Renal Physiology Flashcards
water distribution in body
intracellular vs extracellular compartments
majority of water is intracellular
types of solutes
two types of solutes: effective and ineffective
effective: can be sequestered in a compartment to contribute to an osmotic gradient - need active transport to get across a membrane ex. sodium, glucose
ineffective: diffuse freely based on relative concentration ex. urea
total blood osmolality
effective osmolality
total osmolality = 2[Na} + [blood glucose}/18 + BUN/2.8
effective osmolality = 2[Na] + [blood glucose]/18
renal autonomic innervation
NOT INNERVATED BY PSNS
SNS activity controls
- vasoconstriction
- Na reabsorption
- renin secretion
basics renal functions/processes
- filtration: movement of plasma constituents from glomerulus into Bowman’s capsule
- reabsorption: movement of constituents from forming urine into renal interstitium/back into circulation [vast majority of filtrate is reabsorbed back into circulation. 1-1.5L of 180L gets excreted daily]
- secretion: movement of constituents from renal circ, interstitium, or tubule epithelium into the forming urine
nephron structure and how it can impact GFR
- afferent arteriole: vsm capable of contraction
- glomerulus: site of filtration via fenestrations (net negative charge; cations move through more easily)
- efferent arteriole
- peritubular capillaries
rise/fall in glomerular bp - rise/fall in filtration
clearance equation
clearance refers to the proportion of a substance that is excreted in urine
C = [urine] * volume of urine / [plasma] C = UV/P
glomerular regulation of intraglomerular pressure
renal autoregulation
- kidneys will act to protect glomerular filtration at level of nephron
- high bp: contraction of afferent arteriole to reduce glom filt low bp: contraction of efferent arteriole to increase glom filt
filtered load vs fractional excretion
filtered load: how much solute makes it into Bowman’s capsule per unit time
fractional excretion: ratio of solute excreted to filtered load (how much of what’s filtered is actually excreted)
give examples of solute that are…
- not filtered.
- filtered; no reabs, no sec.
- filtered; partly reabs.
- filtered; mostly reabs.
- filtered; completely reabs.
- filtered; secreted.
- not filtered. - large proteins
- filtered; no reabs, no sec. - inulin
- filtered; partly reabs. - urea
- filtered; mostly reabs. - albumin
- filtered; completely reabs. - glucose
- filtered; secreted. - creatinine
virtually no pressure drop occurs between afferent and efferent ends of glomerulus, even in cases where MAP changes a lot describe the mechanisms that regulate glomerular filtration pressure
glomerular pressure regulated mainly at afferent artiolar level
- efferent constriction can also raise glomerular pressure afferent arteriolar vsm constriction/dilation can be triggered by…
1. SNS tone - norepi adrenoceptor dependent vasoconst
2. autoregulation - concerted action of SNS, natriuretic peptides, paracrine factors (NO, prostaglandins), and RAAS - happens due to either PRESSURE INDUCED DISTENSION OF AFF ART or TUBULAR GLOM FEEDBACK SYSTEM
describe how distension of vsm and vascular endothelium in efferent arteriole can affect autoregulation
stretch induced activation of cation channels, depolarization, mobilization of Ca within vsm, contraction!
TGF - tubular glomerular feedback
describe one physiological conditions where TGF varies from its normal functioning
regulated by concentrations of sodium in forming urine in the thick ascending limb
how it works:
- urine in TAL flows past macula densa, whose cells sense Na concentration (in close proximity with JG cells that secrete renin)
- elevated Na conc stimulates macula densa cells to release factors that stimulate aff arteriole to vasoconstrict (ATP, adenosine, thromboxane)
- GFR lowered
special case: volume expansion
-in these cases, you DONT want TGF to work because you need pressure natriuresis to run its course -increased water content keeps Na conc relatively low, so TGF is desensitized! and diuresis can occur
name the key hormones involved in renal regulation of GFR and RBF
- renin
- angiotensin
- atrial natriuretic peptide
- arginine vasopressin (ADH, vasopressin)
- norepi
- aldosterone [no direct effect - resp for Na retention]
name the key players in the RAS and where they are typically found
- angiotensinogen [in proximal tubule cells - also hepatocytes]
- renin [from renal JG cells]
- ACE [in proximal tubule brush border - also lungs/heart/periph vasc/brain]
describe the function of ACE2
found in renal and cardiac tissues
ACE2 converts AII into angiotensin 1-7
- angiotensin 1-7 binds to Mas receptor (Gprotein coupled) and stimulates:
- vasodil, blocks prolif
- promotes bradykinin -counteracts effects of AII
- possibly cardioprotective and antiHTN
how is renin regulated?
renin secretion from jg cells is REGULATED in response to:
- negative feedback from AII
- SNS tone (jg cells have beta1 receptors)
- -distension of aff arteriole (high bp)*
- -macula densa signals (TGF)*
- -ANP*
- [volume related]*
how does ACE effect vasoconstriction?
