Renal Flashcards
(112 cards)
1
Q
What might renal disease be a result of?
A
- Age
- Viral, fungal or bacterial infections
- Parasites
- Cancer
- Amyloidosis – abnormal deposits of a type of protein in the kidney
- Inflammation
- Autoimmune disease
- Trauma
- Toxic reaction to poisons or medications
- Congenital and inherited disorders
2
Q
What are the 6 renal functions?
A
- Regulation of water balance between intake and output
- Regulation of salt balance – performed by the kidney alone in most animals
- Conservation and regulation of essential substances, such as glucose, amino acids and calcium ions
- Removal of metabolic waste products, such as urea, uric acid, creatinine and ammonia
- Removal of foreign substances such as drugs or metabolites
- Regulation of pH via ions such as H+ and HCO3-
3
Q
What are the 3 renal endocrine functions?
A
- Active form of vitamin D – important for calcium and phosphate absorption from the gut
- Renin – renin-angiotensin-aldosterone system for control of blood pressure
- Erythropoietin – synthesis of red blood cells
4
Q
What is water balance and what affects it?
A
Water in = water out
- Dry food or wet food will effect water intake
- Physiological factors, such as lactation
- Dry vs humid environment will effect water output
5
Q
Describe isotonic conditions.
A
- No net movement of water
- No change in cell volume
- Effective osmotic pressure is the same in ECF and ICF
- Normal saline (0.9% NaCl)
6
Q
Describe hypotonic conditions.
A
- Net inward movement of water
- Cell volume increases and may lead to lysis
- Effective osmotic pressure/tonicity is lower in ECF then ICF
- Pure water
7
Q
Describe hypertonic conditions.
A
- Net outward movement of water
- Cell volume decreases in crenation
- Effective osmotic pressure/tonicity is greater in ECF than ICF
- Sea water or fluid in renal medulla
8
Q
How do kidneys differ between vertebrates?
A
Common to all vertebrates and all can produce hypotonic or isotonic urine.
Birds and mammals have hypertonic urine and have the distinguishing feature of the Loop of Henle.
9
Q
Describe the position of the kidneys.
A
- Retroperitoneal
- Connected to bladder via ureters
- Bladder connected to outside world via urethra
- Each has an adrenal gland sitting over the top of it
10
Q
How are the kidneys supplied?
A
The kidneys receive 20% of cardiac output.
- Supplied by renal arteries, branches of the aorta
- Venous drainage through the renal veins, which feeds into the caudal vena cava
- Blood vessels, sympathetic nerve supply and ureter enter and exit the kidney via the renal hilus
11
Q
Describe the general structure of the kidneys.
A
- Each kidney is surrounded by renal capsule
- Renal cortex around the outside
- Renal medulla on the inside
- Renal pelvis in the centre
- Medulla divided into renal pyramids
- Renal artery branches up in medulla and cortex
- Nephrons in renal pyramids
- Collecting duct from renal medulla to renal pelvis through the renal papilla
- Region outside each papilla is a calyx, a part of the renal pelvis
12
Q
Distinguish juxtamedullary nephrons and cortical/subcapsular nephrons.
A
Juxtamedullary nephrons – long proximal tubule, long Loop of Henle, 20% of nephrons
Cortical/sub-capsular nephrons – short proximal tubule, short Loop of Henle, 80% of nephrons
13
Q
Describe the structure of the nephron.
A
- Glomerulus – arterial blood forms a capillary network within a Bowman’s capsule. Site of ultrafiltration.
- Proximal tubule – most of the filtrate is reabsorbed along with vital nutrients.
- Loop of Henle and collecting duct – control urine concentration in medullary nephrons.
- Distal tubule – fine tuning of electrolyte concentrations.
- Juxta-glomerular apparatus – production of renin hormone
14
Q
What is the blood supply to the nephron?
A
Afferent arteriole > Bowman’s capsule > efferent arteriole > peritubular capillaries – which descend and ascend into the medulla to allow full flow between the limbs of the Loop of Henle.
15
Q
What 3 layers is fluid filtered across in the glomerulus and Bowman’s capsule?
