Renal System Flashcards
What is found in normal urine?
Water
Creatinine
Urea
H+, NH3
Na+, K+
Drugs (Anti-viral, diuretics)
What percentage of normal urine is water?
95-98%
What is found in pathologic urine?
Glucose
Protein
Blood
Haemoglobin
Leucocytes
Bacteria
If there is glucose in the urine what does it suggest?
Glucosuria
Diabetes
If there is protein in the urine what does it suggest?
Proteinuria
If there is blood in the urine what conditions does it suggest?
Erythrocytes
Haematuria
If there is haemoglobin in the urine what does it suggest?
Haemoglobinuria
What should urine look like?
Clear, light or dark amber dependant on hydration
What should urine taste like?
Acidic (pH 5-6) therefore not sweet - but pH is dependant on diet.
E.g., veggies have less protein than meat therefore vegetarians will have a higher pH than meat eaters
What does urine smell like?
Unremarkable smell (should smell like nothing)
What does pathological urine look like?
Golden , red, brown, blue
What does pathological urine taste like?
Sweet (if diabetes mellitus)
What does pathological urine smell like if there is an infection or tumour?
Rotten
What does pathological urine smell like if patient is ketosis/fasting, diabetic or chronic alcohol abuse?
Like fruits
What are the key components of the urinary system?
Diaphragm
Kidney
Ureter
Bladder
Urethra
How many kidneys do we have?
2
What gland sits on top of the kidneys?
Adrenal glands (left and right)
What percentage of body weight is the kidney?
0.4%
What percentage of blood flow do they kidneys receive?
25%
What is the KEY function of the kidney?
Regulation of composition and volume of body fluids - homeostasis.
Achieved by FILTERING THE BLOOD
What are the functions of the kidney?
Filter blood
Water homeostasis
Reabsorption of nutrients
Salt/ion homeostasis
Excretion of drugs
pH-regulation
Gluconeogenesis
Metabolism
Hormone production erythropoietin
How many L of plasma does the kidney filter per day?
180 L (of the 5L of blood in our body 3L of it is plasma so it is that 3L getting filtered about 60 times per a day).
What percentage of filtrate is reabsorbed?
99% (the remaining 1% becomes urine)
What supplies the kidneys with blood?
Renal arteries (takes blood from the heart to the kidneys)
What do the renal arteries divide to form?
Glomerular capillaries
Peritubular capillaries and the vasa recta which surround the nephrons (so that substances continue be reabsorbed and secretion into or out of the blood).
What do renal veins do?
Take filtered blood away from the kidney to the heart
What is a nephron?
The functional unit of the kidney
What is the order of blood flow around the nephron bowman space?
Renal artery → Afferent arteriole → Glomerulus capillary → Efferent arteriole → Renal vein.
What are the key structures of the nephron?
Glomerulus
Bowman’s Capsule
Proximal Convoluted Tubule (PCT)
Loop of Henle: thin descending limb (tDLH) and thick ascending limb (TAL).
Distal Convoluted Tubule (DCT)
Cortical Collecting Tubule (CCT)
What is reabsorption?
Movement from the nephron lumen back into circulation (blood) - this can occur through transcellular or paracellular pathways.
This is how essential nutrients, water, and ions that were taken into the nephron during filtration are reclaimed from the filtrate and returned to the bloodstream.
What is secretion?
Movement from circulation (bloodstream) into the nephron lumen - via para or transcellular pathways.
These substances are added to the filtrate to be excreted in the urine, helping to eliminate waste products and regulate the body’s chemical balance.
What is filtration?
Filtration is the first step in the formation of urine - it is the movement of ECF of the blood (plasma) into the bowman space of the nephron to produce filtrate. Filtrate contains everything in blood plasma except proteins and RBC.
What is excretion?
Excretion is the urinary elimination from the body (peeing).
What is excreted is = what is filtered - what is reabsorbed + what is secreted.
Draw the tubular epithelium structure:
Should involve: tubular lumen, tubular epithelial cells, tight junctions, luminal membrane, basolateral membrane, basement membrane, interstitial fluid, peritubular capillary.
How many nephrons are there in each kidney when we are young and how does this change as we get older?
1.2 Million when we are young but this number declines by about 50% by about 60 years old.
What are the two types of nephrons?
Cortical nephrons
Juxtamedullary nephrons
Is a cortical or juxtamedullary nephron got a shorter loop of henle?
Cortical nephrons
What are the three processes that occur in the nephron in order for the kidney to filter blood?
1) Glomerular filtration
2) Tubular secretion
3) Tubular reabsorption
What is glomerular filtration?
The formation of filtrate.
Bulk flow of protein-free plasma into the bowman’s space to form the filtrate.
What does filtrate contain?
Everything in plasma except RBC and proteins (big stuff stays in and the small stuff is filtered out).
What is the structure of the glomerulus?
Endothelium fenestrated with basement membrane (sieve action)
What is the cells of the Bowmans capsules?
