PBL 7 Flashcards
How many nephrons does each kidney have roughly?
1.25 million
What are podocytes?
Specialised cells within the visceral epithelium that have pedicals with filtration slits between each pedical - this allows small molecules to filter out of the blood
What are mesangial cells?
Supporting cells that lie in between adjacent capillaries and control capillary diameter and the rate of capillary blood flow
What are the four parts of the loop of Henle?
Thick descending limb
Thin descending limb
Thin ascending limb
Thick ascending limb
What is the difference in epithelium between the thick and thin limbs of the loop and Henle?
Thick limb - cuboidal epithelium
Thin limb - squamous epithelium
Where is the juxtaglomerular complex found?
Near the renal corpuscle
What does the juxtaglomerular complex secrete?
Erythropoietin and the enzyme renin
Where can the macular densa be found?
In the juxtaglomerular complex
What percentage of nephrons are cortical nephrons in the kidney?
85%
Which type of nephron enable the kidney to produce concentrated urine?
Juxtamedullary nephrons
What are the two kinds of barrier that are present in the glomerulus?
Charge barrier - negatively charged molecules on basement membrane act to repel negatively charged ions but encourage positive charged ions through
Size barrier - so only small molecules are filtered through
Which components of the GFR equation favour and oppose filtration?
Hydrostatic pressure in glomerulus capillaries - favours filtration
Oncotic pressure in glomerulus capillaries - opposes filtration
Hydrostatic pressure in bowman’s capsule - opposes filtration
How does GFR remain the same despite changes in blood pressure?
Due to auto regulation by increased vascular resistance - afferent arteriole will constrict so that glomerular capillary pressure remains the same and renal blood flow remains the same
What are the two mechanisms by which autoregulation occurs?
Myogenic - vascular smooth muscle responds to stretch by vasoconstriction
Tubuloglomerular - distal tubular flow regulates vasoconstriction
How does tubuloglomerular feedback regulate increased GFR?
An increase in BP leads to increased GFR
Macula densa cells sense increased Na+K+2Cl- concentration by taking up Na+K+2Cl- by the NKCC2 transporter
This causes ATP release which triggers calcium release
This causes secretion of renin which produces angiotensin II
Angiotensin II acts as a vasoconstrictor to increases preglomerular resistance, decreasing GFR and keeping it maintained
What is the best marker for GFR used currently in clinical practice?
Creatine
What is the gold standard for estimating GFR?
Insulin
What is the point of filtering out so much sodium just for it to be reabsorbed?
Sodium is “cheaper” to regulate opposed to other substances e.g, water and glucose
If you regulate sodium then water will follow via osmosis
If you regulate sodium then it can give glucose a “free ride”
What percentage of sodium is reabsorbed at the different parts of the nephron?
Proximal tubule - 67%
Loop of Henle - 25%
Distal tubule and collecting duct - 8%
What is the mechanism for sodium reabsorption at the late proximal tubule?
Na+K+ pump sets sodium gradient on basolateral membrane
NHE-3 exchanger brings Na+ into cell in exchange for H+
What is the mechanism for sodium reabsorption at the late distal tubule?
Na+K+ pump on basolateral membrane sets sodium gradient
Aldosterone causes insertion of ENaC channels on apical membrane
ENaC is a sodium channel which allows sodium reabsorption
What 2 channels does aldosterone initiate the transcription of to then be inserted into the apical membrane of the distal tubule?
ENaC - sodium channel
Potassium channel
Why are the effects of aldosterone slow acting?
Because it combines with cytoplasmic receptor to form a hormone receptor complex
Alters transcription so has a slow genomic effect (24-48 hours)
How many glucose and sodium does the SGLT1 transporter carry?
1 glucose
2 Na+
How many glucose and sodium does the SGLT2 transporter carry?
1 glucose
1 Na+
Where are the SGLT1 and SGLT2 transporters found in the kidney?
SGLT1: late proximal convoluted tubule
SGLT2: early proximal convoluted tubule
Where does glucose reabsorption occur in the nephron?
Proximal convoluted tubule
Describe how glucose is reabsorbed at the early proximal convoluted tubule
Na+K+ pump sets up sodium gradient at basolateral membrane
SGLT2 brings in 1 Na+ with 1 glucose
Glucose enters circulation via GLUT2
Describe how glucose is reabsorbed at the late proximal convoluted tubule
Na+K+ pump sets up sodium gradient at basolateral membrane
SGLT1 brings in 2 Na+ with 1 glucose
Glucose enters circulation via GLUT1
What is the difference between glucose absorption at the early proximal and late proximal convoluted tubule?
Early proximal - low affinity, high capacity
Late proximal - high affinity, low capacity
What is the transport maximum for glucose?
1.2mmol/min
When does glucose appear in urine?
When glucose conc is so high that it exceeds the Tm, therefore it cannot all be reabsorbed so it is excreted in urine
What is splay?
