Renal Flashcards
What is the primary determinant of body water load?
body sodium load
importance of location of nephron
medulla provides a high-salt (high osmotic) environment for loop of Henle
glomerular filtration rate
tells how well the initial filter is working; the amt of fluid filtered by the kidney over time; self-limiting process
physiology of glomerulus
surrounds a capillary bed fed by renal arterioles; size-based filter; slurry of high-osmotic fluid exits here
physiology of proximal tubule
permeable to water & most salts; fluid is iso-osmotic with blood; site of 65% of water/K/Na/bicarb reabsorption; 2nd site of entry into nephron; primary site at which highly protein-bound molecules can gain entry
function of Na/K ATP basolateral antiporter pump in the proximal tubule
pushes Na out of cytoplasm & brings K in; sets up Na conc gradient; drives import of organic acids
function of Na/H+ antiporter in luminal membrane in the proximal tubule
takes up Na from luminal space & exchanges Na for a proton; proton gradient drives organic bases into luminal space
physiology of loop of Henle
fluid becomes concentrated as it flows through medullary space; descending thin limb & ascending thick limb are key areas
thin descending limb
highly permeable to water; impermeable to salts/urea; concentrating action
thick ascending limb
impermeable to water; highly permeable to NaCl; end w/ small volume of very dilute fluid
osmolality of loop of Henle
increased osmolality as you descend; decreased osmolality as you ascend; active transport of NaCl out of ascending limb feeds high salt interstitial envir. (drives water absorption in descending loop); Na/K pumps in basolateral membranes of epithelial cells
physiology of vasa recta
highly permeable to salt & water to reclaim what is removed by loop of Henle and deliver it back to circulation; salt picked up by descending vasa recta; water picked up by ascending vasa recta
physiology of the macula
specialized epithelial cells at the distal end of the ascending thick limb; sense osmolality of urine; reduces flow in afferent arteriole (constricts) if NaCl is too high in urine
tubuloglomerular feedback (TGF)
reduces the amt of fluid that enters the tubular network; makes nephron less effective & lessens the material presented for elimination; preserves the organism from Na loss (Na diuresis is self-limiting d/t TGF)
physiology of distal convoluted tubule
actively transports out NaCl but not water; fluid here is hypotonic urine relative to circulatory fluid
physiology of collecting tubules
water pores responsive to ADH; vasopressin opens pores to reabsorb water; distal ducts permeable to urea (adds to medullary salt gradient)
What is the major site of bicarbonate reabsorption and acidification?
proximal tubule
Where is acid secretion inhibited?
proximal tubule & distal collecting duct
carbonic anhydrase
speeds up the equilibrium of H2CO3CO2 + H2O
involves Na/K ATPase, Na/bicarbonate ion symporter, Na/H antiporter; *read through this
mechanism of action of carbonic anhydrase inhibitors
interfere w/ the reabsorption of bicarbonate ion; mess up the cyclical exchange that provides the proton for the antiporter; reduces import of Na across the membrane; increases urine pH and decreases circulating pH
effects of carbonic anhydrase inhibitors
5% increase of Na excretion; modest diuretic effects; increase in K secretion; cause metabolic acidosis d/t loss of circulating bicarbonate (base)
If you deliver Na late in the distal tubules…
you will increase K and H excretion
*except for carbonic anhydrase inhibitors
Which medication is used in combination with a diuretic to counter metabolic alkalosis?
Acetazolamide (Diamox)
mechanism of action of osmotic diuretics
act on tissues by drawing water into the blood to increase circulatory volume; dilutes & reduces circulatory viscosity; act on kidney by increasing renal blood flow and washing out medullary salt gradient; increased excretion of higher volume/higher salt conc fluid
The reduced medullar salt gradient created by osmotic diuretics…
affects the ability of ADH to act to reclaim water during dehydration.
sites of action of osmotic diuretics
loop of Henle (vasa recta); proximal convoluted tubule
dialysis disequilibrium syndrome
results when solutes are removed too rapidly during dialysis
mechanism of action of loop diuretics
inhibit Na/K/2Cl symporter in thick ascending limb of loop of Henle; enter urine via organic ion transporters in proximal tubules b/c they’re highly protein-bound; K wasting
explain the Na/K/2Cl symporter
transports 2Cl with every 1Na & 1K into the epithelial space (sets up negative potential); K enters lumen via channel to hyperpolarize the luminal membrane; Cl enters interstitial space to depolarize the basolateral membrane; positive potential in luminal space drives transport of positively charged Ca+2 and Mg+2 into intracellular space
effects of loop diuretics
Na/Cl/K stay in thick ascending limb with water so increased flow of concentrated urine is created; accounts for 25% of NaCl excretion
How is uric acid secretion affected by loop diuretics?
acute increase of secretion; decrease in secretion if used chronically
Why is furosemide good for heart failure and pulmonary edema?
