4 Flashcards
Explain the sodium balance in the ECF (expansion)
- ingestion of sodium can vary (low salt diet 0.5 g/d to 20 g/d)
- kidney Na+ excretory rates must vary over wide range depending on diet
- Match excretion to ingestion
- urinary water excretion can be varied physiologically by the kidney
- if sodium ion excretion is LESS than intake, then a pt. Is in positive balance; extra Na ions are retained in the body primarily in the ECF
- when Na ion content of the ECF increases, there is a corresponding increase in ECF volume since water from nephron is drawn out
- blood volume and arterial pressure increase and oedema may follow
Why can’t we just add/remove water to plasma to change its volume?
- because that would change the plasma osmolarity
- need to add isosmotic solution to increase volume
- or remove isosmotic solution to reduce volume without changing osmolarity
- how do we add/remove an isosmotic solution?
- need to make water want to move
- so need to actively add/remove Na so water passively follows
Explain the sodium balance in the ECF (contraction)
- if Na ion excretion is greater than ingestion, then a pt. Is in negative balance
- excess Na ions are lost from body so Na ion content of ECF decreases and water remains in nephron
- ECF volume decreases so does blood volume and arterial pressure
- AMOUNT is affected not CONCENTRATION
Explain reabsorption of Na in kidneys
- 2 membranes are involved
- luminal/apical membrane and basolateral membrane
- involves 3Na2K ATPase
- different segments of the tubule have different types of Na transporters and channels on the apical membrane
- can occurs in paracellular fashion: between the gaps of the cells
- can occur in transcellular fashion: through the cell
What Na channels are in each area of the nephron?
Proximal tubule -Na/H anti porter -Na/Glucose symporter -Na/AA co-transporter -Na/pi Loop of Henle -NaKCC symporter Early DT -NaCl symporter Late DT and CD -ENaC (Epithelial Na channels)
Describe the PCT in regards to Na reabsorption
- 2 segments
- Early PCT: S1
- Late PCT: S2 and S3
- both segments have active Na/K ATPase on basolateral membrane
- uptake into capillaries governed by oncotic forces and hydrostatic forces
- different nephron segments use different apical transporters or channels for transcellular Na reabsorption
Describe the function of PCT in S1
-has basolateral 3Na2K ATPase
-also NaHCO3 co-transporter (acids and bases)
Apical channels
-Na/H exchange
-co-transport with glucose
-co-transport with AA or carboxylic acids
-co-transport with phosphate (NaPi channel sensitive to increase in PTH)
-Aquaporin 1 allows water move from lumen into cell
-Urea and Cl are left behind and increase in S1 to increase for the loss of glucose
-increase in Cl concentration creates a conc. Gradient for Cl reabsorption in S2-3
-Actively removing Na ions from inside tubular cell
-lower Na concentration inside the cell
-as a result a concentration gradient is established from high in lumen
-allows for glucose to go into cell and then eventually into interstitum, then into capillary
-sometimes transport of glucose can be against conc. Gradient thus It is active
Explain the relationship between glucose filtration, reabsorption and excretion to the plasma glucose concentriation
- as much glucose cam be reabsorbed back into plasma until it hits the transport maximum (Tm)
- when we exceed transport maximum, glucose ends up being excreted
- occurs in diabetic patients
- see graph
Explain Na and HCO3 reabsorption in PCT S1
- NaHCO3 splits in lumen
- Na goes into Na/H anti porter
- H comes out of lumen to make H2CO3 with HCO3
- H2CO3 goes through carbonic anhydrase to make H2o and CO2 which go into tubular cell
- rejoin as H2CO3 and then split into H and HCO3
- HCO3 goes through anion exchanged into capillary by exchanging with Cl
- allows for an osmole effect to bring water in
What is amiloride?
- diuretic that inhibits ENaC in DCT
- BUT also blocks the Na+/H+ anti porter in PCT, abolishing about 80% of the action of AGII on the secretion of H ions in PCT
What is isosmotic reabsorption?