- produce vasoconstrictor: renin conversion to AII can happen, leading to vasoconstriction
- degrade vasodilator: ACE, while in town to convert AI to AII, also degrades bradykinin (vasodilator)
how does renin secretion help correct hypovolemia?
- AII leads to systemic vasoconstriction, higher bp
- facilitates RENAL CONSERVATION
- AII vasoconst of renal arteries steadies glomerular pressure AND drops flow in peritubular capillaries
- key for establishing hemodynamics favoring reabsorption of water, sodium
describe the expression AT1 receptors and the effects of binding
AT1 = main receptor form in humans
expression
- vsm (afferent and predominantly efferent artioles, renal tubules, periph vasc)
- adrenal cortex
- renal tubule epithelium/JG cells
effects of binding to AT1
- vasoconst in efferent arterioles = maintains optimal filtration
- might activate Na reabs through transporters NHE3, NKCC2, NCC, ENaC as well as Na/K ATPase
- stimulus for aldosterone production/release from zona glom in adrenal cortex
describe the expression AT2 receptors and the effects of binding
AT2 involved in fetal organogenesis
expression in adult: lung, renal coronary, myocardial tissues, cardiac fibroblasts
effects of binding to AT2
- might mediate natriuresis and vasodilation via NO, guanylyl cyclase, bradykinin
- regardless, AT2 has a more modulatory effect (AT1 vasoconst effects will predominate)
how do renin and ACE inhibitors work?
how does this link to ACE escape???
block active sites within renin and/or ACE disrupts production of AII, which precludes its vasoconstrictive and antrinatriuretic effects.
also stops ACE-dependent bradykinin degradation to preserve its vasodil effect
- also knocks out the negative feedback of AII on renin, which means more renin, which means ACE escape…
what is ACE escape?
- drop in AII also leads to drop in feedback inhibition on renin, which leads to upregulation of renin
- even with ACE blocked, this renin can lead to AII formation if it finds pathways of ACE-independent II production (chymases)
describe the effect of norepi on renal regulation
norepi targets both afferent and efferent arteriors, effecting…
- vasoconstriction : lowers gfr and renal blood flow via ALPHA1 RECEPTORS (to maintain volume/conserve/establish favorable hydrostatic gradients)
- renin secretion : stimulates secretion of renin from JG cells via BETA1 RECEPTORS
- some Na/water reabs : high SNS activity can enhance reabs from tubules via ALPHA2 RECEPTORS
describe how AVP is secreted and the effect of AVP on renal regulation
AVP is produced by cells of the hypothalmic supraoptic and paraventricular nuclei and stored in/released from the posterior pituitary -secreted in response to hyperosmolarity
effects of AVP
- vasoconstriction within renal microcirculation and peripheral arterioles via V1 receptor
-
water reabs (AQP2) and Na reabs (ENaC) via V_2 receptor_
* also increases rate of Na reabs via NKCC (TAL), NCC (DCT), and ENaC (DCT)
*V3 receptors are expressed in corticotrops of ant pit - leads to secretion of ACTH
describe how ANP is secreted and the effect of ANP on renal regulation
secreted by atrial myocytes in response to increased RAP
- will exert vasodilatory effects within afferent and efferent arterioles
- will decrease sensitivity of TGF mech
in total
- increases GFR and RBF
- desensitizes TGF allowing for diuresis
- also supresses renin secretion
renal hypoperfusion can lead to ischemic acute renal failure.
describe some mechanisms in place to prevent this
- autoregulation sustains normal blood flow and GFR in low perfusion P states (mediated by prostaglandins)
what about lower perfusion Ps?
mobilization of locally produced vasoconstrictors that hit the afferent arteriole (drop GFR and RBF, but create gradients better for reabs)
renal hypoperfusion can lead to ischemic acute renal failure.
describe some things that increase susceptibility to renal failure
- structural changes in renal arterioles and small arteries
- impaired production of vasodil prostaglandins
- aff arteriolar vasoconst
- inability to increase eff arteriolar vasoconst
basically, things that drop GFR (aff vasoconst, eff inability to vasocont)
what are some clinical signs of renal hypoperfusion?
- increased urinary specific gravity (1.015)
- decreased urinary Na
- urea elevated plasma BUN:creatinine (> 20:1)
name and describe the two mechanisms of reabsorbtion
-
transcellular: movement across apical and basolateral pl membranes via transporter or channel
* requires metabolic energy either to establish gradient or power transport directly - paracellular: movement through tight junctions between tubule epithelial cells
- passive mechanism due to eletrochem/concentration gradients
- SOLVENT DRAG (movement of Na with water) occurs this way
describe Na reabsorbtion in the proximal tubule
what role does GFR play?
approx 70% of filtered load Na is reabsorbed in first half of prox tubule
transport across apical membrane:
Na-glucose cotransporters (SGLT1, SGLT2)
Na-H exchangers
transport across basolateral membrane into interstitium:
Na/K ATPases
Na-HCO3 symporters
- filtration leads to relatively low pressure in eff arteriole and peritubular capillaries
- hydraulic gradient exists
- high GFR means lower pressure in efferent arteriole and peritubular capillaries
- even greater hydraulic gradient for reabs!
