Lecture 23

Lecture 23 – Renal Function:

The Kidney:

• Regulates the composition and volume of bodily fluids by Ultrafiltration of the blood plasma
  
• Re-absorbs various needed metabolites from the filtrate
  
• Secretes the waste products into the filtrate, and the excretion is urine
  

 
 

Filtration:

• It can only filter things up to 10nm in diameter (this is the largest size of something that can pass through)
  
• Smaller than the Fenestrations of the endothelial cells of the glomerulus are about 90nm.  Smaller than the Slit pores which are approximately 25nm.  These things aren't doing the filtering.
  
• Filtering is the Double Basilar Membrane
  
  • Double Basilar Membrane is filled w/ negatively charged and ionic molecules.
    
  • Large negatively charged particles have trouble passing through the membrane.
    
  • The largest negatively charged molecule that can get through is about 6nm
    
  • The largest neutral particle that can get in is to 8nm.
    
    • Largest positively charged particle that can get in is 10nm, b/c the positive charged particles attracted to negative charged particles.
      
    • The blood/plasma tends to be negative, and the filtrate tends to be positive.
      
• This is for very large particles.
  
• There are smaller monovalent ions traveling through this system (ex. Sodium and Chlorine).
  
  • Sodium and Chlorine are so much smaller than these large particles that they are not affected by the charges of the proteins but they are affected by the charges of the blood and filtrate.  
    
  • The plasma is 5% higher in Sodium than the filtrate (the Chlorine is repelled from the plasma more)
    
  • The filtrate is 5% higher in Chlorine (the Sodium is repelled from the filtrate more)
    
  • The Donnan Effect –the difference in the amount of Sodium and Chlorine. It is the effect of the larger molecules on the smaller molecules.
    
• At rest the kidneys receive just under 25% of the Cardiac Output – this is a lot.
  
• On a daily basis, approximately 1000 liters of plasma a day will be filtered – it goes through the glomerular capillaries.
  
  • Bowman's capsule receives 18% of the plasma volume as filtrate – this is the Filtration Fraction.
    
  • As a result of an at rest Filtration Fraction of 18%, we are filtering 125ml of filtrate per minute. This means that 180 liters will be filtered in a day.
    
  • This 125ml/min is termed the Glomerular Filter Rate (GFR) – which is how much filtrate is going through on a daily basis. This results in 180 liters of filtrate per day.  GFR depends on several factors:
    
    • 1.) Membrane Permeability – it stays fairly constant
      
    • 2.) Surface Area available for filtration – it can be adjusted, mesengial cells when they are contracted will bulge into the lumen of the capillary possibly closing it, reducing the flow, and reducing the area possible for filtration.
      
      • Mesengial cells will contract in response to factors that raise blood pressure, and relax in response to factors that lower blood pressure.
        
    • 3.) The net filtration pressure – this stays fairly constant over the period of normal blood pressures.
      
• Starling Forces in the Glomerular Capillaries:
  
  • Afferent End of Arteriole – the Hydrostatic pressure is 61mmHg (an outward flow), and the Osmotic Gradient pressure is 28mmHg (a draw in).
    
  • Efferent End of Arteriole – the Hydrostatic pressure is 59mmHg, and the Osmotic Gradient pressure is 36mmHg
    
  • Bowmann's Capsule – the Hydrostatic pressure is 18mmHg, and the Osmotic Gradient pressure is 0mmHg because the filtrate is moving away.
    
  • There is always a 2mmHg drop between the efferent and afferent ends and the average is 60mmHg. This is how they get such exact numbers. (This is how they got 61 and 59)
    
  • At the afferent end it is 61 – 28 – 18 = 15mmHg out.
    
  • At the efferent end it is 59 – 36 – 18 = 5mmHg out.
    
  • It is never an inward flow, it always flows out.  It never goes to 0mmHg.
    
  • The Glomerular Hydrostatic pressure stays fairly constant through everything.
    
  • GFR stays fairly stable over the range of normal blood pressures, which is due to Autoregulation of the kidney.
    
