Renal anatomy, disease and gene models Flashcards
What are the proportions of each type of fluid in the body?
Transcellular- 1.5-2L
Plasma- 3-4L
Interstitial- 3-4L
Intracellular- 15-30L
What are the two types of nephron and how common are they?
Superficial nephron- mostly in the cortex, 85%
Juxtamedullary nephron- mostly in the cortex and outer medulla, loop of henle in the inner medulla 15%
What are examples of kidney congenital abnormalities?
Renal agenesis- absence of one or both kidneys
Ectopic kidney- leads to damage and stones
Horseshoe kidney- kidneys fused across the midline, renal stones
General kidney morphology
5.5 x 10 cm, 150g
From 12th thoracic to 3rd lumbar
What is renal failure? What are the two types of renal failure?
A fall in glomerular filtration rate- leads to an increase in serum urea and creatinine
Acute- reversible
Chronic- irreversible and needs dialysis or transplant
What is peripheral neuropathy? What type of renal failure is it present in?
Peripheral nerve damage leading to problems with sensations and movement
Chronic renal failure
What happens as renal failure progresses? What are this group of symptoms known as?
Thickening of glomerular membranes
Damaged glomeruli and progressive scarring which is called glomerulosclerosis
Tubular atrophy, interstitial inflammation and fibrosis
Reduction in renal size
Uraemia
What does failure to reabsorb salt and water lead to ?
Hypertension
The causes hyperkalaemia and mild acidosis
What does glomerular filtration permit and restrict?
Permits- water and small molecules
Restricts- blood cells and proteins
What is ultrafiltrate?
Consists of protein free plasma
What is transcellular reabsorption and secretion?
Transcellular reabsorption- from lumen of tubule to the peritubular capillary
Transcellular secretion- from the peritubular capillary to the lumen of the tubule
What is the function of the proximal tubule?
Bulk reabsorption, 70% of filtrate
70% of water and Na+
100% of glucose and amino acids
90% of HCO3-
What moves into the apical membrane of the proximal tubule? What channels are used?
Na+ and PO42- co-transported by NaPi II
Na+ and glucose- co-transpsorted by SGLT1 and SGLT2
Amino acids + Na+ also move in, water follows and is reabsorbed
What moves out of the basolateral membrane of the proximal tubule into the blood?
Glucose, PO42-, amino acids and K+
3Na+ out, 2 K+ in using ATPase pump
What happens when NaPi II gene is knocked out?
Less phosphate reabsorption
More loss in urine
Renal mineralisation
What is nephrolithiasis and nephrocalcinosis?
Nephrolithiasis- intraluminal kidney stones
Nephrocalcinosis- stones in renal parenchyma
From lack of phosphate re-absoprtion using NaPi II
What is the function of NHE3?
On the apical membrane of proximal tubule
As a Na+ ion comes in, H+ leaves and then forms carbonic acid with bicarbonate
Carbonic anhydrase dissociates it into CO2 and water which then move into cell
Reabsoprtion of sodium and bicarbonate into the plasma for pH regulation, water follows
What happens when NHE3 is knocked out?
Inhibition of sodium secretion- can’t reabsorb bicarbonate which leads to acidosis
Systolic BP falls due to reduction in ECF volume
What are the 2 systems of secretion in the proximal tubule?
What is the purpose of secretion here?
Organic anions
Inorganic cations
Removal of plasma protein bound substances and foreign compounds
What is the function of the loop of henle?
Concentration of urine
Reabsorption of Na+, Cl-, H2O, Ca2+, Mg2+
Site of action of loop diuretics
What is the structure of the loop and what does each part do?
Thin descending limb- water moves out
Thin ascending limb- Na+ and Cl- moves out
Thick ascending limb- Na+ and Cl- moves out
What proteins are found on the apical side of the thick ascending limb?
NKCC2
ROMK
What is the purpose of the Na+/K+ ATPase pump and the K+ channel on the basolateral membrane of cells in both the proximal tubule and the thick ascending limb of the loop?