A
Endothelial cell of capillary
- Flattened cells with thin cytoplasm
- Fenestration of diameter 60nm are lined with negatively charged glycoproteins and increase permeability
- Prevent red blood cells and platelets leaving capillaries
Glomerular basement membrane
- Non-cellular, continuous layer of collagen and glycoproteins
- Main function is to act as a barrier to filtration of large molecules
Visceral epithelial cell/podocyte of bowman’s capsule
- Made up of cell body, trabeculae and pedicels
- Main functions: maintenance of basement membrane, and slit pores between pedicels are lined with negatively charged molecules for perm selectivity
16
Q
What is the composition of ultrafiltrate?
A
- Small molecules and ions in almost exactly same concentration as plasma
- No proteins such as albumen
- No blood cells
- Greater restrictions on filtration for negatively charged molecules
17
Q
Why is glomerular filtration rate clinically important and what are the forces determining it?
A
GFR is clinically important, as it is vital for normal kidney function. GFR can be impaired in many conditions: infections, parasites, congenital conditions.
The forces that determine GFR are Starling’s Forces – the oncotic and hydrostatic pressures.
18
Q
How is net filtration pressure calculated?
A
Net filtration pressure, NEP = forces out – forces in
= (Pcapillary +oncotic bc) – (Pbc + Pbowman’scapsule)
0 = oncotic bc under normal conditions
= Pcap – (oncotic cap +Pbc)
19
Q
What is the effect of constriction in the afferent and efferent arterioles?
A
Constriction of afferent arteriole > decreased hydrostatic pressure and blood flow in glomerular capillary > reduced filtration
Constriction in efferent arteriole > increased hydrostatic pressure and decreased blood flow in glomerular capillary > little change in filtration
20
Q
Name some other factors that affect glomerular filtration rate.
A
- Low blood pressure – renal failure, no filtration
- Long term high blood pressure – damage to the filtration barrier
- Kidney stones – blockage in the ureter, decreased filtration
- Low protein – decreased oncotic pressure, increased filtration
- Nephrotic syndrome – failure of filtration barrier. Increased oncotic pressure and increased filtration
21
Q
Define clearance.
A
A measure at the efficiency or effectiveness of the kidney in removing a substance from the blood. For example, how quickly does the kidney remove a drug from the circulation, so that the right dosage and regime can be used.
22
Q
Describe the process of clearance.
A
- Concentration of [molecule] is [6] per unit volume of blood.
- These enter the kidney at the glomerulus via the afferent arteriole.
- They flow round and into the glomerular capillaries and along with filtration, a proportion of these molecules are filtered into the Bowman’s space and inner proximal tubule along with the filtrate.
- Remaining [molecules] will flow out through the efferent arteriole and into the peritubular capillaries.
- Because some [molecules] have been lost in filtration, the concentration in the peritubular capillaries is only 3 [molecules] per the original volume of blood.
- Some [molecules] that have been filtered out of the blood may be reabsorbed back into the peritubular capillaries. So the amount of [molecules] left in the filtrate may be 2.
- There is a lower concentration of [molecules] in the blood leaving the kidney.
- So the clearance is an indication of how much blood would have been cleared of that substance on 1 passage through the kidney in ml/min.
23
Q
How is clearance calculated?
A
= (concentration in urine x volume of urine produced) / concentration in plasma
(ml/min)
24
Q
How is creatinine used as a measure for glomerular filtration rate?
A
Creatinine is a breakdown product from muscles.
- It is present in steady concentrations in the blood.
- Can be used to measure GFR because it is freely filtered into the filtrate.
- Some is filtered and some remains in the blood but there is no reabsorption or secretion of creatinine.
- So the clearance of creatinine is equal to the GFR because none of it is secreted or reabsorbed and it is freely filtered.
- Amount per minute in urine = amount filtered per minute.
25
How is inulin used as a measure for glomerular filtration rate?
Inulin is the gold standard to measure GFR but you would need to give an inulin infusion, as it is not a naturally occurring substance. Creatine is acceptable but not gold standard.
