Renal Physiology 2 Flashcards
transcellular vs paracellular reabsorption (renal)
transcellular: through apical and basolateral plasma membranes via transporter or channel, requires metabolic energy
paracellular: through tight junctions (extracellularly) between tubule epithelial cells, passive process relying on electrochemical or concentration gradient
which transporters enable sodium reabsorption in the proximal tubule? (4)
most Na+ reabsorption occurs in PCT
apical membrane:
1. SGLT1/2 (Na+/glucose co-transporter) - most glucose is reabsorbed here as well
2. NHE (Na+/H+ exchanger)
basal membrane (from tubule epithelial cells to renal interstitium:
3. Na+/K+ ATPases
4. Na+/HCO3- symporters
how do the Starling forces within the peritubular capillaries change as GFR increases?
filtration results in low hydraulic pressure and high oncotic pressure in efferent arteriole, which provides driving force for reabsorption of H2O and Na+
increase in filtration fraction (increased GFR) enhances this drive for reabsorption
which transporters enable sodium reabsorption in the thick ascending limb (TAL)? (3)
apical membrane:
1. Na+/H+ exchangers
2. NKCC (Na+/K+/Cl- co-transporter)*
basolateral:
3. Na+/K+ ATPase
*NKCC is target of certain loop diuretics (ex, furosemide)
describe how the gradient for the NKCC sodium reabsorption transporter is maintained in the thick ascending limb (TAL)?
NKCC: apical Na+/K+/Cl- co-transporter in thick ascending limb (TAL), translocates Na+ from lumen into epithelium
ROMK2 K+ transporter in renal outer medulla maintains favorable gradient for NKCC
which segment of the nephron is referred to as the “diluting segment”?
thick ascending limb: impermeable to H2O but reabsorbs ions, thereby decreasing the tonicity of the forming urine in the region
aka “diluting segment”
describe how loop diuretics work
loop diuretics are secreted from blood into PCT transporters (bound to plasma albumin), then use forming urine as vehicle to reach/block NKCC (Na+/K+/Cl- co-transporter) in the thick ascending limb (TAL)
—> decreased NaCl and K+ reabsorption (“K+ wasting diuretic”)
—> decreased H2O reabsorption/ diuresis because H2O follows Na+
—> Ca2+ wasting because of decreased activity of NKCC+ROMK, which recycle K+ to generate lumen-positive potential that drives Ca2+ reabsorption
describe the effect of proteinuria (hyperalbuminuria) on the efficacy of loop diuretics
loop diuretics are secreted from blood into PCT transporters bound to plasma albumin, then use forming urine as vehicle to reach/block NKCC (Na+/K+/Cl- co-transporter) in the thick ascending limb (TAL)
because they are bound to plasma albumin, they cannot be freely filtered through glomerular capillaries
therefore in patients with hyperalbuminuria, a higher dose of loop diuretic is required
given loop diuretics such as furosemide block the NKCC (Na+/K+/Cl- co-transporter) in the thick ascending limb (TAL), then explain how they also promote Ca2+ wasting
—> decreased NaCl and K+ reabsorption (“K+ wasting diuretic”)
—> decreased H2O reabsorption/ diuresis because H2O follows Na+
—> Ca2+ wasting because of decreased activity of NKCC and ROMK (K+ transporter in outer medulla), which recycle K+ to generate lumen-positive potential that drives Ca2+ reabsorption
what kind of drug is furosemide and how does it work?
furosemide: loop diuretic - secreted from blood into PCT transporters, uses forming urine as vehicle to reach/block NKCC (Na+/K+/Cl- co-transporter) in the thick ascending limb (TAL)
—> decreased NaCl and K+ reabsorption (“K+ wasting diuretic”)
—> decreased H2O reabsorption/ diuresis because H2O follows Na+
—> Ca2+ wasting because of decreased activity of NKCC+ROMK, which recycle K+ to generate lumen-positive potential that drives Ca2+ reabsorption
which transporters enable Na+ reabsorption in the DCT (distal convoluted tubule)?
all Na+ movement in DCT is transcellular (via transporters)
via apical NCC (Na+/Cl-) co-transporters and basal Na+/K+ ATPases
how do thiazide diuretics work?
thiazide diuretics: block apical NCC (Na+/Cl- co-transporter) in DCT (distal convoluted tubule)
enhance K+ secretion by inducing aldosterone + AVP secretion and alkalosis —> K+ wasting diuretic
what is the function of principal cells in the cortical collecting tubules (CCT)?
principal cells: control Na+ reabsorption under the hormonal influence of AVP (vasopressin), aldosterone, and AII (angiotensin II)
*note the actual amount of Na+ reabsorption at this point is modest because there is very little Na+ remaining in the forming urine
what is the effect of the following molecules on the principal cells of the CCT (cortical collecting tubules)?
