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What are the functions of the kidneys?

  • Regulation of ECF volume and blood pressure. 
  • Regulation of osmolarity.
  • Maintenance of ion balance. 
  • Regulation of pH → HCO3- and H+.
  • Excretion of waste.
  • Production of hormones.


Approximately how many nephrons are found in each kidney?

  • ~1000,000
  • This number naturally declines with age or in disease.


Describe the structure of a nephron.

  • Each nephron contains:
    • A tuft of glomerular capillaries (glomerulus), through which large volumes of fluid are filtered from the blood. 
    • A long tubule in which the filtered fluid is converted into urine on its way to the renal pelvis. 


Describe the structure of the glomerulus. 

  • Glomerulus contains a network of branching and anastomosing glomerular capillaries that have a high hydrostatic pressure (~60mmHg). 
  • Glomerulus is covered by epithelial cells → total glomerulus is encased in the Bowman's capsule. 


Describe the system of tubules in the nephron. 

  • Fluid → filtered from the glomerular capillaries into the Bowman's capsule → then into the proximal tubule → loop of Henle, which dips into the renal medulla. 
  • Thin segment of the loop → the walls of the descending limb and the lower end of the ascending limb are very thin. 
  • At the end of the thick ascending limb → a short segment that has a segment of specialised epithelial cells = macula densa. 
  • The fluid then enters the distal tubule, which similarly to the proximal tubule, lies in the renal cortex. 
  • The distal tubule is followed by the connecting tubule and the cortical collecting tubule, which leads to the cortical collecting duct
  • The initial parts of 8-10 cortical collecting ducts join to form a single larger collecting duct that runs downward into the mediulla and becomes te medullary collecting duct. 
  • The collecting ducts merge to form progressively larger ducts, that eventually empty into the renal pelvis through the tips of the renal papillae. 
  • In each kidney there are ~250 of the very large collecting ducts, each of which collects urine from ~4000 nephrons.


Describe the structure of cortical nephrons. 

  • Cortical nephrons → glomeruli are located in the outer cortex, and have SHORT loops of Henle, that penetrate only a short distance into the medulla. 
  • Vascular structures of the cortical nephrons differ to the juxtamedullary → the entire tubular system is surrounded by an extensive network of peritubular capillaries.


Describe the structure of juxtamedullary nephrons. 

  • LONG loops of Henle that dip deeply into the medulla. 
  • The vascular structure:
    • Long efferent arterioles extend down into the outer medulla and then divide into specialised peritubular capillaries → the vasa recta → that extend downward into the medulla, lying side by side with the loops of Henle. 
    • As with the loop of Henle, the vasa recta return toward the cortex and empty into cortical veins → this specialisd network of capillaries in the medulla plays an essential role in the formation of highly concentrated urine. 


Describe glomerular filtration. 

  • ~180L / day is filtered in the Bowman's capsule → most of this filtrate is reabsorbed, leaving ~1L fluid excreted each day
  • The high glomerular filtration rate depends on a high rate of renal blood flow, as well as the special properties of the glomerular capillary membranes. 
  • GFR → is ~20% of the renal plasma flow and is determined by:
    • The balance of hydrostatic and colloid osmotic forces acting across the capillary membrane. 
    • The capillary filtration coefficient (Kf) → the product of the permeability and filtering surface area of the capillaries. 
    • The glomerular capillaries have a MUCH HIGHER rate of filtration that most other capillaries because of a high glomerular hydrostatic pressure and a large Kf.
    • GFR is ~125ml/min OR 180L/day. 


Describe the structure of the glomerular capillary membrane. 

  • Glomerular capillary membrane is similar to that of other capillaries, except that it has 3 (instead of 2) major layers:
    • The endothelium (innermost) layer.
    • A basement membrane.
    • A layer of epithelial cells (podocytes) surrounding the outer surface of the capillary basement membrane. 


Describe the structure of the glomerular capillary endothelium. 

  • Fenestrated → they are relatively large fenestrae.
    • Endothelial cell proteins are negatively charged → they repel the passage of plasma proteins. 


Describe the structure of the basement membrane of the glomerular capillaries. 

  • Consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces through which large amounts of water and small solutes can filter. 
    • The basement membrane effectively prevents the filtration of plasma proteins. 


What are podocytes?

Describe them.

  • Epithelial cells line the outer surface of the glomerulus → these cells are not continuous, but have footlike processes (podocytes) that encircle the outer surface of the capillaries.
    • Podocytes have slit pores through which the glomerular filtrate moves. 
    • The epithelial cells also have negative charges, providing additional restriction of the filtration of plasma proteins. 
      • Allows free passage of solutes up to ~60kDa.
      • Opposes movement of cells and large proteins. 
      • Negatively charged molecules are filtered less easily than positively charged molecules. 


  • What comprises:
    • Renal blood flow?
    • Renal plasma flow?