26
How are clearance ratios used to show how substances are handled within the kidney?
* If the clearance of substance X is lower = X is not freely filtered OR X is reabsorbed. A common example being glucose.
* If the clearance of X is higher = X is secreted from the tubule into the peritubular blood supply. This is the only explanation, as the plasma can only be filtered at the same rate as filtration is occurring. A common example being penicillin.
27
What is para-amminohippuric acid?
An organic acid that is freely filtered into the filtrate and the remainder is secreted into the proximal tubule.
It has a transport maximum limit, but below that limit, it is all secreted into the tubule.
PAH that appears in the urine = the amount that is + the amount that is secreted.
As all the plasma is cleared of PAH secretion into the tubule, we can see that the clearance of a substance = the amount of plasma that flows through the kidney.
28
What is filtration fraction and how is it calculated?
The filtration fraction – the proportion of the plasma flow through the glomerulus that is filtered. This can be calculated using:
• GFR – from clearance of inulin or creatinine
• Renal plasma flow – clearance of PAH
FF = GFR / RPF
Normally between 0.15-0.2
29
What is the effect of autoregulation of renal blood flow?
Acts to maintain the consistency of blood flow and GFR.
- Renal blood flow is approximately 20% of cardiac output.
- Renal blood flow and GFR are very constant and independent of arterial blood pressure, which is around 80-180mmHg.
- In renal blood flow between 80-180mmHg, there is a plateau, showing that is very constant in between these values.
- When the renal blood flow is kept relatively constant between 80-180mmHg, GFR remains at a relatively constant level.
- Unlike this, the change in urinary volume does increase more linearly as blood pressure increases.
30
How is renal blood flow intrinsically controlled?
* Myogenic activity – increased arteriole pressure lead to stretch in the arteriole wall, causing smooth muscle to contract and therefore reduce flow.
* Tubulo-glomerular feedback – due to tasting of fluid in the distal tubule within the macula densa within the duct to the glomerular apparatus. This is tasting by the sodium or chloride levels. This leads to a constriction of afferent arterioles, likely via a vasoconstrictor from the juxtaglomerular apparatus.
31
How is renal blood flow extrinsically controlled?
* Sympathetic vasoconstrictor activity – minimal at rest but increases with changes, such as exercise, pain or cold
* Vasoconstrictors in kidneys is attenuated by local release of vasodilators, such as prostaglandins and nitrogen oxides.
* Severe reduction in arterial blood pressure will depress RBF and may lead to acute renal failure.
32
What is reabsorbed in the proximal tubule?
* Sodium
* Chloride
* Glucose
* Amino acids
* Peptides
* Metabolites
* Urea
* Water
33
Name the 2 mechanisms that substances can be secreted into the tubule.
* Organic acids
| * Organic bases
34
Describe the structure of the proximal convoluted tubule.
- Tubular lumen
- The cells that make up the tubular/nephron wall – single layer of cuboidal epithelial cells
- Peritubular capillary cells
- Interstitial fluid between the tubular cells and the capillary
- Side of tubular cells closest to the tubular lumen is the apical surface
- Side of the tubular cells closest to the interstitial fluid is the basal surface
- Basolateral spaces on basal side of tubular cells caused by invaginations of the basal lateral membrane
35
Describe reabsorption across the proximal convoluted tubule.
- Reabsorption of substances occurs by the movement of solutes form the tubular lumen to the capillaries
- Secretions of substances refers to the movement of solutes from the capillaries to the tubular movement, and eventually into the urine
There are different routes that substances can take:
- Paracellular route that substances can be reabsorbed by, which goes in between the tubular cells
- Transcellular route where substances move from the tubular cell lumen and through the cells to the capillary lumens
36
Which transport mechanisms are used for reabsorption?
* Active – metabolic energy is required
* Passive – no metabolic energy required
* Primary active transport – coupled to ATP hydrolysis. In the kidney, the most important are sodium-potassium-ATPase, but you can also find calcium-ATPase, hydrogen-ATPase and hydrogen-potassium-ATPase.
