occur
Hyperventilating at altitude
Why may metabolic acidosis occur
Diabetic ketoacidosis
Sever diarrhoea
Why may metabolic alkalosis occur
Prolonged vomiting
Why are non compensated metabolic acid base disorders rarely seen
Respiratory compensation is usually v quick
What is the Davenport diagram used for
Diagnosis of acid base disorders
True or false:
Urine osmolarity is regulated by controlling the amount of water in the urine
True
NOT by controlling its solute content
What mainly controls the amount of water in the urine
ADH, released from the posterior pituitary in response to changes in osmolarity
What are the 3 priorities for the body
Avoid hypotension
Maintain ECF volume
Maintain ECF osmolarity
Why does osmoregulation take precedent over volume regulation normally
ECF volume should not drop by >10-20% to threaten blood pressure
What is the major determinant of ECF osmolarity
NaCl
Why does changing NaCl in the body not change plasma osmolarity (2)
1) Most NaCl reabsorption is isotonic
2) ADH and thirst adjust water excretion to maintain osmolarity
Where are water movements not isotonic in the nephron
LoH
DCT
CCT
What is the range of osmolarity of urine
How does this compare to plasma
30 to 1200 mOsm/kg
Between 1/10 and 4x osmolarity of plasma
What are the 2 problems with the range of the osmolarity of urine
Give a solution to each
1) problem: no such thing as an active water pump so water must flow according to a gradient (osmotic or pressure)
Solution: pumping ions across water impermeable cells builds an osmotic gradient that can later be used to transport water
2) problem: max transcellular osmotic gradient= 200mOsm/kg
Solution: employing countercurrent multiplication
Why is the the max transcellular osmotic gradient 200 mOsm/kg
Ion transport becomes less energetically favourable and back leakage increases
How does the kidney produce anisosmotic urine
by first separating ion transport and water in LoH (where ions enter the interstitium and water is retained, making the fluid dilute)
As the fluid leaving the LoH is hypo-osmotic it is v easy to make hypo-osmotic urine; in the absence of ADH the nephron is impedance to water and other solutes are reabsorbed, making the fluid increasingly hypo-osmotic
How do we produce hyperosmotic urine
Separate ions from fluid in LoH while retaining water
ADH makes the rest of the nephron water permeable so water is drawn out of the distal tubule and CCD into the isosmotic cortex. Therefore, the fluid entering the medullary collecting duct is hyperosmotic to plasma due to the action in the LoH, thus water is reabsorbed from the medullary collecting duct and hyperosmotic urine is produced
4 steps of water movements in the diluting kidney
1) Ions pumped out of LoH but water doesn’t follow
2) This Medulla becomes hyperosmotic
3) and makes the tubular fluid leaving the LoH hypo osmotic
4) absence of ADH makes water permeability low in the nephron and further ion reabsorption gives hypo osmotic urine
5 steps of water movements in the concentrating kidney
1) Ions pumped out of LoH but water doesn’t follow
2) This Medulla becomes hyperosmotic
3) and makes the tubular fluid leaving the LoH hypo osmotic
4) high ADH allows water to move from hypo osmotic fluid into isosmotic cortex in DCT and CCT
5) from the now isosmotic tubular fluid, water is drawn into the hyperosmotic medulla
How do we know the medullary interstitial space is significantly hypertonic to plasma
Microcryoscopy (rapid freezing and sectioning of the kidney allows estimation of solute concentrations bf measuring the melting point of different regions, as solute depresses the melting point
Give the 4 stages of the process to Make the medulla interstitium hypertonic
Which are only significant in the concentrating kidney
1) active active NaCl reabsorption
2) countercurrent multiplication
3) urea cycling
4) passive NaCl reabsorption
3 and 4 are only relevant in the concentrating kidney
Where are ions removed from water to make the medulla hypertonic
TAL of the LoH
How effective is the ion transport in the TAL
Very
One cycle of the Na/K pump could allow transport of 12 ions across the luminal membrane
Why is K+ allowed to leak across the luminal membrane in the TAL
To keep the tubule fluid positive with respect to the interstitial fluid
Ion transporters are energy favourable. True or false?