- graph that shows the levels of reabsorption for different molecules, compared to the distance from Bowman’s space
- amount of Cl increases in the filtrate as other ions are removed, preferentially leaving it behind
- osmolarity remains unchanged
- ordinate=tubular fluid to plasma concentration ratio (TF/P)
- TF/P= 1 for a substance that is the same concentration in the tubular fluid and plasma (anything freely filtered at the glomerulus would have a TF/P=1 at the glomerulus)
Describe the action of early PCT at S2/3
- contains a basolateral 3Na-2K ATPase
- apical Na+ reabsorbed in S2-3 via Na-H exchange and one or more Cl-anion antiporters
- apical membrane has Na/H exchanger
- has a paracellular Cl transport (done freely)
- Movement of Cl results in positive transepithelial charge which helps drive Na and Cl via paracellular route
- about 4mOsmol gradient favouring water uptake from lumen
- aquaporin 1
How does the late PCT (S2/3) function?
- as Cl increases, paracellular reabsorption occurs with no use of energy
- diffusion through tight junctions
- proportion of tubular Cl- as the major anion increases as HCO3 decreases
Explain the amino acid reuptake in the proximal tubules
-on apical membrane there are sodium-dependent AA transporters
-on basolateral membrane there are passive AA transporters
At least 7 different transporters
-Basic AA/cysteine
-Glutamic and aspartic acids
-neutral amino acids
-imino acids
-glycine
-cystine and cysteine
-beta and gamma amino acids
How is the peritubular capillary isosmotic?
- proximal tubule is highly water permeable
- bulk transport or obligatory water reabsorption
- reabsorption is isosmotic with plasma
- PCT reabsorbs 65% water, 100% glucose and AA and 67% Na
- driving force is osmotic gradient established by solute absorption (ex. Osmolarity in interstitial spaces increase)
- hydrostatic force in interstitum increases
- increase in oncotic force in peritubular capillary due to loss of 20% filtrate at glomerulus but cells and proteins left in blood
- so that things can be rapidly reabsorbed back into blood
- increase in plasma concentration in efferent arterial goes to peritubular capillaries = increased osmotic force to reabsorb fluid in PCT
Explain how effectors can change renal sodium excretion
-changes in osmotic pressure and hydrostatic pressure alter the proximal tubule Na reabsorption (and thus water)
-PCT Na reabsorption is stimulated by AG2 (RAAS) under conditions of low BP (inhibited by amiloride)
-principle cells of DCT and CD targets for the hormone aldosterone
-when renal artery BP INCREASES
-reduced Na/H anti porter and reduced Na-K ATPase activity in PCT
-causes reduction in sodium resorption in PCT (glomerular tubular balance)
-leads to reduction in water resorption in PCT
-results in increased sodium (natriuresis) and increased water (diuresis) excretion
ECF volume decreased and initial BP rise diminished
-natriuresis and diuresis occur together
Explain the movement of fluid in the loop of Henle
Descending: squamous epithelium so no transport of solutes, just water reabsorption, but no NaCl
Ascending: no aquaporin channels so impermeable to H2O, but reabsorbs NaCl
-thus ascending limb is known as the DILUTING SEGMET
-tubule fluid leaving loop is therefore hypo-osmotic (more dilute) compared to plasma
What occurs in the descending limb of the loop of Henle?
- cortex to papilla interstitial concentrations gradient allows paracellular reuptake of water from descending limb
- this concentrates the sodium and chloride ions in the lumen of the descending limb ready for active transport in the ascending
Explain passive Na reuptake by the thin ascending limb
- water reabsorption in descending limb creates a gradient for passive Na ion reabsorption in thin ascending limb
- epithelium in thin ascending limb permits passive reabsorption by paracellular route
What is ROMK?
- Renal Outer Medullary K Channel
- expressed on apical membrane
- very efficient and good to take K out of cell and into lumen
- helps NKC22 in the Na reuptake at the thick ascending limb
- helps ClC-KB (chloride) to transporting Cl from cell to capillary
What is furosemide?
- a loop diuretic
- can block NKCC2 on the apical membrane of the thick ascending limb
- prevents active transport of Na, K and 2 Cl
- can cause hypokalemia
Explain K reuptake and secretion in the thick ascending limb
- NKC22 only works because ROMK gives K to it
- see diagram
What is spironolactone?
- is a K sparing diuretic
- stops ROMK which will cause diuresis
- prevents transport of Na into cell
What occurs in the DCT?