Setting a negative membrane potential and a low intracellular Na+ concentration to drive the influx of Na+ into the cell
What is the function of NKCC2?
Brings 2 chloride ions and 1 potassium ion into the cell along with Na+
What substances experience net reabsorption in the TAL? What is the purpose of this?
Na+ and Cl-
Provides driving force of the transport of water in other segments as it sets up osmotic gradients for the other parts of the nephron
What channel does Cl- move out of on the basolateral side of the TAL?
CLCK
What is Barttin?
Not a channel- protein classes as a beta/accesspry subunit
Regulates CLCK- they only function when Barttin is also present
What is the function of ROMK on the apical membrane of the TAL?
Allows recycling of the K+ which is essential for TAL function- K+ needs to be high enough for NKCC2 to work and reabsorb Na+/Cl-
Sets negative membrane potential
What does the reabsorption of Na+ and Cl- in the TAL drive? How is this different in terms of transport?
Reabsorption of Ca2+ and Mg2+ between cells
Example of paracellular transport
What are the symptoms of Bartter’s syndrome?
Salt wasting and polyuria (not reabsorbing salt and therefore water)
Hypotension due to decrease in ECF volume
Hypokalaemia
Metabolic alkalosis
Hypercalciuria as less calcium is reabsorbed
Nephrocalcinosis as a result
How do Bartter’s syndrome symptoms occur?
Genetic and recessive
Loss of function mutation in NKCC2
Mutation in CLCK means Cl- accumulates and stops NKCC2 function
Mutation in Barttin means CLCK doesn’t work
What is fractional excretion?
Fractional excretion- amount in urine / amount filtered
100% = everything filtered is excreted
<100% = some has been reabsorbed
>100% = some has been secreted
What happens when ROMK is knocked out?
Inability to recycle K+ means Na+ and Cl- can’t be reabsorbed
Salt wasting and polyuria
What are furosemide and bumetanide examples of? How do they work?
Loop diuretics that inhibit NKCC2
Loss of Na+ and Cl- in the urine, higher urine flow rate
Reduces excess ECF volume- treats hypertension but Bartter’s like side effects
What is the function of the early distal tubule?
Reabsorption of Na+ and Cl-
Reabsorption of Mg2+
Sensitive to thiazide diuretics
What are the symptoms of Gitelman’s syndrome?
Salt wasting and polyuria Hypotension Hypokalaemia Metabolic alkalosis Hypocalciuria
What is Gitelman’s syndrome?
Genetic and recessive
Loss of function mutation in the NCC protein of the early distal tube
What is chlorothiazide and how does it help to reduce blood pressurre?
Thiazide diuretic which blocks the NCC protein of EDT cells
Also treats high blood pressure to reduce reabsorption of salts and therefore less water, which removes excess ECF volume
What is the function of the late distal tubule, collecting tubule and the collecting duct?
Concentration of urine
Reabsorption of Na+ and H2O
Secretion of K+ and H+
What are the two types of cells in the late distal tubule?
Principle cells- important for Na+ and H2O reabsorption, and K+ and H+ secretion
Intercalated cells- alpha and beta, H+ secretion/reabsorption, or HCO3- secretion/reabsorption
What proteins are found on the apical surface of principle cells of the LDT?
ENaC
ROMK
Aquaporin 2
What proteins are found on the basolateral surface of principle cells of the LDT?
Kir2.3
AQP3 + AQP4
ATPase
What is the function of ENaC
Sodium selective channel that allows it to move into principle cells, drives movement water too as it moves out via ATPase
The more Na+ absorbed the more K+ and H+ is secreted and lost in urine
What aquaporin acts as the rate limiting step in principle cells?
Aquaporin 2
What are examples of diseases of principle cells?
Diabetes insipidius- problem with AQ2, can’t reabsorb water
Liddle’s syndrome- gain of function mutation in ENaC so too much is reabsorbed, hypertension as a result
Pseudohypoaldosteronism
What is amiloride?