* Secondary active transport – relies on the sodium gradient set up by sodium-potassium-ATPases, leaving low sodium concentration inside cells, which drives the transport of sodium coupled with other solutes
37
What are the adaptations of the proximal tubule for reabsorption?
* Located immediately after the glomerulus – so reabsorption can occur as soon as possible following filtration
* Convoluted – twists so a longer length of tubule can fit in the same volume of kidney tissue
* Peritubular blood from efferent arteriole has a high oncotic pressure due to the bulk filtration of water and oncotic solutes. This will favour the movement of water from the tubule to the peritubular capillaries
* Cells of proximal tubule are tightly adhered to each other at the basal side by tight junctions, preventing too much movement of solutes between cells rather than transcellular movement.
38
What are the adaptations of tubular cells in the proximal convoluted tubule for reabsorption?
- Brush border on the apical surface that increases the surface area of the nephron lumen
- Infolding in the basal membrane is a site where high osmolarity can build up
- Many mitochondria for high levels of ATPase activity in the transport of different substances
- Carriers and transporters for different solutes
39
What is the presence of sodium-potassium-ATPase
The presence of sodium-potassium-ATPase in the basal/basolateral membranes is the main driving force for the reabsorption. This sets up a low intracellular sodium content and a negative intracellular potential of -70mV. There are many proteins carriers on the apical surface that take advantage of these things.
40
What are the 2 types of movement across the apical membrane?
Symport – co-transport in the same direction as sodium transport
Antiport – sodium travelling down concentration gradient will drive exchange of counter transport with another ion
41
How is glucose reabsorbed?
- Reabsorption occurs against its concentration gradient in co-transport with sodium out of tubular lumen > into the cell > transporters on the basal membrane > bloodstream.
- Relies on sodium being moved into the cells down its concentration gradient
- Glucose is freely filtered
- Normally almost all filtered glucose is reabsorbed in the proximal tubule
- However, there is a transport maximum (Tmax) that is reached when all sodium-glucose transporters are fully occupied and no more reabsorption can occur.
- This is when glucose is excreted in the urine, glucosurea.
- Glucosurea can occur transiently in pregnancy or in diabetes mellitis.
- When glucose is excreted it can lead to excessive water loss, leading to dehydration and excessive thirst. This is because osmolarity of the tubular fluid is increased and will automatically take water with it.
42
How is chloride and bicarbonate reabsorbed?
- Chloride concentration in the tubule increases as sodium is reabsorbed
- Chloride reabsorption occurs via the transcellular or paracellular route, particularly paracellular in the later proximal tubule.
- Bicarbonate is reabsorbed from the proximal tubule, which is significant in pH control.
43
How is potassium reabsorbed?
Potassium is at a much lower concentration than many other ions in plasma and extracellular fluid. But potassium is reabsorbed in the proximal tubule, mostly passively via the paracellular route as the concentration increases due to the absorption of water.
44
How are peptides reabsorbed?
Peptides are removed from the tubule by endocytosis at the apical membrane and within the vesicles, they are broken down into amino acids. These amino acids are then reabsorbed back into the blood supply by co-transport with sodium on the basal membrane and then into the capillary.
45
How is water reabsorbed?
- 60-70% of the filtered water is reabsorbed in the proximal tubule
- Reabsorption is passive and water follows the movement of solutes out of the tubules via osmosis
- Osmotic effect is aided by the build-up of solutes in basolateral spaces between tubule cells
- Osmolarity of tubular fluid does not change in the proximal tubule
- There is variable reabsorption that also occurs in the collecting duct
46
What is secreted in organic anions/acids mechanism?
Endogenous anions: cAMP, bile salts, prostaglandins, oxalate, urate
Drugs/exogenous anions: aspirin, penicillin, several diuretics
47
What is secreted in organic cations/bases mechanism?
Endogenous cations: adrenaline, noradrenaline, dopamine
Exogenous cations: morphine, isoprenaline, amiloride, atropine
48
What is the function of the distal tubule?
More fine tuning of electrolyte concentrations.
49
What is the juxtaglomerular apparatus and its function?