Podocytes
What size solutes are freely filtered through the glomerulus?
Solutes smaller than 10,000 MW
What forms the filtration barrier?
Endothelial cells of the glomerular capillaries + the basement membrane + the podocytes = filtration barrier
What is fenestrated endothelium permeable to and not permeable to?
Water, ions and small solutes but not permeable to cells
What is the basement membrane?
A matrix of negatively charged proteins - acts as a charged-based filtration barrier to proteins.
What are podocytes?
Specialised epithelial cells of the bowman’s capsule
What are “foot processes”?
The structure of podocytes that forms the filtration barrier and prevent large molecules being filtered
What forces are at play during glomerular filtration?
Hydrostatic pressures and osmotic pressures
What pressure is favouring filtration?
Glomerular capillary hydrostatic pressure (PGC)
*this is essentially blood pressure because if blood pressure is high then more blood will go through renal arteries and thus increase filtartion load.
What pressures are opposing filtration?
Hydrostatic pressure of bowman’s space (PBS)
and
Osmotic force due to proteins in the glomerular capillary (TTGC)
What is the equation for net glomerular filtration pressure?
PGC - PBS - TTGC
Hydrostatic pressure in glomerular capillary - hydrostatic pressure in bowman’s space - osmotic force due to protein in the glomerular capillary
What is GFR?
Glomerular filtration rate is the amount of filtration produced per unit of time.
What is the normal value for GFR?
125 mL/min (for all functioning nephron’s of both kidneys)
What is GFR a useful indicator of?
Renal function
What is Renal Clearance (RC)?
The volume of plasma that is cleared from a substance by the kidneys per unit of time
What must you know in order to work out clearance?
Concentration of the substance in the urine and plasma + the rate of urine produced
What is the equation for clearance?
Clearance = concentration of substance [x] in urine times the volume of urine produced per unit time divided by concentration of [x] in plasma.
Clearance = Us x V / Ps
What does the equation for clearance describe?
The rate (per unit of time) at which the kidney clears/removes a substance from the bloodstream to be excreted in the urine. (substances does not have to be filtered to have a clearance value)
To be used as a measure of GFR a substance must what?
Not be reabsorbed from the tubule
Not be secreted into the tubule
Not be metabolised
What are the two main substances that are fit to be used as a measure of GFR?
Inulin
Creatinine
What is inulin?
A polysaccharide not metabolised by the body - not found in the body it must be injected.
What food are high in inulin?
Wheat
Shallots and red onions
Jerusalem artichokes
Rye
Choirocy root
The bulb of leeks
What is creatinine?
Waste product produced by muscles - it is already in the body so most commonly used clinically.
Is creatinine filtered freely at the glomerulus?
Yes
Is creatinine secreted?
No
Why is creatinine ideal for clinically estimating GFR?
because it is not reabsorbed, secreted or metabolised
What is the relationship between creatinine and GFR (graph)?
Creatinine and GFR are both indictors of kidney function - but inversely related in regards to healthy kidney function.
Where GFR is high creatinine is low - where creatinine is low kidney function is healthy.
Where GFR is low the kidneys ability to filter blood is low and creatinine concentration is high indicating unhealthy kidney.
If plasma creatinine is low how are the kidneys functioning?
Well - low creatinine is an indicator of healthy kidneys.
If only one kidney is working how is plasma creatinine concentration affected?
Minimally - it will still be fairly normal (this is because they kidneys have a reserve capacity).
If GFR is really really low what has happened?
Renal failure
If GFR drops to below approximately 25mL/min what needs to happen?
Below 25mL/min is the point of critical kidney function and there is a need for medical intervention (drugs).
What is a critical level of plasma creatinine?
Around 10-20 mg/dL - normal plasma creatinine concentration is lower around 1mg/dL or less.
What is the filtered load equation?
Filtered load = GFR x [substance]plasma
What units is filtered load given in?
g/min or mmol/min
How does the kidney handle filtered load of ions and glucose?
Via ion channels and transport proteins
What substances are partly reabsorbed in the nephron?
Na+ and K+
What substance is entirely reabsorbed?
Glucose
What substance is entirely secreted in urine?
PAH (p-aminohippurate)
What is the transport maximum (Tm)?
The maximal amount of a substance that can bind to tarnsport protein.
Reabsorption is enabled by transport proteins along the length of the nephron, but these have a maximal capacity until they become saturated and can not bind anymore substance.
Where is glucose reabsorbed?
PCT
Early PCT and Late PCT
How is glucose reabsorbed?
Using Na+-glucose cotransporters = SGLT2 (early PCT) and SGLT1 (late PCT)
What is the main glucose transporter in the kidney?
SGLT2 - responsible for 90% and the remaining 10% by the SGLT1.
What results in glucose being in the urine?
The capacity of SGLT2 being saturated and then SGLT1 being overwhelmed by what is left over so that all glucose cannot be reabsorbed.
E.g., the transport maximum being met because SGLT’s saturated therefore glucose unable to be reabsorpted.