a. AVP
b. aldosterone
c. AII
a. AVP (vasopressin): activates ENaC on apical membrane, stimulates the recruitment of Na+/K+ ATPases into basolateral membrane
b. aldosterone: Na+ reabsorption via ENaC, Na+/K+ ATPases (*CCT = ASDN, aldosterone-sensitive distal nephron)
c. AII (angiotensin II): stimulates ENaC (also stimulates AVP and aldosterone secretion, enhancing above effects)
which part of the nephron is referred to as the aldosterone-sensitive distal nephron (ASDN)?
cortical collecting tubules (CCT): contain principle cells which reabsorb Na+ under the direction of aldosterone (as well as AVP and AII)
explain the effects of ENaC activation on K+ levels
ENaC = epithelium Na+ channel, found on apical membrane, activated by AII (angiotensin II), AVP (vasopressin), aldosterone
translocation of Na+ by ENaC creates a lumen-negative charge that favors K+ secretion
why is it so important that the basolateral Na+/K+ ATPases found through the nephron are functional? (basically, what is their overarching purpose?)
basolateral Na+/K+ ATPases establish the driving force for Na+ influx from the forming urine - if these were to fail, Na+ reabsorption would fail also
*note Na+ influx also depends on membrane potential that is maintained via ROMK2-mediated K+ secretion
what kind of drug is amiloride and how does it work?
amiloride: K+ sparing diuretic, blocks ENaC to disrupt Na+ reabsorption
blocking ENaC causes hyperpolarization of the apical membrane, which disrupts electrochemical gradient that would favor K+ secretion (—> K+ sparing)
what kind of drug is spironolactone?
spironolactone: K+ sparing diuretic, competitively inhibits aldosterone by binding to the mineralocorticoid steroid receptor within principal cells (CCT)
recall aldosterone stimulates Na+ reabsorption and K+ secretion by stimulating ENaC and Na+/K+ ATPases
what stimulates cells in the zona glomerulosa (of adrenal cortex) to secrete aldosterone? (2)
- activation of AT1 receptors via angiotensin II
- hyperkalemia (high plasma K+)
what kind of receptor does aldosterone bind, and what is the effect of this (how does the receptor respond)?
aldosterone: steroid mineralocorticoid hormone, secreted from zona glomerulosa of adrenal cortex
—> binds mineralocorticoid type steroid receptor within cells (steroid hormones are lipid soluble) - recall steroid receptors are transcription factors which bind steroid hormone response elements within gene promoters —> induce gene transcription
aldosterone acts on principal cells of CCT (Na+ reabsorption) and vascular smooth muscle cells (vasoconstriction)
describe the acute vs chronic effects of aldosterone on nephron functioning
acute (1-4h): activation of signal transduction motifs which stimulate ENaC activity
chronic (4+h): up-regulation of expression of ENaC and Na+/K+ ATPases (recall aldosterone is steroid hormone, so its receptor is a transcription factor within the cell)
explain the “aldosterone paradox”
during volume depletion, RAAS is activated —> Na+ reabsorbed at proximal (AII via NHE3) and distal (AII via NCC and aldosterone via NCC/ENaC) nephron
during euvolemic hyperkalemia, K+ increases aldosterone secretion without a rise in AII (stimulates adrenal zona glomerulosa) —> without AII, effects of aldosterone are skewed towards increasing ROMK activity —> more profound K+ secretion over Na+ reabsorption
describe the “pressure natriuresis” phenomenon
as aldosterone induces volume expansion, “pressure natriuresis” induces Na+ and H2O excretion to compensation for elevated MAP
—> high volume/flow in distal nephron promotes K+ secretion until aldosterone secretion is terminated (“aldosterone escape”)
mechanism provides a fail-safe against chronically elevated BP
note patients with hyperaldosteronism are often hypokalemic but have normal Na+ levels
what type of hyponatremia do the following conditions cause? (euvolemic, hypovolemic, hypervolemic)
a. aldosterone deficiency
b. glucocorticoid deficiency
c. diarrhea
d. heart failure
a. aldosterone deficiency (also diuretics) —> intra-renal hypovolemic hyponatremia: loss of TBW and Na+ with more Na+ lost relative to H2O, increased urine [Na+] (when cause is intra-renal)
b. glucocorticoid deficiency (lacking negative feedback on AVP from cortisol) —> euvolemic hyponatremia: decrease in H2O excretion only, increased urine [Na+]
c. diarrhea (also vomiting, excessive sweating, etc) —> extra-renal hypovolemic hyponatremia: loss of TBW and Na+ due to profound decrease in intravascular fluid, increased urine [Na+] via kidney conservation (when cause is extra-renal)
d. heart failure —> hypervolemic hyponatremia (dilutional hyponatremia): increase in H2O retention, decreased urine [Na+] (RAAS is trying to increase cardiac output)
A patient with glucocorticoid deficiency is presenting with signs of hyponatremia - What kind of hyponatremia do they have, what will urine testing show, and how are you going to treat them?
glucocorticoid deficiency causes euvolemic hyponatremia because cortisol normally exerts negative feedback on AVP secretion
Euvolemic hyponatremia: increased retention of H2O/increase in TBW (but volume status is still within normal limits) —> urine [Na+] is elevated
Treatment protocol is to restrict H2O intake
what causes intrarenal hypovolemic hyponatremia vs extrarenal hypovolemic hyponatremia? How does the presentation of each of these differ?