describe Na reabsorbtion in the loop of henle and thick ascending limb
thin ascending limb: active Na reabsorbtion (important part of counter current multiplier mechanism to maintain tonicity in renal interstitium)
TAL: impermeable to water, but Na reabs takes place (TAL aka “diluting segment)
apical membrane:
Na-H exchangers
Na/K/Cl via NKCC2 (whose gradient is maintained by ROMK2)
basolateral membrane: Na/K ATPases
how and where do loop diuretics act?
loop diuretics are bound to albumin in plasma and CANNOT be filtered through glomerulus. end up moving into forming urine via prox tubule transporters. travel to TAL via urine to block NKCC2
mech of action:
- blocks Na reabs through NKCC2
- simultaneously promotes elimination of NaCl and K [K wasting], as well as Ca wasting
describe Na reabsorbtion in the distal convoluted tubule
apical membrane: Na/Cl cotransporter (NCC)
*can be blocked via thiazide diuretics
basolateral membrane: Na/K ATPases
how and where to thiazide diuretics act?
thiazide diuretics block action of NCC in the DCT
describe reabsorbtion in the cortical collecting tubules
“aldosterone sensitive distal nephron” bc it reacts to the secretion of aldosterone
apical membrane:
- ENaC - Na reabs
*stimulated by AVP, AII and aldosterone *sets up an electrochem gradient that favors K secretion
- ROMK2 - K secretion
basolateral membrane:
- Na/K ATPases
*stimulated by AVP
name the K sparing diuretics where and how do they work?
amiloride, spironolactone
amiloride works by blocking ENaC in the DCT by blocking Na reabs
spironolactone works by blocking mineralocorticoid/aldosterone receptor in DCT, indirectly blocking Na reabs
thus prevent creation of the gradient that would favor K secretion, so they are K sparing diuretics
how/where is aldosterone secretion stimulated?
aldosterone is secreted from zona glomerulosa cells of adrenal cortex (mineralocorticoid)
- triggered by either
1. AII binding to AT1 receptors in adrenal cortex
2. hyperkalemia
describe the effects of aldosterone on reabsorbtion (general effects; acute vs. chronic)
- causes vasoconstriction in vsm, has effects on transcription
- aldosterone acts on distal nephon, primarily on Na reabs and POTENTIALLY K secretion
two phases: acute (1-4h) and chronic (beyond)
acute: stimulate ENaC activity in DCT
- increased Na reabs might directly activate ROMK2 K secretion to balance electrochem gradient created
chronic: increase expression and import of ENaC and Na/K ATPase into principal cell plasma membranes
general idea: conserve Na, create a gradient for water reabs too, battle volume depletion
describe the aldosterone paradox
in volume depleted conditions, RAAS is activated to conserve sodium/water.
- proximally: NHE3/AII
- distally: NCC/AII; NCC/aldosterone, ENaC/aldosterone
in euvolemic, hyperkalemic conditions: high K stimulates change in expression of aldosterone-sensitive kinases (WNK1, WNK4, SGK1) in distal nephron AND release of aldosterone from adrenal cortex aldosterone WITHOUT AII
- activity of ROMK2 more affected than Na reabs, so you get more K secretion
what is aldosterone escape
- when kidneys are exposed to continuous high levels of aldosterone, pressure natriuresis occurs to get rid of Na/water and avoid a hypertensive state
- due to increased aldosterone activity in hyperald, patients are usually NOT hypernatremic, but often ARE hypokalemic!
therefore the excretion of water and Na allows them to avoid the edema/HTN state that might otherwise be induced
describe the difference between salt-sensitive and salt-insensitive HTN
normally, ingestion of salt leads to higher Na blood levels leads to hypervolemia corrected by pressure natriuresis
in salt-sensitive individuals, increases in salt might reset the renal fx curve such that pressure natriuresis doesn’t occur like it should
- salt-sensitive HTN patients experience increase in bp on ingesting salt
salt-insensitive HTN patients experience no change in bp on ingesting salt
describe the working theory of how the brain’s RAAS can impact bp
- brain possesses salt sensors coupled to bp
- elevated csf [NaCl] leads to upreg of brain AII binding to brain AT1
- brain has enzymes needed for aldosterone synthesis - starts synthesizing aldosterone -aldosterone binds to mineralocorticoid receptors, leading to changes in ENaC flux
- leads to generation of cardiotonic steroids like OUABAIN
ouabain: -affects NCX in arteriolar vsm, favoring vasoconstriction -potentiates activation of brain AT1 (more aldosterone production AND more SNS tone) *higher SNS tone = more alpha1 vasoconstriction systemically) -impairs NO production in renal medullary vasa recta (no vasodil) in total, shifts the pressure natriuresis plot to the right and messes with ability to excrete NA/water when needed
describe Na reabsorbtion in the collecting duct
1-3% of remaining filtered load
apical membrane: ENaC
basolateral membrane: Na/K ATPase
general mech and major risks of hypernatremia
- disprop loss of water
- disprop gain of Na
