Renal Physiology and Drugs Flashcards
erythropoietin release and function
released in response to hypoxia in renal circulation which stimulated erypthropoeisis in the bone marrow
vitamin D in the kidneys
activated to calcitriol which promotes intestinal absorption of calcium and renal absorption of phosphate
diuretics definition and used in treatment of
drugs that increase the excretion of sodium, chloride ions and water from the renal tubules- increasing urinary flow
treatment of conditions where there is accumulation of excess sodium and water in body (eg. heart failure, renal failure, liver failure, hypertension)
mechanism of loop diuretics (eg. furosemide)
act by inhibiting the Na-K-Cl cotransporter (NKCC) in the thick ascending limb of the loop of Henle, reducing the absorption of NaCl, norm responsible for 15-25% of sodium resorption, efficacious
some direct vasorelaxant properties
thiazide diuretics mechanism
inhibiting sodium reabsorption at the beginning of the distal convoluted tubule (DCT) by blocking the thiazide-sensitive Na+-Cl− symporter which increases NaCl excretion and increases urine output
types of thiazide diuretics
true thiazide and thiazide like diuretics- different chemical structure but similar pharma actions
potassium sparing diuretics mechanism
inhibit sodium resorption by blocking luminal sodium channels, reducing availability of sodium to exchange with potassium at basolateral membrane
types of potassium sparing diuretics
- directly inhibit actions of aldosterone at receptors (spironolactone, eplerenone)
- indirectly affect the resulting exchange of cations by blocking sodium channels (amilioride)
osmotic diuretics mechanism
create osmotic drag that prevents passive resorption of water in renal tubule areas that are freely permeable: LoH descending limb, PCT, CD
Inc flow of water carries other electrolytes also
carbonic anhydrase inhibitors mechanism and indications
prevent reabsorption of bicarb ions with sodium and chloride ions in the PCT, mild diuresis
used in management of glaucoma or prevent altitude sickness
indications of loop diuretics
heart failure: both acute (usually intravenously) and chronic (usually orally)
resistant hypertension, particularly in patients with renal impairment
administration of loop diuretics
typically 40-80mg, IV in emergency situations, words within 1 hour
Loop diuretics reach their site of action in the Loop of Henle after being secreted by organic acid transport proteins in the proximal convoluted tubule.
adverse effects of loop diuretics
hypotension, hyponatremia, hypokalaemia- lethargy, metabolic alkalosis, ototoxicity
SE of carbonic anhydrase inhibitors
metabolic acidosis and inc secretion of potassium= hypokalaemia
why are carbonic anhydrase inhibitors weak?
majority of the Na+ that doesn’t get resorbed in PCT gets resorbed in DCT
why are thiazide diuretics weak?
they act on DCT but majority of NaCl resorption occurs before DCT
SE of thiazide diuretics
dehydration postural hypotension hyponatraemia, hypokalaemia, hypercalcaemia- met alkalosis gout impaired glucose tolerance impotence
SE of potassium sparing diuretics
hyperkalaemia, mentraul irregularities and gynocomastia
indications for osmotic diuretics
acutely raised intracranial pressure, to increase urine output in ARF, promote urinary excretion of toxic substances
SE of osmotic diuretics
hypervolemia/dehydration, electrolyte imbalances
ACE Inhibitors mechanism
(e.g. ramipril, lisinopril) inhibit the enzyme that catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, which is a powerful vasoconstrictor
indications of ACE inhibitors and angiotensin receptor antagonists
hypertension, chronic heart failure, MI, diabetic nephropathy
SE of ACE inhibitors
dry cough, hypotension, angioedema, hyperkalamia and metabolic acidosis
angiotensin receptor antagonist
(e.g. losartan, candesartan) block the effect of angiotensin II at its receptor, rather than preventing its generation. main effects: dilate arterioles, reduce peripheral vascular resistance, reduce blood pressure and reduce blood volume
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors mechanism and indication
(e.g. canagliflozin, dapagliflozin) inhibit the co-transporter protein that reabsorbs glucose with sodium. They increase the urinary excretion of glucose and are indicated for the treatment of type 2 diabetes.