  • Renal blood flow = the total volume of blood that transverses the renal artery or vein per unit time = 1100ml/min. 
  • Renal plasma flow = the total volume of plasma that transverses the renal artery or vein per unit time.
    • Haematocrit = 45%
    • RPF = 55% x 1100 
      • = 600ml/min.
  • Intra-renal differences may occur between nephrons in the cortex and medulla and change with hydration state. 


How do the kidney tubules produce filtrate?

  • There is a balance of pressures → Starling's forces.
    • States that fluid movement due to filtration across the wall of a capillary is dependent on the balance between the hydrostatic pressure gradient and the oncotic pressure gradient across the capillary. 
  • Favouring movement into the tubule:
    • Glomerular hydrostatic pressure of the blood → +55mmHg.
    • Bowman's capsule colloic oncotic pressure of the tubule → 0mmHg. 
  • Opposing movement into the tubule:
    • Bowman's capsule hydrostatic pressure of the TUBULE (-15mmHg). 
    • Glomerular capillary colloid oncotic pressure of the BLOOD (-30mmHg). 


What is autoregulation of glomerular filtration?

  • Autoregulation mechanisms → intrinsic or local control → enables the kidneys to maintain a relatively constant GFR and to allow precise control of renal excretion of water and solutes. 
  • There are 2 mechanisms:
    • Myogenic mechanism
    • Tubuloglomerular feedback (nephrogenic)


Describe the myogenic mechanism of the autoregulation of glomerular filtration. 

  • The ability of the individual blood vessels to resist stretching during INCREASED arterial pressure.
    • Individual vessels throughout the body (especially small arterioles) have been shown to respond to increased wall tension by contraction of the vascular smooth muscle. 
      • Prevents excesive stretch of the vessel and also raises vascular resistance
  • It is thought that the myogenic mechanism may be important in protecting the kidney from hypertension-induced injury → sudden increases in BP cause the afferent arteriole to constrict → attenuating the transmission of increased arterial pressure to the sensitive glomerular capillaries. 
  • Control of GFR:
    • Major changes to blood flow / pressure 
    • Afferent arteriole dilation → increases GFR
    • Efferent arteriole dilation → decreases GFR
      • In reality, both happen at the same time. 
  • Renal blood flow:
    • 1-1.2L/min (20-25% of CO) → renal blood flow is essentially constant over a wide range of blood pressure, hence, GFR is essentially constant over a wide BP range. 


Describe the tubuloglomerular feedback of the autoregulation of glomerular filtration. 

  • Feedback mechanism that links changes in NaCl concentration at the macula densa with the control of renal arteriolar resistance and autoregulation of GFR. 
  • The tubuloglomerular feedback mechanism has 2 components that act together to control GFR:
    • An afferent arteriolar feedback mechanism
    • An efferent arteriolar feedback mechanism
    • These feedback mechanisms depend on the juxtaglomerular complex. 
  • The juxtaglomerular complex consists of:
    • Macula densa cells in the initial portion of the distal tubule.
    • Juxtaglomerular cells (specialised smooth muscle cells) in the walls of the afferent and efferent arterioles. 
  • Decreased macula densa NaCl causes DILATION of afferent arterioles and increases RENIN release.


What is the macula densa?

Closely packed, specialised cells lining the distal tubule, at the point where the thick ascending limb meets the distal convoluted tubule. 


What is the role of the macula densa in response to a decrease in NaCl?

  • decreased GFR SLOWS the flow rate in the loop of Henle, causing increased reabsorption of the percentage of sodium and chloride ions delivered to the ascending loop → thereby REDUCING the concentraion of NaCl at the macula densa cells. 
  • This DECREASE in [NaCl] initiates a signal from the macula densa that has 2 effects:
    • It DECREASES resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic pressure and helps to increase GFR back to normal.
    • It INCREASES renin release from the juxtaglomerular cells of both the afferent and efferent arterioles → these are the major storage sites for renin. 


Decreased [NaCl] reaching the macula densa has caused:

  • Decreased resistance to bloo flow in the afferent arteriole
  • Renin release from juxtaglomerular cells

What effect does this renin release have?

  • Renin released from the juxtaglomerular cells functions as an enzyme → to increase the formation of angiotensin I, which is then converted to angiotensin II by ACE in the lung. 
  • Angiotensin II then constricts the efferent arterioles, thereby increasing glomerular HYDROSTATIC pressure and helping to return GFR back to normal. 


What effect does an ACE-I have on a patient's kidneys?

  • Blockade of angiotensin II formation (by an ACE-I) further reduces GFR (worsens) during renal hypoperfusion. 
    • Angiotensin II is not available as a constrictor of the efferent arteriole → this would normally prevent serious reductions in glomerular hydrostatic pressure and GFR when renal perfusion pressure drops below normal. 


What is the effect of prostaglandins on the kidney?