Accounts for the different capacity of each individual nephron to absorb glucose
What is the difference in glucose metabolism in the kidney cortex and medulla?
Cortex - Gluconeogenesis
Medulla - glycolysis
Which nephrons are involved in concentrating urine and why?
Juxtamedullary nephrons - due to their long loop of henle
How do the permeabilities differ in the descending and ascending limb of the loop of henle?
Descending limb - permeable to water (but not ions)
Ascending limb - permeable to ions (but not water)
What is countercurrent multiplication?
Sodium and chloride are pumped out of ascending tubule
This raises osmotic concentration in peritubular fluid
This causes osmotic water flow out of thin descending limb
What is the horizontal gradient at any one point between the interstitial fluid and and the tubular fluid?
200Osm/Kg
What is the most concentrated urine can get at the bottom of the loop of henle?
1200mOsm/Kg
How does ADH/Vasopressin cause water retention
Vasopressin binds to receptor on basolateral membrane in the distal tubule/collecting duct
This causes the insertion of aquaporin 2 on apical membrane
Water flows into the cell following Na+ Reabsorption which was previously set up by aldosterone insertion of ENaC
Water leaves the cell through AQP3/4
Why do diabetics get thirsty?
Glucose levels exceed transport maximum
Glucose leaks out into urine
Glucose is osmotically active and pulls water out with it
Loss of water causes patient to become thirsty
What are the consequences of hypokalaemia and hyperkalaemia?
Hypokalaemia - hyperolarisation and death
Hyperkalaemia - depolarisation and death
How much K+ is absorbed at the different places in the nephron?
Proximal tubule - 65%
Loop of Henle - 25%
Distal & Collecting Ducts - variable reabsorption
How is K+ reabsorbed in the proximal convoluted tubule?
Na+K+ pump on basolateral membrane allows intake of K+ ions
K+ channel on basolateral membrane allows K+ recycling
K+ channel on apical membrane allows secretion of K+
Charge of tubular fluid increases in positivity through the PCT, causing K+ to diffuse down electrochemical gradient through tight junctions back into the blood
How is K+ reabsorbed in the thick ascending limb?
Na+K+ pump on basolateral membrane allows intake of K+ ions
K+ channel on basolateral membrane allows K+ recycling
NKCC2 channel brings K+ into cells on apical membrane
ROMK2 channel allows outflow of K+ into tubular fluid to also be recycled
What are the two cell populations found in the collecting duct?
Principal cells
Intercalated cells
How do the two cell types in the collecting duct differ in their regulation of K+
Principal cells - secrete K+ into urine
Intercalated cells - reabsorb K+ from urine
How do principal cells in the collecting duct allow secretion of K+ ions?
Na+K+ pump on basolateral membrane pumps K+ into cell
K+/Cl- cotransporter secretes K+ and Cl- into urine
ROMK1 K+ channel secretes K+ into urine
Where can the ROMK1 channel be found?
What is it stimulated by?
On the principal cells of the collecting duct
Stimulated by:
High K+ levels
Aldosterone
How do the intercalated cells in the collecting duct cause Reabsorption of K+?
K+/H+ exchanger on apical membrane brings in K+ in exchange for H+
What activates intercalated cells in the collecting duct?
Acidosis
Low plasma K+
How do bone cells regulate the levels of calcium and magnesium in the body?
Osteoblasts - uptake calcium and magnesium into bones
Osteoclasts - remove calcium and magnesium from bones
How are calcium and magnesium reabsorbed in the proximal tubule & loop of Henle?
Passively unregulated paracellular reabsorption
How is calcium reabsorbed in the distal convoluted tubule?
Via TRPV5 on apical membrane
Bound to calbindin in the cell, which moves Ca2+ to basolateral membrane
Ca2+ then exits the cell into the blood through:
NCX1 (Na+/Ca2+ exchanger)
PMCA1b (plasma membrane calcium ATPase pump)
How is TRPV5 regulated in the distal tubule?
The following cause insertion/activation of TRPV5:
- parathyroid Hormone
- vitamin D
- sex hormones
- klotho
How is magnesium reabsorbed in the distal tubule?
ROMK K+ channel pumps K+ into tubule
Mg2+ moves down electrochemical gradient into cell via TRPM6 channel
Mg2+ is exchanged on basolateral membrane
What does TRPM6 transport and where?
What is it activated by?
Transports Mg2+ into cells at proximal tubule
Activated by epidermal growth factor
What are the two different isoforms of carbonic anhydrase and where are they found?
CA II - cytoplasm
CA IV - extracellular, linked to cell membrane by GPI anchor
How is HCO3- reabsorbed in the kidney?