False
They’re more like energy efficient
How does countercurrent multiplication work
1) TAL makes medulla hypertonic
2) water is drawn out of descending limb
3) fluid entering ascending limb is hypertonic
4) therefore the TAL can make the medulla more hypertonic and back to step 2
Why is K+ allowed to leak across the luminal membrane in the TAL
To keep the tubule fluid positive with respect to the interstitial fluid
Ion transporters are energy favourable. True or false?
False
They’re more like energy efficient
How does countercurrent multiplication work
1) TAL makes medulla hypertonic
2) water is drawn out of descending limb
3) fluid entering ascending limb is hypertonic
4) therefore the TAL can make the medulla more hypertonic and back to step 2
How many DCTs feed into the collecting tubule
Many
How much of the medullary tonicity is countercurrent multiplication directly responsible for?
600 mOsm/kg: Half the maximum possible medullary tonicity
What is the concentration of urea in the renal medulla thanks to urea cycling
How much does this contribute to the osmolarity
600 mmol/kg
600mOsm/kg
What is the range of concentrations of urea in the filtrate
2.5-7.5mmol/kg
What happens to urea in the PCT
Freely filtered in the glomerulus and 50% is passively reabsorbed in the PCT
How is urea reabsorbed in the PCT
A gradient for passive reabsorption is created by the reabsorption of water
Where is the distal nephron permeable to urea
How is permeability increased
In the inner medullary collecting duct ONLY
Increased by ADH
How much of the urea reaching the IMCD is reabsorbed
> 50%
How is urea reabsorbed from the IMDC
Water is reabsorbed in the DCT, CCD and outer medullary collecting duct in the presence of ADH but these are impermeable to urea so tubular [urea] increases
This creates an outward gradient for urea reabsorption in the IMCD so [urea] is high in the medullary interstitium
What is the urea cycle in the nephron
1) water reabsorbed in the DCT and CCT
2) this makes a steep gradient for urea reabsorption in the IMCD
3) as medullary [urea] is high, and the deepest thin limbs of the LoH are urea permeable, urea is secreted into the deep LoH, increasing overall tubular [urea]
Does the thick ascending limb actively extrude NaCl
No NaCl is reabsorbed passively due to gradients that result from urea cycling
In the maximally concentrating kidney what is the composition of medullary tonicity
What about in the tubular fluid?
Half due to NaCl and half due to urea
(600mOsm/kg each )
Fluid has more NaCl (300mmol/kg of NaCl) and much less urea
How is NaCl reabsorbed in the thin ascending limb
It is permeable to NaCl and the fluid ascending through the thin limb has a much higher [NaCl] than the medullary interstitium, increasing the NaCl concentration in the deepest parts of the medulla
Why must active transport be limited in the deep renal medulla
How is this overcome for NaCl reabsorption
It has a poor blood supply so active transport must be minimal
Transport in the TAL in the outer medulla powers NaCl reabsorption in the thin limb in the inner medulla
How does urea concentration in the medulla vary between the diluting and concentrating kidneys
[urea] in the medulla of the diluting kidney is far lower because without ADH no water is reabsorbed in the DCT, CCT and MCD so urea does not become concentrated in these segments
How long does it take [urea] to build up in the medulla after release of ADH
Several hours ago
Fluid in the descending limb of the LoH is always hypertonic and it is always hypotonic as it leaves the ascending limb. How is it pattern affected by ADH?
Why?
The degree of hyper tonicity increases as ADH levels increase
ADH does not act on the LoH so this effect is due to the effect of ADH on urea cycling
Why can there not be a simple capillary network in the renal medulla
Water would move into the vessels via osmosis and solutes would diffuse in, dissipating the medullary concentration gradient
Where do the vasa recta come from
From the efferent arterioles of nephrons closest to the medulla (juxtamedullary nephrons)
What is the course of vasa recta after they leave the efferent arterioles of juxtamedullary nephrons?
