Kidney anatomy &physiology Flashcards
What is the kidney derived from
Derived from the MESODERM
Position in abdomen
Retroperitoneal
Between which vertebrae
Between T12 & L3
Why is right kidney lower than the left kidney
Right kidney is lower than than the left since its pushed down by the liver
What level is the hilum of the right kidney
Hilum of right kidney: at L2
What level is the hilum of the left kidney
Hilum of left kidney: at L1 (transpyloric plane)
Three distinct structures from out till in
Three distinct structures (from outside in); cortex, medulla & pelvis
How thick is is cortex in a healthy adult
Cortex: should be 7mmthick in a healthy adult
whats in the medulla of the kidney
Medulla: Consists of 20 upside down pyramids
loop of henle & collecting ducts
What is in the pelvis of the kidney
Pelvis: Contains fat & urine collecting system
Histology of kidney pelvis
transitional epithelium
What is within the cortex
Composed of renal corpuscles (glomerulus & bowan’s capsule) and the proximal & distal (PCT & DCT respectively)convoluted tubules
Within the cortex is the medullary ray - a collection of loop of Henle tubules (they CONCENTRATE URINE using a countercurrent multiplier system) and collecting ducts that originate from the nephrons which have their renal corpusclesin the outer part of the cortex
essentially:proximal & distal convoluted tubules & renal corpuscles (consists of the glomerulus & bowman capsule)
what give the cortex its striated appearance
medullary rays
Where does the renal artery come off the abdominal artery
and then what
The renal artery comes off the abdominal aorta at L1
It then divides into segmental arteries which then lead to a radial network of arcuate arteries
How do the arcuate arteries travel
The arcuate arteries travel circumferentially(around) at the junction between the cortex & medulla and then give off interlobar arteries
What do the interlobular arteries supply
Interlobar arteries supply each lobe (a medullary pyramid and the overlying cortex) and then divide to form interlobular arteries which then terminate in the form of afferent arterioles
Whats in the pelvis of the kidney
receives the collecting ducts
who many nephrons in total
Have around2 million nephrons in total (1 million in each kidneys)
5 components of the nephron
Composed of 5 distinct segments each with their own specific function:
- Renal corpuscle - the filter
- Proximal convoluted tubule - for reabsorbing solutes
- Loop of henle: for concentrating urine
- Distal convoluted tubule - for reabsorbing more water and solutes
- Collecting duct - for reabsorbing water and controlling acid base & ion balance
the distal convoluted tubule comes back up and meets with the same glomerulus
Function of Renal Corpuscle
The filter
Function of proximal convoluted tubule
For reabsorbing solutes
Function of Loop of henle
For concentrating urine
Function of Distal convoluted tubule
For reabsorbing more water and solutes
Function of collecting
for reabsorbing water and controlling acid base and ion balance
what is the renal corpuscle
The whole unit of the glomerular tuft & bowman capsule is the renal corpuscle
The whole unit of the glomerular tuft & bowman capsule is the renal corpuscle
What is the glomerular tuft supported by
smooth muscle mesangial cells
Outside of glomerular membrane and opposite it
Outside the glomerular capillaries is a basement membrane - the glomerular basement membrane
-On the opposite side of the glomerular basement membrane is a layer of cells called podocytes - the glomerular basement membrane is a fusion of the 2 basement membranes - the capillary basement membrane and the podocyte basement membrane
What is the glomerular membrane
fusion of the 2 basement membranes - the capillary basement membrane and the podocyte basement membrane
3 Functions of the smooth muscle of the mesangial cells
- Structural support for the capillary and production of extracellular matrix protein
- Contraction of these muscles in the glomerulus tightens the capillaries and reduces the glomerular filtration rate (GFR) - this is important in tubuloglomerular feedback - where chemical changes in the tubules feedback to alter the GFR
- Involved in the phagocytosis of the glomerular filtration membrane breakdown products
2 Components of the juxtaglomerular apparatus
afferent arteriole & distal convoluted tubule
Function of granular cells
GRANULAR CELLS are able to DETECT BLOOD PRESSURE and secrete renin in response to a reduction in blood pressure
what is MACULA DENSA
The distal convoluted tubule is closely aligned to the glomerulus and afferent arteriole and has an expansion of cells at the juxtaglomerular apparatus
what can the macula densa do
detect sodium levels
function of macula densa
If filtration is slow then more sodium will be ABSORBED and the macula dense cells will send a signal to REDUCE the afferent arteriole resistance and increase glomerular filtration
What are the macula densa associated with
Macula densa are associated with the distal convoluted tubule!!