What hormone strictly controls plasma glucose to 150mg?
insulin
What does the lack of control by insulin in diabetes mellitus cause?
Hyperglycaemia (too much glucose in the blood)
What is it called when glucose appears in the urine?
Glucosuria
Explain how diabetes results in glucosuria (glucose in the urine):
Blood glucose levels are controlled by insulin to ensure that they do not exceed the TM (saturate SGLT’s) so that all glucose can be reasbsorbed.
Diabetes is a disease that effecst the control of insulin therefore it effects the control of blood glucose levels. Without adequate control of insulin there is a significant increase in the filtered load of glucose and TM of SGLT’s met. Therefore not all glucose can be reabsorbed and some ends up on the urine.
What is the other word for glomerulus?
Renal corpuscle
What is PAH?
P-aminohippurate which is an organic anion
When PAH transporters get saturated what is decreased?
Clearance (the clearance of PAH is transporter dependant) –> this means that as soon as transporters are saturated the excretion of PAH is affected and the clearance drops
*clearance being the amount cleared from the body.
At high concentration of PAH what is excretion mostly facilitated by?
Filtration
Does PAH exist in our body?
No - but is represented in a wide range of drugs
What is the normal blood pressure reading?
120/80 (systolic/diastolic pressure)
If you want to decrease your blood pressure what diet would help?
A low sodium diet (because sodium and water related with less sodium there is less water - this decreases blood volume which relates to pressure)
What part of the body is responsible for the excretion of sodium that we take up with our diet?
Kidney
What is the filtered load of sodium?
100%
What are the four places in the nephron where sodium is re-absorbed? (include relative percentages)
PCT 66%
Thick Ascending Loop (TAL) 25%
DCT 5%
Cortical Collecting Tubule (CCT) 3%
*Therefore, Na+ is not reabsorbed in the tDLH = ONLY water can leave in tDHL.
What is the urinary excretion of Na+?
Only 0.5-1% of the filtered load
How much active secretion of sodium is there?
None
What generates the sodium gradient on the luminal side of epithelium?
Na+/K+ ATPase
What cannot pass the luminal membrane without any transporter or channel even in the presence of a sodium gradient?
Sodium and glucose
What type of epithelium is the PCT?
Leaky epithelium
What are the tight junctions of leaky epithelium permeable for?
Na+ and Water
Is there trans, para-cellular or both methods of Na+ reabsorption in leaky epithelium?
Both
*Trans and Para in PCT
What is isotonic re-absorption and where does it occur?
Predominately occurs in the PCT.
It means equal amounts of sodium and water reabsorbed so there is no change in osmolarity.
Is the apical or the basolateral side sodium dependant?
The apical side is sodium dependant and the basolateral side is not because it only contains facilitators.
What are the key differences between the PCT and the CCT?
Epithelium type = PCT is leaky whereas CCT is tight epithelium.
Water permeability = PCT has high water permeability because para and tarnscellualr water pathways whereas CCT has low water permeability because only transcellular water pathway.
In the PCT what AQP is used?
AQP1
(AQP2 used in CCT)
What is the TAL?
Thick ascending limb of Henle
In the TAL what is the paracellular pathway permeable to and not permeable to?
Permeable to Na+ and not permeable to water
(Salt can leave but water cannot resulting in a hyperosmotic gradient in the nephron medullar).
What percentage of Na+ filtered load is reabsorbed in the TAL?
25%
What type of epithelium is in TAL?
Semi-tight because tight junction only permeable for Na+ and not to water.
What is the ratio of Na+ reabsorption through trans and paracellular pathways of TAL?
50:50
What inhibits NKCC2 in TAL?
Loop diuretics (furosemide)
Loop diuretics are a class of medications that act on the kidneys to increase urine output by inhibiting the reabsorption of sodium, chloride, and water in the loop of Henle, a part of the nephron in the kidney. By blocking sodium and chloride reabsorption in this region, loop diuretics cause a significant amount of sodium and water to be excreted in the urine, leading to increased fluid loss.
What part of the kidney is the counter-current multiplier system in?
Loop of Henle
What is the application of loop diuretics commonly used for?
Treating hypertension (high blood pressure) to reduce blood volume and pulmonary edema (fluid build up in the lungs) or oedema in the legs (build up of fluid in the legs).
Edema and oedema are used interchanagably to describe the same thing. Edema is the US spelling whilst oedema is the UK spelling.
What is the counter current multiplier system?
The counter-current multiplier system is how the kidneys make urine more or less concentrated. It helps your body save water when needed by concentrating the urine, so you don’t lose too much water.
It works by the TAL enabling Na+ to leave the filtrate but not water, and then the tDLH enabling water to leave but not Na+.
What does the TAL re-absorb Na+ into the interstitium via?
NKCC2
What are the two parts of the loop of henle called?
Descending = thin descending loop of henle (tDLH)
Ascending = thick ascending limb (TAL)
What occurs in the TAL vs tDLH?