major risk: can shift osmostic gradient such that water is pulled out of cells, causing shrinking of organs like BRAIN
symptoms: muscle weakness, lethargy, restlessness; coma/death if v severe
general mech and major risks of hyponatremia
symptoms (hyponat vs severe hyponat)
excessively dilute [Na] plasma
3 types: hypo, eu, hypervolemic
- major risk: can draw water into intracellular space, cause swelling
symptoms: lethargy, nausea, muscle weakness, irritability, anorexia
severe hyponatremia symptoms: drowsiness, confusion, depressed reflexes, seizures, coma, death
causes of euvolemic hyponatremia
too much AVP or hyperthyroidism
- glucocorticoid deficiency (cortisol normally exerts negative feedback on AVP - deficiency means extra AVP)
- SIADH (inappropriate levels of AVP)
- hypothyroidism (not well understood)
causes and effects of hypovolemic hyponatremia
causes:
intrarenal: diuretics, osmotic diuresis, aldosterone deficiency
*urine chemistry would show high Na
extrarenal: fluid loss (diarrhea, vomiting, sweating)
*urine chem would show low Na because compensation would be in effect
effects: tachycardia, flattened neck veins, orthostatic hypotension high BUN (decreased renal perfusion)
causes of hypervolemic hyponatremia
- heart failure (conservation mode to raise volume and CO)
- renal failure: decreased GFR means less filtration but more excretion
- overhydration
Type I hypoaldosteronism
psuedohypoaldosteronism seen in infants once they don’t have mother’s endocrine system protecting them
- might stem from mutations in SCNN1 - messes with amount and/or function of ENaC
- impairs Na reabsorption, leading to mass excretion of Na and water
diabetes insipidus (DI)
LACK OF AVP SIGNAL/RECEPTION
involves either:
- lack of AVP secretion
- mutations that disrupt V2 receptors (in nephron - ENaC Na reabs and AQP2 water reabs)
- symptoms
- mass diuresis (polyuria) of dilute urine [IMPORTANT - DM URINE WILL BE SOLUTE RICH. DI URINE IS TASTELESS/SOLUTE-POOR]
- volume loss triggers osmoreceptors to combat hypoosmolality via thirst (polydipsia) since water is moving through the system steady, ions may be drawn to it
- ion imbalance!
SIADH (syndrome of inappropriate ADH secretion)
EXTRA AVP SIGNAL/RECEPTION
involves either
- erratic/unpredictable elevations in serum AVP
- constitutive activation of V2receptor [despite low AVP levels]
_***euvolemic hyponatremia_
- patients cant diurese the way they need to to maintain normal plasma osmolality
- defining characteristics:
- highly conc urine
- urine Na > 40
- euvolemic hyponatremia
- hypoosmolality
*all must be present WITHOUT glucocorticoid and thyroid hormone deficiency*
dehydration can drop plasma sodium and chloride levels - how else can chloride levels be affected?
metabolic acidosis can lead to hyperchloremia (in non-AG metabolic acidosis)
how is NaCl transport modulated in the kidneys
glomerular-tubule balance (GT balance) : healthy nephron can reabs more Na when more Na is filtered
RAAS:
- AII - hits Na/H exchanger proximally, hits ENaC distally, stimulates aldosterone secretion
- aldosterone - hits ENaC/NCC distally
SNS-norepi: stimulates RAS via beta1 receptors in JG cells so indirectly promotes Na retention
- activates type alpha receptors in tubule epithelium
- coupled to activation of Na/H exchangers and Na/K ATPases [net effect, Na reabs, H secretion]
ANP, prostaglandins, bradykinin, dopamine: impair Na reabs
importance of K regulation
K is the most abundant INTRAcellular cation
- critical in maintaining resting membrane potential in cells
- extracellular K is closely monitored and adjusted
- kidneys help manage reabs/excretion (approx 80-90% of filtered load has to be reabs)
describe K reabsorption in nephron
prox tubule: majority of filtered K is reabsorbed here via paracellular jx (PASSIVE) and basolateral K pumps/channels
desc and asc limbs: lots of recycling here. secretion on way down, reabs on way up. generally, reabs>secretion.
TAL: _charge-driven reabs via para and trans_cellular routes
CCT: roles of principal cells AND rate of flow principal
- secrete K due to LUMEN-NEGATIVE TRANSEPITHELIAL VOLTAGE gradient via ROMK2
- faster flow = relatively greater removal of positive charge from forming urine than negative charge
- apical ROMK2 and K/Cl symporters AND basolateral K channeles and Na/K ATPases support secretion
*intercalated cells mediate K reabs through coordinated action of apical K/H ATPases and basolateral Na/K ATPases and K channels
what effect does aldosterone have on K secretion? what other factors can affect this effect?
in general, aldosterone will act at distal ENaC to upreg Na reabs this will create the electrochem gradient that is corrected by K secretion by ROMK2
chronic aldosterone will also upreg expression of Na/K ATPases
**in cases of hypovolemia, GFR and flow will be decreased, which in turn will decrease the gradient for K secretion
- takeaway: Na/K trade is NOT ABSOLUTE
how does SNS activity affect K secretion?
