Term 2 Lecture 10: Secretion, Exchange And Clearance Flashcards
Tubular secretion
Trans-epithelial transport
Another route for selected substances to enter tubules from peritubular capillaries to be eliminated in the urine
(Filtration at Bowman’s capsule)
Secreted by tubules:
H+ K+ organic anions and cations
Filtration of blood to lumen
Glomerulus → Bowman’s capsule
Reabsorption from lumen to blood
From Proximal tubule, D l of H, thick , ascending l of H and distal tubule
→ peritubular capillaries
Secretion blood to lumen
Peritubular capillaries → proximal tubule and distal tubule
Excretion lumen to external environment
From end of distal tubule → ureter→ bladder→ urethra→external environment
Renal H+ secretion in acid-base balance regulation
H+ in the proximal,distal and collecting tubules is eliminated in the urine
The extent depends on the acidity of body fluids.
K+ ion secretion is controlled by aldosterone
98% of K+ is intracellular fluid because Na+ K+ pump actively transports K+ into cells.
ECF has a relatively small amount of K+
Change in ECF K+ load can have a pronounced effect on plasma K+ concentration
Active reabsorption in proximal tubule occurs without regulation
K+ is actively secreted by principal cells in the distal and collecting tubules (variable and under regulation)
Intercalated cells secrete and reabsorb linking them to H+ transport
Filtered K+ is almost completely reabsorbed in proximal tubule, any K+ in urine is derived from controlled K+ secretion in distal parts of the nephron.
H+ depletion causes reduction in K+ secretion into the distal nephron so that only a small percentage of filtered K+ that escapes reabsorption in the proximal tubule is excreted in the urine.
K+ that normally would be lost in the urine is conserved.
K+ elevation in the plasma causes k+ secretion into the distal nephron to be adjusted so that just enough K+ is added to the filtrate for elimination to reduce K+ concentration to normal level
Thus K+ secretion (not the filtration or reabsorption) is varied in a controlled manner to regulate the rate of K+ excretion and maintain the desired K+ concentration
Ability to contract cardiac muscle and generate CO is completely reliant on L+ and Na+ so a lack of K+ would reduce cardiac function
Mechanism of K+ secretion
K+ ion secretion is coupled to Na+ reabsorption (Na+-K+ pump)
Na+ is transported into the lateral space and into the principal cells.
High intracellular concentration of K+ favours net movement of K+ from cells into the tubule lumen via:
-passive diffusion
- K+ leaky channels
Interstitial fluid concentration of K+ is low so passive movement of K+ out of the peritubular capillary plasma occurs
Basolateral pump actively induces net secretion of K+ from the peritubular capillary plasma into the tubular lumen when in the distal parts of the nephron.
Mechanism of K+ secrerion
K+ pumped into cells moves back into the interstitial fluid via leaky channels
In this way the proximal tubule Na+ - K+ pump is able to reuse K+ so that the pump can continue Na+ reabsorption with no local net effect on K+
→ in distal principal cells leaky channels are into the interstitial space and in the proximal tubule the leaky channels are in the other side
How does aldosterone effect the K+ secretion
Raised plasma K+ level increases aldosterone production levels increasing tubular and urinary K+ secretion
Aldosterone increases K+ secretion by the principal cells whilst enhancing these cells reabsorption of Na+
Aldosterone produces 2 pathways and always promotes K+ secretion and Na+ reabsorption
Aldosterone causes rise in plasma K+ directly stimulating the adrenal cortex
Fall in plasma Na+ concentration stimulates the RAAS pathway
If you have Na+ depletion, ECF volume reduction or fall in BP unrelated to K+ balance then inappropriate K+ secretion leads to K+ deficiency
Electrical excitability cells are altered especially in the heart
Acid-base balance - intercalated cells secrete either H+ or K+ ions for balance
Increased secretion of one decreases secretion of the other.