TAL = salt re-absorption (water impermeable) therefore makes the urine hypotonic and the interstitium hypertonic.
tDHL = water re-absoroption (water permeable) therefore makes the urine hypertonic.
Where is the final osmolarity of the urine defined?
The CCT
*but the counter-current system helps keep the interstitium hypertonic.
What pathway is Na+ reabsorption in the DCT and CCT?
Only transcellular because it is tight epithelium
What inhibits NCC in the DCT?
Diuretics (Thiazides) = mild diuresis
What is diuresis?
The production of urine (the increased production).
What inhibits ENaC in CCT?
Diuretics (Amiloride) = very mild diuresis
What hormone regulates Na+ reabsorption in the CCT?
Aldosterone!
What AQP does CCT transcellular pathway use?
AQP2
*PCT uses AQP1
What are the three important diuretics in Na+ reabsorption?
Loop diuretics (inhibit NKCC2)
Thiazides (inhibit NCC)
Amilorides (inhibit ENaC)
What is a diuretic?
A diuretic is any substance that promotes diuresis
Diuresis is the increased production of urine.
What is NCC?
NCC is the renal thiazide-sensitive NaCl co-transporter (NCC). The NCC is the major salt transport and limiting step for salt reabsorption in the distal convoluted tubule (DCT) of the kidneys.
What are the luminal glucose and Na+ transporters in PCT?
SGLT2 (early PCT) and SGLT1 (late PCT)
What is the luminal transporter in TAL?
NKCC2
What is the luminal transporter in DCT?
NCC
What is the luminal transporter in CCT?
ENaC
What is the fast and slow system of water homeostasis?
Fast = reacts to changes in osmolarity (ADH)
Slow = reacts to changes in volume (Renin-Ang2-Aldosterone & ANP)
Does diuresis occur faster after drinking water or a NaCl solution?
Water
Diuresis starts 20-30 minutes after drinking water whereas it takes 8-10 for diuresis to start after drinking NaCl solution
*This is because the detection of NaCl levels (volume) is a change in volume which uses the slow system of water regulation whereas, increase in water changes osmolarity therefore uses the fast system.
Where is renin release from and what causes it’s release?
Released from Junxtaglomerular cells
Released in repsonse to increased sympathetic nerve activity, decreased arterial pressure and low NaCl volume.
What detects low NaCl volume?
Macula densa cells
What do macula densa cells do?
They detect low NaCl levels and increase renal sympathetic nerve activity
What is Tubulo-glomerular feedback?
This mechanism involves the macula densa in the distal tubule detecting changes in sodium chloride levels in the filtrate. When sodium chloride levels are too high or too low, the macula densa signals the afferent arteriole to either constrict or dilate, adjusting the filtration rate at the glomerulus.
What is renin?
A protease (meaning that it cleaves proteins)
What does renin do?
Converts Ang into Ang 1
What converts Ang 1 (ATI) into Ang 2 (ATII)?
ACE
What effect does Ang 2 have on the adrenal gland?
It increases secretion of aldosterone from adrenal glands
What does high plasma aldosterone increase?
Na+ and water reabsorption in the CCT by upregaulting Na+ channels and NaK-ATPase activity.
What is ACE?
Angiotensin converting enzyme
Where is ACE?
In the lungs.
Therefore Ang1 is converted to Ang2 in the lungs.
What does aldosterone bind to?
Mineralocorticoid receptor
What are the possible non-genomic effects of aldosterone?
Up-regulation of Na+ channels and Na+/K+ ATPase
What is meant by a non-genomic effect?
A non-genomic effect refers to a biological response that occurs independently of gene transcription or protein synthesis, meaning it does not involve the activation of a cell’s DNA to produce proteins. Instead, these effects are rapid and are usually mediated through other mechanisms, such as changes in enzyme activity, ion channels, or signaling pathways.
What are the genomic effects of aldosterone?
De novo (from scratch) synthesis of Na+ channels, Na+/K+ ATPase and other proteins
Where is ANP released from?
Cardiac atria (in response to high plasma volume)
What does ANP do?
Reduces plasma aldosterone (and therefore reduced Na+ and water reabsorption)
What percentage of total body weight is water?
55-60%
What percentage of total body water is ECF and ICF?
1/3 ECF (1/5 of which is plasma and 4/5 interstitial fluid) and 2/3 ICF
What is the effect on osmolarity when there is an increase in body water?
Decreased osmolarity
How does the kidney respond to a decrease in osmolarity?
Decrease in osmolarity is an increase in body water and this is met with an increase excretion of water by the kidney
How does the kidney response to an increase in osmolarity?
Increased osmolarity is a decrease in body water and this is met with increased reabsorption of water by the kidneys
What are three important places within the nephron where water reabsorption occurs?
PCT (66%)
tDLH (25%)
CCT (2-8% depending on hydration)
*TAL is semi-tight so does not allow for water movement.
Is the descending or ascending limb of the loop of henle tight?
Ascending
*semi-tight
What is water re-absorption in the proximal tubule driven by?