Another group of cells in the juxtaglomerular apparatus are the
Lacis cells
Why does PCT have lots of mitochondria
The cells of the proximal convoluted tubule have lots of mitochondria because they actively transportions from the glomerular filtrate including TWO THIRDS of the sodium & potassium
What do the cells of PCT reabsorb
NaCl, proteins, polypeptides, amino acids & glucose
These cells also absorb the small protein molecules that got through the glomerulus
What do the lysosomes present in the cells of the PCT
Lysosomes are present which are involved in the degradation of small protein molecules that are reabsorbed from the urinary space
NOTE: there are more lysosomes in the proximal convoluted tubule that in the distal
What do the lysosomes of the pct cells appear
black dots
What is the loop of henle supplies by
rich vasa recta
What passes out of the descending limb
Water but NOT ions passively flow out of the thin descending limb into the high osmolarity interstitium - thereby concentrating the urine
What happens in the ascending limb
The ions the body wants back are then actively pumped out of the ascending limb - leaving water & waste products
Why is the loop of henle prone to ischaemia
The vasa recta are quite far from the glomerulus (where the afferent arterioleenters to supply O2) - meaning before blood has reached it, it has alreadylost some of the oxygen it is carrying - consequently the loop of henle deep in the medulla is prone to ischemia (temporary loss of blood supply/inadequate blood supply)
What is the DCT involved in (2)
Involved in regulating acid base balance:
•Acts to acidify the urine by secreting H+ ions into it (derived from an intracellular carbonic anhydrase)
-Exchanges urinary Na+ for body K+ - this effect is mediated by aldosterone (which can lead to hypernatraemia (high Na+) & hypokalaemia (low K+))
Function of renal pelvis
- Transmits filtrate from nephron to the ureters
- Collecting duct drains into the pelvis
how is urine propelled along the ureter
peristalsis
3 MAJOR functions of kidney
- Endocrine function (secreting hormones)
- Maintain balance of salt,water & pH
- Excrete waste products
How much of cardiac output do kidneys receive and what is total renal bloodflow
Each kidney receives 20% of cardiac output
-Total renal blood flow (both kidneys) = 1L/min - this is not just to meet their own metabolic demands but to filter and excrete the metabolic waste products of the whole body
what is total urine flow
1ml/min
9 divisions of renal artery
- Renal artery
- Segmental artery
- Interlobar artery
- Arcuate artery
- Interlobular artery
- Afferent arteriole
- (Nephron) - Glomerular capillary
- Efferent arteriole
- (Nephron) - Peritubular capillary
How many capillary beds does each nephron have and where
Each nephron has 2 capillary beds (in series); one at the glomerulus and one at the peritubular area
How are the capillary beds of the kidneys connected
Within each nephron, the two sets of capillaries in the kidneys - the glomerular capillaries (glomeruli) & the peritubular capillaries, are connected to each other by an efferent arteriole, the vessel by which blood leaves the glomerulus
why is renal circulation unusual
the renal circulation is very unusual in that it includes TWO sets of ARTERIOLES and TWO sets of CAPILLARIES:
•Afferent arteriole comes BEFORE efferent arteriole since A COMES BEFORE E
What do the peritbular capillaries do and where do they go
After supplying the tubules with blood, the peritubularcapillaries then join to form the veins by which blood leaves the kidneys
what is the peritbular capillaries covered by
The entire capillary is covered by podocytes
why do the tubular processes require blood
Many of the tubular processes of secretion & reabsorption are ACTIVE (thus require oxygen & energy) thus blood supply is crucial
what is the renal corpuscle
The whole unit of the glomerular tuft & bowman capsule is the renal corpuscle
It is the combination of the glomerulus and bowman’s capsulethat constitutes the renal corpuscle
what does the renal corpuscle form and where does this go
Forms a filtrate from the blood that is free of cells, larger polypeptides & proteins
This filtrate then leave the renal corpuscle and enters the tubule
As it flows through the tubule, substance are added to or removed from it
The fluid remaining at the end of each nephron combines in the collecting ductsand exits the kidneys as urine
What does the filtrate coming from the renal corpuscle not contain
free of cells, larger polypeptides & proteins
what does the renal corpuscle contain
Each renal corpuscle contains a compact tuft of interconnected capillary loops called the glomerulus or glomerular capillaries
what supplies the glomerulus
Each glomerulus is supplied with blood by an arteriole called an AFFERENT ARTERIOLE
what does the glomerulus portrude into
The glomerulus protrudes into a fluid-filled capsules called Bowman’s capsule
How much of the blood goes into the bowman capsule from the glomerulus
As blood flows though the glomerulus, about 20% of the plasma filters into Bowman’s capsule
The remaining blood then leaves the glomerulus by the efferent arteriole
what covers the bowmans capsule
The glomerulus is surrounded by Bowman’s capsule which is covered in parietal epithelium
what happens to the bowmans capsule when blood flows through it
The part of the Bowman’s capsule in contact with the glomerulus becomes pushed inward slightly but does not make contact with the opposite side of the capsule - a fluid-filled space called BOWMAN’S SPACE exists within the capsule (protein-free fluid filters from the glomerulus into this space)
The filtrate from the glomerulusCOLLECTSin Bowman’s space before flowing into the proximal convoluted tubule
Blood in the glomerulus is separated from the fluid in Bowman’s space by a filtration barrier consisting of three layers:
- Single-celled capillary endothelium
- Basement membrane (also referred to as the basal lamina)
- Single-celled epithelial lining of Bowman’s capsule:
- The epithelial cells in this region are called PODOCYTES and are very different from the rest of the cells lining the rest of Bowman’s capsule
- They have an octopus like structure in that they possess a large numberof extensions or foot processes which acts as the GLOMERULAR FILTRATION BARRIER
What are the epithelial cells of the bowmans capsule and what do they
- The epithelial cells in this region are called PODOCYTES and are very different from the rest of the cells lining the rest of Bowman’s capsule
- They have an octopus like structure in that they possess a large numberof extensions or foot processes which acts as the GLOMERULAR FILTRATION BARRIER
So what are the fluid filters from the glomerulus to the bowmans capsule
First, across the endothelial cells
•Basement membrane
•Between the foot processes of the podocytes
what do the effetent arterioles supply
Efferent arterioles carry blood away from the glomerulus and then supply the peritubular capillaries which supply the proximal & distal convoluted tubules
-The efferent arterioles also supply the vasa recti which supply blood to the loop of Henle
what do both the peritubular capillaries & vasa recti supply
Both the peritubular capillaries & vasa recti supply:
- Water & solutes to be secreted into the filtrate