Where the distal tubule comes back into close contact with the glomerulus and the afferent and efferent arterioles.
- In this region, there is a low and constant permeability to water
- Some water is reabsorbed variably by osmosis
- Reabsorption of sodium and chloride to a much lesser degree than the proximal tubule, as the sodium concentration is lower
- Mechanism of sodium reabsorption is a sodium-chloride symporter in the apical membrane
- This activity is driven by the activity of sodium-potassium-ATPase in the basal membrane
50
What is the normal osmolarity?
290 mmol/l
51
What are the mechanisms that allow urine to be concentrated to an osmolarity higher than that of plasma?
* Generation of an osmotic gradient in the medulla is essential for formation of concentrated urine
* Anatomical arrangement of Loop of Henle and collecting duct and their specialisations are key
* Maximum urine concentration is directly proportional to the length of the Loop of Henle
52
Describe the difference in osmolarity in the Loop of Henle.
Fluid enters the descending limb of the LOH down into the medulla and then returns back up in the reverse direction in the ascending limb to the cortex, then flowing into the distal tubule.
The fluid entering the LOH is of normal body fluid osmolarity of around 300 osmol/l.
Down in the medulla, fluid has a very high osmolarity of around 1200 osmol/l.
Fluid leaving the LOH has a much lower osmolarity, lower than the fluid entering the LOH, at 100 osmol/l.
53
If the LOH is responsible for concentrating urine then how come the fluid leaving the LOH is dilute?
- The descending limb – fluid flows down into the medulla and is freely permeable to water.
- The thin ascending limb is impermeable to water but permeable to sodium and urea.
- The thick ascending limb is impermeable to water and urea but sodium and chloride are actively removed from the tubule. This is done via sodium-potassium-ATPase and other transporters on the apical membrane from the thick ascending limb to the interstitial fluid.
- Solute build up here lead to water leaving the descending limb via osmosis and fluid is concentrated.
- In the ascending limb, the fluid becomes more dilute. Salts removed increase the osmolarity of the interstitial fluid.
- This is a countercurrent multiplier, which acts to increase the osmolarity in the renal medulla.
- At any point, there is a difference in osmolarity for up to 200 mosmol/l in a horizontal gradient. So the limit of the horizontal gradient is the reason why the longer the LOH, the greater the build up of solutes in the medulla and the greater the ability of the kidneys to concentrate urine.
54
Describe the blood supply in the medulla.
- Vasa recta are the capillaries that descend into the medulla and then back up again before the blood flow from the kidney leaves the cortex.
- The countercurrent flow in these blood vessels acts to prevent washout of solutes in the medulla.
- The blood entering the descending limb of the vasa recta becomes very highly osmotic due to them being freely permeable to solutes and water.
- As vasa recta return up into the medulla, this countercurrent flow means that the osmolarity of the blood is restored.
- There is minimal washout of these solutes that have been built up in the medulla of the cortex.
55
How is urea reabsorbed?
- Freely filtered
- 50% is reabsorbed at the proximal tubule
- Urea concentration increases in the LOH due to high urea content in the medulla
- In cortical collecting duct, the urea concentration increases as water is removed in the presence of ADH and not urea.
- In the medullary region with ADH, there is reabsorption of urea into the medullary interstitial fluid
- Builds up concentration and recycling of urea adds to the high osmolarity within the medulla
56
How is plasma osmolarity controlled?
By a negative feedback mechanism:
- Any change to plasma osmolarity is detected by osmoreceptors in the hypothalamus.
- Hypothalamus initiates a change to restore plasma osmolarity to the set point of 290 mosmol/l +/- 3 mosmol/l.
- Response is the hypothalamus thirst response and release of ADH from the posterior pituitary.
- These act to return the plasma osmolarity to normal
57
What is the effect of ADH/vasopressin?
- Plasma osmolarity detected by osmoreceptors in hypothalamus
- Osmoreceptors regulate release of ADH from neuroendocrine cells
- ADH release form posterior pituitary gland into the circulation
- Excess fluid lowers body fluid osmolarity and fluid deprivation increases body fluid osmolarity. These changes in osmolarity lead to the appropriate changes in ADH release.