Na+ re-absorption (isotonic)
What is trans cellular water re-absorption facilitated by in PCT?
Aquaporins
What is paracellular water reabsorption facilitated by in PCT?
Via leaky tight junctions
What drives trans and para-cellular absorption of water?
The water gradient created from paracellular chloride and sodium absorption
What AQP is in the PCT?
AQP1
What organism are aquaporin’s found in?
bacteria, plants and animals
What are AQPs impermeable to?
Charged species
What movement of water do AQPs enable?
single file movement
What part of the nephron is water impermeable?
TAL
*semi-tight epithelium and no water transporter
How does the osmolarity of urine change throughout the nephron?
PCT = isotonic
tDHL = hypertonic (due to water re-absorption)
TAL = hypotonic (due to Na+ reabsorption via NKCC2)
CCT = hypertonic for anti-diuresis and hypotonic for diuresis (dependant on hydration).
What part of the nephron determines the final osmolarity of urine?
CCT
What AQP are found in the collecting duct?
2, 3 and 4
Are AQP2 distributed on the basolateral or apical membrane of collecting duct?
Apical (inside)
Where are AQP3 and AQP4 distributed in collecting duct?
AQP3 = basal and lateral location
AQP4 = basal location
Where is vasopressin/ADH secreted from?
posterior pituitary gland
What is the inductor for ADH release?
Low blood pressure sensed by baroreceptors or high blood osmolarity sensed baby osmoreceptors
What is the target organ of vasopressin?
The principal cell in the collecting duct of the kidney
What does vasopressin bind to and where?
V2 receptor on basolateral membrane
What does vasopressin activate and what is the effect?
Adenylate Cyclase which increases cAMP levels - which then activates PKA - and phosphorylation leads to sub-apical AQP2 vesicles moving to the membrane via exocytosis
= increase apical membrane H2O permeability.
What is water re-absorption in the principle cell of the CCT regulated by?
Vasopressin (ADH)
Do we actively secrete water?
No
If ECF K+ is greater than 5mM what is the condition?
Hyperkalemia (high K+ in blood)
If ECF K+ is less than 3.5mM what is the condition?
Hypokalemia (low K+ in blood)
What are the roles of intracellular K+?
Cell-volume maintenance
Intracellular pH regulation
Cell enzyme functions
DNA/Protein synthesis
What effect does a lack of K+ have on protein synthesis?
Reduction of protein synthesis = stunted growth
If there is a net loss of K+ what is the pH of the cell?
Acidosis
(gain of K+ = cell alkalosis)
What effect does low plasma K+ have on vascular resistance?
Low plasma K+ = vasoconstriction
Therefore high plasma K+ = vasodilation
What effect does low plasma K+ have on cardiac activity?
Low plasma K+ = slowed conduction of pacemaker activity (arrhythmias)
What effect does high plasma K+ have on cardiac activity?
Conduction disturbances, ventricle arrhythmias and ventricular fibrillation
What effect does high and low plasma K+ have on neuromuscular activity?
Low = muscle weakness, muscle paralysis, intestinal distention, peripheral vasodilation, respiratory failure
High = increased muscle excitability, and later can cause muscle weakness/paralysis
What effect does an increase and decrease of K+ have on the RMP?
Reduced K+ = membrane depolarisation
Increased K+ = membrane hyperpolarisaton
What organ does hyperkalemia effect that can result in death?
The heart
How much of our daily intake of K+ is excreted?
All of it
Daily K+ intake = K+ excreted.
Therefore net change of 0
How does the body respond to changes in K+ to maintain K+ homeostasis (extrarenal)?
Extrarenal = mechanisms outside of the kidney
Increases K+ uptake into cells (skeletal muscle, bone, liver and RBC).
Stimulated by the release of epinephrine, insulin and aldosterone
What hormones are released rapidly to prevent hyperkalemia?
Epinephrine
Insulin
Aldosterone
How does the body respond to changes in K+ to maintain K+ homeostasis (intrarenal)?
Intrarenal = mechanisms inside the kidney
Regulation of reabsorption and secretion of K+ along the nephron (this is a slower response than extrarenal responses as it occurs over several hours)
Are intrarenal or extrarenal responses to changes in K+ fast?
Extrarenal
What is the effect of epinephrine on uptake of K+?
Epinephrine increases Na+-K+-ATPase activity therefore increases intracellular K+
Where is epinephrine released from?
Chromatin cells in adrenal medulla
What is the effect of insulin on the uptake of K+?
Increases Na+-K+-ATPase activity therefore increases intracellular K+
Where is insulin released from?
Beta cells of the pancreas
What is the effect of aldosterone on the uptake of K+?
Increases Na+-K+-ATPase activity therefore increases intracellular K+.
Where is aldosterone released from?
Zona glomerulosa cells of the adrenal cortex
What does the filtered load of K+ depend on?
K+ diet
A high K+ diet will lead to an increased filtration rate of K+
What foods are high in K+?
