REN
HANNAH COOKE
Physiology
Key Values To Remember
Filtrate Osmolality
Bowman’s Space 300mOsm
End of PCT 285mOsm
Tip of Loop of Henle 1200mOsm
Start of DCT 85mOsm
End of Collecting Duct 60 – 1400mOsm (normally 500-
800mOsm)
Normal Body Fluid 285mOsm
Key Values To Remember
Structure Flow Rate
Blood 1.2L/min
Plasma 600ml/min
Glomerular Filtration 120-125ml/min
Urine 1.25ml/min (average, 17ml/min
maximum)
The Glomerulus
The pressure in the glomerular capillary is always a net outward pressure, promoting filtration rather than
reabsorption
• Bowman’s capsule osmotic pressure = 15mmHg
• Glomerular capillary osmotic pressure = 55mmHg The afferent and efferent
arterioles maintain this gradient
• Glomerular capillary oncotic pressure = 22 – 30mmHg
Several layers separate plasma from filtrate
1. Endothelial cells of the glomerular capillary (fenestrations prevent cells from leaving)
2. Glomerular basement membrane (negatively charged glycocalyx)
3. Visceral epithelial cells of the Bowman’s capsule (podocytes, trabeculae and pedicles)
The Glomerulus
The glomerulus is therefore filtering based on CHARGE and SIZE
•Large and negatively charged substances (ie. Proteins) cannot get through
Filtration fraction the proportion of the plasma flow that is filtered by the glomerulus
Glomerular flow rate/ renal plasma flow rate = 120 ml.min-1/ 600 ml.min-1 = 0.2
•In the plasma that isn’t filtered, its concentration of non-filterable substances increases, and
concentration of filterable substances stays the same
•The filtration fraction is much higher for small positive substances than for large negative ones
GFR
To measure GFR, you need a substance that is freely filtered but not reabsorbed or secreted by
the nephron
•IV inulin can be used, but creatinine is easier as it is produced by the body at a constant rate
GFR can be calculated by the formula below
But, as this requires 24 hour urine monitoring we use eGFR instead
GRF differs between individual nephrons (SNGFR), this is higher in juxtamedullary nephrons
Proximal Convoluted Tubule
Transport in the proximal convoluted tubule is due a mixture of ion channels and both primary
and secondary active transport in the apical and basolateral membranes
•This selective distribution of channels is key to directional ion movement
Water is passively absorbed through transcellular and paracellular movement
•Transcellular routes occur through the channel aquaporin 1
•Water flows through the paracellular routes because of the net outward hydrostatic and osmotic
forces (mainly determined by sodium)
As the PCT is very water soluble, the filtrate becomes isomolar with the plasma
Proximal Convoluted Tubule
Molecule Absorbed? Concentration at end of
tubule
Inulin No Higher
Urea Slower than water Higher
Cl- Slower than water Higher
Na+, K+ Same speed as water Same
HC03- Yes Lower
Amino Acids Yes Considerably Lower
Glucose Yes Considerably Lower
Proximal Convoluted Tubule
Sodium is absorbed along the PCT
•80% via Na/H antiport
•The remainder via ENaC channels (more prominent distally)
Glucose transport is coupled to sodium
SGLT2 is low affinity high capacity
SGLT1 is high affinity low capacity
Proximal Convoluted Tubule
Bicarbonate is closely regulated due to acid/base balance
• The H+/Na+ exchanger pumps H+ ions into the
tubule lumen
• Here they react with HCO3- to form carbonic acid,
under the influence of the enzyme carbonic
anhydrase, and dissociate to form water and
carbon dioxide
• Water and carbon dioxide diffuse into the
epithelial cell, reforming HCO3- and H+
• 3 HCO3- then exit basolaterally, through a HCO3-/
Na+ symporter
Loop of Henle
The function of the loop of Henle is to manufacture a hypertonic interstitial fluid in the medulla
to maximise concentration of urine as the collecting ducts pass through the medulla
NKCC2 in the ascending limb actively pumps sodium, chloride
and potassium out of the filtrate and into the interstitium