Uricosuric drugs (e.g. febuxostat, sulfinpyrazone) mechamism and indication
block reabsorption of uric acid in the PCT
indicated for the long-term prevention of gout.
vasopressin analogues eg.desmopressin indication
patients with high urinary flow (diabetes insidious) and develop dehydration because vasopressin can’t be produced
vasopressin inhibitors eg.demeclocycline indications and mechanism
SIADH
inhibits responsiveness of collecting duct cells to vasopressin and reduces water reabsorption when fluid restriction becomes ineffective
epoetins
recombinant human erythropoietin that are used to treat the anaemia associated with erythropoietin deficiency in chronic renal failure
why and when is vitamin D therapy needed?
Vitamin D requires hydroxylation by the kidney to its actve form, therefore the hydroxylated derivatives alfacalcidol or calcitriol should be prescribed if patents with severe renal impairment require vitamin D therapy.
what can be offset by prescribing sodium bicarb supplements?
Sodium bicarbonate is normally reabsorbed from the proximal convoluted tubule and patients with advanced renal impairment develop a metabolic acidosis, which can be offset by providing sodium bicarbonate supplements.
presentations of renal drug toxicity
acute tubular necrosis or interstitial nephritis
acute tubular necrosis
process of direct injury to the renal tubules resulting in dysfunction and death of the cells, and obstruction of the tubules caused by cellular debris
drug and non drug causes of acute tubular necrosis
drug causes: gentamicin (aminoglycoside antibiotics), chemotherapy, calcineurin inhibitors (cyclosporin), acyclovir
non drug causes: bacterial sepsis, renal ischaemia
acute interstitial nephritis
acute hypersensitivity reaction manifesting as inflammation in the interstial spaces around the renal tubules.
clinical features of acute interstitial nephritis
Clinical features: low grade fever, a skin rash, eosinophilia and a urine sample containing protein, and white blood cells
causes of acute interstitial nephritis
drug-induced: antibiotics (e.g. cephalosporins, sulfonamides), NSAIDs (e.g. ibuprofen, diclofenac) and proton pump inhibitors
tubular dysfunction caused by lithium
Lithium is a small cation that can compete with other cations in tubular cells and cause polyuria secondary to impairing urine concentrating ability.
slit diaphragm
blood capillary with podocytes wrapped over, it is a thin line of protein with holes between them.
Only 3% of the total area is actually slit, the rest is obstruction > the slit diaphragm is therefore a major source of resistance to fluid flow- need large amounts to get enough flow and need pressure
Restrict afferent arteriole ->
Blood pressure in capillaries drops
Filtration rate drops
Restrict efferent arteriole->
Blood pressure in glomerular capillaries rises
Filtration rate rises
Anticlogging of the renal filter is carried out
pinocytosis of trapped proteins (most likely to clog)
Pinocytosis- small vesicles of membrane with receptors for protein, take them into cells & exporting them/degrading them with endosomes
GBM functions
- large proteins enter GBM which stops large protein complexes from jamming up diaphragm
- constantly degrade existing membrane and renew
GBM renewed by
mesangial cells
nephron number associated with mothers amino acid nutrition
Nephron number follows mother’s amino acid nutrition- fewer if protein starvation in fetal life
% of plasma removed as filtrate before entering PCT
20% of plasma is removed as filtrate but the amount of filtration that occurs declines in people with renal problems
which part of nephron has microvilli?
proximal tubules have microvilli (huge SA, not completely blocked), distal tubules don’t
define resorption and secretion
Reabsorption- movement of water and solutes from the nephron tubules back into circulation
Secretion- movement of solutes and water from circulation into the nephron tubule
what can be used to power movement of passive import of cotransporters?
Deficit of sodium in cell compared to surrounding fluid caused by Na/K ATPase transporter on basal side
Transporters involved in recovery in PCT
Sodium recovery: Na/H exchanger
Import= Na+
Export= H+
Phosphate Recovery:
Sodium flows down its concentration gradient from apical side into cell, allowing symport of phosphate back into the cell.
Import: Na+, PO4
Amino Acid Recovery:
Sodium flows down concentration gradient from apical side into cell as well as chloride ions accompanied by neutral amino acids. There are different SLC transporters for different types of amino acids.
Import= 2Cl-, Na+, neutral amino acids
Glucose Recovery:
Import: Na+, glucose
Sodium flows down concentration gradient rom apical side into cell, allowing glucose symport.
glucose recovery in PCT
Glucose recovery = rate limited.
- amount filtered is proportional to the concentration in the plasma.
If the amount of glucose in the plasma is high, such as in diabetes mellitus, glucose will remain in the urine (hence ‘mellitus’ = sweet) and will have the effect of drawing water and impeding water recovery.
