Urine production

Question 1

Steps of urine formation

Answer 1

Filtration:

• Water and solutes move out of the glomerular capillary into the capsular space via filtration (driving force = hydrostatic and colloid osmotic pressures)
• Larger molecules such as plasma proteins cannot easily leave the blood
• Filtration is dependent only on size of molecules (i.e. not chemically specific)

Reabsorption:

• Movt of water + solute from tubular fluid back into blood
• Unlike filtration, reabsorption is usually highly selective involving either diffusion or carrier proteins (pumps)
• = kidneys can modify the content of this fluid and start making it more like urine
• Water reabsoprtion occurs via osmosis (“follows” salts)

Secretion:

• The removal (transport) of additional solute from the blood into the tubular fluid
• A back-up for filtration
• Many drugs are eliminated from the body via secretion

Question 2

Final urine content of a substance = calculation

Answer 2

• The glomerular filtrate gets modified in the nephron tubule by the processes of reabsorption and secretion
• Therefore the amount of any given solute eliminated in the urine can be determined by the following equation:

amount filtered - amount reabsorbed + amount secreted = amount of solute excreted

Question 3

Step 1 of urine production: glomerular filtration

Answer 3

• Glomerular filtration is the same process of filtration of blood that occurs in all capillaries
• It is just filtering…
  
  • Solution
  • Filter (endothelium of the glomerular capillary)
  • Filtrate
• The solution moves by bulk flow (driving force is a pressure gradient)
• The kidney works more like a Reverse Osmosis (RO) filter, where the solution is divided into 2 components
  
  • Solution
  • Filter
  • Filtrate
  • Bypass (this is the waste in a RO filter, but it’s the blood in the body)

Question 4

Structure of the renal corpuscle

Answer 4

• Glomerular filtration occurs in the renal corpuscle
• Renal corpuscle comprises the glomerulus and Bowman’s capsule
• Bowman’s capsule consists of 2 layers of epithelia
  
  • Parietal (outer) layer
  • Visceral (inner) layer
• B/w these 2 layers is the capsular space, where the filtrate collects
• The visceral layer consists of specialised epithelial cells called podocytes (podos = foot) = type of epithelial cell
• The podocytes form filtration slits = for material to be filtering out of the glomerular capillary + into the capuslar space it has to pass through these filtration slits

Question 5

glomerular capillary is leakier than normal = basal lamina

Answer 5

• The endothelium of the glemorular capillary is fenestrated
  Latin: fenestra “window”
• The fenestrations or hole are large enough to allow most content in the blood to pass through
  
  • With the exception of red + white blood cells, platelets
• What about protein? The size of a ‘typical’ protein is <=10 nm in diameter
• The podocytes are wrapped around the capillary, with the filtration slits reducing the pore size to ~40nm
• The main barrier to protein diffusion is the negatively charged basal lamina, which electrically repels the negatively charged proteins
• BASAL LAMINA: is an acellular secretion from the podocytes that sits on the capillary = is negatively charged = because most proteins are also negatively charged, they are electrically repelled from the basal lamina, preventing proteins from diffusing out of the blood

Question 6

Filtration Membrane

Answer 6

• For material to filter out of the blood and enter into Bowman’s capsule it crosses first through the fenestration → then has to cross the filtration membrane which comprises also the basal lamina → then the podocytes (the visceral layer of Bowman’s capsule)

Question 7

Why is capillary hydrostatic pressure higher than normal in the glomerular capillary

Answer 7

• Whole point of the glomerular capillary is to drive filtration to get friltrate, then to get filtrate into the nephron = way that works is by having a higher BP in the glomerular capillary (get due to the afferent arteriole being so big = bigger radius = more blood into capillary = higher BP)
• Glomerular cap pressure is higher because of low resistance afferent arteriole
• Filtration driving pressure:
  = Pg - (Pcf + piG)
• note: the other factor for filtration is the permeability constant (k), which is high in a fenestrated glomerular capillary

Question 8

What is the normal glomerular filtration rate (GFR)?