Normally more K+ than H+ is present
If fluids are acidic H+ is secreted and K+ retained to restore balance
Summary of transport across proximal and distal portions of the nephron
Proximal tubule reabsorption
-67% of filtered Na+ actively reabsorbed (not subject to control) and Cl- follows passively
- all filtered glucose and aas are reabsorbed by secondary active transport (not subject to control)
- variable amounts of PO4³-
(phosphates) and other electrolytes reabsorbed (subject to control) - 65% of filtered H2O osmotically reabsorbed (not subject to control)
- 50% of filtered urea is passively reabsorbed ( not subject to control)
Proximal tubule secretion
- variable H+ secretion depends on acid-base status of the body
- organic ion secretion (not subject to control)
Distal tubule and collecting duct reabsorption
-variable Na+ reabsorption is controlled by aldosterone and Cl- follows passively
- variable H2O reabsorption is controlled by vasopressin
Distal tubule and collecting duct secretion
-variable H+ secretion depending on acid-base status of the body
- variable K+ secretion controlled by aldosterone
Urine excretion
-Excretion = what the body is eliminating but tells us nothing about renal function
- excretion rate tells us nothing about the kidney handling that substance
-excretion rate depends on filtration rate and whether the substance is reabsorbed, secreted or both
Urine excretion - renal handling and GFR clinical relevance
GFR is an indicator of overall kidney function
Pharmaceutical companies developing drugs must show how kidneys handle each new compound
‘Clearance’ describes the renal systems removal of the drug e.g. if there’s no clearance this means the drug is 100% retained and not excreted
Assessing renal function: clearance
Clearance compares the composition of blood entering the kidney through renal arteries to blood leaving the kidneys through the renal veins to find out what materials the kidney has ‘cleared’ from the blood stream.
This is referred to as ‘plasma clearance’ this is the volume of plasma completely cleared of a substance by the kidneys per minute.
NOT the amount of substance removed but the volume of plasma from which that volume was removed
Plasma clearance is a non invasive way to measure GFR, which is a good way to check if an individuals kidneys are functioning properly or not.
(GFR is usually constant at 125ml/min and only varies at BP extremes)
How do you calculate plasma clearance?
Plasma clearance expresses the kidneys effectiveness in removing various substances from the internal fluid environment
Plasma clearance can be calculated for any plasma constituent
Clearance rate of substance (ml/min) = urine conc. of substance (quantity/ml of urine) X urine flow rate (ml/min)
Divided by
Plasma conc. of the substance (quantity/ml of plasma)
Plasma clearance rate varies for different substances depending on how the kidneys handle each substance
If a substance is filtered but not reabsorbed it’s plasma clearance is equal to GFR
Hypothetical substance X
Substance X is freely filtered at the glomerulus but is not reabsorbed or secreted.
As 125ml/min of plasma are filtered (GFR) and subsequently reabsorbed
Quantity of substance X what was originally in 125ml plasma is left behind in the tubules for excretion.
So 125ml plasma are cleared of substance X per minute.
In reality no normally occuring chemical in the body has the characteristics of substance X
Measuring GFR using solutes that are fully excreted
LIke substance X inulin a foreign (and synthetic) carbohydrate behaves like substance X and is freely filtered without reabsorption or secretion.
Therefore inulin can be used to measure GFR. Inulin must be injected into a person at a specific rate and measure urine output by production per minute. This will give a clearance rate of 125ml/min equal to GFR
Clearance rate for inulin = 30mg/mlx1.25ml urine/min divided by 0.30mg/ml plasma = 125ml plasma/min
It is not a very convenient test as inulin must be infused continuously throughout the determination to maintain a constant plasma concentration- so quite invasive.
Another way to measure GFR is using creatinine a metabolic product of muscle metabolism and is continually produced so works as a proxy to inulin because all of the creatinine is cleared from blood plasma filtrate and excreted - but there’s also slight secretion into the tubule giving a slightly higher GFR of 127-128 ml/min for an average human - a nearly accurate measure of GFR - an approximation that is more readily determined than inulin clearance.
So for a clinician to test the handling of a drug to see if all is excreted or some retained GFR is determined by creatinine measure and then blood concentration of drug in plasma compared to that in the urine to get a number that is equal to/higher or lower than GFR determining how the drug is handled.
If a substance is filtered and reabsorbed but not secreted its plasma clearance rate is always less than the GFR
If all is reabsorbed
- some or all of a reabsorbable substance that has been filtered is returned to the plasma
Because less than the filtered volume of plasma will have been cleared of the substance the plasma clearance rate of a reabsorbable substance is always less than GFR
All reabsorbed
Plasma clearance of glucose is normally 0 so all the filtered glucose is reabsorbed with the rest of the returning filtrate and no plasma is cleared
Partially reabsorbed
E.g. urea, only part of the filtered plasma is cleared of it. So approximately 50% of filtered urea is passively reabsorbed and only half of the filtrate or ~62.5ml is cleared of urea per minute
Penicillin and drug clearance
Originally penicillin used as a medicine had a high excretion index so during WW2 penicillin treated patients urine was collected and freeze dried then the penicillin was extracted, cleaned and readministered for treatment.
Penicillin today is tagged to another molecule that modifies it’s movement through the proximal tubule so that it remains in the blood stream for therapeutic use.