- water permeability of early DCT is fairly low
- active Na+ reabsorption (up to 5-8%) results in further tubular dilution: stimulated by aldosterone (RAAS)
- late DCT and collecting duct
- water permeability is variable depending on ADH (low Bp stimulates ADH, which increases water reuptake by aquaporin channels)
- extra water comes through DCT because of ADH
Explain Na reuptake by the DCT
- hypo-osmotic fluid enters
- active transport of 5-8% of Na by NCCT and ENaC
- water permeability is fairly low
- DCT has two regions: DCT 1 (early) and DCT2 (late)
- in DCT 1 NaCl enters across apical membrane via electro-neutral NCCT
- 3Na/2K ATPase in basolateral membrane
What diuretics is NCCT sensitive to?
- thiazides
- more hypo-osmotic fluid leaves resulting in further dilution
What happens in late DCT 2?
- NaCl enters by NCCT and ENaC leaving 3Na-2K ATPase in basolateral membrane
- movement through ENaC is not electroneutral and difference drives paracellular Cl ion reuptake
- at the end of the DCT, fluid is more hypo-osmotic (i.e. further dilution)
What is ENaC sensitive to?
Amiloride
Explain how calcium is transported in the DCT
- apical calcium transport
- cystosolic calcium is immediately bound by CALBINDIN, which shuttles calcium to the basolateral aspect of the DCT cell
- transported out by NCX
- tightly regulated by hormones such as PTH and 1,25-dihydroxyvitamin D
What 2 regions is the collecting duct divided into?
-CD divided into Cortical Collecting Duct (CCD) and medullary regions (MCD)
What are the two distinct cell types found in the CCD?
Principal cells and intercalated cells
What are principal cells?
- make up 70% of the cells
- reabsorption of Na ions via ENaC on apical membrane
- driving force is the 3Na2K ATPase on the basolateral membrane
- active Na ion uptake through a channel and not a cotransporter means there is no accompanying anion
- produces a negative charge in the lumen providing a driving force for Cl ion uptake via paracellular route
- negative charge in the lumen has an important role in K secretion into the lumen
- variable H2O uptake through AQP dependent on action of ADH
What are intercalated cells?
Type A (A1C) or type B (B1C) cells
- intercalated cells secrete H+ ions (A1C) or HCO3 (ions) more in acids and bases
- in cortical and outer medullary CD
- type A1C express H+ ATPase and H/K ATPase at the apical membrane
- type B1C express the Cl/HCO3 exchanger at their basolateral membrane
Compare how sodium and water are reabsorbed along the nephron
Proximal tubule: Na (67%) H2O (65%)
Descending thin limb of Henle: Na (0%) H2O (10-15%)
Ascending thin and thick limb of Henle: Na (25%) and H2O (0%)
DCT Na (5-7%) H2O (0%)
CD system Na (3%) H2O (5% during water loading and >24% during dehydration)
What sensors detect the increase in ECF volume?
-low-pressure baroreceptors
What is the Bainbridge reflex?
-when high-pressure baroreceptors in the arterial side of circulatory system respond to pressure and send impulses
-increase in HR due to increase in central venous pressure
Compensatory mechanism when HR increases
-acts in opposition to baroreceptors
How does the kidney detect that it has reduced blood flow?
Through baroreceptors
-detects it as a reduction in ECF
What hormonal responses does the kidney do in response to reduced ECF?
- RAAS
- sympathetic nervous system
- prostaglandins
- ADH
What pathologies can occur in a reduction of effective arterial blood volume with a normal or expanded ECF?
- heart failure
- liver cirrhosis
- nephrotic syndrome
- renal artery stenosis
- conditions causing salt and or water-wasting
What risk can occur when the kidney responds to reduction in perfusion?
- kidney will respond by activatin mechanisms to increase blood volume
- thus fluid overload can occur
How can oedema occur in certain pathologies because of the kidney?
-due to excess salt and water retention by the kidney
How does the kidney respond to hypertension?
- tries to reduce ECF through the loss of salt and water
- ANP and a reduction in aldosterone are two mechanisms which lead to increased secretion of salt wand water
What are some common examples of secondary hypertension caused by perturbations in the renal blood volume?
