Formation of urine Flashcards
What are the 5 major stages of urine formation?
1: Glomerulus: Filtration of blood
2: Proximal tubule:
- Reabsorption of filtrate
- Secretion into tubule
3: Loop of Henle: Concentration of urine
4: Distal tubule: Modification of urine
5: Collecting duct: Final modification of urine
What are the 3 major functions of the nephron?
FILTRATION of blood to produce a filtrate
REABSORPTION of water, ions and organic nutrients
from filtrate
SECRETION of waste products into tubular fluid
What is the force for filtration?
–Blood pressure
–Differing diameter of afferent and efferent arterioles
What is glomerular filtration rate?
Glomerular Filtration
Rate (GFR) = 125 mL/min (º 180 L/day)
Normal plasma volume = 2-3 L
= Rate at which glomerular filtrate is produced
- GFR can be measured clinically and used as an
indicator of renal function
What is the first stage of urine formation?
Ultrafiltration: filtration on a molecular scale
All small molecules are filtered:
- Electrolytes
- Amino acids
- Glucose,
- Metabolic waste
- Some drugs, metabolites
Cells and large molecules remain in the blood:
- Red blood cells
- Lipids
- Proteins,
- Most drugs, metabolites
What is filtration dependant on?
Filtration is dependent on two factors:
blood pressure
renal blood flow
What does the filtrate have to pass through during glomerular filtration?
Filtrate has to pass through
(in sequence):
1: Pores in glomerular capillary endothelium
2: The basement membrane of Bowman’s capsule
(includes contractile mesangial cells)
3: Epithelial cells of Bowman’s capsule (Podocytes) via filtration slits into capsular space
What are the 4 types of pressure in the glomerulus?
What are the equations for pressure in and out of the glomerulus?
What is the equation for filtration pressure?
What type of pressure is shown?
How does filtration pressure change from the start of the glomerulus to the end?
How does blood pressure change GFR?
GFR generally remains constant even when systemic BP changes
This involves a regulatory mechanisms known as autoregulation of renal blood flow
What is autoregulation of renal blood flow?
Renal blood flow subject to autoregulation over broad range of systemic BPs (90-200 mmHg)
Autoregulation persists in denervated kidneys and isolated perfused kidneys …so it is NOT a neuronal or hormonal response but instead, a local effect
What are the 2 hypotheses for the autoregulation of renal blood flow?
Myogenic - autoregulation is due to response of renal arterioles to stretch (re: Starling’s Law):
e.g. if BP decreases, renal artery and efferent arterioles automatically constrict to maintain a constant renal blood flow (1,200mL/min) and GFR (~125 mL/min)
Metabolic - renal metabolites modulate afferent and efferent arteriolar contraction and dilation (e.g. adenosine, nitric oxide)
Most likely to be a combination of both
_______ and glomerular filtration rate (GFR)
are maintained even when systemic BP changes (______ mmHg)
Renal blood flow (RBF) and glomerular filtration rate (GFR)
are maintained even when systemic BP changes (90-200 mmHg)
Complete the diagram on the mechanisms of glomerulus blood vessels
How can changes in GFR alter systemic blood pressure?
- A drop in filtration pressure (e.g. due to declining BP) causes a drop in GFR
2: Lower GFR means less Na+ enters the proximal tubule
3: The macula densa senses a change in tubular Na+ levels
4: This stimulates juxtaglomerular cells to release renin into the blood
5: Renin release leads to generation of angiotensin II
6: Ang II is a vasoconstrictor which causes BP to increase
7: Increased BP causes filtration
pressure to increase and
GFR returns to normal
Complete the diagram on the RAS system
What are the 5 major stages in the process of urine formation?
1: Glomerulus: Filtration of blood
2: Proximal tubule:
- Reabsorption of filtrate
- Secretion into tubule
3: Loop of Henle: Concentration of urine
4: Distal tubule: Modification of urine
5: Collecting duct: Final modification of urine
What is reabsorbed from the proximal tubule?