H+ is secreted into the filtrate
CA IV catalyses reaction of H+ + HCO3- to CO2 + H20
CO2 is passively absorbed into the cell
CO2 is split back up in the cell by CA II to HCO3- + H+
HCO3- leaves at the basolateral membrane
H+ is recycled
Where are the sites of bicarbonate reabsorption in the kidney and what percentage is reabsorbed at each site?
Proximal convoluted tubule - 80%
Thick ascending limb - 10%
Distal convoluted tubule - 6%
Collecting duct - 4%
What are the different types of Na+HCO3- transporters found in the kidney?
NBC3
KNBCe1
What is the difference between proximal renal tubular acidosis (pRTA) and distal renal tubular acidosis (dRTA)?
PRTA - mutation in kNBCe1, so bicarbonate cannot be absorbed at the basolateral membrane in exchange for Na+
This is not treatable by HCO3- supplementation
DRTA - mutation in alpha intercalated cell transport
This can be treated by HCO3- supplementation
In which cells of the collecting duct does bicarbonate reabsorption occur?
Alpha-intercalated cells
How is H+ excreted as a titratable acid (TA) in the kidney?
H+ is excreted out in to the filtrate and is buffered by filtered phosphate (HP04) into H2PO4
How is HCO3- reabsorbed in the kidney?
H+ is secreted into the filtrate
CA IV catalyses reaction of H+ + HCO3- to CO2 + H20
CO2 is passively absorbed into the cell
CO2 is split back up in the cell by CA II to HCO3- + H+
HCO3- leaves at the basolateral membrane
H+ is recycled
Where are the sites of bicarbonate reabsorption in the kidney and what percentage is reabsorbed at each site?
Proximal convoluted tubule - 80%
Thick ascending limb - 10%
Distal convoluted tubule - 6%
Collecting duct - 4%
What are the different types of Na+HCO3- transporters found in the kidney?
NBC3
KNBCe1
What is the difference between proximal renal tubular acidosis (pRTA) and distal renal tubular acidosis (dRTA)?
PRTA - mutation in kNBCe1, so bicarbonate cannot be absorbed at the basolateral membrane in exchange for Na+
This is not treatable by HCO3- supplementation
DRTA - mutation in alpha intercalated cell transport
This can be treated by HCO3- supplementation
In which cells of the collecting duct does bicarbonate reabsorption occur?
Alpha-intercalated cells
How is H+ excreted as a titratable acid (TA) in the kidney?
H+ is excreted out in to the filtrate and is buffered by filtered phosphate (HP04) into H2PO4
How is H+ excreted as ammonium?
Glutamine metabolism in the cell produces NH4+ + OH ions
NH4+ is split into NH3+ and H+
These are secreted into tubular fluid where they recombine to make NH4+
How can NH4+ be reabsorbed in the thick ascending limb?
Through NKCC1 or ROMK2, NH4+ is selected for instead of K+
Once in cell NH4+ splits into NH3 + H+
NH3 diffuses through basolateral membrane as there is higher permeability for it there
What are the main features of diabetic nephropathy?
Thickening of glomerular basement matrix membrane
Expansion of mesangial cells
Kimmelstiel-Wilson nodules
Disruption of podocytes
What is nephrotic syndrome?
The clinical appearance of protein in urine
What happens to the GFR in diabetic nephropathy?
It decreases as symptoms get worse
What is the percentage of people with diabetes who develop nephropathy?
40%
What is the pathophysiology of diabetes nephropathy?
Hyperfiltration of kidney to remove excess glucose
Glomerulus suffers under excessive workload and becomes damaged
This leads to protein leakage in urine
Declining renal function over time
How is Aliskiren used to treat diabetic nephropathy?
Inhibits the action of renin
Decreases blood pressure
How do diuretics work?
Prevent ion reabsorption
This causes more fluid to be expelled in urine
Lowers blood pressure
What kind of diuretic is mannitol and where does it work?
Osmotic diuretic
Woks in the late PCT and the descending loop of henle
What kind of diuretic is furosemide and where does it work?
Loop diuretic
Loop of Henle
What kind of diuretic is bendroflumethiazide and where does it work?
Thiazide Diuretic
Works in the DCT
What kind of spironolactone is mannitol and where does it work?
Potassium sparing
Collecting duct
What type of drug is Glifozin and what is it used in?
SGLT2 inhibitor
Inhibits sodium-glucose transport in PCT
This inhibits glucose reabsorption
This allows the body to lower blood glucose
Used to treat diabetes
What is the difference between haemodialysis and peritoneal dialysis?
Haemodialysis - uses an external machine to filter the blood, requires a fistula (blood vessel linking an artery and vein)
Peritoneal dialysis - blood is filled inside of the peritoneum
What is nephritic syndrome?
The clinical appearance of blood in urine
What are the ranges for microalbuminuria and macroalbuminuria?
Microalbuminuria: 30-300ug/mg
Macroalbuminuria: >300ug/mg
What level is GFR maintained at?
125ml/min