It acutely increases systemic venous capacitance that reduces pressure behind the left ventricle and relaxes the vasculature.
Why are loop diuretics not limited by TGF (tubuloglomerular feedback)?
They block salt transport into the macula.
How does the action of loop diuretics lead to volume depletion?
Their action collapses the medullar gradient, eliminating the ability to reclaim water from the collecting ducts.
How do NSAIDs affect diuretic activity?
NSAIDs reduce GFR, which antagonizes diuretic activity and reduces efficacy. (loop & thiazides)
How does Probenecid affect diuretic activity?
It may increase the effective dose needed. It competes for the transporter. (loop & thiazides)
mechanism of action of thiazide diuretics
block Na/Cl symport but not K; enter the urine via organic ion transporters in proximal tubules b/c they’re protein-bound; act in the late distal convoluted tubule; K wasting
Does the Na/Cl symporter affect the medullary gradient?
No, because the distal tubule resides in the cortex. (thiazide diuretics)
How do thiazide diuretics affect Ca reabsorption?
High Na conc in the interstitial space drives the Na/Ca antiporter in the basolateral membrane. This increases Ca reabsorption and decreases elimination.
Why are thiazide diuretics safer than loop diuretics?
They act distal to the macula so are not limited by tubuloglomerular feedback. This maintains the ability to reabsorb water from the collecting ducts.
Which diuretic is best for HTN and why?
thiazides: no risk of hypovolemia (don’t affect water reabsorption and urine conc in the collecting tubules)
effect of renal Na channel inhibitors
act on distal convoluted tubule and collecting duct; cause small increases in NaCl excretion; block K excretion in combo w/ other diuretics; K sparing
function of renal Na channels
Na channels on luminal membranes of epithelial cells in the late distal tubules; ATPase brings Na into the cell which depolarizes the membrane and increases negative potential in the lumen; drives K secretion out of cell; the more Na in the lumen, the more depolarization and K excretion occurs
mechanism of action of renal Na channel inhibitors
block luminal Na channels which lowers K secretion; inhibits H secretion by raising intra-luminal positive potential
What is Liddle’s syndrome?
It is a mutation in renal Na channels; causes channel stabilization; hypokalemia w/ HTN
Which diuretic is best for African Americans with HTN and why?
renal Na channel inhibitors b/c they have a polymorphism in the ENaC beta subunit (target of these drugs)
How do mineralocorticoids function in renal physiology?
Mineralocorticoids (aldosterone) are secreted by the adrenal glands. They cause retention of salt and water, while increasing excretion of K and protons.
mechanism of action of mineralocorticoid antagonists
receptors in distal convoluted tubule & collecting duct; act the same as renal Na channel blockers; act in the nucleus to change DNA expression of aldosterone-induced proteins; increase transport of K and H out of lumen; K sparing
Which 2 types of diuretics function in the same way?
renal Na channel blockers & mineralocorticoid antagonists
function of aldosterone-induced proteins (AIPs)
activate previously silent Na channels and pumps; increase expression and deposition of channels & increase ATPase activity; promotes Na (& water) reabsorption
What affects the efficacy of mineralocorticoid antagonists?
how much aldosterone-mediated Na channel activity is occurring in these cells
diuretic summary
carbonic anhydrases: weak, counteract alkalosis
osmotic agents: very effective, collapse medullar salt gradient & inactivate loop of Henle
loop diuretics: most effective, collapse medullar salt gradient & inactivate macula to reduce feedback
thiazides: not much Na left to act upon so not efficacious
mineralocorticoids: least efficacious, reverse increased K excretion of other agents
V1 effects of antidiuretics
reduce medullary blood flow; increase medullary salt gradient; water reabsorption from distal tubules & collecting ducts
V2 effects of antidiuretics
stimulate production of aquaporins in the epithelium for more water reabsorption; more aquaporins in apical membrane d/t recycling, more permeability of distal duct to urea, increased activity of Na/K/2Cl symporter in thick ascending limb
receptors & functions for antidiuretics
V1: pressor effects, increase vascular constriction to reduce medullar blood flow
V2: renal antidiuretic effects
Explain the biphasic effect of uricosuric agents.
first cause decreased excretion of uric acid; once in the lumen, inhibit urate reabsorption and increase excretion
mechanism of action of probenecid
competes w/ urate for access to antiporter that brings urate back into the epithelia cell; increases urate excretion; block export of urate from epithelial cells back into tubular lumen so increases hyperuricemia acutely