• As the descending limb is in contact with the thick ascending
limb, there is counter-current exchange
• The descending limb is permeable to water, therefore the
fluid in the descending limb will come into osmotic
equilibrium with the surrounding interstitial fluid
• The ascending limb is impermeable to water, and ions are
actively pumped from it - lowering the osmolarity of the
filtrate again
Loop of Henle
• The tubules pass deep into the medulla and osmolarity of the interstitial fluid increases,
removing water from the descending limb; as filtrate flows up the ascending limb salts are
moved out at a gradient of 200mOsm between the two limbs
• In this configuration the ions can be reabsorbed into the blood stream, and the osmolarity of
the medulla becomes very high
◦ This process is enabled by the vasa recta, also forming a hairpin loop alongside the loop of Henle
◦ These blood vessels serve to provide nutrients to and wash away wastes from the medulla, without
washing away the solutes responsible for medullary hypertonicity
◦ As the capillaries are highly permeable, excluding proteins, the osmotic pressure in the vasa recta
changes with the increasing osmolarity in the medulla. Diluting the interstitium with the descending
limb, but concentrating it on the ascending limb
Urea Countercurrent
The late distal tubule and cortical collecting duct are impermeable to urea, hence as water is
removed the concentration of urea rises. The medullary collecting duct however is permeable to
urea, so urea diffuses out
• Urea in the medullary interstitial space increases the osmolarity of the medulla
•Urea permeability is increased by ADH, by increasing the expression of the UT-A1 channel
• Urea is absorbed into the filtrate through the UT-A2 channel in the descending limb of the loop
of Henle
Hence, there is a urea countercurrent out of the collecting duct and into the loop of Henle,
further aiding water reabsorption
Distal Tubule and Collecting Duct
The DCT and collecting duct enable further sodium absorption
• Na/Cl co-transport
• ENaC channels Aldosterone
regulates the
• The gradient for this exchange is maintained by basolateral Na/K transport expression of
these two
Urine Concentration
Urine concentration can range from 60mOsm to 1400mOsm, and the amount produced in 24
hours ranges from 400ml to 25L. Average urine flow rate is 1.25ml/min
• This is determined mainly by ADH, released in response to plasma osmolarity increasing
>285mOsm
The AV3V region of the hypothalamus senses increasing osmolarity and triggers the release of
ADH, this acts on V2 receptors of the collecting duct
• V2 receptors are coupled to Gs g-proteins. When bound to ADH, there is an activation of
adenylyl cyclase and an increase in [cAMP]
• cAMP triggers an increase in AQP2 through two pathways
• Insertion of pre-formed AQP2 in vesicles into the apical membrane
• Increase in the transcription of AQP2 synthesis genes
Diuretics
Spironolactone
• This acts in the collecting tubule to block the effect of aldosterone, stopping reabsorption of
sodium and loss of potassium
•Side effects include gynaecomastia, menstrual disorders, testicular atrophy and hyperkalaemia
Thiazides
• These act at the Na/Cl co-transporter in the DCT
•Side effects include mild metabolic acidosis, increased uric acid and hyperglycaemia
Diuretics
Furosemide
• This blocks the action of the NKCC2 transport in the ascending Loop of Henle
•Side effects include hypokalaemia, hypovolaemia, metabolic alkalosis and loss of Mg2+ and Ca2
Acetazolamide
• This blocks bicarbonate re-uptake in the PCT
•This can be used to treat acidosis, but also works as a weak diuretic
Clearance
Don’t worry about integration/ differentiation!!!
Renal Clearance Explanation Examples
0 Neither filtered, nor secreted. Or Large proteins, Glucose
filtered and completely reabsorbed
Therefore not introduced to the
filtrate or urine.