SNS activity causes reduction in K secretion/excretion
- _conservation of wate_r is a theme for SNS
- part of this process is uptake of K by cells, which reduces filtered load of K
- SNS also directly downmodulates K secretion
how does the kidney contribute to acid/base balance in the body?
kidneys are responsible for keeping acids under control by…
- reabs/reclaiming HCO3 : majority of HCO3 action occurs in proximal tubule, some in distal
- excreting nonvolatile acids
**in general, preventing loss of HCO3 is more important than excreting H
net urinary acid secretion
difference between HCO3 excretion in urine AND collective loss of H in urine
describe how bicarbonate is reclaimed and where this process takes place
almost all filtered bicarb is “reabsorbed” BUT NOT DIRECTLY
- biochemically cumbersome instead, bicarb is broken down and reassembled = reclamation
- in the proximal tubule, CA IV breaks bicarb down into CO2 and OH
- H secretion provides H for formation of water
- CO2 and water are both moved into tubule epithelial cell, where CA II catalyzes reassembly of bicarb, which is moved out into interstitium for delivery to circulation
what are the roles of H secretion in proximal tubule?
- bicarbonate reclamation [dissociation and reassembly via CA IV and CA II]
- excretion via NH3-NH4 buffering system
describe the ammonia-ammonium buffering system
in the proximal tubule, NH3 buffers H to make NH4
NH4 moves through nephron to TAL [less acidic], where it dissociates into NH3 and H again
NH3 moves into interstitium and then goes one of two places…
- back to proximal tubule to jump into the earlier part of the cycle again
- to collecting tubule to combine with H to form NH4 which is ultimately excreted
describe typical renal management of an aklalosis
NOT more excretion of bicarb!!! instead, reduce excretion of titratable acid and ammonium (raise urine pH)
rationale: every time H is secreted (like for those processes), MORE bicarb is made to be reclaimed!
- excreting less acid means it stays in circ to lower pH AND that even more bicarb isnt generated = win/win
why are hypokalemia and hypochloremia often seen in metabolic alkalosis?
usually some defect in renal bicarb secretion and excretion due to ECV depletion and Cl loss
- hypokal: H moves out from interior of cells, K moves into cells via ion swap
- hypochlor: excess bicarb leads to inability to move additional negative charge (chloride ion) via reabs
how can the level of aldosterone alter acid/base balance?
in principal cells:
- Na reabs creates a gradient that favors H secretion
in intercalated cells:
- aldosterone stimulates H/K exchanger and H ATPase that mediate H secretion
give a general overview of renal tubule acidoses
impaired net H secretion
- Type 1 RTA - distal - autoimmune or drugs/toxins
- Type 2 RTA - prox - prox tubule ability to reabs HCO3 impaired
- Type 4 RTA - distal - aldosterone deficiency or resistance
Type 1 RTA
- distal tubule
- autoimmune or drugs/toxins in origin
-
net reduction in H secretion within collecting tubules, which means secretion of ammonium and titratable acid impaired
- H RETENTION and ACIDEMIA
mechanism: impaired funxtions of H-ATPase and Cl/HCO3 exchanger
- high pH urine
- acidemia also results in bone resorption (part of buffering!), so might see hypercalciuria, hyperphosphaturia, kidneys stones
- hyper or hypokal can be seen
Type 2 RTA
- proximal tubule
-
prox bicarb reabs is impaired BUT distal works fine!
- just too weak to actually do all thats required, so plasma bicarb is low
mechanism: defects in Na/H exchanger, Na/K ATPase, carbonic anhydrase are all implicated
- problems in K and NaCl reabs and ultimately Na wasting/hyperaldosteronism
*hyperald ends up exacerbating the hypokal often seen phosphate wasting and vit D deficiency also often seen (…WHY?)
Type 4 RTA
- distal tubule
- aldosterone deficiency or resistance
- usually volume-depleted, hyperkal, with a HCO3 no less than 15
-
H-ATPase activity is lowered bc of lack of aldosterone…
- which has direct effects on H-ATPase
- which drives distal Na reabs to create an electronegative lumen and gradient for H secretion
- which has direct effects on H-ATPase
ultimately, impedes NH4 production and excretion, which blocks NH4 recycling and NH3 secretion in distal nephron
how can urine anion gap be used to inform cause of metabolic acidosis?
UAG = Na + K - Cl
in metabolic acidosis that is NOT KIDNEY RELATED,
- kidneys will attempt to compensate through distal acidification and NH4 production.
- NH4 will pull Cl with it to be excreted as NH4Cl
- SO in summary: good kidneys working with a metabolic acidosis will have extra Cl and a NEGATIVE UAG
in RTAs,
- kidneys arent doing their job, so you WONT see a higher level of Cl in urine, and POSITIVE UAG is the result
what is urea?
describe the purpose of urea recycling describe urea recycling (process and transporters involved)
urea is the nitrogenous end product of a.a. metabolism
- freely filtered, reabs, secreted
- reabs > secretion, so not all that is filtered is excreted
HOWEVER, v little is returned to circulation so where does it go?