- Blood to carry away water & solutes reabsorbed by the kidneys
What does the PCT look like
Longest & most coiled with a simple cuboidal brush border
what drains the bowmans capsule
The segment of the tubule that drains Bowman’s capsule is the proximal tubule, comprising the proximal convolutedtubule and the proximal straight tubule
what is the next portion of the tubule after the pCT
•The next portion of the tubule is the loop of Henle, which is a sharp, hairpin likeloops consisting of a descending limb coming from the proximal tubuleand an ascending limb leading to the next tubular segment, the distal convoluted tubule
Where does fluid flow after the loop of henle then what
DCT
Fluid flows from the distal convoluted tubule into the collecting-duct system, which is comprised of the cortical collecting duct and then the medullary collecting duct
From Bowman’s capsule to the collecting-duct system, each nephron is completely separate from the others until what
This separation ends when multiple cortical collecting ducts merge
what does the end merging of the collecting ducts mean
The result of additional merging from this point on is that the urine drains into the kidney’s central cavity - the renal pelvis via several hundredlarge MEDULLARY collecting ducts
The medullary collecting ducts pass through the medulla on their way to the renal pelvis
The renal pelvis is continuous with the ureter draining that kidney
where are all the renal corpuscles
cortex
ALL ALONG ITS LENGTH the part of each tubule in the CORTEX is surrounded by
PERITUBULAR CAPILLARIES
Types of nephron
- 15% are juxtamedullary - meaning the renal corpuscle lies in the part of the cortex closest to the cortical-medullary junction:
- 85% are cortical - meaning their renal corpuscles lie in the outer cortex and their loop of henleDO NOT PENETRATE DEEP into the medulla:
15% of nephron are juxtamedullary what does this mean
meaning the renal corpuscle lies in the part of the cortex closest to the cortical-medullary junction:
- The loop of henle of these nephrons plunge deep into the medulla and are responsible for generating an osmotic gradient in the medulla that is responsible for the REABSORPTION OF WATER
- In close proximity to the juxtamedullary nephrons are long capillaries called the vasa recta which also loop deeply into the medulla and then return to the cortical-medullary junction
85% of nephrons are cortical what does this mean
meaning their renal corpuscles lie in the outer cortex and their loop of henleDO NOT PENETRATE DEEP into the medulla:
-Some cortical nephrons do not have a Henle’s loop at all - they are involved in reabsorption & secretion but DO NOT CONTRIBUTE to the hypertonic medullary interstitium
Near its end, the ascending limb of each loop of Henle passes between the afferent and efferent arterioles of that loop’s own nephron:
•At this point what is there
At this point, there is a patch of cells in the wall of the ascending limb as it becomes the distal convoluted tubule called the MACULA DENSA, and the wall of the afferent arteriole contains GRANULAR CELLS known as juxtaglomerular (JG) cells
afferent arteriole contains GRANULAR CELLS known as
juxtaglomerular (JG) cells
what is juxtaglomerular apparatus(JGA)
The combination of macula densa & juxtaglomerular cells is known as the
what do granular cells do
The granular cells secreteRENIN into the blood (initiating the renin angiotensin-aldosterone system)
What do the macular dans cells do
The macula densa cells detect how much NaCl is passing through the distal convoluted tubule and sends signals to the granular cells to produce renin
what is Glomerular filtration
The passage of fluid from the blood into Bowman’s space to form the filtrate:
- Surface area is approximately 1m2
- The distal part of the nephron (tubule) is responsible for secretion and reabsorption
Flow of glomerular filtrate (12)
- Glomerular capsule
- Proximal convoluted tubule
- Nephron loop
- Distal convoluted tubule
- Collecting duct
- Papillary duct
- Minor calyx
- Major calyx
- Renal pelvis
- Ureter
- Urinary bladder
- Urethra
Urine formation begins with glomerular filtration, and the filtrate is called the glomerular filtrate: what does this contain
what is the exception
It is cell-free and except for larger proteins contains VIRTUALLY all the substances in virtually the same concentrations as in plasma - this type of filtrate is also called the ultra filtrate
The only exception to rule that all non-protein plasma substances have the same concentrations in the glomerular filtrate as in the plasma are certain low-molecular-weight substances that would otherwise be filterable but are BOUND to plasma proteins and thus are not filtered e.g. half the plasma calcium and virtually ALL of the plasma fatty acids are bound to plasma protein and thus are not filtered
During its passage through the tubules, how is the filtrate’s composition altered
During its passage through the tubules, the filtrate’s composition is altered by movement of the substances from the tubules to the peritubular capillaries and vice versa
what is TUBULAR REABSORPTION
When the direction of movement is from the tubular lumen to peritubular capillary plasma the process is called TUBULAR REABSORPTION
What is TUBULAR SECRETION
Movement in the opposite direction - from the peritubular capillary plasma to the tubular lumen is called TUBULAR SECRETION
what can pass the filtration barrier
- Small molecules & ions up to 10kDa can pass freely e.g. glucose, uric acid, potassium & creatinine
- Larger molecules are increasingly restricted
what sort of -ve charges anions are repellent and why
in the glomerular basement membrane
Fixed negative charge in the glomerular basement membraneREPELS negatively charged anions e.g. ALBUMIN
why can’t albumin pass into the tubule
Albumin has a molecular weight of around 66kDa and is NEGATIVELY CHARGED meaning it CANNOT easily pass into the tubule
what is the only protein normally found in the glomerular filtrate
The only protein thats normally found is TAMM HORSFALL PROTEIN (uromodulin) in the urine that is produces by the thick ascending limb of the loop of henle
What can damage in the filtration barrier lead to
Damage to the filtration barrier can lead to protein leak and a condition known as nephrotic syndrome - causes include immune conditions, genetic abnormalities or proteins involved in podocytes/slit diaphragm
What disease damages the filtration barrier
Diabetes also damages the filtration barrier - early sign of diabetic nephropathy is by microalbuminuria (low levels of albumin in the urine)
What are the 5 determinants of the filtration barrier
Hydrostatic pressure
PGC= 45mmHg
PBS= 10mm
Osmotic pressure
πGC= 25mmHg and rising
πBS= zero
- Size of the molecule
- Charge of the molecule
- basement membrane is NEGATIVELY CHARGED
- Rate of blood flow
- Binding to plasma proteins e.g. calcium, hormones (e.g. thyroxine)
What is the hydrostatic pressure like in the glomerular capillary
Hydrostatic pressure is constant along the length of the glomerular capillary
Why does the bowman capsule provide no oncotic pressure
The Bowman’s capsule provides NO ONCOTIC PRESSURE due to the fact that there are no proteins
What is the oncotic pressure like along the glomerular capillary
Oncotic pressure INCREASES as you go along the glomerular capillary as proteins become more concentrated