<GFR Filtered, then partially reabsorbed Na+
=GFR Filtered, but not reabsorbed Inulin, Creatinine
<PFR but >GFR Filtered and partially secreted
=PFR Filtered and secreted PAH
>PFR Miscalculation, as the kidneys cannot
remove more substance than what
arrives in the blood
Clearance
The renal clearance of any substance is equal to the concentration of the substance in the urine, multiplied
by the urine flow rate divided by the concentration of the substance in the plasma
The numerator here is
“excretion rate”
Where the excretion rate cannot be measured clearance is measured by drawing a plasma concentration –
time graph, whole body clearance equals
Initial dose of substance/ area under curve
Renin-Angiotensin System
Renin release is triggered by
1. Low blood pressure in the afferent arteriole is sensed by the granular cells
2. Activation of the baroreceptor reflex releases noradrenaline, which also acts directly at the
granular cells
3. Low Na in the distal tubule indicates a fall in GFR, this triggers the macula densa to increase
renin release from the granular cells
Renin AT1 AT2 Aldosterone
Renin-Angiotensin System
There are 5 key actions of AT II that increase circulating volume
1. Vasoconstriction, increasing peripheral resistance
2. Increasing Na/H exchange in the proximal tubule, and hence proximal Na+ reabsorption and
water reabsorption
3. Increasing aldosterone release from the adrenal cortex, which increases distal Na+
reabsorption
4. Causes ADH release, increasing water retention
5. Causes thirst, increasing water intake
Acid-Base Balance
The pH of the blood must be maintained between 7.35 – 7.45
• The main buffer that enables us to do this is the bicarbonate buffer, the Hendelson-Hasslebach
equation for this is summarised below
This buffer is important as the concentrations of CO2 and bicarbonate can be controlled by the
kidney and lungs respectively
Acid-Base Balance
In the distal tubule H+ is actively secreted from the blood into the filtrate
• This occurs primarily through the apical H+/K+-ATPase and H+-ATPase on α-intercalated cells that are
specialised for H+ transport
Free hydrogen in the urine must be buffered to maintain the concentration gradients
• The hydrogen phosphate buffer is important for this
• The other buffer is the ammonium buffer
Acid-Base Balance
Davenport diagram
Horizontal lines represent constant values of HCO3- at changing CO2 levels. As CO2 increases, pH decreases
Curved lines represent constant CO2 concentrations at different partial pressures, as [HCO3-] increases, pH
increases
Acid-Base
Acidosis Alkalosis
Respiratory Hypoventilation Hyperventilation
• Lung disease e.g. COPD • Altitude
• CNS depression • Anxiety
• Neuromuscular lung • Hypoxia
dysfunction
Metabolic Renal Failure Vomiting
Bicarbonate loss in diarrhoea Hyperaldosteronism
Increased anion gap (>11)
• DKA, sepsis, lactic acidosis,
salicylate poisoning
Clinical
Renal Failure
The consequences of renal failure are in three main areas
• Endocrine dysfunction
• Homeostasis
• Acid-Base
• Electrolytes
• Water balance
• Failure to excrete toxic substances
Renal Failure
Failure to excrete enough water causes
• Dilutional hyponatraemia
• Fluid overload and oedema (nb: protein loss and hypoalbuminaemia)
Potassium builds up, causing hyperkalaemia
• This causes cardiac arrhythmias, the changes can be seen on ECG
• Treatment is to promote potassium uptake into cells, remove potassium from the blood
(dialysis) and restrict intake
Renal Failure
No synthesis of 1,25-OH Vitamin D
• Calcium will not be absorbed from the gut, therefore there is secondary hyperparathyroidism
(leading to tertiary hyperparathyroidism in the long term)
•Demineralisation of bone leads to osteodystrophy
•Another effect of this is mineralisation of soft tissue due to free calcium and phosphate
precipitating
Loss in EPO synthesis and secretion
• This can lead to anaemia
In kidney disease, there is a reduced GFR that stimulates renin release. This activates the renin-
angiotensin system, which will increase blood pressure and further drive kidney damage
Renal Failure
Toxic waste products begin to accumulate in the blood
• Uraemia results from accumulation of nitrogen containing compounds
• There is also a failure in the excretion of renally cleared drugs (insulin, opiates, antibiotics,
sedatives and digoxin)
It is this toxic accumulation that leads to symptoms
• Encephalopathy • Anorexia
• Peripheral neuropathy
• Seizure
• Pruritis
• Nausea and vomiting
AKI
There are three main divisions of the causes of AKI
Pre-renal
• This is due to a failure of kidney perfusion. It can be caused by hypotension, hypovolaemia and