They descend straight down into the deepest medulla, form a hair pin loop, then ascend up to the cortex, forming veins.
Describe the countercurrent exchange of the vasa recta
As blood descends, the surrounding interstitium becomes increasingly hypertonic, so water moves out and urea and NaCl move in. However, as it ascends, the blood is hypertonic to the interstitium so water moves in and urea and NaCl moves out
Is the vasa recta’s countercurrent system perfect?
No some solute is retained from the descent so some water is accumulated in the ascent
Is it good that vasa recta does remove some solute and water?
Yes because the action of the LoH and MCD makes NaCl, urea and water build up in the medulla and the vasa recta is the only route for these to leave
What can cause plasma hypo-osmolarity
Extremely excessive and rapid water intake
Excessive Na+ loss (eg in severe diarrhoea and only water, not electrolytes, is replaced)
Inappropriate ADH secretion (eg head injuries, severe infections and some cancers cause abnormally high ADH secretion)
What can cause hyper osmolarity
Dehydration
Very high blood glucose
Is hyper osmolarity seen in badly treated type 1 diabetes
No
They become ill due to ketosis before glucose levels can become high enough to significantly influence plasma osmolarity
Why can we tolerate slow changes to plasma osmolarity (over days or weeks rather than hours)
Why is it important to remember this
Many cells types (including brain Cells) can regulate volume by eliminating or synthesising intracellular osmoles, minimising the effect of extracellular osmolarity
Rapid correction of long standing abnormality in extracellular osmolarity is very dangerous
How long does it take for the diuretic response to begin once you start drinking
Within minutes because drinking causes inhibition of ADH from the posterior pituitary by a nervous reflex from the throat and gut
How is the liver involved in the reflex when drinking
Osmo receptors in the liver contribute to the diuretic response because the osmolarity of the hepatic Portal blood falls due to water arriving in the guts
How would the response drinking isotonic saline differ from drinking freshwater
A small initial diuresis via nervous inhibition of ADH occurs however there is no change in osmolarity so the response is short lived
What is the maximum concentration of eerier in the interstitium of the kidney?
What is the maximum area of concentration in urine
600 mOsm
600 mOsm
Because the inner medullary collecting duct is freely permeable to area under the conditions of the concentrating kidney
What is the net gain of water if you drink 1 L of seawater
There is a net loss of of 0.67 L (you in take 1L but have to loose 1.67)
What is the effect of salt water on the gut
The salt concentration of seawater is 3 to 4 times higher than that of plasma
Once in the gut it would draw water into it and promote diarrhoea thus enhancing dehydration
As seawater draws water into the gut, how is ECF affected
What will this lead to
Osmotic pressure will increase
Hypothalamic osmoreceptor is will be stimulated: this has 3 effects: stimulate ADH release, stimulate hyperosmotic thirst and promote antidiuresis
ECF volume decreases, reducing blood volume and eventually arterial blood pressure which is detected by baroreceptors which will decrease the firing, disinhibiting the thirst centre of the hypothalamus
Why might you want to drink more seawater after drinking some already
Water absorption into the gut, increases ECF osmotic pressure, stimulating hypothalamic osmo receptors which in turn stimulate hyperosmotic thirst
True or false
Hypovolaemic thirst occurs if you drink sea water
True
ECF volume decreases, reducing blood volume and eventually arterial blood pressure which is detected by baroreceptors which will decrease the firing, disinhibiting the thirst centre of the hypothalamus
What effect will a fall in arterial blood pressure to the kidney in haemorrhage have (2)
Why is each done
It will reduce Sodium excretion:
1) the glomerular capillary pressure will decrease - GFR and filtration of sodium will decrease