- Renal artery stenosis and coarctation of the aorta
2. Primary hyperaldosteronism (Conn’s syndrome) and Cushing’s syndrome
A 50 year old man presents with abd pain, temperature and vomiting. These are his obs: HR 130 BP 90/50 RR 22 O2 sat 94% in room air Cap refill 5 seconds peripherally Temperature 38.4 C What is his CVS doing to address the hypotension?
- increasing HR to deliver more blood
- possibly due to sepsis
What is the normal cap refill time?
Less than 2 seconds
A 50 year old man is diagnosed with sepsis. What are his kidneys doing?
- first response of kidney is to keep blood for itself
- self-preservation
- baroreceptors in JGA
- AA detects drop in BP and dilates as a result
- pt. Will get an increase in GFR
- body wants to vasoconstrict but kidneys vasodilate in order to get more blood
- produces prostaglandins in order to vasodilate and maintain GFR
What are the mechanisms for renin release from the kidney?
- release of dopamine will cause direct sympathetic stimulation of JGA
- reduced renal blood flow detected by baroReceptors in JGA
- reduced NaCl to JGA
How does renin act?
-it doesn’t do much but is capable and will start a new pathway
Describe the relationship between renin and angiotensin
- angiotensinogen comes from liver
- renin from the kidney will convert angiotnensinogen into angiotensin 1
- ACE from lungs and kidney will convert angiotensin 1 to angiotensin 2
How does renin-angiotensin act on the kidney?
- decrease in renal perfusion at JGA
- stimulates tubular Na??CL reabsorption and K excretion, H2O retention
- stimulates H2O reabsorption in collecting duct
- see diagram
What are the actions of aldosterone?
- upregulates Na/K pump in basolateral membrane of DCT
- upregulates Na channels in collecting duct and colon
- stimulates secretion of K into tubule
- stimulates Na and H2O in gut, salivary and sweat glands
- stimulates H+ secretion in CD
- upregulates Na/Cl cotransporter in DCT
What inhibits the positive action of RAAS on decreasing renal perfusion?
- water and salt retention
- effective circulating volume increases
- so perfusion of JGA increases
What is the action of ADH? What stimulates/inhibits it?
- increases permeability in the CD
- H2O is reabsorbed to prevent further dehydration
- Positive feedback: Angiotensin 2, blood osmotic pressure increases (acts on osmoreceptors in the hypothalamus)
- Negative feedback: when H2O is reabsorbed, thirst results in drinking water to reduce blood osmotic pressure (acts on osmoreceptors in the hypothalamus)
What are aquaporins?
- come in 4 subunits
- are in CD
- lots of Na is in renal medulla
- since osmotic gradient is formed, water can move out passively through CD
How would you treat the 50 y/o man? He had appendicitis
- Give IV fluids and antibiotics
- remove appendix
2 days later, the 50 y/o man developed peripheral oedema and had puffy eyes, why?
- RAAS system was still functioning due to increased sympathetic activity
- thus positive feedback was occuring due to the decrease in renal perfusion
- more salt and water was retained
- have to wait a while for the negative feedback to kick in
- can also be caused by leaky capillaries from the sepsis
How would you treat the 50 y/o man with puffy eyes and oedema?
-give diuretics
After treating with diuretics, these were the obs of the 50 y/o man: HR 90 BP 160/90 RR 14 O2 sat 98% Cap refill 2 seconds Temp 36.4 Why was his BP still high?
- could be a range of things
- underlying hypertension
- liver disease
- kidney disease
- fear
- white coat effect
- pain
- CVS disease
- drug effect
- fluid overload
What is the pressure-natriuresis curve?
- graph depicting Na excretion against mean arterial pressure
- if someone is hypertensive for a very long time, it develops a new normal range
- so when BP drops to actual normal (120/80), body thinks it is hypotensive and reacts
- you need a higher BP to excrete the same amount of Na
- hypertension leads to microvascular damage which leads to an increase in systemic vascular resistance which results back to hypertension (cycle)
What could a blocked renal artery mean?
- renal artery stenosis
- can be congenital (fibromuscular dysplasia)
- in pt’s with atherosclerotic problems
- vasculitis patients
How will the kidney respond if its renal artery is blocked?
- blood flow to whole kidney is reduced
- affected kidney will respond by trying to increase BP
- surgical solution: ballon dilation
What channel is important in uptake of sodium in the late DCT?
ENaC