- hangs out in medullary interstitium to contribute to relatively high osmolarity this allows it to…
1. help concentrate urine (pulling water into hyperosmolar renal interstitium)
2. stick around in medullary interstitium for eventual excretion
PROCESS/TRANSPORTERS
prox tubule: most of filtered load (50%) is reabs
thin desc/asc limbs: lots of urea secreted via UT2 facilitated transporter (up to 110% filtered load)
medullary collecting ducts: reabs back into medullary interstitium via UT1, UT4 faciliated transporters
identify the players in plasma glucose regulation
plasma glucose should be 75-115
two hours post-prandial, shouldnt exceed 120
increase plasma glucose: glucagon, epi, cortisol, GH
decrease plasma glucose: insulin mechanisms:
- -glucose uptake and glycogenesis/adipogenesis
- -absorbtion of dietary glucose from GI
- -glycogenolysis
- -gluconeogenesis
describe the functional roles of the pancreas and its cellular organization
dual function:
- digestive/exocrine - acini glands
-
endocrine - islets of Langerhans localized around pacreatic cap beds
- islets of L have 3 populations of cells:
- alpha - glucagon
- beta - insulin
- delta - somatostatin
- islets of L have 3 populations of cells:
insulin functions
STORAGE HORMONE: promotes glycogenesis and lipogenesis
- works with GH to promote muscle anabolism
- production/secretion is triggered by a rise in plasma glucose
- functions to stimulate glucose uptake in liver, sk muscle, fat
- BLOCKS liver gluconeogenesis
***stimulates cellular uptake of K and FFA
describe the signalling cascade through which insulin is released
how does it circulate?
- glucose binds to GLUT2 in pl membrane of beta cells (islets of L) and moves into cell
- inside beta cells, glucose –> G6P via glucokinase
- G6P signals a cascade which involves increase in intracellular ATP, which causes ATP-sensitive K channels to close, causing depol
- depol causes voltage-gated Ca channels to open, leading to influx of Ca leading to activation of secretory mechanism
insulin circulates in bioactive form! not bound to anything
how does insulin work?
insulin circulates in bioactive form and activates specific cell surface receptors in target cells
complex signaling mechanisms activate glucose carrier proteins which mediate uptake via facilitated diffusion
how does insulin affect carb metabolism in the liver
insulin promotes glycogenesis and glucose use by the kidney
insulin inhibits gluconeogenesis and glycogenolysis
describe glycogenesis
- takes place in liver cells
- glucose diffuses into hepatic cells
-
glucose converted to G6P via glucokinase G6P…
- cant exit the cell (making glucose movement one-way)
- intermediate that can be used for glycogen synthesis or ATP production pathways
describe the effects of increased plasma glucose on the pancreas
changes in intracellular glucose can stimulate changes in beta cell glucokinase activity
***mediates secretion of insulin!
what effect does insulin have on skeletal muscle
- promotes uptake of glucose
- promotes glycogenesis so as to provide muscle with stored glucose when muscle becomes metabolically active
describe the effects of insulin on fat metabolism
skeletal muscle: inhibits activity of lipoprotein lipase (blocks muscle from using FFA oxidation for energy)
adipose tissue: promotes uptake of glucose, promotes use of glucose (instead of FFA) for energy
liver: MAKES A TON OF FAT stimulates fatty acid synthesis, augments conversion of excess glucose into fatty acids, increase systhesis of hepatic triglyceride and lipoprotein
describe the effects of insulin on protein metabolism
strong anabolic effects (esp in concert with GH)
- can impair some protein catabolism
- increases uptake of some amino acids into muscle
- can stimulate translation
how is insulin secretion regulated?
what happens when there is no insulin secretion?
- rapid secretion in response to glucose > 100
- quick drop in the 80-90 range
- no insulin? fat metabolism in most tissues
glucagon basics
- secreted from alpha cells of islets of Langerhaans
- thought to act only in liver
-
HYPERGLYCEMIC HORMONE (promotes hyperglycemia)
- upreg gluconeogenesis
- upreg glycogenolysis
how is glucagon secretion regulated?
inversely to blood glucose levels and serum insulin levels
high in fasted state (glucose < 80-90)
what is the importance of glucagon in neonates
transitional period of adjusting from maternal nutrients to nutrition from ingested food = risk of hypoglycemia
- glucagon makes sure that proper glucose levels are maintained
somatostatin basics
- secreted by DELTA CELLS of islet of Langerhans
- usually increase during post-prandial period
- has transitory inhibitory effects on insulin and glucagon secretion
diabetes mellitus
disturbance in normal carb metabolism that results from insulin insufficiency via…
- LOSS OF ENDOGENOUS INSULIN PRODUCTION
- INSULIN INSENSITIVITY/RESISTANCE
diabetes mellitus: 3Ps and symptoms
polydipsia: increased glucose content means increased pl osmolality = thirst/POLYDIPSIA
polyuria: increased filtered glucose = more glucose in forming urine = POLYURIA
polyphagia: lack of insulin leads to less anabolism = weight loss/POLYPHAGIA
how is metabolic demand met in DM?
impaired glucose uptake means body shifts to other sources of energy
-
FATS: lipolysis through FFA oxidation and formation of ketoacids
- could lead to DKA!!!