Bananas
Brussel sprouts
Mushrooms
Kiwifruit
Steak (red meat)
Is potassium excreted in urine?
Yes
How is potassium secreted?
Actively
How does the nephron handle a low K+ diet compared to a normal or increased K+ diet?
Reabsorption is consistent between the two bit secretion is increased in DT and CCD for a normal or increased K+ diet.
What pathway is K+ mainly reabsorbed through in the proximal tubule (67%)?
Paracellular pathway
How is K+ reabsorbed in the thick ascending limb of the loop of henle (20%)?
K+ is reabsorbed via the transcellular (NKCC) and paracellular pathways
What is the cellular pathway transporter in the thickening ascending limb?
Na+-K+-2CL- cotransporter
What are the two types of cells contained in the cortical collecting duct?
Intercalated cells
Principal cells
What are the relative percentages of intercalated cells and principal cells in the CCD?
30% intercalated cells and 70% principal cells.
What do intercalated cells do in the CCD?
K+ reabsorption via the K+ / H+ ATPase
What do principal cells do in the CCD and LDT?
K+ secretion through luminal K+ channel (ROMK) under the influence pf aldosterone and the K+-CL- channel.
+ also Na+ reabsorption
How is K+ excretion regulated?
Aldosterone
Flow rate of filtrate by vasodilation
High plasma K+ concentration
What does ANP do to aldosterone secretion?
Inhibits it
What effect does K+ have on aldosterone synthesis?
Increases it by stimulating the adrenal cortex
What is the effect of aldosterone?
Activation of Na+-K+-ATPase which increases intracellular K+ resulting in increased exit of K+ across the apical membrane (K+ secretion by the cells of the LDT and CCD).
How does aldosterone cause an increase in LDT and CCD secretion of K+?
*LDT = late distal tubule
Increases the activation and amount of epithelial sodium channels (ENaC)
Increases the amount and activity of the Na+-K+-ATPase energy of K+ across the basolateral membrane
The entry of Na+ makes the cell potential more positive enhancing the driving force for K+ exit across the apical membrane (secretion)
What is the K+ channel on the apical membrane of the LDT and CD?
ROMK1
What is the effect of a low K+ diet on flow and secretion?
Low K+ diet = low flow rate = low K+ secretion
Therefore normal or high K+ diet = high flow rate = high K+ secretion in comparison
What is the pH equation?
pH = -log [H+]
What does pH indicate?
The degree of acidity or alkalinity
What is the pH range?
0-14
0 being very acidic and 14 very alkaline
What is the neutral pH value?
7
A blood pH greater than 7.4 means what?
Alkalosis (excess base)
A blood pH less than 7.4 means what?
Acidosis (excess H+)
Is an average diet slight acidic or alkaline?
Acidic
What is the pH of ECF?
7.4
How much HCO3- does the body produce a day?
70 mmol / day
In order to neutralise slightly acidic diet
How much CO2 do we expire per day?
15,000 mmole
How much H+ ions are taken up or produced via metabolism a day?
70 mmol
How is HCO3- excreted?
Via urine as titrate acids (phosphate) or NH4+ (ammonium)
What are the sources of H+ gain?
CO2 = Generation of H+ from Co2
Metabolism = Production of nonvolatile acids from the metabolism of proteins and other organic molecules
Diarrhea = Gain of H+ due to loss of bicarbonate in diarrhoea or other non gastric GI fluids
Urine = Gain of H+ due to loss of bicarbonate in the urine
What are the sources of H+ loss?
Utilisation of H+ in the metabolism of various organic anions
Loss of H+ in vomit
Loss of H+ in the urine
Hyperventilation
What are the main problems for pH regulation?
(1) CO2 produced by the cells - volatile acid
(2) Acid produced from metabolism - “non volatile acids”
What is meant by non-volatile acids?
An acid produced in the body from sources other than carbon dioxide, and is not excreted by the lungs (cannot be expired via the lungs therefore must be dealt with by the kidney).
What is H+ buffered by?
Hb
In order to match the metabolic production rate of CO2 what do you need to do to regulate pH?
Breath - exhaling CO2
What are examples of non-volatile acids ?
Sulfuric acid
Phosphoric acid
Organic acids
Ketoacids
What happens to the H+ ions of non-volatile acids?
(1) Buffered
(2) Secreted
What percentage of HCO3- is reabsorbed in the TAL?
10%
Where is 80% of HCO3- reabsorbed?
Proximal tubule
where can HCO3- be reabsorbed and secreted?
DT and CDD of the kidney (10%)
Explain the overall replacement of HCO3- consumed due to the excretion of non-volatile acids:
A non volatile acid is produced during metabolism.
It dissociates into A- (conjugate base) and H+ (a hydrogen ion).
The H+ ion is buffered by bicarbonate resulting in the removal of H+ as CO2 and water.
In the kidney the A- is filtered and excreted.
What does buffer mean?
Resist pH change
What is RTA?
Renal Tubular Acidosis = an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine.