60-70% of filtered water, Na+, HCO3-, Cl-, K+ and urea are reabsorbed from the PT
There is almost complete reabsorption of:
– Glucose
– Amino acids
– Small amount of filtered
proteins
What is the driving force for reabsorption from the proximal tubule?
The driving force for this reabsorption is Na+K+ATPase
How does Na+-K+-ATPase drive reabsorption?
Na+-K+-ATPase pumps out Na+ from cells into the blood against chemical and electrical gradients
This process requires energy in the form of adenosine triphosphate (ATP)
Accompanied by entry of K+ ions which rapidly diffuses out of cell
The ratio of transport is 3 Na+ leaving cell: 2 K+ entering cell
How does sodium reabsorption happen in the proximal tubule?
PT cells have a low intracellular Na+ concentration (less than 30 mM) due to the action of the Na+K+ATPase.
PT cells have an overall negative charge due to the presence of intracellular proteins.
Therefore Na+ enters PT cells.
Cl- follows Na+ by facilitated diffusion. Phosphate (PO42-) and sulphate (SO42-) are also co-transported with Na+
How does water reabsorption occur in the proximal tubule?
60-70 % filtered water reabsorbed in the PT - active transport of Na+ out Of PT cells is the driving force
Movement of solutes (Na+, HCO3- and Cl-) reduces osmolality of tubular fluid…and increases osmolality of interstitial fluid
A net flow of water from tubule lumen to lateral spaces occurs by transcellular and paracellular routes
Transcellular routes involve aquaporin (AQP) channels located on apical and basolateral surfaces
Is the reabsorption of water in the proximal tubule an active process?
There is no active water reabsorption along nephron - it occurs by osmosis and it follows sodium
What routes does water take to be reabsorbed from the proximal tubule?
PT is highly permeable to water. Water flow from tubule lumen to lateral spaces occurs by paracellular and transcellular routes
What transcellular routes does water take to be reabsorbed from the proximal tubule?
Transcellular routes involve aquaporins (AQPs) – specific water channels located in the cell membranes. 13 different types identified, 6 in the kidney, these are the 4 major renal AQPs:
What are the aquaporin channels in the proximal tubule?
Aquaporin-1 (AQP1): Abundant distribution in proximal tubule. Also other parts of tubule where water is reabsorbed, e.g. descending limb of LOH
Aquaporin-2 (AQP2): Present in collecting duct on apical surface AQP-2 channel expression is controlled by antidiuretic hormone (ADH)
Aquaporins-3 & 4 (AQP3 & AQP4): Present on basolateral surface of tubular cells involved in water reabsorption
How is glucose reabsorbed from the proximal tubule?
Glucose is co-transported into the PT cell with sodium
Glucose is co-transported into the PT cell with sodium
very efficiently so very little is excreted…
Why do diabetics get glucose in their urine?
How do SGLT2 inhibitors work?
New Drugs for Controlling Type II Diabetes?
Idea here is to make diabetic patients excrete more glucose leading to an overall hypoglycaemic effect
Where is the action of SGLT2 inhibitors?
List some SGLT2 inhibtors
Dapagliflozin
Canagliflozin
Empagliflozin
Ipragliflozin
Topogliflozin
Ertugliflozin
Remogliflozin
Sergliflozin
What other molecules are reabsorbed from the PT?
Potassium (K+) - 70 % of filtered K+ is reabsorbed in the PT, mostly passively via tight junctions (i.e. paracellularly)
Urea - 40–50 % filtered urea is reabsorbed passively in the PT down its concentration gradient
Amino Acids - 7 independent transport processes for reabsorbtion of AAs from the PT – depends on type of AA
- High Tm for transport so that as much as possible is reabsorbed from PT
Proteins - Reabsorbed from the PT via receptor-mediated endocytosis…
How are proteins reabsorbed from the proximal tubule?