hypovolemic hyponatremia = loss of TBW and Na+ where more Na+ is lost relative to H2O - treat with isotonic saline
Intrarenal: diuretics, osmotic diuresis, aldosterone deficiency —> increased urine [Na+]
Extrarenal: diarrhea, vomiting, third space fluid shifts, excessive sweating —> decreased urine [Na+] via kidney conservation, elevated BUN via decreased renal perfusion, signs of low intravascular volume (tachycardia, flattened neck veins, orthostatic HTN)
Pt is presenting to the ED after 24 hours of intense vomiting following food poisoning. PE reveals tachycardia and flattened neck veins. Labs reveal decreased urine [Na+] and increased BUN. What is this patient experiencing (in their kidneys) and how will you treat it?
Extrarenal hypovolemic hyponatremia: loss of TBW and Na+
diarrhea, vomiting, third space fluid shifts, excessive sweating —> decreased urine [Na+] via kidney conservation, elevated BUN via decreased renal perfusion, signs of low intravascular volume (tachycardia, flattened neck veins, orthostatic HTN)
Treat with isotonic saline
A marathon runner is taken to the ED after collapsing on the course. They had been carrying three bottles of water with them. Labs show a decrease in urine sodium. What renal impairment is going on?
Hypervolemic hyponatremia: sign in ordinate retention of H2O, which causes a decrease in the plasma concentration of sodium
basically, the runner drank too much water and diluted their blood
what kind of hyponatremia is caused by heart failure vs renal failure?
heart failure: hyperactive RAAS in response to decreased CO causes kidneys to retain a lot of H2O and some Na+ —> dilutional hypervolemic hyponatremia, patient will have decreased urine Na+
renal failure: decreased GFR —> hypervolemic hyponatremia, patient will have increased urine Na+ due to impaired reabsorption
what is the mechanism around mineralcorticoid hypertension?
heightened ENaC-dependent Na+ reabsorption at the expense of K+ excretion
Commonly caused by hyperaldosteronism - aldosterone, secreting tumor, adrenal hyperplasia, adrenal carcinoma
Characterized by hypertension, hypokalemia, metabolic alkalosis, and decreased plasma renin
how does pseudo-hypoaldosteronism or Type I Hypoaldosteronism present?
fatal syndrome that presents in infants once they are removed from the in-utero protection afforded by mothers endocrine system
Causes “salt wasting” (natriuresis) due to non-functional ENaC
associated with mutation in SCNN1 (encodes EnaC)
describe the pathophysiology of diabetes insipidus (DI)
diabetes insipidus: disruption in the AVP system results in hypotonic polyuria and polydipsia
Due to either loss in AVP production (neurogenic/central) or mutations of V2R or AQP2 receptors (nephrogenic) —> decreased AVP-mediated H2O reabsorption in renal tubules
Reduced plasma volume triggers activation of osmoreceptors that stimulate hypothalamic thirst centers —> polydipsia
Because ions follow water, patients will likely have ion imbalances
how will patients with diabetes insipidus present?
diabetes insipidus: disruption in the AVP system results results in hypotonic polyuria - high urine volume with low osmolarity and negative for glucose/proteins
Reduced plasma volume triggers activation of osmoreceptors that stimulate hypothalamic thirst centers —> polydipsia
Because ions follow water, patients will likely have ion imbalances
How will urine testing differ for diabetes insipidus versus diabetes mellitus?
diabetes insipidus - hypotonic polyuria due to disruption of AVP
diabetes mellitus – solute-rich polyuria
describe the pathophysiology of syndrome of inappropriate anti-diuresis (SIAD) - what are the 4 defining characteristics?
SIAD: increase in AVP activity (neurogenic) or GOF mutation in V2 receptor (nephrogenic)
—> reduced ability to excrete enough H2O to maintain normal plasma osmolarity —> euvolemic hyponatremia as H2O distributes evenly throughout body compartments
defining characteristics:
1. highly urine osmolarity
2. high urine [Na+]
3. euvolemic hyponatremia
4. hypoosmolarity of plasma
what mutation is associated with a congenital form of syndrome of inappropriate antidiuresis (SIAD)?
SIAD: increase in AVP activity (neurogenic) or GOF mutation in V2 receptor (nephrogenic) —> euvolemic hyponatremia
congenital form presents in neonate, due to X-linked GOF mutation in V2 receptor —> constitutively active in absence of AVP (nephrogenic SIAD)
patients with congenital SIAD will have very low levels of serum AVP due to negative feedback, but activity of renal AQP2 will remain high
which two compounds can be given to patients with the nephrogenic form of syndrome of inappropriate antidiuresis (SIAD) to reduce activity of the V2 receptor?
SIAD: increase in AVP activity (neurogenic) or GOF mutation in V2 receptor (nephrogenic) —> euvolemic hyponatremia
1.demeclocycline (preferred) and 2. lithium (toxic) can be used for nephrogenic SIAD - target signaling molecules involved in V2-R mediated activation of AQP2 (aquaporin)