GFR definition and equations
the volume of fluid filtered from the glomeruli into Bowman’s space per unit time (minutes)
GFR (PGC - PBS) - (πGC – πBS)
GFR = KF (PGC - PBS) - (πGC – πBS)
GFR = KF (PGC - PBS - πGC)
PGC: Glomerular capillary hydrostatic pressure (favours filtration)
- PBS: Bowman’s space hydrostatic pressure (opposes filtration)
- πGC: Osmotic/oncotic pressure of the glomerular capillary (opposes filtration)
- πBS: Osmotic/oncotic pressure of Bowman’s space (since there are no proteinsin the filtrate due to the unique structure of the areas of filtration in the glomerulus meaning the osmotic force is zero)
KF is the filtration coefficient - the product of the permeability of the filtrationbarrier and the surface area available for filtration
What is the average GFR in a 70kg person
•In a 70kg person the average GFR = 125ml/min
The determinants of GFR
- Net filtration pressure
- Permeability of the corpuscular membranes
- Surface area available for filtration
At any given net filtration pressure, the GFR will be what to permeabilty and SA
directly proportional to the membranePERMEABILITY &SURFACE AREA
GFR is not a fixed value but is subject to physiological regulation: how so
- This is achieved mainly by neural & hormonal input to the afferent & efferent arterioles, which cause changes in net glomerular filtration pressure
- The glomerular capillaries are unique in that they are situated between two setsof arterioles - the afferent & efferent arterioles
What does constricting afferent arterioles do to the GFR
- DECREASEShydrostaticpressure in the glomerular capillaries (PGC) - this is similar to arteriolar constriction in other organs and is due to a greater loss of pressure between arteries and capillaries
- Thereby decreasing GFR
What does constricting the efferent arteriole do to GFR
Constricting efferent arterioles:
- INCREASES hydrostatic pressure in the glomerular capillaries (PGC) - this occurs because the efferent arterioles lie beyond the glomerulus, so that efferent arteriolar constriction tends to “dam back” the blood in the glomerular capillaries, thereby raising PGC
- Thereby increasing GFR
What does dilating afferent arterioles do to glomerular filtration rate
Dilating afferent arterioles:
-INCREASES the PGC and thus the GFR
What does dilating efferent arterioles do to GFR
Dilating efferent arterioles:-DECREASES the PGC and thus the GFR
What does the simultaneous constriction and dilation of both sets of arterioles do
the simultaneousconstriction or dilation of both sets of arterioles tends to leave PGC unchanged due to the opposing effects
how is GFR calculated
Calculated by measuring the excretion of a MARKER SUBSTANCE (M)
What must the marker substance to calculate GFR be??
This marker substance must be:
- Freely filtered (same concentration in blood and tubular fluid)
- Not secreted or absorbed in the tubules
- Not metabolised
why is GFR are good measure and why is it bad?
if a disease causes you to lose nephrons then the GFR will fall - meaning GFR is a good measure of kidney function (how much fluid the kidneys can handle a minute). HOWEVER GFR only describes one aspect of kidney function - even with a normal GFR there can be other problems with the kidneys e.g. nephrotic syndrome or problems with tubular function (secretion & absorption)
what is the grr measurement equation
Amount of M in fluid = concentration in fluid x volume of fluid
what is normal GFR
how often is the entire plasma volume filtered
Normal GFR = 125ml/min - this is 180 litres in 24 hours since total plasma volume is 3 litres (interstitial fluid = 2L & transcellular = 1L) means that the entire plasma volume is filtered around 60 times every 24 hours
Example of M
Creatinine is used to estimate GFR (i.e. used as M)
What is creatinine (4)
Its a muscle metabolite with constant production
•Serum creatinine concentration varies with muscle mass
•Its freely filtered by the glomerulus
•But there is some additional secretion by the tubules
what is Filtration fraction = GFR/ renal plasma flow
Its the proportion of renal blood flow that gets filtered
•Renal blood flow = 1000ml/min
•Since 40% of the blood is cells then 60% will be plasma
•Renal plasma flow = 600ml/min
So what is filtration fraction then
Take GFR = 120ml/min (really is 125 but just rounded down to get better filtration fraction!)•Filtration fraction = 120/600 = 0.2 = 0.2%
whats urine flow
Urine flow = 1ml/min meaning most of the filtered fluid is REABSORBED
•Urine output = 0.5ml/kg/hr
-e.g. in 64kg man would be 32ml/hr
What is renal clearance
the volume of plasma from which a substance is completely removed by the kidney per unit time (usually a minute)
how is the plasma cleared of M
Substance M is freely filtered at the glomerulus and is neither reabsorbed nor secrete in the tubule thus all the M that is filtered will end up in the urine - no more(since its not secreted) no less (since its not reabsorbed)
Thus, all the plasma that is filteredis cleared of M
•So the clearance of substance M is 125ml/min (equal to the GFR
What is the equation for the clearance of M
clearance = urine conc x urine vol / plasma conc
what is the clearance of substance M equal to
GFR
If GFR = 125ml/min
Urea :65ml/min freely filtered
what does this mean
, but clearance is less than GFR meaning some urea is reabsorbed
If GFR = 125ml/min
PAH (para-aminohippurate): 625ml/min - freely filtered
what does this mean
but clearance is morethan GFR meaning that PAH is secreted by the tubules
If GFR = 125ml/min
Glucose: 0ml/min - freely filtered
but clearance is zero thus showing that glucose is completely reabsorbed
Renal blood flow, capillary pressure and GFR are maintained almost what over systemic mean arterial pressure range 90-200mmHg
constant
How is Renal blood flow, capillary pressure and GFR maintained in an denervated kidney
Renal blood flow, capillary pressure and GFR are maintained almost constant over systemic mean arterial pressure range 90-200mmHg
•This maintenance occurs even in a denervated kidney (i.e in a kidney transplantedinto someone) and in isolated perfused kidneys thus the constriction and dilation of the arterioles to control GFR is not dependent on nerve supply or on blood borne substances
constriction and dilation to control GFR is an intrinsic property of vascular smooth muscle:
- Pressure within the afferent arteriole rises
- Stretching the smooth muscle wall
- Triggering the contraction of smooth muscle = arteriolar constriction
- NOTE: the range of this autoregulation is from 90-200mmHg
- This mechanism prevent an increase in systematic arterial pressure from reaching and damaging the capillaries
How is the GFR of an individual nephron regulated
regulated by the rate at which filtered fluid REACHES the distal tubule
what do the cells of the macula densa detect and how do they respond
The cells of the MACULA DENSA (distal tubule) detect NaCl arrival
•Macula densa cells release PROSTAGLANDINS in response to a reduction in NaCl
What happens after prostaglandins are released in response to a reduction in Nacl by macula densa
This in turn acts on granular cells, triggering RENIN release, thereby activating the RENIN-ANGIOTENSIN SYSTEM
How much filtrate a day passes through the tubules
180L/day of filtrate passes through the tubules