- At normal plasma osmolarity/290mosmol/l, there is ADH present in the blood.
- An increase in osmolarity increases circulating levels of ADH, increasing water reabsorption.
- A decrease in osmolarity reduces circulating levels of ADH and decreased water reabsorption.
- ADH acts on the collecting duct.
58
How can ADH be released in response to blood pressure?
- Negative feedback from the baroreceptors in the medulla.
- Increase in arterial blood pressure leads to reduction of ADH release and therefore diuresis, increased fluid loss from the body, which acts to reduce blood pressure.
- Not as effect as osmolarity stimulus.
59
How does ADH act on the principle cells of the collecting duct?
- Delivered to principle cells via the bloodstream.
- Acts on receptors on the basal surface
- ADH causes aquaporins to be inserted on the apical membrane, allowing water to be reabsorbed into the cell transcellularly
- When ADH levels drop, these aquaporins channels are internalised and so no longer allow water to be reabsorbed into these cells
- ADH also acts on urea transporters in the apical surface of the medullary section to allow reabsorption of urea
60
How is circulating ADH controlled?
- ADH responds within minutes to changes in osmolarity
- Therefore for an effective regulatory system, ADH must be rapidly removed from the blood
- Half-life for ADH in blood is 15minutes
- Removed by the kidneys are excreted or metabolised
61
Name and describe the 2 types of cells in the collecting duct.
Principal cells:
- Can still get reabsorption of sodium in apical ion channels, driven by sodium-potassium ATPase
- Chloride is reabsorbed driven by the luminal negative charge
- Secrete potassium via ion channels on apical surface
- These are the cells that have variable permeability by responding to ADH
Intercalated cells:
- Can either be bicarbonate secreting or H+ secreting, both removing excess in the urine
- Both are important for pH regulation
- Can reabsorb potassium
62
How does ADH cause constant osmolarity?
High sodium intake > increase in plasma osmolarity > more ADH > less urine produced > increase in ECF
Low sodium intake > decrease in plasma osmolarity > less ADH > more urine produced > decrease in ECF or no change, as if intake = output
63
Describe how osmolarity is kept constant when sodium intake is increased.
1. Increased sodium intake and sodium content of ECF
2. Osmolarity of ECF increases
3. Osmoreceptors cause increased ADH, increasing water retention and ECF volume
4. Osmoreceptors cause thirst response, causing increased fluid intake and increases ECF volume
5. Increased osmolarity of ECF increases osmotic withdrawal from cells and increases ECF volume
64
Why is ECF volume regulated?
* Increased ECF causes stress on the CVS system
| * Decreased ECF causes poor perfusion of tissues
65
What is ECV?
Effective circulating volume, essentially the fluid circulating around the vasculature.
66
How is body fluid volume regulated?
Via renin-angiotensin-aldosterone system.
Renin is an enzyme produced by juxtaglomerular apparatus. Released into plasma when body sodium is reduced. Stimulus for release is not reduced sodium itself but via ECV as sodium content determines ECV via osmoregulation.
- The juxtaglomerular apparatus is the region where the distal tubule comes into very close contact with the vascular pole of the glomerulus.
- There are specialised sensing/tasting cells called the macula densa of the distal tubule.
- There are granulosa cells in the region, which are responsible for renin secretion.
- Sympathetic innervation to afferent arteriole and juxtaglomerular cells within the apparatus.
67
What causes renin to be released?
Decreased sodium content causes a decrease in ECF volume.
- Increased sympathetic activity
- Decreased afferent arteriolar activity
- Decreased sodium at macula densa
68
Describe the effects of renin.
1. Renin acts on angiotensinogen, a hormone precursor released from the liver, in blood to split off angiotensin I.
2. Angiotensin I flows through the circulatory system and when it flows through the lung, it is converted to angiotensin II by a converting enzyme that is present in the endothelial cells of the lung.
3. Angiotensin II flows into the circulation. All its effects are to increase effective circulating volume or extracellular volume.