renal artery occlusion
Renal diseases and immunological disease
• This includes systemic diseases like SLE, vasculitis and myeloma, infections, acute interstitial
nephritis, drug toxicity, primary glomerulonephritis
Post-renal
• This is due to obstruction of the urinary tract
CKD
Stage Description eGFR
1 Kidney damage, but normal GFR >90
2 Kidney damage with mild decrease in GFR 60-89
3 Moderate decrease in GFR 30-59
4 Severe decrease in GFR 15-29
5 Kidney failure <15
• Systemic diseases such as diabetes mellitus, hypertension and immune diseases
(membranous/ IgA nephropathy)
• Infectious diseases, such as HIV, TB and hepatitis
• Genetic diseases such as polycystic kidneys
• Ischemia due to vascular disease and atherosclerosis
• Obstruction due to tumours, stones and fibrosis
Dialysis
Dialysis is a renal replacement therapy
• This is necessary in stage 5 CKD
There are several limitations of dialysis
• The GFR achieved is low
• Dietary restriction of fluids and electrolytes is necessary,
• EPO and vitamin D need to be replaced, and blood pressure control is necessary
• In peritoneal dialysis adhesion of the peritoneal cavity can occur, and the application of high
levels of dextrose to diabetic patients can be dangerous
• Infection is a risk with haemodialysis
Peritoneal Dialysis
In peritoneal dialysis, the body’s own peritoneal membrane acts as a semi-permeable membrane to separate
the patient’s blood from the dialysis fluid
• The dialysis solution contains dextrose, some electrolytes and HCO3- buffer
• Water is removed from the blood by osmosis, the gradient for which is created by the dextrose.
• The solutes in the blood are removed by diffusion and convection
8-10L of fluid are exchanged per day, typically in 2.5L batches over 4-6 hours
Haemodialysis
In haemodialysis the patient’s blood is removed and introduced to an artificial semi-permeable
membrane to separate the blood from the dialysis fluid
• In the dialyser, the blood and dialysis fluid flow in opposite directions separated by the artificial
membrane, this counter-current ensures that concentration gradients between the blood and
fluid are maintained
This is an intermittent therapy that is usually undertaken in hospital outpatient clinics, generally
in four hour intervals three times per week.
Practice Questions
Discuss the renal handling of potassium
This question has come up two years in a row…!
• PCT = passive reabsorption
•Thick ascending limb = NKCC2
• DCT and collecting duct = influence of aldosterone and relation to blood pressure/ blood
potassium
• ROMK channel
• Basolateral Na/K transporter
Describe the renal response to shock
• In shock, blood pressure drops and the organs are inadequately perfused
• There is renal artery vasoconstriction, dropping glomerular blood pressure and GFR
• Activation of the renin-angiotensin system follows
• Increased basolateral Na/K and apical ENaC
• Sodium reabsorption increases water retention, increasing blood pressure
Describe the bladder voiding system
• The voiding reflex occurs when pressure in the bladder surpasses a threshold point
• The pressure in the bladder is sensed in the pelvic nerve afferents in the trigone, these go to the
peri-aquiductal grey in the spinal cord which coordinates the central control of micturition
• Signals pass to the pontine micturition centre which inhibits the sympathetic system and
somatic pudendal nerve, relaxing the sphincters
• There is then activation of the parasympathetic system and contraction of the detrusor muscle
Describe the renal contribution to
haematopoiesis
• EPO is synthesised by the mesangial cells and renal tubular cells in response to hypoxia (hypoxia is most
easily sensed in the renal medulla, as this is perfused by a secondary capillary bed)
• Hypoxia induces prostaglandin release, which stimulates the mesangium and tubular cells to increase
EPO synthesis and secretion. This is mediated by hypoxia-inducible transcription factors (HIF) that are
activated within these cells
• Autonomic nervous control of EPO release is mediated by sympathetic noradrenaline binding to β-
adrenoceptors in the kidney
• When EPO is secreted, it travels in the blood to the bone marrow where it binds to the EPO receptor
and increases the production of pro-erythroblasts, which will later differentiate to erythrocytes
Discuss the body’s compensation to metabolic acidosis, and
draw a Davenport diagram to support your answer
• Hyperventilation
•Decrease CO2, and readjust the Hendleson-Hasslebach equation to restore the ratio between
bicarbonate and CO2
• Possible causes
• Davenport diagram as before
Questions?