because PCT is leaky and DCT is impermeable what does this mean
- The proximal convoluted tubule is responsible for BULK ABSORPTION (leaky)
- The distal convoluted tubule is responsible for FINE TUNING (impermeable)
What does PCT reabsorb
bulk reabsorption: Na, Cl, glucose, amino acids, HCO3 (bicarbonate) & secretion of organic ions
Loop of henle function
more Na reabsorption, urinary dilution & generation of medullary hypertonicity (where medulla is very concentrated meaning water wants to flow into it)
What does DCT do
Fine regulation of Na,K,Ca, Pi & the separation of Na from H20 - essentially where the separation of salt (Na) from water occurs
Function of collecting duct
similar to the distal tubule, also acid secretion and regulated H20 reabsorption thereby concentrating the urine
What drives the reabsorbtion in PCT
basolateral NaKATPase
How is glucose amino acid and lactate reabsorbed in PCT
secondary active transport
Where does most of reabsorption occur in PCT
Highly efficient - mostly achieved in first half of tubule
Where is Cl absorbes in the PCT
Cl follows Na in the second half of tubule
How permeable is PCT to water
High H20 permeability
Why is the pct vulnerable to ischaemia
Vulnerable to ischaemic injury due to the distance it is from the glomerulus
•Tubule works very hard, so if there is damage to perfusion to the kidneys then these are the cells that will suffer
Primary active Na+ reabsorption (1)
What is Na+ transported via and where
what does this cause
The primary active transport of Na+ via a basolateral NaKATPase pumpout of the proximal tubule cells and into the interstitial fluid
-The active transport of Na+ out of the cell (3Na+ OUT exchanged for 2K+ IN) keeps the intracellular concentration of Na+ low compared to the tubular lumen so Na+ moves “down hill” out of the tubular lumen and into the tubular epithelial cells
Primary active Na+ reabsorption (2)
What happens after Na+ moves ‘downhill’ out of the tubular lumen and into the tubular epithelial cells
As Na+ moves into the proximal tubule cells other substances such as glucose and phosphate also follow - they are said to be cotransportedand can be said to have moved into the cells via secondary active transport (secondary to the primary active transport of the Na+ out by the NaKATPase pump)
Primary active Na+ reabsorption (3)
What also happens as Na+ moves into the proximal tubule cells
what does this mean
As Na+ moves into the proximal tubule cells, H+ moves out into the lumen
Thus, in the proximal tubule, Na+ reabsorption drives the reabsorptionof the cotransported substances and the secretion of H+
Primary active Na+ reabsorption (4)
How does water respond to the movement of Na+ into the proximal tubule
As Na+ and other ions are reabsorbed, water FOLLOWS PASSIVELY by osmosis-Glucose & phosphate reabsorption also contribute to this osmosis since the removal of solutes from the tubular lumen decrease the local osmolarity of the tubular fluid adjacent to the cell (i.e local water concentration increases).
Simultaneously the presence of solute in the interstitial fluid just outside the cell increases the local osmolarity (i.e. the local water concentration decreases) - the difference in water concentration between the lumen & interstitial fluid results in net diffusion of water from the lumen across the tubule cell’s plasma membrane and tight junctions into the interstitial fluid
Proximal bicarbonate reabsorption (1)
what is this and what does it depend on
An active process that depends on the tubular secretion of H+ which then combines in the lumen with filtered HCO3-
Proximal bicarbonate reabsorption (2)
Inside the tubular cellsCO2 & H20 combine to form H2CO3 (carbonic acid)
under the action of which enzyme
Carbonic anhydrase
Proximal bicarbonate reabsorption (3)
What happens after CO2 and H2O combine to form H2CO3
The newly formed H2CO3 rapidly dissociates to form H+ & HCO3-
Proximal bicarbonate reabsorption (4)
What happens after The newly formed H2CO3 rapidly dissociate to form H+ & HCO3-
The HCO3- moves down its concentration gradient via facilitated diffusion across the basolateral membrane into the interstitial fluid and then into the blood
Proximal bicarbonate reabsorption (5)
what happens after the The HCO3- moves down its concentration gradient into the blood
At the same time, the H+ is secreted into the lumen via a Na/H+ counter transporter
Proximal bicarbonate reabsorption (6)
what happens to the H+ secreted into the lumen
The secreted H+ is NOT EXCRETED but instead combines in the lumen with the filtered HCO3- to generate H2CO3 which then is converted to CO2 & H20 under the action of carbonic anhydrase in the lumen of the proximal tubule
Proximal bicarbonate reabsorption (7)
what happens to the CO2 & H2O produced from H2CO3
The CO2 & H20 then diffuse into the tubular cells and can then be available for another cycle of hydrogen ion generation
Summarise proximal bicarbonate reabsorption in (8)
- From the diagram, the Na+ HCO3
- transporter actively pumps Na+ and 3HCO3- from the tubular cells into the peritubular capillary
- Also the NaKATPase pump pumps 3Na+ out for every 2K+in via active transport
- The CO2 & H20 react to form H2CO3 which then disassociates to form H+ and HCO3-, the HCO3- can then be pumped out of the cell into the capillary
- The H+ ions can then be counter transported via the entering Na+
- In the lumen, it can be seen that the H+ reacts with the filtered HCO3- to from H2CO3 which is then converted to CO2 & H2O under the action of carbonic anhydrase
- The CO2 & H2O can then diffuse into the tubular cells and the process then repeated
- Overall resulting in the reabsorption of HCO3-
Amino acid reabsorption (1)
how is the absorption of AA similar to that of glucose and phosphate
Similar to that of glucose & phosphate i.e cotransported by Na+
-There are various cotransporters responsible for the reabsorption of different amino acids
Aminoaciduria (amino acid in urine), glycosuria/glucosuria (glucose in urine) & bicarbonate wasting are all a feature of what
feature of proximal tubule pathology
what is falcon syndrome
amino acid, glucose and bicarbonates leaking into the urine
Why is the pct leaky
the transcellular & paracellular membranes of the proximal convoluted tubule are somewhat leaky due to the fact there are weak tight junctions at the borders of the membrane cells of the proximal tubule - meaning that Na+ & Cl-can freely flow into or out of the tubule cells
What is a transport maximum
Many of the mediated-transport-reabsorptive systems in the renal tubule have limit to the amounts of material they can transport per unit time
Why is there a transport maximum
This is because binding sites on the membrane transport proteins become saturated when the concentration of the transported substance increases to a certain level
Important example of transport maximum
An important example is the secondary active transport of GLUCOSE in the PROXIMAL CONVOLUTED TUBULE
Plasma glucose concentration in a healthy person normally does not exceed150mg/100ml even after a person eats a sugary meal
•When plasma glucose concentration exceeds the transport maximum for a significant number of nephrons, glucose starts to appear in the urine (glucosuria)
what is GLOMERULOTUBULAR BALANCE
the concept that More filtered load is matched by more proximal tubule reabsorption e.g.