  • Prostaglandins DECREASE renal resistance, increasing GFR.
  • Prostaglandins, by opposing vasoconstriction of the afferent arterioles → they help to prevent excessive reductions in GFR and renal blood flow. 
  • Clinical: following volume depletion e.g. surgery and the administration of NSAIDs → the inhibition of prostaglandin synthesis may cause significant reductions in GFR. 


What are the extrinsic hormonal factors affecting renal blood floow and GFR in response to:

  • Decreased afferent blood flow?
  • Increased afferent blood flow?

  • Decreased afferent blood flow = vasoconstriction.
    • Sympathetic nerves release noradrenaline.
    • Circulating adrenaline.
    • Angiotensin II (efferent vasoconstriction).
  • Increased afferent blood flow = vasodilation.
    • Renal prostaglandins.
    • Atrial natriuretic peptide → main function is to cause a reduction in circulating ECF by increasing renal sodium excretion → drags water via osmosis → more urine. 


Describe tubular reabsorption and excretion.

  • Unlike glomerular filtration → tubular reabsorption is HIGHLY selective.
  • Glucose and amino acid reabsorption is almost complete, so excretion is ZERO.
  • Many ions e.g. sodium, chloride and bicarbonate are also highly reabsorbed, but their rates of reabsorption and thus excretion are highly variable and controlled. 
  • Waste products e.g. urea and creatinine → poorly absorbed and EXCRETED in large amounts. 
  • Thus, controlling the rate at which the tubules REABSORB different substances independently of one another permits the control of body fluid composition. 


Describe tubular reabsorption of water and solutes.

  • Active transport
    • Active transport → can move a solute against an electrochemical gradient and REQUIRES energy derived from metabolism → it needs a pump that uses ATP. 
    • Tubular cells are an example of this → the transport of sodium through the tubular epithelia. 
    • The sodium-potassium pump transports sodium from the INTERIOR of the cell across the basolateral membrane, creating a LOW INTRACELLULAR [sodium] and NEGATIVE intracellular electrical potential.
      • This causes sodium to diffuse from the tubular lumen into the epithelial cells through the BRUSH BORDER. 
  • Secondary active transport → simultaneous facilitated diffusion
    • 2 or more substances interact with a specific membrane protein (carrier molecule) and are transported together across the membrane. 
    • As one of the substances diffuses DOWN ITS electrochemical gradient (e.g. sodium), the energy RELEASED is used to drive another substance (e.g. glucose) against its electrochemical gradient.
      • SGLT - sodium glucose co-transporter.
      • NHE → Na+ and H+ exchanger → excrete H+ to make acidic urine and reabsorb Na+.
      • Basolateral Na+-KATP pump is generated the Na+ 


Describe the primary transport in the proximal tubule.

  • 65% of filtered load of Na+ and water are reabsorbed here.
  • PCT has a high capacity for reabsorption with highly metabolically active cells. 
  • Lots of co-transport
  • Secretion also occurs
    • Organic acids / bases
    • Metabolic products
    • Drugs and toxins


Describe the cellular ultrastructure and transport characteristics of the loop of Henle.

  • 20% of filtered water and 25% of filtered sodium, chloride and potassium are reabsorbed. 
  • Thin descending segment → permeable to water
  • Ascending limb → impermeable to water. 
  • Thick ascending limb → has active transporters and absorbs NaCl and potassium. 
  • Other ions are absorbed too.
  • Co-transporters are important here.


Describe the mechanisms of sodium, chloride and potassium transport in the thick ascending limb. 

  • The sodium-potassium ATPase pump in the basolateral membrane maintains a low intracellular [Na+] and NEGATIVE electrical potential in the cell.
  • The 1-sodium, 2-chloride, 1-potassium co-transporter in the luminal membrane transports these 3 ions from the tubular lumen (filtrate) into the cells, using the potential energy released by diffusion of sodium DOWN an electrochemical gradient into the cells. 
  • Sodium-hydrogen counter-transporter → also transports sodium from the tubular lumen (filtrate) into the cell.
  • The positive charge (+8mV) of the tubular lumen relative to the interstitial fluid FORCES CATIONS (repels) such as Mg2+ and Ca2+ to diffuse from the filtrate into the interstitial fluid via the paracellular (between the epithelial cells) pathway. 


Describe the characteristics of the early and late distal tubule. 

  • 5% of the filtered load of sodium is reabsorbed here. 
  • It is impermeable to water.
  • Pumps / absorbs sodium, chloride and potassium just like the thick ascending limb.
  • Urine becomes MORE DILUTE.
  • The late section of the distal convoluted tubule has 2 cell types:
    • Principal cells → absorb water and sodium ions. 
    • Intercalated cells → absorb potassium and secrete H+ ions. 


Describe the mechanism of NaCl transport in the early distal tubule. 

  • From the filtrate, Na+ and Cl- are co-transported by the sodium-chloride co-transporter into the tubular cell.
  • Sodium is ACTIVELY pumped out at the basolateral membrane by the sodium-potassium ATPase. 
  • Chloride DIFFUSES into the interstitial fluid via the chloride channels.