2) peritubular capillary pressure will decrease - This favours reabsorption of fluid from interstitial space into peritubular capillary. This will reduce the renal interstitial hydrostatic pressure which will favour reabsorption of fluid from the PCT into the interstitial space, slowing moving of tubular fluid
How does colloid osmotic pressure change in haemorrhage
Usually it does not change as both ECF and plasma proteins are lost
However during severe haemorrhage which result in a fall in a BP, COP will fall – this is because the decreased ultrafiltration would reduce blood COP
Give an overview of the result of a fall in ABP after a haemorrhage
An increase in sympathetic discharge which will affect both cardiovascular and renal systems to restore blood pressure
What is the cardiovascular response to a fall in ABP after haemorrhage?(4)
Baroreceptors will decrease frequency of discharge to the medulla oblongata
This will stimulate vasoconstriction to increase TPR and venoconstriction to increase VR - Starling’s Law
Sympathetic nerves also innovate pacemaker cells of the heart increasing both heart rate and contraction
This is all reinforced by sympathetic signals to the adrenal medulla via splanchnics to release adrenaline
Describe the endocrine factors affecting the kidney after a haemorrhage
Angiotensin II concentration increases:
This causes vasoconstriction via AT1 receptors thus increasing TPR
Also increases sodium retention by mimicking RSNA and stimulating aldosterone secretion via AT2 from the zona glomerulosa
2 behavioural effects of angiotensin II after haemorrhage
Sodium appetite
Thirst
What does hypocalcaemia result in
Reduced action potential threshold, causing spontaneous activity
As muscles are particularly susceptible, tetanus occurs. Death by asphyxiation can result due to tetanic contraction of larynx muscles
What is the effect of hypercalcaemia
Raises threshold for action potentials, resulting in sluggish CNS function, muscle weakness and arrhythmia
Calcium phosphate may precipitate leading to kidney stones
(Moans, groans, bones, stones)
How is calcium found in the body
99% is found in bones
What is the most common form of calcium in bone
Hydroxyapatite (1Kg of Ca2+ is stored this way)
What is the extracellular fluid calcium content in weight
What is plasma calcium concentration? How is this found?
What is the weight of calcium present in cells? How is this mostly found?
1g
2.5 mM: either free (1.075mM) or bound to proteins/ anions (1.2mM)
10g
Sequestered in organelles but free [Ca2+]i =50-100nM
What is bone resorption
Breakdown of bone
What are the three Endocrine control factors of calcium
Parathyroid hormone
Calcitonin
Calcitriol
What secretes PTH
Chief cells in the parathyroid glands
What is the effect of parathyroid hormone basically
Raises ECS calcium concentration and lowers ECF phosphate concentration
How is PTH regulated
Arise in plasma concentration reduces PTH secretion
This works through a GPCR which has a low calcium affinity
How does PTH work
Axed directly on bone and kidney and indirectly via calcitriol on the gut
What to osteoblasts do
How are they affected by PTH
Laid out new bone
They synthesise collagen and secrete calcium and phosphate to calcify surrounding matrix
Inhibited
What happened to osteoblasts once they are surrounded by calcified bone matrix
They become osteocytes
Why do bone lining cells have PTH receptors
What do these cells do
They are of osteoclastic lineage
Separate normal interstitial fluid from that filling bone canals
How does PDH affect osteocytes
Stimulates taking up of calcium from bone fluid and transferring it to bone lining cells which secrete calcium into the ECF
How are osteoclasts activated
They are stimulated by cytokines such as interleukin-6 but not by PTH as they lack PTH receptors
What happens when PTH binds to PTH receptors on bone lining cells
PTH stimulates them to decrease in size and attract, exposing bone surface to the osteoclast action
How does calcitonin affect osteoclasts
Calcitonin directly inhibits osteoclast differentiation from progenitors