What are the four types of Acid-Base Disturbances?
Acidosis
(1) Respiratory
(2) Metabolic
Alkalosis
(3) Respiratory
(4) Metabolic
What is respiratory acidosis?
Respiratory acidosis is a state in which decreased ventilation increases the concentration of carbon dioxide in the blood and therefore decreases the blood’s pH.
Increases PCO2 = Increases H+ = increase in HCO3- reabsorption to compensate
What compensates for respiratory acidosis?
Increase in HCO3- reabsorption to compensate
What are the reasons for respiratory acidosis?
Depression of the central respiratory centre (cerebral disease or drugs)
Asthma, chronic obstructive disease
Neuromuscular diseases (ALS)
What is metabolic acidosis?
Increase in acid in the body as a result of metabolism
Decrease in HCO3- = increase in H+ = lungs exhale for CO2 to compensate and decrease CO2.
What is respiratory alkalosis?
Respiratory alkalosis is a medical condition in which increased respiration elevates the blood pH beyond the normal range with a concurrent reduction in arterial levels of carbon dioxide.
Decrease in CO2 = decrease in H+ = decrease in HCO3 as a result of increased secretion
What is metabolic alkalosis?
Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range. This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations.
Where is HCO3- mainly generated?
Proximal tubule cells from glutamine (Liver)
Can NH4+ be reabsorbed?
No
What are intercalated A cells?
Cells that secrete renal H+ during acidosis
they reabsorb bicarbonate by secreting H+ which can be increase during acidosis
What is the difference between intercalated A and B cells?
A cells involved in acidosis = H+ secreting intercalated cell
B cells involved in alkalosis = HCO3- secreting intercalated cell
Are principal cells or intercalated cells first in sodium reabsorption?
Principal
What do loop diuretics inhibit?
NKCC2
Where is the NKCC2?
Apical membrane of the Thick Ascending Limb of Henle (TAL)
What is Bartter’s syndrome?
Bartter’s syndrome is an autosomal recessive disorder of salt reabsorption resulting in an extracellular fluid volume depletion and low blood pressure. It is caused by a mutation to channels and cotransporters of the Thick Ascending Limb (TAL) affecting the transport of sodium, potassium, and chloride.
What does Bartter’s syndrome cause?
Loss of NaCL in the urine
Metabolic alkalosis
Hypokalemia (low blood K+)
Hyperreninemia and hyderaldosteronism
Low to normal BP
What is hyperreninemia?
High renin in the blood
What is hyperaldosteronism?
High aldosterone in the blood
What does hyperreniniemia cause?
Hyperaldosteronism (because more renin means more Ang 2)
What does a mutation in NKCC2 lead to?
Bartter syndrome type 1
What are three types of bartter’s syndrome?
Bartter’s Syndrome Type 1, Type 2 and Type 3
What causes Bartter’s Syndrome Type 2?
Caused by a defect in apical K+ channel (ROMK)
What causes Bartter’s Syndrome Type 1?
Caused by a defect in the apical Na+-K+-2CL- cotransporter (NKCC2)
What causes Bartter’s Syndrome Type 3?
Caused by defect in basolateral Cl- Channel (CLC-Kb)
What do mutations in NKCC2, ROMK, and CLC-Kb cause?
Non-functional channels or co-transporters
Ineffective biosynthesis of protein
Simple binding impairment of NKCC2
Intracellular trafficking problems
Accelerated degradation of the channels or co-transporters
What causes salt-wasting in Bartter’s Syndrome?
Defective NKCC2 increases diuresis due to a reduction of reabsorption of sodium, potassium, and chloride ions in the thick ascending limb of the loop of Henle in the kidney.
What causes metabolic alkalosis in Bartter’s syndrome?
Due to defective NKCC2 there is less potassium reabsorbed in TAL leading to low K+ in the blood (Hypokalemia) - this activates RAAS = Aldosterone increases, which promotes sodium reabsorption in exchange for potassium and hydrogen ion secretion in the distal tubule.
Secretion of H+ = system becomes more alkalosis
What are the two places where K+ is secreted?
TAL and Principal cells of collecting duct
What goes through the paracellular pathway of the TAL?
Na+
K+
Mg2+
Ca2+
What is the sensor for NaCl in macula dense cells?
NKCC2
What causes hyperreninism?
If NKCC2 transporter is defective then macula densa cells are signalled that there is low NaCl all the time leading to constant secretion of renin from the cells
Hyperreninism is the result of a defective sensor.
What does increased aldosterone increase the activity of?
ENaC
What is the result of increased ENaC activity?
Increased K+ secretion (which also leads to loss of H+)
What is K+ secreted from in the LDT ad CD?
ROMK
What is diabetes insipidus?
Water diabetes - rare disease in which the kidney produce abnormally large volumes of dilute urine.
How is diabetes insipidus related to concussions?
A concussion squeezes the pituitary gland and impairs the release of stored ADH.
ADH regulates water reabsorption in the kidney and triggers thirst.