Small amounts of protein pass into filtrate via the glomerulus
These are reabsorbed by pinocytosis…
…vesicles transported into cell, degraded by lysosomes and amino acids returned to blood
Only limited transport capacity (low Tm)…
What does proteinuria indicate?
…proteinuria is a sign of glomerular damage and impending renal failure
What is the role of secretion into the PT?
Some endogenous substances and drugs cannot be filtered at the glomerulus…
this may be due to their size or protein binding
Specialised pumps in the PT can transport compounds from the plasma into the nephron
What 2 pumps are used for secretion into the PT?
For organic acids
(e.g. uric acid, diuretics, antibiotics - penicillin)
For organic bases
(e.g. creatinine, procainamide)
Name 3 examples of pumps used to secrete into the proximal tubule
OAT = Organic Anion Transporter
MRP = Multi-drug Resistance Protein
a-KG = a-ketoglutarate
How is PAH secreted into the proximal tubule?
Para-amino hippurate (PAH) is secreted into PT from blood
Transported into PT cells from blood with a-ketoglutarate or other di/tri carboxylates
Transported out of PT cells in exchange for another anion present in the PT lumen
How can PAH be used?
Not an endogenous compound so PAH can be used as a tool to measure tubular secretion
Name some organic acids secreted into the PT
Name some organic bases secreted into the PT
What is the role of the loop of henle?
- Tubular fluid is further modified in this part of the nephron
- The aim here is to recover fluid and solutes from the glomerular filtrate
What are the 2 stages of the loop of henle?
(1) Extraction of water in the descending limb (D)
(2) Extraction of Na+ and Cl- in the ascending limb (A)
What happens in the thin descending loop of henle?
(1) Extraction of water in the thin descending limb
What are the features of the thin descending loop of henle?
Cells are flat, no active transport of salts (e.g. Na+, Cl-)
- But freely permeable to water via Aquaporin-1 channels
- Also some passive movement of water via tight junctions
What happens in the thick ascending limb of the loop of henle?
(2) Extraction of Na+ and Cl- in the thick ascending limb
What are the features of the thick ascending limb of the loop of henle?
Tubular wall is impermeable to water
- But has specialised Na+/K+/2Cl- (NKCC2) co-transporters
- Transport: Na+, K+, Cl- reabsorbed – but no water
How does solute reabsorption occur in the ascending loop of henle?
The Na+/K+/2Cl- (NKCC2) co-transporter (electroneutral) transports all 3 ions into the loop of henle
+ve charge repels Ca2+, Mg2+
What happens to the concentration of the filtrate throughout the loop of henle?
Fluid entering LOH from proximal tubule is isotonic (300 mOsm)
Water reabsorbed out of descending LOH
By the tip of the LOH, the filtrate is hypertonic (i.e. very concentrated, 1,200 mOsm)
Solutes (e.g. Na+, Cl-) are then pumped out of the ascending LOH
By the end of the LOH, the filtrate entering the distal tubule is hypotonic (150 mOsm)
“But how can the concentration of the filtrate vary from isotonic (300 mOsm) to hypertonic (1,200 mOsm) to hypotonic (100 mOsm) over a short distance in the medulla?”
Countercurrent Multiplication
Creates large osmotic gradient within medulla
Facilitated by Na+/K+/2Cl- transport in ascending limb of LOH
Permits passive reabsorption of water from tubular fluid in descending LOH…
What is the role of urea in countercurrent multiplication?
Active transport of NaCl contributes 600-1000 mOsm… the remainder is due to urea
Urea freely filtered at glomerulus
Some reabsorption in proximal tubule, but LOH and distal tubule relatively impermeable to urea
Urea can diffuse out of collecting duct into medulla down its concentration gradient
This adds to the osmolality of medullary interstitium
What percentage is reabsorbed and where is it reabsorbed?
What happens in the distal tubule?