Type 1 DM
HYPOINSULINEMIA and HYPERGLYCEMIA
Type 1A: autoimmune in nature, resulting from degeneration of beta cells or suppression of beta cell fx
Type 1B (idiopathic, nonautoimmune diabetes): undefined cause
- beta cell destruction
- TX? insulin replacement!
Type 2 DM
INSULIN RESISTANCE
- hyperglycemia and normal/elevated insulin
- approx 90% of all DM
- more prevalent in women
- defect at level of insulin receptor, transport, or insulin-dependent signal transduction
- combos of resistance and abnormal insulin levels lead beta cells to try to compensate and ultimately fail
android obesity
connection: how does visceral fat respond to insulin resistance?
- accumulation of f_at distributed around abdominal wall and visceral mesenteric_ locations
- correlated with devpt of hypertension and dyslipidemia and other CVD risk factors
- increased waist-to-hip ratio and elevated BMI
- mutations and/or abnormal expression/activity of adipokines (adiponectin and leptin), cytokines (TNFalpha) and FFA can alter glucose metabolism and insulin sensitivity
under conditions of insulin resistance, lipolysis of visceral fat leads to high triglycerides and LDL and low HDL
- drives atherogenic potential up to increase CV risk
how do adipokines, cytokines, and FFA alter glucose metabolism and insulin sensitivity?
leptin and adiponectin (adipokines) - increase sensitivity to insulin
TNFalpha - impede insulin-dep glucose metabolism; exert positive feedback on FFA secretion
FFA - stimulate secretion of TNFalpha by adipocytes
what is glucose counterregulation? what role do the kidneys play?
glucose counterregulation is the sum of the body’s actions to prevent hypoglycemia and address it if it occurs
the kidneys:
- use lactate, glutamine, and glycerol for gluconeogenesis - stimulated by glucagon/glucocorticoids/norepi/epi
- account for up to 20% of gluconeogenesis (in fasting, hypoglycemia, acidosis)
how is glucose reabsorbed in the kidney?
glucose is freely filtered and reabsorbed - usually complete reabs in the prox tubule
apical: Na-glucose cotransporters: SGLT1, SGLT2
basolateral: GLUT1, GLUT2 facilitated diffusion transporters
what is the normal range of plasma glucose?
how does diabetes and effects on insulin affect serum glucose and the filtration/reabs process?
normally 65(fasting)-125(postprandial). normal max 180. HEALTHY KIDNEY CAN HANDLE THIS via SGLTs and GLUTs
DM (lack of insulin or insulin resistance) leads to hyperglycemia - massive increase in filtered load - glucosuria once the reabs machinery is saturated
what factors affect glomerular proteinuria?
progression: microalbuminurea → proteinuria/macroalbuminurea → diabetic nephropathy → loss of renal fx
glom proteinuria determined by:
- mean transcapillary hydraulic pressure diff
- glom surface area
- size and charge selectivity of the glom membrane
***microalbuminurea increases probability of CV morbidity
why is albuminurea/proteinurea a problem?
in diabetics, albumin is in glycosylated state = glycated albumin
glycated albumin functions as an antigen causing immune/cellular responses in nephron
- generation of ROS which can chelate proteins and damage glom
- overload tubule intracellular lysosomes
- produce inflammatory cytokines
- increase synth of ECM proteins in tubular tissues
all leads to GLOMERULOSCLEROSIS, fibrosis, renal failure
effects of diabetes on glomerular function/progression
- early on, glomerulus and tubular epithelium can hypertrophy and develop thick basement membranes
- accompanied by high GFR and microalbuminuria
- unfavorable remodeling increased by: HTN, hyperlipidemia, hyperglycemia
- poor glycemic regulation and diabetic HTN cause pressure-induced capillary stretch in endothelium
- increased vasc permeability = glom injury
- amplifying cycle of increased reabs in prox tubule and stimulatory effect on GFR
how do aberrant signals re: ECF volume and/or bad interpretation of ECF volume feedback affect renal function?
jcan lead to osmotic imbalanced and increased tubule reabs within the nephron, which stimulates GFR
can mess with TGF function too
tubulointerstitial fibrosis
unchecked extracellular glucose assaults renal interstitial and tubule cells
high glucose = RAS triggered = promotes release of intrarenal fibrogenic substances AND inhibits production of antifibrogenic factors
leads to glomerulosclerosis, promotion of epithelian-to-mesenchymal cell transitions
how can overactive RAS affect kidney function
- promotion of tubulointerstitial fibrosis through release of fibrogenic factors and inhibition of antifibrogenic compounds
- AII induces phosphorylation of IRS1 (insulin receptor substrate 1) - key component of insulin dependent signal transduction = insulin resistance
- can impair nephrin - typically aids in restricting protein filtration across diaphragm slit pores - which leads to leaky glom
- elevated aldosterone causes high Na retention = high water retention = elevated bp/diabetic HTN
tx: renin inhibitor, ACE inhibitor, ARBs
- benefits seen to prescribing them in combo
how does diabetic ketoacidosis affect total and plasma K?