    • Autoregulation – it is inherent to the kidney; when they first did kidney transplants back in the 1950's they found that even when they cut all of the innervations from the kidney removed and they noticed that the kidney was still regulating itself.  So it was in the kidney where the regulation was happening, the maintenance of the blood pressure and the GFR.  There are 3 mechanisms to the Autoregulation:
      
      • 1.) Myogenic  mechanism: When systemic blood pressure stretches the smooth muscle of the afferent arterial, it will contract its lumen maintaining the blood pressure. The 2 arteries, the Arcuate and the Interlobular Arteries, prior to the afferent arteriole secrete Nitric Oxide in response to an increase of blood pressure, which causes an expansion of the blood vessels, and therefore the arteries dilate and the blood pressure drops.
        
      • THIS IS AN EXAMPLE OF SELF-DELUDING LOGIC
        
  • A study that shows self-deluding logic:
    
    • GFR (or pressure) (Y) and Mean Aortic Pressure (X) (this means that if your pressure is 120/80 then your Mean Aortic Pressure is 100) - see chart.
      
      • GFR stayed level from about 90 to 180bpms (this is the normal blood pressure ranges of all of the physiological blood pressures that you will run into, and what happens is the GFR will rise when you go up to 90, and at 90 it levels off and then at 180 it will start to rise again.
        
      • Wanted to say that Nitric Oxide was not Part of the Kidney – the fact that GFR is level when NO blocker is present means that NO is not part of the auto-regulation. However, Autoregulation did occur, but it occurred at a different level (it changed the level of the GFR) – and therefore NO did have a role – why did they end at 140 – there was no linear relationship? They never drew the line to 180.
        
      • This data is illogical – if NO was not involved, then it would have come up the same level, which did not happen. That is bad logic to good science.
        
      • NO is an integral part of the Tubuloglomerular Feeback System
        
  • Tubuloglomerular Feeback System
    
    • The Macula Densa cells of the JGA (Juxtaglomerular apparatus) are osmotic feedback receptors
      
    • They monitor rate of Chlorine movement across the cell directly and rate of Sodium movement across the cell indirectly.
      
    • The Macula Densa cells are regulating the afferent arteriole at the Juxtaglomerular Apparatus.
      
    • If the flowing is going slow through the Thick Ascending Loop of Henle you are pumping a lot of Sodium and Chlorine.  If the fluid is going back fast there is a higher amount of Sodium and Chlorine there, and if the fluid is going back slow there is a lower amount of Sodium and Chlorine there.
      
    • When the Macula Densa cells see the crossing of chlorine/sodium is low (flowing too slow), they will vasodilate the arteriole.  When the Macula Densa cells see the crossing of the chlorine/sodium is high (flowing too fast) they will vasoconstrict the arteriole.
      
      • The exact mechanism is not know, but the Macula Densa finds a happy medium and stays there and so does the GFR.
        
      • Nitric Oxide is mediating the dilation. This proves that is must be involved in the Autoregulation.
        
      • The Thick Ascending Loop of Henle cells are very good at removing Sodium and Chlorine from the filtrate.
        

  
 

• The Renin-Angiotensin System:
  
  • Renin is released by the Juxtaglomerular cells of the JGA, and Renin is an enzyme that splits the circulating blood protein Angiotensinogen into Angiotensin I
    
    • Angiotension I is converted to Angiotensin II by Angiotension Converting Enzyme (ACE) – it is at the surface of virtually every endothelial cell in our circulation.  Most of the conversion will occur in the Lungs b/c that is when the Angiotensin has the best chance of hitting the ACE receptors in the capillary
      
    • Angiotensinogen is mainly created by the Liver, however a variety of other tissues do too.
      
    • Angiotensin II is a powerful systemic blood pressure raiser.
      
  • How Angiotensin II works in the kidney (this also tells how the sympathetic nervous system works in the kidney):
    
    • We have our Glomerular capillaries sitting inside the Capsule, and we have the afferents going to this and the efferents coming from this.  The blood in these are eventually going to go to tubule capillaries. Reabsorption is going to be taking place by these efferent blood vessels.
      
    • A single capillary in the capsule – Angiotensin II preferentially constricts the efferent arteriole – this:
      
      • Slows the flow of blood (by constricting this) through the arteriole
        
      • GFR is regulated/maintained here by other factors and stays the same
        
      • This will do 2 things: 1.) It will make the blood go more slowly though these capillaries (meaning you are taking more fluid from a smaller amount of blood), and 2.) GFR will stay the same.
        