Transporters involved in sodium recovery in DCT
Na/Cl cotransporter
Import= Cl-, Na+
Sodium flows down concentration gradient from apical side into cell allowing symport of chloride ions from apical lumen into cell
Transporters involved in potassium recovery in LoH
Na-K-Cl transporter
Sodium flows down concentration gradient from apical side into
cell.
Chloride also enters cell in symport with sodium and potassium (SLC12A2).
Import: K+, Na+, 2Cl-
action of OCTs:
SLC22A1
ABCB1/MDR1
MATE antiporter
SLC22A1 creates a H+ loop to actively pump cations into the apical side.
ABCB1/MDR1 is an important transporter which uses ATP to export cations out, so more cations diffuse in passively from the basal side
MATE antiporter- antiporter gradient that uses proton gradient to pump out cations
why are OCTs safe?
This is ‘safe’ in the sense that cations drift into the cell and are pumped out. The cytoplasmic concentration should therefore not exceed that of plasma.
action of OATs:
SL13A3
alpha ketoglutarate
SL13A3 parasitizes Na+/alpha ketoglutarate.
Alpha ketoglutarate builds up in the cell, and another carrier allows alpha ketoglutarate to leak out of the cell in order to transport anions into the apical side of the cell through various organic anion transporters (passive).
why are OATs not safe?
the passive drifting of anions out of the cell are weak, or not as good as the active transporters, the metabolite can build up inside the cytoplasm of the cell
why is the targeting of ketoglutarate by new drugs good?
- New drugs target ketoglutarate which prevents toxic anion build up inside cells > allows kidneys to be saved in situations where nephrotoxic drugs have to be used
Bicarbonate and H+ Recovery: Proximal Tubule
Sodium flows down its concentration gradient from apical side into cell.
Proton exporter: In the lumen of the tubule, HCO3-and H+ combine to form carbonic acid, which is catalysed by carbonic anhydrase to form CO2 and H2O. CO2 diffuses into the cell and recombines with H2O to make carbonic acid again, which dissociates back into H+ and HCO3-.
SLC4A4: Bicarbonate is then symported out of the cell with the sodium from the Na+/K+ ATPase, and H+ is exported back out into the apical lumen when sodium is transported in from the apical lumen. Cl-is exchanged for HCO3-, known as ‘chloride shift’.
effect on acid/base by Bicarbonate and H+ Recovery in Proximal Tubule
that there is no net secretion of H+/HCO3-, so there is no effect on acid/base.
what happens to bicarb and H+ recovery when the bicarbonate has been taken up?
When the bicarbonate has been taken up:
- Metabolic acidosis is likely when most HCO3 is depleted
- Instead HPO4 + H+ H2PO4
- H2PO4 excreted in the urine, excreting an H+ ion
- Essentially sets up an excretory H+ loop
Change in net secretion of H+ > acid/base affected
ammonia transport impact on acid base
The ammonia/ammonium can come from amino acid reactions (eg. glutamine) which causes H+ to leave the body with ammonia as it can cross the cell membrane to go into urine space> loss of H+ which affects acid/base
types of intercalated cells in the collecting ducts
Type A cells: excrete H+ out of the body (to apical side to be excreted in urine)
Type B cells: throw H+ back into the body (to basal side to return to circulation)
how is calcium recovered?
• Calcium is recovered mainly passively by the paracellular route, through leaky tight junctions, and is driven by osmosis once the urine has become more concentrated.
how are proteins crossing the glomerular filter recovered?
• Proteins which manage to get through the glomerular filter are recovered in the PCT using general receptors like megalin. This is typically by clathrin receptor mediated endocytosis.
what is resorbed in the proximal tubule?
sodium, chloride, phosphate, glucose, amino acids, urea, bicarb
The PCT recovers about 65% of sodium, potassium, chloride, phosphate etc, and a similar amount of water.
Formation of Hypertonic Solution in PCT:
- An SLC cotransporter moves sodium, potassium, chloride ions from the apical side into the cell using sodium concentration gradient which has been set up
- Sodium and chloride ions from the cell can be exported onto the basal side
- Water stays in the tubule as there are no aquaporins to allow water to move down its concentration gradient in the cells that do this
when can water move into the hypertonic area of tissue?
water moves from the descending limb into the locally hypertonic area
of tissue bc the descending limb is permeable to water
qualities of limbs of the LoH
- The descending thin limb is permeable to water, but impermeable to urea and ions
- The ascending thick limb is impermeable to water, but permeable to urea and ions
water movement and urine concentration in the LoH
Therefore water moves from the descending limb into the locally hypertonic area
of tissue. At this point the urine is getting more concentrated. In the ascending
limb, water stops moving out of the tubule, and ion recovery continues –this starts to dilute the urine again, in fact diluting it to a lower osmolarity than it began when it was in the PCT, and keeps the tissue locally hypertonic.
what is resorbed in the LoH?
sodium, chlorine, potassium
This mechanism recovers about 10% of the filtered water, and 25% of the solutes.