How much calcium is usually reabsorbed in the kidney
99% (mostly paracellularly)
70% in PCT and 20% in thick ascending limb - This is fixed
Regulation is over the last 10% in the DCT and collecting duct
Which channel is used for calcium reabsorption
What happens when it is in the cell
TPRV5 and 6
Binds to calbindin D and is then transported out by the Ca2+ ATPase or by NCX
What is TRPCV5 also called
TRPV6
ECaC1
CaT1 (Calcium transport protein 1)
What is the calcium reabsorption in the distal convoluted tubule like
What does PTH do
Transcellular
(Paracellular is impossible due to negative transepithelial potentials here )
Stimulates NCX in DCT and CD
How is Vit D3 formed
The action of ultraviolet light on a cholesterol derivative in skin
A similar vitamin can be ingested from plants
How are Vit D3 and its derivatives metabolised
What is the end product
Addition of hydroxyl groups in the liver and then in the kidney
1,25-(OH)2D3 : AKA calcitriol
What are the three functions of calcitriol
AIDS calcium mobilisation from bone
Facilitates calcium renal reabsorption
Increases calcium uptake from gut
How does PTH influence calcitriol
Name another hormone that is involved
Increases calcitriol when Ca2+ levels drop
Prolactin also stimulates calcitriol synthesis
What secreted calcitonin (CT)
What is its main action
What is its aim
Parafollicular cells (C cells) in the thyroid
Inhibit osteoclast activity and favour osteoblasts activity
To prevent hypercalcaemia (rather than cause hypocalcaemia)
What is calcitonin important in
Protecting maternal bone against excessive demineralisation during pregnancy when there is a high flux of calcium to the fetus and during lactation when there is secretion of calcium in milk for the neonate
CT ensures Ca2+ demand is met by the gut rather than resorption of bone
What is EGTA
A calcium chelator
What stimulates calcium secretion
A rise in ECF [Ca2+] directly
Gastrin also directly stimulates CT release as a feedforward mechanism to direct new Ca2+ to the bone
What does hypoparathyroidism lead to?
What are the consequent effects
PTH deficiency
Low ECF calcium concentration result in reduced threshold for action potentials and moderate cases may involve Trousseau’s sign and Chvostek’s sign
Severe cases can result in Long QT syndrome and even death from larynx muscle contraction and asphyxiation
What is Trousseau’s sign
Sustained wrist spams
What is Chvostek’s sign
Contraction of facial muscles
What kind of animal is known to be hypocalcaemic
High yielding dairy cattle at the onset of lactation (milk fever)
Although this appears to result from in sensitivity to PTH rather than PTH deficiency
Will hypocalcaemia always be PTH deficiency
May also be calcitriol insufficiency
The primary symptoms of calcitriol insufficiency is abnormal bone demineralisation and presents as a Ricketts or osteomalacia
What is the most common cause of hypercalcaemia?
Hyperparathyroidism
This may be due to malignant disease of bones causing erosion and calcium release
What does hypercalcaemia lead to
Raised threshold for action potentials as well as bone erosion and pain and renal stones, abdominal pain and psychiatric troubles
(Bones, Moans, groans, stones)
What is a common problem related to secondary hyperparathyroidism
Chronic kidney disease
Deficient renal response to pH leading to concentrations of calcium in the blood insufficient to promote negative feedback at the parathyroid glands. As a result there are sustained PTH levels which affect bones primarily
Osteitis fibrosis cystic may occur (similar to osteoporosis)
Name some symptoms of chronic kidney disease (5)
Diabetes
Hypertension
Autoimmune glomerulonephritis
Polycystic kidney disease
Myeloma
When does the secondary hyperparathyroidism occur
When the response of the target organs to decreased calcium or increased phosphate is deficient
Name an anti insulin protein hormone
GH
How is vitamin D3 metabolised
3 functions of it
By addition of hydroxyl groups, first in the liver then in the kidney
AIDS calcium mobilisation
Facilitates calcium renal reabsorption
Increases calcium uptake from the gut
AKA calcitriol