–Active absorption and secretion of solutes takes place here
–Sodium (Na+) and chloride (Cl-) ions are actively reabsorbed from the tubular fluid
–This is in exchange for potassium (K+) or hydrogen (H+) ions which are secreted into the tubular fluid
What is the role of sodium in the principle cells?
- Na+ and Cl- exchanged for K+ throughout the DT
- Na+ exchanged for K+ in late DT and early collecting duct
- This involves specialised cells called PRINCIPAL CELLS
- These cells are sensitive to aldosterone
What is the role of principal cells?
•Exchange Na+ for K+ in the late DT and early collecting duct
This involves specialised cells called PRINCIPAL CELLS which are sensitive to aldosterone
This exchange forms part of the renin-angiotensin-aldosterone system (RAAS):
What is the role of sodium in intercalated cells?
•Na+ exchanged for H+ in DT and early collecting duct
- This involves specialised cells called INTERCALATED CELLS
- Subtypes exist called a and b intercalated cells
What is the overall renal effect of aldosterone?
More Na+ reabsorbed so more water moves into plasma so BP increases
What do a-intercalated cells do?
Secretes acid (H+) via H+/Na+ or H+/K+ exchange, involving ATPase or H+ATPase
Reabsorbs bicarbonate (HCO3-)
What do b-intercalated cells do?
Secrete bicarbonate (HCO3-) via Pendrin
Reabsorbs acid (H+)
What is ADH?
- Anti-diuretic hormone
- The most important hormone that regulates water balance - it is a nonapeptide with Mw of just over 1000
- Also known as ‘vasopressin’ or 8-arginine-vasopressin (to distinguish it from ADH of some other species, e.g. ADH is 8-lysine-vasopressin in pigs)
When is the collecting duct permeable?
The Collecting Duct is relatively impermeable to movement of water and solutes
However, the permeability of the collecting duct can be considerably increased the action of antidiuretic hormone (ADH)
How does ADH work?
- Released from the posterior pituitary subsequent to hypothalamic inputs
- ADH acts on vasopressin V2 receptors on basal membrane of principal cells in DT and collecting duct cells leading to activation of intracellular (aquaporin-2 or AQP2) water channels…
What is the half life of ADH?
- Plasma half life is 10-15 min (liver and renal metabolism)
Complete the diagram
How does the concentration of the solutes change in collecting duct?
No net movement of solutes (water only)
What is the effect of maximal circulating ADH?
•Collecting duct becomes permeable to water due to maximal AQP2 insertion so water reabsorption occurs
–Reabsorbs up to 66 % of the water entering the collecting duct
–Delivery of fluid to the collecting duct is low (~ 8 L/day)
–Urine volume can be reduced to 300 mL/day
What is the effect of no circulating ADH?
- Reabsorption of water occurs at various sites in the nephron as described previously
- However, the collecting duct wall becomes impermeable to water due to no AQP2 so a large volume of water is excreted (up to 30 L/day !!!)
What is diabetes insipidus?
•Lack of ADH: Diabetes insipidus – treated using synthetic ADH
What are the 2 major types of diabetes insipidus and how are they treated?
What are the other types of diabetes insipidus?
Other types: Dipsogenic, Gestational
What is SIADH and how is it treated?
Syndrome of Inappropriate ADH
Excessive release of ADH, e.g. due to head injury, unwanted effects of drugs, (e.g. ecstasy)
SIADH can cause hyponatraemia and possibly fluid overload
Treatment: V2 receptor blockers (ADH inhibitors), e.g. demeclocycline, Tolvaptan
Where does ADH come from?
•ADH synthesised in hypothalamus, then stored and released from posterior pituitary
Name agents which increase ADH release?
–Nicotine
–Ether
–Morphine
–Barbiturates
Name an agent which inhibits ADH release?
–Alcohol
Complete the percentages
Q: What happens to all that water and solutes reabsorbed from the tubule?
It is all taken back into the peritubular vessels and vasa recta surrounding the tubule