Therefore ADH impairment causes impairment in water regulation (reduced H20 reabsorption = dehydration).
What are the symptoms of DI?
Polyuria
Polydipsia
Severe dehydration
Vomiting, fever, slow growth, developmental delay (in the first year of life)
+ In severe cases mental deficiency due to dehydration of the brain
What is polyuria?
Condition of body making too much urine = hypotonic urine
What is polydipsia?
Excess drinking (of water)
What are the two types of DI?
Central diabetes insupidus
Nephrogenic diabetes insupidus
What is central diabetes insupidus?
(Also called neurogenic DI)
It is the lack of production of vasopression/ADH by the hypothalamus or release from the posterior pituitary gland
What is Nephrogenic DI?
problem at the level of the kidney
Where is ADH secreted from?
Posterior pituitary gland
What is the inductor of ADH release?
low BP sensed by baroreceptors or high osmolarity sense by osmoreceptors
What is the target organ of ADH?
Principal cell in the collecting duct of the kidney
What is the membrane shuffle hypothesis for the cellular mechanism of ADH?
The membrane shuffle hypothesis explains how antidiuretic hormone (ADH), or vasopressin, regulates water reabsorption in the kidneys by altering the permeability of the renal collecting duct cells. Specifically, this hypothesis focuses on the role of aquaporin-2 (AQP2) water channels in the apical membrane of the principal cells of the collecting duct.
Process:
ADH binds to V2
Activates GPCR leading to cAMP pathway - PKA - phosphorylation
Causes exocytosis of stored AQP2 to apical membrane resulting in increased water permeability
When ADH levels drop AQP2 endocytosied from apical membrane
What does ADH bind to on the basolaterial membrane of Principal cells?
V2 receptor
What is Nephorngenic DI caused by (2 possible reasons)?
Mutated V2 receptor or mutated AQP2 channel
What percentage of NDI patients have mutated V2 receptor vs mutated AQP2 channel?
90% V2 mutation
10% AQP2 channel
If someone has a mutated V2 receptor is the AQP2 affected?
No would have normal AQP2 protein (and vice versa).
How many different types of V2 mutations are there?
Approx around 200
What do mutations of V2 receptor and AQP2 result in (list of symptoms)?
Non-functional
Ineffective biosynthesised of protein
Simple binding impairment of V2 receptor
Intracellular trafficking problems
Accelerated degradation of AQP2 channel or V2 receptor to the proteasome or lysosome
What section of sodium reabsorption has the most significant effect on homeostasis?
The 3% reabsorbed in the CCT
What inhibits ENaC?
diuretics (Amiloride)
What is the composition of ENaC?
3 subunits - alpha, beta and gamma
How many transmembrane domains does each ENaC subunit have?
2
What does each ENaC subunit have?
A large extracellular loop
What amino acids are involved in the ENaC PY motif and what are they important in?
Proline and Tyrosine
Important in protein-protein interactions
What is the general sequence of the PY motif?
PPPXY
Name a protein that recognises the PY motif?
Nedd4-2
What is a proline-rich domain?
A proline-rich domain (PRD) is a segment within a protein that contains a high concentration of the amino acid prolin - the domains that are often involved in mediating protein-protein interactions.
Is the proline-rich domain intracellular or extracellular?
Intracellular
Where is the aldosterone receptor?
The aldosterone receptor is in the cytosol not the membrane
How does aldosterone change ENaC ubiquitination?
(1) Aldosterone rapidly unregulated SGK1 expression
(2) Insulin activates SGK1 via the P13K signalling pathway
(3) SGK1, in turn, phosphorylates and inhibits Nedd4-2
(4) Nedd4-2 inactivation results in increased abundance of ENaC and hence Na+ transport
*Nedd4-2 normally causes degradation but here it is inactivated
*In Liddle’s disease, mutations in ENaC subunits (usually in the beta or gamma subunits) alter the ENaC structure, making it less responsive to Nedd4-2.
What is the result of Nedd4-2 inactivation?
Increased abundance of ENaC and hence Na+ transport
What is the importance of SGK1?
SGK1 is an important facilitator for aldosterone
The effect being more sodium reabsorption and more potassium secretion
What is pseudohypoaldosteronism type 1?
It is the loss of ENaC function due to a mutation of NH2- terminus of the alpha subunit (meaning there is too few channels = decrease).
Why is it called pseudohypoaldosteronism?
Because aldosterone is not actually involved
Pseudo = fake
What is Liddle’s Syndrome?
It is the gain of function of ENaC due to mutations of COOH- termini of beta and gamma subunits (too many channels = increase).
What do mutations of the COOH terminus of ENaC cause?
Causes the channel to remain at the membrane indefinitely
What does hyperabsorption of Na+ cause?
Hypertension
The ENaC channels remaining int eh membrane indefinitely leads to what conditions?
Hyperabsorption of Na+ with increased secretion of K+
Do Bartters and Liddle’s have the same symptoms?
Yes - but they have different causes