The greater filtration fraction (due to the increased load) will increasethe osmotic pressure in the downstream peritubular capillaries resulting in more reabsorption - “more is pulled back”
Efferent arteriolar constriction reduces peritubular capillary hydrostatic pressure
Function of the loop of henle
More Na reabsorption, urinary dilution & generation of medullary hyperosmoticity (where medulla is very concentrated meaning water wants to flow into it)q
Descending/ ascending limbs of loop of henle are what with regard to water
The descending limb is water PERMEABLE•The ascending limb is water IMPERMEABLE
Where does ute reabsorption occur in the loop of henle
Solute reabsorption occurs in the thick ASCENDING LIMB
how does the loop of henle generate a hyper osmotic interstitium
via countercurrent multiplication
COUNTERCURRENT MULTIPLICATION
STEP 1
Urinary concentration takes place as tubular fluid flows through the medullary collecting ducts
-The interstitial fluid surrounding these ducts are very hyperosmotic - in the presence of VASOPRESSIN (ADH), water diffuses out of the ducts into the interstitial fluid of the medulla and then enters the blood vessels of the medulla to be carried away
COUNTERCURRENT MULTIPLICATION
2
The fluid entering the loop from the proximal convoluted tubule flows down the descending limb then turns a corner and then flows up the ascending limb
- these opposing flows in the two limbs are called countercurrent flows and the entire loop functions as a countercurrent multiplier system to create a hyperosmotic medullary interstitial fluid to enable water to be drawn out from the collecting ducts under the actionof vasopressin/ADH thereby concentrating the urine
COUNTERCURRENT MULTIPLICATION
3
what happens at ascending limb
Along the entire length of the ASCENDING LIMB, Na+ & Cl- are reabsorbed from the lumen into the medullary interstitial fluid (see picture) via many channels/pumps one of which being the NKCC2 pump (transports 1Na+,1K+ & 2Cl- into the ascending limb)
In the upper THICK portions of the ascending lib, this reabsorption is achieved by transporters that actively cotransport Na+ & Cl-
These cotransporters are NOT PRESENT in the lower ascending limbso reabsorption there occurs via simple diffusion
COUNTERCURRENT MULTIPLICATION
4
as a result of the ascending limb being impermeable to water, what happens
Since the ASCENDING LIMBis IMPERMEABLE TO WATER very little waterfollows the salt
•This results in the interstitial fluid of the medulla being very hyperosmotic compared to the fluid in the ascending limb due to the fact that the solutes are reabsorbed without water
COUNTERCURRENT MULTIPLICATION
5
what happens in the descending limb
In the DESCENDING LIMB it is PERMEABLE TO WATER and DOES NOT REABSORB NA+ OR CL-
•Thus meaning that a net diffusion of water occurs out of the descending limb into the concentrated interstitial fluid (see picture) until the osmolarities inside the limb and in the interstitial fluid are again equal
COUNTERCURRENT MULTIPLICATION
6
how is interstitial hyperosomolarity is maintain during this equilibration
The interstitial hyperosomolarity is maintain during this equilibration due to the fact that the ascending limb continues to pump Na+ & Cl- to maintain the concentration difference between it and the interstitial fluid
COUNTERCURRENT MULTIPLICATION
7
so summarise this system
Thus the loop countercurrent multiplier system produces a hyperosmotic medullary interstitium - it is this hyperosomolarity that will draw water out of the collecting ducts and concentrate the urinethereby ensuring maximum water retention which in turn minimises the rate at which dehydration occurs during water deprivation in the presence of vasopressin (ADH)
How does diuretic called Furosemide work
can inhibit the NKCC2 pump on the thick ascending part of the loop of Henle thereby reducing the amount of Na+, Cl- & K+ ions able to enter the medullary interstitium thereby reducing hyperosomolarity meaning that less water will diffuse out of the collecting ducts into the blood resulting in more water loss in the urine and thus dehydration
You would think that the capillaries running in the medulla of the kidney close to the loop of Henle would eliminate the countercurrent gradient set up by the loops of Henle since as the capillaries enter the highly concentrated environment there would be a massive net diffusion of Na+ & Cl- into the capillaries and water out of them thus “washing away” the interstitial gradient
why doesn’t this happen
However, this does not occurdue to the specialised blood vessels of the medulla known as the VASA RECTA
•The vasa recta from hairpin loops that run PARALLEL to the loops of Henleand medullary collecting ducts
How does the vasa recta work (1)
Blood enters the top of the vessel loop and as the blood flows down the loop deeper & deeper into the medulla - Na+ & Cl- do indeeddiffuse into & waterout of the vessel
How does the vasa recta work (2)
what happens after the bend in the loop
However, after the bend in the loop is reached, the blood then flowsup the ascending vessel loop where the process is almost completely reversed
•Thus, the hairpin-loop structure of the vasa rectaminimiseexcessive loss of solute from the interstitium by DIFFUSION
Who does the vasa recta work (3)
At the same time, both the salt & water being reabsorbed from the loops of Henle and collecting ducts are carried away by bulk flow - this maintains the steady-state countercurrent gradient set up by the loops of Henle
•Because of the NaCl and waterreabsorbed from the loop of Henle & collecting ducts, the amount of blood flow leaving the vasa recta is at least twofoldhigher than the amount of blood entering the vasa recta
What happens to urea as it passes through the remainder of the nephron
As urea passes through the remainder of the nephron, it is reabsorbed, secreted into the tubule and then reabsorbed again
What does Urea being reabsorbed, secreted into the tubule and then reabsorbed again cause
This traps urea - an OSMOTICALLY ACTIVE MOLECULE in the medullary interstitium thus increasing its osmolarity
How is urea filtered in the glomerulus