Diuretic of principle cells used to treat high blood pressure
Antagonist of ENaC so it blocks net reabsorption of sodium and therefore water to reduce excess ECF
What is the function of alpha intercalated cells? How does the structure of their apical membranes relate to this?
Secretes H+ and absorbs HCO3-
Proton pump on the apical membrane hydrolyses ATP to secrete H+ out against gradient
What is the structure of alpha intercalated cells on the basolateral side?
AE1- bicarbonate chloride exchanger which pumps bicarbonate out
Chloride channel- recycles chloride to allow AE1 to work
What is the function of beta intercalated cells?
H+ and Cl- reabsorption
HCO3- secretion
How are beta IC cells different to alpha IC cells? why?
AE1 and proton pump are swapped around to have opposite functions
They can be interchanged depending on the needs of the body- pH dependent
What is the function of the medullary collecting duct?
Low Na+ permability
High water and urea permeability in response to vasopressin
What are the symptoms of acute renal failure?
Hypervolaemia- increase in ECF due to oliguria (low urine flow due to low GFR)
Hyperkalaemia- lack of K+ secretion leads to cardiac excitability
Acidosis- lack of secretion of halogen ions leads to depression of the CNS
High urea and creatinine- leads to loss of mental function, nausea and vomiting
Where are hypothalamic osmoreceptors located? When are they stimulated?
Supra-optic and paraventricular nuclei
Stimulated when there is an increase in osmolality
Where is vasopressin released from?
Posterior pituitary
When is the release of vasopressin increased?
Increases in osmolality of plasma
Solute ingestion or H2O deficiency
Stress and drugs- nicotine and ecstasy
When is the release of vasopressin decreased?
Decreases in osmolality of plasma
Excessive fluid ingestion
Drugs and alcohol
Vasopressin mechanism of action
Binds to V2 receptors on the basolateral membrane of principle cells
Stimulates PKA which mediates phosphorylation
Leads to insertion of vesicles that have aquaporin channels into the apical membrane
More AQP2 in the apical membrane when vasopressin is high, more water absorption so plasma osmolality is brought back down
Where is aldosterone release from?
Zonal glomerulosa layer of the adrenal cortex
What is the function of aldosterone?
Type of mineralocorticoid that regulates plasma Na+, K+ and fluid volume
Slower responding than the vasopressin system
Increases reabsorption of Na+ and therefore water, increases secretion of H+ and K+
When is aldosterone released?
Rise in plasma K+
Fall in plasma Na+ (minor)
Fall in ECF volume
Where does aldosterone act on?
Late distal tubule and the collecting duct
Aldosterone mechanism of action in principle cells
Crosses membrane and binds to mineralocorticoid receptor in principle cells
Receptor aldosterone complex goes to the nucleus
Stimulates RNA transcription and the synthesis of proteins involved in Na+ absorption, K+ and H+ secretion (ENaC, ROMK, ATPase)
What is the net effect of aldosterone on principle and intercalated cells?
Increase in plasma Na+ so therefore increase in ECF volume
Decrease in plasma K+ and H+
What is the renin-angiotensin system?
Regulates body fluid volume, plasma Na+ and K+
Cascade system that works with aldosterone
Where is renin released from and when does this happen?
Juxtaglomerular apparatus in the kidney
When there is a decrease in ECF volume
How does renin start the cascade to produce angiotensin II?
Renin goes into circulation and catalyses the production of angiontensin I from the protein angiotensinogen
Angiotensin I is then converted into angiotensin II by ACE which is found in capillaries
What does angiotensin II do?
Works at the site of release of aldosterone and stimulates it
Causes vasoconstriction of arterioles to increase blood pressure
What happens to plasma concentrations when salt is ingested?
Increase in Na+ in plasma and water moves out of the interstitial fluid
Increase in ECF volume and osmolality of plasma
