physiology and Ix Flashcards
JG cells - where and what signals do they receive?
around afferent arteriole
1. mechanoreceptors -> stimulated when low BP
2. chemoreceptor: have SNS innervation from aortic arch > stimulated adrenergically with low BP
3. PGE2 from macula densa
–> to secrete renin
macula densa cells - where and what do they do?
part of DCT wall
if GFR low > low SODIUM (i.e. a chemoreceptor) > send signal to JG cells via PGE2
describe RAAS pathway
renin cleaves angiotensinogen to leave ACEI
Angiotensin I converted to angiotensin II by ACE (found on endothelial cells, esp in lungs)
ang II binds to its receptors in smooth muscle cells, inc at kidneys
— efferent more responsive than afferent
paradox of low ang II vs high ang II action on GFR
low ang II - only efferent arteriole constricts –> inc GFR
high ang II - both afferent and efferent constrict –> low renal blood flow, therefore, low GFR
actions of Ang II
PCT: inc Na absorption > inc H2O
hypothal: inc ADH > inc H2O
glom: constricts eff > aff arterioles
increased thirst
adrenals: zona glomerulosa > aldosterone (MC) > inc Na/K ATPase expression
other arterioles: inc TPR
how can inc RAAS activity cause hypokalaemia?
aldosterone > inc Na/K ATPase > inc Na absorption, inc K excretion
how many nephrons per kidney at birth?
1mil per kidney
what is the rate limiting step of the RAAS?
the JG production of renin
ACEI vs ARB
ACEI = ‘prils’ = inc BK > cough, angioedema risk
ARB = ‘sartan’ = no dry cough
both - need low K diet, not in pregnancy
actions of aldosterone
Stimulates Na/K/ATPase pump on basolateral side of cortical collecting tubule AND increases sodium permeability on luminal side of the membrane (activates ENAC)
ANP - what triggers its release, and what does it do?
from atria in response to atrial stretch > main job: lower BP
Acts to:
i.Dilates afferent + constricts efferents = ↑ GFR > diuresis
ii. Inhibits aldosterone + renin secretion
iii. Inhibits Na Cl reabsorption in CD
iv. Inhibits ADH action on kidney
what does PGE2 do for renal blood flow?
released to dilate afferent arteriole and inc BF
how do NSAIDs affect the kidney?
inhibit PG production > less dilation of afferent arteriole > reduced GFR
what happens in renal artery stenosis?
renal artery stenosed > reduced afferent arteriolar flow
so kidney increases BP > systemic HTN and renal atrophy from low flow
how do caffeine and alcohol act to increases diuresis?
caffeine - dilates afferent arteriole > plasma too quick
alcohol - inhibits ADH
when does renal growth and GFR cease?
GFR increases until renal growth ceases (18-20 years)
When does GFR reach adult values?
GFR >100 by 12/24mo
filtration through BM depends on what 3 factors?
- charge (neg will bounce)
- size <3mm
- binding to proteins - e.g. Ca and FFA bound to plasma proteins
what is the triple whammy and how does it affect the kidney?
ACE-I = Dilates the efferent arteriole reducing the GFR
NSAID = Prevents PG mediated vasodilation of the afferent arteriole to maintain GFR; thereby further reducing GFR
Diuretics = reduce plasma volume and GFR
How do the following move through the PCT?
Na
HCO3
urea
water
glucose
Sodium:
1) cotransporters e.g. Na-glucose on apical
2) Na/K ATPase on basolateral keeps gradient
3) Na /H exchanger
4) paracellular route via leaky tight junctions
HCO3:
H and HCO3 = H2CO3 with CA => CO2+H2O => both diffuse into the cell, then another type of CA puts them back together = H2CO3 => H and HCO3 again
urea and water = diffusion
glucose:
Na-glu cotransporter on apical > GLUT1/2 on basolateral
What happens at the loop of Henle?
countercurrent multiplication:
Thin descending limb
- inc concentration from passive absorption of water (via aquaporins) up to 1200osm in medulla at the end
Thin ascending limb
- no aquaporins, water doesn’t move
- has Na and Cl channels -> start moving out
Thick ascending limb (cuboidal epithelium)
- Active reabsorption of 15-25% of filtered Na+/K+/Cl- via the cotransporter!
- Secondary resorption of Ca2+ and Mg2+
- impermeable to water as well - no aquaporins
what gets excreted in the PCT?
ammonia
organic acids e.g. penicillins
what is 100% absorbed in the PCT?
glucose and amino acids
How and where do these diuretics act:
- carbonic anhydrase inhibitors
- loop diuretics
- loop diuretics in thick ascending limb on Cl portion of Na/K/Cl transporter»_space; more Na and therefore H2O excreted
what is absorbed in the DCT?
early DCT:
- active Na and Cl absorption 5% via co-transporter- Na is LOAD dependent absorption
- Ca2+ reabsorption under PTH control
late DCT:
ENAC at principal cells, Na in and K out
alpha intercalated cells - H ATPases to pump H into wee
and ADH -> aquaporins!
how does PTH work at the DCT?
inc Ca channel on apical side, and Na/Cl transporter on basolateral side
how does aldosterone act to increase Na reabsorption?
at DCT. increases ENAC, and Na/K ATPase on basolateral
where is most Mg absorbed?
loop of Henle - 70-80%
what do the beta-intercalated cells do cf the alpha cells, in the collecting duct?
beta = secrete bicarb, resorb H+ i.e. help in alkalosis
alpha = secrete H, resorb bicarb i.e. help in acidosis
how does H+ excretion differ in the CD vs PCT?