How is the high osmolarity due to the salt in the LoH area stopped form being washed away due to normal blood flow?
- Anatomy: all of the loops are located in the same cortex and drive down into renal medulla which the renal corpuscles are in the cortex, the medulla is hypertonic and salty
- Anatomy: the blood vessels that leave the glomeruli form a secondary network of capillaries: the vasa recta which dive down into the medulla with the LoH : gain salt and lose water as they go down, gain water and lose salt as they come up maintains the same concentration= countercurrent exchange
DCT resorption
Na+/K+ ATPase: Na+ and K+
Cells of the distal convoluted tubule also recover Ca2+ from the filtrate.
effect of AVP on CD cells
causes aquaproins to be moved from storage vesicles and inserted onto plasma membrane so water can be dragged out of collecting duct- can inc total volume of fluid in body and BP
If plasma osmolarity rises,
more water is recovered (inc AVP) and urine volume decreases
secretion in CD
when passing down the collecting duct, the urine can receive K+ and H+ (acid/base balance). It also loses some urea, which is also controlled by vasopressin
urea secretion
urea, which is controlled by vasopressin, which contributes yet more to the hypertonic zone in the medulla. This might seem counterproductive, however it is only allowed to move into the medullary zone to add to the hypertonicity –it doesn’t go back to the body. It really adds to the amount of water being recovered.
renal artery branches
renal artery > segmental arteries > arcuate arteries directly to glomeruli
countercurrent exchange of oxygen in arteries and veins
The long runs of parallel arteries/arterioles and veins/venules mean that there is counter-current exchange of oxygen so that it gets shunted from artery to vein before the blood reaches the capillaries = kidneys are sensitive to ischemia
It is also used adaptively because if the kidneys sense low oxygen levels, they release more erythropoietin > more RBCs being made in bone marrow
constriction of afferent and efferent arterioles
- Constriction of afferent arterioles- lowers glomerular pressure
- Constriction of efferent arterioles- raises glomerular pressure ( diabetic changes in cells can cause this too can drive glom pressure too high)
mechanisms of control of blood flow to kidney
- Direct pressure sensing in the afferent arteriole- the myogenic mechanism- stretch activated cation channels depolarise the membrane and cause smooth muscle to contract > fast and protective against acute surges
- Monitoring the performance of the nephron by assessing salt concentration in the distal tubule and feeding information back into efferent & afferent arterioles at the glomerulus- tubuloglomerular feedback. This is sensed by a group of epithelial cells known as the macula densa.
juxtaglomerular apparatus
distal convoluted tubule is actually in ‘kissing distance’ of the glomerulus. The cells of the macula densa interact with a group of cells surrounding the arterioles, known as the ‘juxtaglomerular apparatus’
How does the macula densa work in high BP?
Elevated glomerular blood pressure > filtrate flows faster > less time for solute recovery > more NaCl remains in the distal tubule > macula densa cells pump out more NaCl than they usually can (because there is more available) > juxtaglomerular cells release adenosine- change flow rate > afferent arteriole constricts in response to adenosine
How does the macula densa work in low BP?
If the flow rate is too slow, this means there isn’t much NaCl left in the distal tubule > renin is released by juxtaglomerular cells and is not inhibited (inhibited in fast flow rate)
function of renin and ACE
Renin enters the circulation and acts to cleave angiotensin I from angiotensinogen. Angiotensin I is then shortened to angiotensin II by ACE.
Actions of Angiotensin II:
- Increasing sodium uptake and proton expulsion
- Sympathetic activity: renal nerves secrete noradrenalin which constricts both vessels serving glomerulus so reduces flow and directly promotes renin release
- Arterial vasoconstriction- increasing blood pressure
- stimulate the adrenal cortex to secrete aldosterone and the pituitary gland to produce AVP which signals to the kidney.