what should the treatment be?
metabolic acidosis can cause hyperkalemia via H/K ion swapping
- hyperglycemia = hyperosmolality = osmotic diuresus
- hyperkalemia but with continuous K excretion leading to drop in total K
- volume depletion from diuresis = RAS triggering = aldosterone
- further K excretion
Tx: insulin! BUT remember insulin also triggers cellular uptake of K - could swing patient into hypokalemic state soooo insulin + monitoring
what is the primary regulator of Ca and PO4 in blood?
PTH
low Ca - PTH secreted
high Ca - PTH secretion decreased
how and where is calcitriol synthesized? what triggers its synthesis?
calcitriol is activated vitamin D
PTH acts in kidney (where key enzymes located) to convert hydroxylate 25-hydroxy vit D to 1,25-dihydroxy vit D aka CALCITRIOL
calcitriol synthesis is stimulated by…
- hypophosphatemia
- PTH
what is the function/effect of calcitriol?
- stimulates Ca reabsorption
- blocks PO4 excretion
acts on…
BONE: stimulates resorption and release of calcium and phosphate
KIDNEY: augments PTH dependent Ca reabs in distal nephron; blocks PTH dependent PO4 excretion in nephron
INTESTINES: stimulates Ca and PO4 uptake in sm int
ENDOCRINE: blocks PTH secretion - can cause secondary hypoparathyroidism
what is the general function of PO4?
describe effects of PTH and calcitriol on PO4
PO4 can serve as a buffer for plasma and urinary titratable acid
usually freely filtered and mostly reabs…
- PTH blocks reabs by blocking Na-PO4 cotransporter, promotes PO4 excretion
- calcitriol blocks the effect of PTH on PO4 excretion
describe the fate of Ca in the nephron
same general pattern as Na
- proximal tubule:
- majority of reabs happens
- Ca reabs coupled to H and Na reabs
- mostly paracellular reabs
- TAL
- coupled to Na by gradients generated by NKCC2
- loop diuretics that block Na reabs also block Ca reabs!
- coupled to Na by gradients generated by NKCC2
- distal tubule
- Ca reabs stimulated by PTH, agumented by calcitriol
- thiazide diuretics also enhance distal Ca reabs
describe effects of PTH and calcitriol on urine concentration
overall, promotes…
Ca reabs x2
PO4 excretion, PO4 excretion block
so…
hypocalciuria
hyperphophaturia
MAKES SENSE! PTH is secreted due to low serum Ca!
secondary hyperparathyroidism
aka HIGH BONE TURNOVER RENAL OSTEODYSTROPY
- chronic renal disease impairs Ca reabs in tubules –> hypocalcemia
- triggers PTH secretion from parathyroid
- which would normally trigger calcitriol formation [which would augment Ca reabs in distal nephron and Ca uptake in sm intestine]
- BUT…chronic renal disease = cant make calcitriol!!!
- ALSO…chronic renal disease = cant reabsorb phosphate!!!
- diminished calcitriol = diminished negative feedback on PTH = secondary hyperparathyroidism
- bone resorption happens, but Ca reabs does not
- hypocalcemia gets worse
- hyperphosphatemia occurs
- directly induces hypocalcemia AND can induce parathyroid hyperplasia
- bone resorption happens, but Ca reabs does not
hypoparathyroidism
inadequate production of PTH or resistance to PTH
- main fx of PTH: Ca reabs in distal kidney, calcitriol production, bone resorption
signs:
hypocalcemia
hyperphosphatemia
low urinary Caj
Tx: vitamin D and maintaining low-normal serum Ca to avoid kidney stones
countercurrent multiplier mechanism and effect on urine production
reabs/secretion capacity of nephron lets it maintain osmotic gradients in medullary interstitium
counter current exchange maintains hypertonicity of interstitium by having vasa recta recycle NaCl, water, and urea back into systemic circulation
- as blood moves down vasa, lots of water loss, but this declines as you go further down
- influx of NaCl and urea increases deeper into the medulla
- higher blood osmolality means water is pulled back in as blood moves up vasa
end result: blood leaving vasa recta has more water and more solute than when it started
characteristics of vasa recta
- looped conformation
- relatively low blood flow
- inability to perform active transport
OUABAIN
can be released in response to brain’s RAAS system responding to salt (ex. in salt-sensitive HTN)
- affects NCX in arteriolar vsm, favoring vasoconstriction
- potentiates activation of brain AT1 (more aldosterone production AND more SNS tone)
- *higher SNS tone = more alpha1 vasoconstriction systemically)
- impairs NO production in renal medullary vasa recta (no vasodil) in total, shifts the pressure natriuresis plot to the right and messes with ability to excrete NA/water when needed