4. Firstly, it increases and stimulates the release of aldosterone from the adrenal gland.
5. Also acts via the hypothalamus to increase ADH release, increasing water reabsorption and volume of ECF.
6. Angiotensin will also act to increase thirst so fluid intake.
7. Angiotensin II is also a powerful vasoconstrictor, which will increase ECV, as the totally volume of the vasculature will decrease in vasoconstriction.
8. Will also act directly on the kidney to decrease sodium excretion rate and also to decrease the rate of water excretion.
9. All these mechanisms act to increase sodium levels in the body and increase fluid levels in the body.
69
What is an aldosterone?
A steroid hormone produced in the adrenal cortex. Its effects are mostly to conserve sodium and reduce sodium excretion.
70
Describe the effects of aldosterone.
- Stimulates sodium reabsorption in distal parts of the nephron
- Promotes hydrogen and potassium secretion via the hydrogen-potassium-ATPase
- Promote sodium absorption from other parts of the body: colon, gastric glands and sweat glands
- Acts via the distal tubule by increasing the number of up regulating sodium channels in the apical membrane and increasing the activity in the sodium-potassium pump in the basal membrane. These increase reabsorption of sodium from the tubular lumen into the capillaries.
- Increases potassium secretion by upregulating potassium channels in the apical membrane of cells in the distal tubule
71
What are the 3 methods of controlling aldosterone?
* Main stimulus is increase in plasma potassium concentration, which is maintained low, and if this increases, it can have serious effects on the functioning of excitable tissues.
* Decrease in plasma sodium concentration is a lesser stimulus
* A decrease in effective circulatory volume due to renin-angiotensin system causes release of aldosterone into the adrenal cortex
72
What is the maximum pH range tolerated in the body?
pH 6.8 - 7.8
Typical mammalian extracellular = 7.36-7.44
Typical mammalian intracellular = 7.10-7.20
73
Describe acids in body fluids.
Water dissociates: H2O <=> H+ +OH-
Volatile acids are derived from CO2 when in the presence of carbonic anhydrase to give carbonic acid, which dissociated to bicarbonate:
CO2 + H2O <=> H2CO3 <=> HCO3- + H+
Non-volatile acids and others, such as products of metabolism = phosphoric and lactic acids
74
Describe the balance between acids and bases in the body.
- Carbohydrates and fats will produce water and CO2. CO2 is excreted via the lings, so essentially removes volatile acids.
- Proteins/amino acids produces non-volatile acids such as hydrochloric acid and phosphoric acid, which are secreted by the kidneys.
- Organic anions, such as citrate, can produce excess bicarbonate, which is excreted by the kidney.
75
How can H+ concentration be regulated?
* Buffer systems in the body
* Respiratory centres respond to changes in [H+] – which reacts un minutes
* Kidney can adjust [H+] – which reacts in several hours.
76
Define buffer.
Buffers – minimise the change in pH when small amounts of acid or base are added. Can be basic or acidic, but are most often amphoteric – can accept or donate protons – such as proteins and amino acids.
A buffer is made up of chemicals in an equilibrium. pK is a constant for a particular buffer.
Henderson Hasselbalch equation:
pH = pK + log([base]/[acid])
77
What are some whole body buffering systems?
* Dilution in while body water
* Buffering in blood – bicarbonate, haemoglobin, inorganic phosphate
* Buffers in ECF – mostly bicarbonate
* Intracellular buffers – protein, inorganic phosphate, organic phosphate
* Carbonate in bone – contributes bicarbonate to ECF
* Ion exchange in bone – H+ exchange for sodium, calcium, potassium and magnesium ions
78
Why is bicarbonate important in the body?
CO2 + H2O <=> H2CO3 <=> HCO3- + H+
This can be regulated by these 2 substances to shift the equilibrium in either direction.
- Kidneys control [H+] in ECF by producing acid of alkaline urine by varying H+ secretion and bicarbonate reabsorption.
- Lungs control the partial pressure of carbon dioxide by varying the respiratory rate.
79
How is bicarbonate reabsorbed?