Urea is freely filtered in the glomerulus; around 50% of the filtered urea is reabsorbed in the proximal tubule, and the remaining 50% enters the loop of Henle
what happens to urea at the loop of henle
In the thin descending and ascending limbs of the loop of Henle, urea that has accumulated in the medullary interstitium is secreted back into the tubular lumen by facilitated diffusion
Function of DCT
- Fine regulation of Na,K,Ca, Pi & the separation of Na from H20 - essentially where the separation of salt (Na) from water occurs
- Continues the active dilution of urine by reabsorption of Na+ in water-IMPERMEABLE setting
What helps the reabsorption of Na+ and Cl- in the DCT
Has NCC (sodium chloride cotransporter) in the plasma membrane which help in the reabsorption of Na+ & Cl-
- this cotransporter can be inhibited by the drug thiazide resulting in less Na+ & Cl- reabsorption
What can be inhibited by the drug thiazide and what does this result in
NCC (sodium chloride cotransporter) in the plasma membrane of DCT which help in the reabsorption of Na+ & Cl-
resulting in less Na+ & Cl- reabsorption
Function of collecting duct
-Similar to the distal tubule, also acid secretion and regulated H20 reabsorption thereby concentrating the urine
what is collecting duct surrounded by and how it it with water
Highly water IMPERMEABLE, surrounded by a hypertonic medullary interstitium (derived from the loop of henle)
2 cell types of the collecting duct
principal cells & intercalated cell
What does the principle cell have in its membranes
as epithelial sodium channels (ENaC) in membrane of cells
what is the aldosterone action of the principle cells
Aldosterone increases the transcription (via a steroid receptor) of ENaC & NaKATPase
•This increases apical Na+ influx
•This charge movement facilitates K+ efflux
•Thus aldosterone drives both Na+ reabsorption & K+ secretion
What is the principle cells role in water regulation
Hypnotic urine enters the collecting duct
•The limits of urine osmolarity are determined by how dilute it can enter the distal segment and how hypertonic the medullary interstitium is(which drives H2O reabsorption)
What is the principles role in Vasopressin (ADH) action
- Acts on principal cells
- Binds to adenyl-cyclase couple vasopressin receptor (V2R)
- Kinase actions resulting in the insertion of vesicles containing aquaporin 2 into apical membrane
- Increases water permeability and thus reabsorption of water resulting in a more concentrated urine and
function of intercalated cell
Secrete acid into collecting duct
H20 takes up around 60% of the adult male body weight what is this made up of
- 2/3rds is intracellular fluid
- 1/3rd is extracellular fluid:
- 75% is interstitial fluid
- 25% is plasma
What is the major cation in extracellular space
Sodium is the major cation (positive) in the EXTRACELLULAR SPACE(140mM), in the intracellular space - 15mM
What is the major cation in intracellular space
Potassium is the major cation (positive) in the INTRACELLULAR SPACE(150Mm), in the extracellular space - 4mM
what is intracellular pH
Intracellular pH = 7.0
what is extracellular pH
Extracellular pH= 7.4
is ph higher inside or outside cells
pH is lower inside the cells than outside
how is plasma osmality calculated and what is it
Plasma osmolality = 285-295mOsM (calculated by; 2x(Na + K) + glucose +urea)
What is fluid movement regulated by
Na movement
What regulates tonicity
controlling h2o movement
What are the volume and osmolarity limits of urine
- Volume: 400ml-20L/24h
- Osmolarity: 50-1200mOsm/kg
what is vasopressin made from
9 amino acid peptide
where is vasopressin made
synthesised in the HYPOTHALAMUS
and where is vasopressin secreted
POSTERIOR PITUITARY
What controls the secretion of vasopressin from th posterior pituitary
explain
Its release is controlled by the hypothalamic osmoreceptors - they detect changes in osmolarity on a minute-to-minute basis:
- If you drank 2L of water - the excess water will decrease the body fluid osmolarity which will be detected by the hypothalami osmoreceptors resulting in an inhibition of vasopressinsecretion
- Consequently the water permeability of the collecting ducts decrease dramatically resulting in decreased water reabsorption and very dilute urine being released
What is the half life of vasopressin and why is it so short
Vasopressin has a very short half-life of only 15 minutes meaning we are able to adapt quickly to osmolarity changes
What does vasopressin also affect as well the collecting duct
As well as affecting the collecting ducts, vasopressin, like angiotensin II, also causes widespread ARTERIOLAR CONSTRICTION which helps restore arterial blood pressure to normal
how sensitive are osmoreceptors
Osmoreceptors are very sensitive - they can detect changes of as small as 1-2% in osmolarity
Effects of substances on vasopressin secretion
MDMA
Alcohol
nicotine
- Alcohol: decreases secretion - resulting in dehydration
- MDMA (ecstasy): increases secretion - resulting in dilute blood - seizures & fits
- Nicotine: increases secretion
What else controls osmolarity other than osmoreceptors
Although the minute-minute control of vasopressin secretion is carried out by the osmoreceptors there are other important controllers - baroreceptors are one
How does a decrease in extracellular fluid volume affects baroreceptors
A decreased extracellular fluid volume due, for example diarrhoea or haemorrhage, will elicit an increase in aldosterone release via the renin-angiotensin system
What else does the decrease in extracellular fluid volume detected by baroreceptors also cause
However, this decrease in extracellular fluid volumealso triggers increased vasopressin secretion - resulting in the increased permeability of the collecting ducts
What happens after permeability of collecting ducts has increased
(decrease in extracellular fluid volume detected by baroreceptors)
More water is passively reabsorbed and less is excreted, so water is retained to help stabilise the extracellular volume
Where are baroreceptors found
several baroreceptors in the cardiovascular system e.g. in the aortic arch & carotid sinus
baroreceptors will decrease their rate of firing in response to what and what does this result in