        • We are taking the same amount of fluid out of a smaller amount of blood – increasing the Filtration Fraction. This means that the blood that is leaving the through the efferent arteriole is going to be lower in Hydrostatic Pressure, and higher in the Osmotic Gradient (b/c more fluid is leaving). This blood is bound for Peritubular Capillaries for reabsorption, this causes more inward flow. The filtration pressure in the Peritubular Capillaries will cause more reabsorption to occur, reabsorbing more amount of fluid from the same amount of filtrate (this is due to changing the Starling Forces and the amount of blood going into the reabsorption areas).
          
        • If the pressure starts to build up in the afferent arteriole, then Angiotensin II will contract that one as well. The mechanism for this is not known.
          
        • The sympathetic nervous system can do the exact same thing, but it does it by firing neurons, but they will only do this during fight or flight.  This is not part of autoregulation b/c it is neural.  The SNS does not innervate the kidneys.
          
      • Renin is released by 2 autoregulation effects:
        
        • 1.) A reduced stretch of Juxtaglomerular cells (sitting in the walls of the afferent arteriole) (Juxtaglomerular cells are stretch receptors, if they contract it will cause the secretion of Renin to try and build up pressure again).
          
        • 2.) The Macula Densa cells are regulated/mediated by prostaglandins and they can cause the release of Renin.
          
      • Things from outside that cause Renin release:
        
        • 1.) Sympathetic neural stimulation will cause Renin to be released, innervations of the kidney.
          
        • 2.) Sympatric stimulation
          
        • Increased circulating catecholamines.
          
      • Sympathetic neural stimulation can work the same way as Angiotensin it can preferentially contract the efferent areteriole increasing re-absorption because it changes filtration pressure in peritubular capillaries.
        
  • 180 liters of filtrate are produced/filtered each day – but under normal circumstances we are on peeing out 1.5 liters. 
    
  • 99% of the filtrate is reabsorbed by the tubules of the nephron. But any substance that is reabsorbed by the tubules of the nephron must be picked up by the Peritubular capillaries (this is where the efferents is going to). There is an inward filtration pressure along the entire length of the Peritubular capillaries.
    
    • Note: Everything of the Glomerulus was going outward
      
    • Alcohol blocks ADH secretion so we pee more. During a party you would kick out a lot more than that because the alcohol is inhibiting ADH.
      
  • Starling Forces of a Peritubular Capillaries, these are when we at rest, no sympathetic or angiotensin II. We talk about either in or outside the Peritubular Capillaries.
    
    • In capillary there is Hydrostatic Pressure of 18mmHg (out).
      
    • In the capillary the Osmotic Gradient is 36mmHg (in).
      
    • In the Interstitium of the kidney has a Hydrostatic Pressure of 6mmHg and an Osmotic Pressure of 15mmHg.
      
    • (18+15-36-6)This comes out to a total of 9mmHg inward. We do not go from one end of the capillary to the other because the filtration pressure stays constant along the entire length.
      
    • This value of 9mmHg is going to be shifted up an down from what we just talked about with the SNS or the Angiotensin II preferentially doing the efferent arteriole that way.  But the 9mmHg doesn't change at all as it goes through b/c any drop in the blood osmotic gradient through the capillaries will be matched by a similar drop in the blood hydrostatic pressure, so theFiltration Pressure stays the same all the way through the Peritubular capillaries.
      
    • The only time it changes in when you preferentially contract the efferent arteriole.
      

 
 

Reabsorption:

      Terminology:

• Tm = Transport Maximum – it is stated in mg/min.  It is the maximum amount of a specific solute that can be transported back and reabsorbed by a nephron. Transport Maximum is a function of the rate of the work in unit and the number of work in units in a system.  Below Tm the amount of solute transported is proportional to the amount of solute in the filtrate.  At the level of Tm we say that it is saturated.  At both Tm excess solute is lost in the urine.  The Plasma solute level at which Tm is released is called the Plasma Threshold.
  
• Transporters that move things, like glucose, so we want to see how much glucose has to be in blood so there is not re-absoprtion mechanism to reabsorb it – the Tm is the peak, the maximization of all the transporters. There are Tm's for other things being taken back in. If it is faster than the transport maximum it is found in the urine.
  
• Locations with Tight junctions are the Apical membrane, the other portion is the basolateral membrane.
  
  • This cell is sitting upon a membrane but it is so porous that it is virtually not there.
    
  • The next cell over is connected at tight junctions.
    
  • The lumen of the tubule is on the side with tight junctions.
    
  • The interstitum is on the side of the basolateral membrane.
    
  • The Peritubular Capillary
    

 
 

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