ANP actions if BP gets too hgih
ANP from the heart blocks the Na+ reuptake channel collecting ducts and causes more sodium loss if BP gets too high.
action of aldosterone on CD a-intercalated cells
acts on gene transcription making more mRNA for the H+ATPase so protons are secreted into urine: less acidic
action of aldosterone on CD principal cells
acts on gene transcription of ASC and allows entry of sodium form apical side (urine) and enter circulation
= inc Na recovery and K secretion
actions of PTH at PCT and DCT
Action at the PCT: blocks sodium phosphate uptake- if you want free calcium in blood, you don’t want phosphate to mop it up= calcium phosphate
Action at DCT: increases activity of calcium export and calcium import: calbindin (need Vit D for synthesis)
fall in intracellular pH leads to
Fall in intracellular pH > apical Na/H exchangers more active > H+ excreted (complexed with buffers once in urine)
potassium resorption + excretion and regulation
Potassium: around 90% is resorbed in collecting duct with no regulation
There is re-absorption by intercalated cells constantly.
Excretion by principal cells is regulated.
impact of diet K+ on K+ channels
High tissue K+ increase K+ flow into channels and thence out:
- Low diet K+ diets > tyrP of apical K+ channel > channels removed from membrane
- High K+ diets cause loss of tyrP and channels accumulate in membrane
potassium flux in alkalosis
In alkalosis: H+ out-pumping by intercalated cells reduced, so less K+ re-uptake (AND apical K+ channel activity increased in Principal cells and so is the Na+/K+ ATPase -> more K+ loss) -> hypokaelaemia
potassium flux in acute acidosis
H+ out-pumping by intercalated cells increases so K+ reuptake increases. Also, apical K+ channels on Principal cells less active (by an effect on their intracellular regulation) so K+ secretion falls -> hyperkalaemia
potassium flux in chronic acidosis
In chronic acidosis: Na pump less efficient in PCT, so urine more copious and helps flush K+ away
Bartter’s syndrome
impaired SLC12A2 in thick ascending loop of Henle –has the same clinical effect as loop diuretics. Hypercalcuria, loss of sodium, water and potassium
Gitelman’s syndrome
impaired SLC12A3 in distal convoluted tubule –same clinical effect as thiazides. Loss of sodium, potassium
Liddle’s syndrome
hyperactive amiloride-sensitive channels -pseudohyperaldosteronism. Sodium retention, increased blood pressure and volume, treat with amiloride to block channels
Pseudohypoaldosteronism
inactive amiloride sensitive channels, clinical effect of amiloride. Sodium loss, water loss, decreased BP
Nephrogenic diabetes insipidus
inactivation of aquaporins, no water recovery therefore too much urine produced
Addison’s disease
same renal result as treatment with spironolactone. Patients can’t produce aldosterone, therefore reduced amiloride sensitive channels, sodium and water loss, reduced BP
Psychogenic polydipsia
whole body hypo-osmolality. Kidneys can only filter so much before they become overloaded
ROMK function
(renal outer medullary K+ channel) creates a ‘‘regulated linkage’’ loop to allow K+ recycling into the ascending limb of the Loop of Henle.
origination of parts of the nephron
CD- nephrite duct
rest of nephron- mesenchyme
where does the bladder begin to form from?
where the nephritic duct and ureter bud diverge
components of semen in the testis
sperm
components of semen in the prostate
citric acid, enzymes, acidic proteins
components of semen in the seminiferous vesicle
fructose, basic proteins and modulators of the immune response
urethra location in males
runs along penis and opens at its end
urethra location in females
urethra ends within vulva and does not run to end of clitoris
renal agenesis
can be detected early, lack of amniotic fluid causes potters facies
potters facies
flat nose, flat chin, ears against head
supernumerary ureter
sometimes nephritic duct gives rise to 2 branches- no consequence if both unit and go into bladder properly
ectopic ureter
joining below bladder so urine wouldn’t be stored in bladder- would dribble out of urethra- increased risk of infection travelling up to kidney
consequences of pelvic kidney
males- little consequence
females- prob in pregnancy, expanding uterus exerts lot of pressure on kidney
horseshoe kidney
2 pelvic kidneys fuse together and can be jammed by inferior mesenteric artery
Failure of correct positioning of Rathke and Tourneaux folds results in;
Rectovaginal/Rectoprostatic fistula Rectoclocal canal (rectum, vagina and urethra unite inside body)
Potter sequence
oligohydramnios (e.g. due to bilateral renal agenesis) + pulmonary hypoplasia (cause of death), clubbed feet