when cardiovascular pressuresDECREASE - as occurs when blood volume decreases
Thus meaning that the baroreceptors transmit fewer impulses via afferent neurones and ascending pathways to the HYPOTHALAMUS resulting invasopressin secretion
how do baroreceptors respond to increased cardiovascular pressure
Conversely increased cardiovascular pressure can result in more baroreceptor firing resulting in a decrease in vasopressin secretion
The baroreceptor reflex for vasopressin secretion has a HIGH THRESHOLD what does this mean
meaning that there must be a sizeable reduction is cardiovascular pressure to trigger it - this means that this reflex is less sensitive than the osmoreceptor reflex
how does vasopressin help to maintain the hyperosomolarity of the medulla
Vasopressin also helps maintain the hyperosomolarity of the medulla by increasing UREA permeability of the collecting duct
how is thirst stimulated
Stimulated by an increase in plasma osmolarity (number of dissolved particles per L) and by a decrease in extracellular fluid volume
- these changes stimulate osmoreceptors-Resulting in vasopressin secretion and thus increased H2O reabsorption
How much Na reabsorption happens in what parts of the nephron
- Proximal tubule: 60% Na reabsorption (BULK REABSORPTION)
- Loop of Henle: 25% Na reabsorption
- Distal tubule: 10% Na reabsorption
- Collecting duct: 4% Na reabsorption - regulated absorption (via vasopressin) occurs here, seems like a small percentage but due to the high volumes of fluid filtered even this small percentage has a large effect
when is urinary na secreted
Normally, urinary Na+ excretionincreases when there is an excess of Na in the body and decreases when there is a Na deficit
•Na+ is freely filterable from the glomerular capillaries into Bowman’s space and is actively reabsorbed but NOT SECRETED: Na+ excreted = Na+ filtered - Na+ reabsorbed
what is the major extracellular solute
Na+ is the major extracellular solute consisting (along with anions (negative ions e.g Cl-) around 90% of the solutes - thus changes in total-body sodium result in similarchanges in extracellular volume
what does extracellular volume consist of
extracellular volume comprises of plasma volume and interstitial volume, plasma volumeis also directly related to total-body sodium
Thus, Low total-body sodium = low plasma volume = decrease in cardiovascular pressure
What does low pressure cause baroreceptors to do
The low pressure, via baroreceptors, initiate reflexes that influence the renal arterioles and tubules so as to DECREASE GFR and INCREASE NA+ REABSORPTION
- these events decrease Na+ excretion thereby leading to the retention of Na+ in the body and preventing further decreases in plasmavolumeand cardiovascular pressure - Increases in total-body Na+ has the reverse effects
Interaction of GFR and na (3)
e.g. when na is low
- When Na+ is low this elicits a decrease in GFR which in turn results in a reduced net glomerular filtration pressure
- This occur both as a consequence of a decreased arterial pressure in the kidneys and as a result of reflexes acting on the renal arterioles
- the reflexes in question are the fact that a decrease in cardiovascular pressure results in a neurally mediated reflex VASOCONSTRICTION, and in this case, vasoconstriction of the AFFERENT ARTERIOLE thereby reducing GFR-Conversely, an increase in GFR is usually elicited by neuroendocrine inputswhen an increased total-body sodium level increases the plasma volume - the increased GFR then results in increases renal loss of Na+ thereby returning the extracellular volume to normal
renin angiotensin - aldosterone system function of
For the long-term regulation of Na+ excretion, the control of Na+ reabsorption is MORE IMPORTANT than the control of GFR
The major factor determining the rate of tubular Na+ reabsorption is the hormone called
aldosterone
1 renin angiotensin - aldosterone system
what initiates it (3 factors)
what happens then
- When the cells of the macula densa in the distal convoluted tubuledetect LESS NaCl in the tubule
- Sympathetic stimulation
- Little or no arteriolar stretch (i.e. low blood volume due to the lack of Na+ and thus H2O)
When any of the above things occur, the JUXTAGLOMERULAR CELLS located in the afferent arterioles are stimulated to release the enzyme RENIN
2 renin angiotensin - aldosterone system
what happens when renin is released
Renin then enters the blood, where it cleaves the large plasma protein called ANGIOTENSINOGEN (produced in the liver) to a smaller polypeptide called ANGIOTENSIN I
3 renin angiotensin - aldosterone system
what happens when angiotensin I is cleaved
Angiotensin I is a biologically inactive peptide which then undergoes further cleavage under the action of the enzyme called ANGIOTENSIN-CONVERTING-ENZYME (ACE), which is produces in the lungs, to form the active agent of the renin-angiotensin aldosterone system, ANGIOTENSIN II
4 renin angiotensin - aldosterone system
what does angiotensin II do
(4)
- Stimulates the cells of the zona glomerulosa in the adrenal cortexof the supradrenal/adrenal glandsto secrete the steroid hormone called ALDOSTERONE
- Is a vasoconstrictor, which results in vasoconstriction especially at the efferent arteriole, this in turn results in the increase in pressure resulting in an increased GFR
- Increases Na+ reabsorption in the PROXIMAL CONVOLUTED TUBULE
- Stimulates thirst•Stimulates vasopressin release (ADH) resulting in water retention
5 renin angiotensin - aldosterone system
actions of aldosterone (4)
- Aldosterone acts on the PRINCIPAL CELLS of the collecting duct
- Stimulates the transcription of Epithelial Sodium Channels (ENaC’s) thereby resulting in increased Na+ reabsorption and also H2O reabsorption
- Acts more slowly than vasopressin since it induces changes in gene expression and protein synthesis
- The ENac enables more reabsorption of Na+ but as Na+ comes into the principal cells, potassium is exchanged for the sodium - so if you reabsorb more Na+ then you will leak out more K+
what is aldosterone and where is it produced
Steroid hormone that is secreted and produced by the zona glomerulosa cellsin the adrenal cortex of the supradrenal/adrenal glands