CD have H/K ATPase so can pump it out againt large concentration gradient
angiotensin vs aldosterone - where do they act to cause Na reabsorption?
angiotensin = PCT
aldosterone = DCT
name some factors that cause K shift into a cell
insulin, aldosterone, beta adrenergic stimulation, alkalosis
where is most Ca reabsorbed in the nephron, and how?
PCT, via paracellular
what is the only electrolyte that is not mostly absorbed at the MCT?
Mg - mostly at loop of henle via paracelular action
what is used as a buffer for H+ for excretion?
- ammonia
- PO4
why is alkalosis associated with hyperkalaemia?
H/K transporter in DCT - they compete.
quick summary of urea resorption
50% in PCT
other 30% via medullary CD - via urea transporters -> can be resorbed in thin descending loop
urea can circulate several times before excretion
osmolality of ECF vs ICF determine by what?
Osmolality of ECF = Na
Osmolality of ICF = K
aetiology of hyponatraemia
- hypovolaemia: GI losses, meds e.g. diuretics, cerebral salt wasting/renal wasting
- euvolaemia but ADH inappropriate:
- dilute urine: adrenal insufficiency / drinking too much
- concentrated urine: SIADH - hypervolaemia: oedema > lower circulating volume > inc ADH: CCF, nephrotic syndrome, cirrhosis
pseudohyponatraemia caused by?
inc lipids/protein causes lab instruments to report it incorrectly - normal Na and TBW
how are serum osm, urine Na and urine osm helpful in hyponatraemia?
serum osm = if low, then its true hypoNa not pseudo
urine Na: high urine Na = renal /cerebral wasting/SIADH, low urine Na = hypovolaemia
urine osm: dilute or concentrated urine (>100mOsm/kg = SIADH)
target rate of Na correction for hypoNa
8mmol/L in 24 hours OR
if seizures: no more than 2mmol/L per hour in first 3-4 hours (because risk of morbidity from delayed treatment is greater than the risk of osmotic demyelination from overly rapid correction)
aetiology of hypernatraemia
- hypovolaemia
- GI losses
- skin losses
- renal losses
- diabetes insipidus - sodium excess
- hyperaldosteronism (primary vs secondary e.g. CCF/nephrotic syndrome, steroids)
- iatrogenic - TPN, hypertonic saline
signs of severe (>160) hypernatraemia
Altered mental status
Lethargy
Seizures
Hyperreflexia
Coma
how does urine/serum osm help in hypernatraemia?
Urine osmolality < serum osmolality
Indicates urinary concentrating defect
central DI, nephrogenic DI, renal disease, osmotic diuresis
Urine osmolality > serum osmolality
Indicates intact urinary concentration
Causes: gastrointestinal losses, increased insensible losses eg burns, excess sodium intake
target rate of Na change in hyperNa
rate of sodium correction should be slow, no more than 0.5 mmol/L/hour
5 types of diuretics, order of potency
LOTCK:
Loop
Osmotic
Thiazide / thiazide like
CA inhibitors
Potassium sparing
loop diuretics:
- examples
- site of action
- receptor of action
- main indications
- side effects
- e.g. frusemide
- thick ascending limb
- Na/K/2Cl- transporter - on the Cl part
- oedematous states
- hypoCa / Mg / K, hypoK metabolic alkalosis, ototoxicity, (less gout than thiazides)
thiazide/thiazide-like:
- examples
- site of action
- receptor of action
- main indications
- side effects
- HCT or thiazide like (sulfonamide derivatives - indapamide, metolazone)
- DCT
- Na/Cl co-transporter
- oedematous states
- hypERcalcaemia, gout+++, hypoK metabolic alkalosis
why do loop and thiazide diuretics cause hypokalaemia and metabolic alkalosis?
they increase sodium delivery to the distal segment of the distal tubule
this increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis
loop vs thiazide effects on Ca, and why
thiazides = hyperCa: reduced Na in cell causes Na/Ca exchanger on the other side to pump Na into cell and Ca into blood
loop: movement of K through the cell causes electrochemical gradient for Ca (and Mg absorption) -> so less K = less Ca
K sparing diuretics:
- examples
- site of action
- receptor of action
- main indications
- side effects
- collecting duct
- Aldosterone antagonist = spiro = MC receptor
- Na+ Channel Antagonist = Amiloride = ENAC
- gynaecomastia, hyperK
how does spiro cause hyperkal?
aldosterone usually acts to inc Na/K ATPase on basolateral and ENAC on apical
so less ENAC action means less Na driven Na/K action, so less K goes out»_space; hyperkalaemia
example of osmotic diuretic
mannitol
CA inhibitors:
- examples
- site of action
- receptor of action
- main indications
- side effects
acetazolamide
PCT
CA enzyme: less action means less H produced to spit out on apical side, so less Na
paraesthesia, drowsiness
Why does Cr overestimate GFR?
because a small amount is secreted - so will overestimate esp in renal disease
what is the gold standard susbtance to measure GFR? the most accurate in a clinical setting?
inulin is gold standard, but research only
51Cr-EDTA/DTPA is most accurate in clinical setting
ddx for bright, echogenic kidneys on neonatal USS - some examples
• Renal dysplasia
• ARPKD, ADPKD
• Glomerulocystic disease (HNF1b deletions)
• Beckwith-Wiedemann syndrome
• Congenital nephrotic syndrome
• Congenital infection