Answer 8

• GFR is the rate at which fluid passes from the blood into the nephrons and its maintenance is crucial for normal kidney functioning
• Recall: (1) renal blood flow is ~20% of cardiac output, and (2) ~20% of the blood plasma passing through the kidney is filtered into the golmerulus
  1. Renal blood flow is 20% of cardiac output
• CO = ~5000-5500 ml/min
• 20% x 5000 ml = 1000 ml blood/min
  2. Blood plasma = 55% whole blood (45% cells)
• 55% x 1000 ml/min = 550 ml plasma/min
  Therefore 20% x 550 = ~110ml blood plasma is filtered by glomeruli each minute
• The usual number in the text books is 125 ml/min Or 180 L/day
• Normal urine output is ~1-2 L/day
• Min urine output ~ 420 ml/day to excrete waste
• The rest of the fluid (178-179L/day or 99%) is reabsorbed back into the blood stream from the renal tubules

Question 9

Regulation of GFR

Answer 9

• Maintaining GFR is crucial for correct renal function
• If GFR is too low → accumulation of wastes in the blood (e.g. urea, acids etc) = kidney damage due to a loss of nephrons
• If GFR is too high → dehydration and electrolyte depletion = some drugs or very very high BP
• GFR is controlled by the filtration pressure, which is normally ~10 mmHg

Question 10

What happens to GFR if arterial pressure changes?

Answer 10

• GFR can be maintained remarkably constant in the face of changing arterial pressure by controlling glomerular capillary pressure.
• Autoregulation of GFR: maintains a nearly constant GFR when mean arterial blood pressure is between 80 and 180 mmHg

Question 11

How is autoregulation of GFR achieved?

Answer 11

• Autoregulation of GFR is achieved by maintaining constant glomerular capillary pressure
• Autoregulation of GFR depends on the ability of the afferent (& to a less extent efferent) arterioles to adjust their radius (& resistance)
• Constriction of the afferent arteriole decreases glomerular pressure (decreasing GFR)
• Constriction of the efferent arterioles increases glomerular pressure (increasing GFR)

FLOW CHART
High MAP –> high glomerular cap pressure –> high GFR –> constriction of afferent arteriole and dilation of efferent arteriole –> reduces glomerular pressure
- response to low MAP is the reverse = dilation of the afferent and constriction of the efferent arteriole

Question 12

Mechanisms that achieve auto-regulation: Myogenic Mechanism

Answer 12

• Intrinsic property of vascular smooth muscle in arterioles
• Stretching the vascular smooth muscle in an arteriole causes the arteriole to contract (the arteriole stretches when pressure increases)
• Stretching the smooth muscle increases its permeability to Ca2+

Question 13

Mechanisms that achieve auto-regulation: Tubuloglomerular feedback

Answer 13

• When [Na+] in distal tubule is low the macula densa cells release prostaglandins. This dilates the afferent arteriole.
• This occurs with low MAP, low GFR
• Increased MAP →↑GFR → ↑tubular flow rate → ↑[Na+] in distal tubule
  → reduced prostaglandin release → constriction of afferent arteriole
  → reduces glomerular pressure & reduces GFR

Question 14

Mechanisms that achieve auto-regulation: Role of renin-angiotensin system in regulation of GFR

Answer 14

• Prostoglandins released from macula densa also activate prostaglandin-sensistive juxtaglomerular cells to release renin → angiontensin II
• AngII preferentially produces constriction of the efferent arterioles (it constricts efferent arterioles more than other arterioles)
• And produces more dilation of efferent arteriole when AngII levels are low
• High MAP + high GFR leads to increase NaCI in the distal tubular fluid and decreased prostaglandin release from macula densa
• Reduces renin secretion + reduces AngII production → dilation efferent arteriole
• In addition, the reduced prostoglandin directly causes constriction of afferent arteriole
  → glomerular capillary hydrostatic pressure reduces
  → GFR reduces

Question 15

The Juxtaglomerular apparatus - related to tubuloglomerular feedback

Answer 15

• In each nephron the beginning of the distal tubule passes b/w the afferent + efferent arterioles
• This region contains a specialised area known as the juxtaglomerular apparatus.
• It comprises:
  (i) A group of Na+-sensitive epithelial cells in the tubule that detect the amount of Na+ in the tubular fluid.
  - known as the macula densa (“dense spot”)
  (ii) Specialized smooth muscle cells in the afferent arteriole called juxtaglomerular cells (granular cells) that produce + secrete the enzyme renin.
  - crucial in production of the hormone angiotensin II