1. H+ ions that are removed from the tubular cells in exchange for sodium into the tubular lumen can then in equilibrium with carbonic acid. So H+ and bicarbonate ions that are freely filtered in the filtrate can combine to give rise to carbonic acid.
2. Carbonic acid in the presence of carbonic anhydrase, which is present in the microvilli of the brush border of the tubular cells, can dissociate to produce water and carbon dioxide.
3. CO2, unlike bicarbonate and carbonic acid, can freely filter across the apical membrane of the tubular cells.
4. This is where CO2 can combine with water in the presence of carbonic anhydrase to become in equilibrium with carbonic acid.
5. Transporters in the basal membrane allow bicarbonate to be diffused back into the blood and H+ ions are excreted by exchange with sodium.
80
How do hydrogen secreting intercalated cells excrete H+?
- H+ can be excreted into the tubular lumen by ATPase and sodium-potassium-ATPase activity in the apical membrane.
- Some H+ go through the mechanism that is done in the reabsorption of bicarbonate.
- Bicarbonate produced by this mechanism is reabsorbed into the capillary lumen via bicarbonate and chloride transporters in the basal membrane.
- H+ then excreted in the urine.
81
How do bicarbonate excreting intercalated cells excrete bicarbonate?
- Excrete excess bicarbonate via the same mechanism as H+.
- But in these cells, it is hydrogen-ATPase activity in the basal membrane act to reabsorb h+ and bicarbonate chloride exchangers in the apical membrane that act to excrete excess bicarbonate ions into the tubular lumen.
82
What is the pH of urine? What buffers are in urine?
Range in 4.5 to 8.0, and below 5 is considered acidic.
- Too acidic urine would cause damage to the lining of the ureters
- So there are buffers in the urine: inorganic phosphate and ammonia/ammonium: NH3 + H+ <=> NH4+
- In the presence of chronic acidosis: NH4+ + glutamine --> glutamate --> HCO3-
83
What are the 2 types of acid-base disturbances? What are the homeostatic mechanisms to regulate these?
Acidosis and alkalosis. Can be respiratory or metabolic.
* Compensation – rapid, short term pH regulation
* Correction – longer term, returning bicarbonate and partial pressures of oxygen to normal levels.
84
Describe the pH nomogram.
Can be used to predict the type of pH disorder that is present: arterial pressure of bicarbonate vs arterial blood pH vs arterial blood [H+].
```
Left = acidosis
Right = alkalosis
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- Top left = chronic respiratory acidosis
- Middle left = acute respiratory acidosis
- Bottom left = metabolic acidosis
- Top right = metabolic alkalosis
- Middle right = cute respiratory alkalosis
- Bottom right = chronic respiratory alkalosis
85
What is ANP?
Atrial natriuretic peptide:
- Actions lead to a reduction in total body fluid volume by increasing sodium excretion
- Synthesised and released from cardiac atrial cells
- Released in response to atrial stretch, which is caused by increased ECV
86
What are the effects of ANP?
- Decreased sodium reabsorption in the collecting duct
- Inhibition of aldosterone production
- Reduction of renin release
- Vasodilation of afferent arteriole, causing an increased glomerular filtration rate
Resulting in increased sodium excretion and reduction in ECV.
87
What is erythropoietin?
- Produced by the kidney
- Stimulates red blood cell production in bone marrow
- Also involved in wound healing, neuronal protection (after a stroke, for example), and angiogenesis (the growth of new blood vessels).
88
Which hormones regulate sodium in order to regulate ECF volume?
Angiotensin II will increase the amount of sodium reabsorbed at the PCT and reduce GFR. Less fluid reaches the tubule, so there is less fluid with less sodium in it.
Aldosterone acts to increase sodium reabsorption in the distal tubule and the collecting duct.
ANP increases GFR and sodium excretion, increasing urine output. Also acts to decrease sodium reabsorption in eth distal tubule and collecting duct.
89
Which hormones regulate potassium?
Distal tubule and collecting duct have variable secretion/absorption according to dietary intake.
Aldosterone promotes potassium secretion in the collecting duct when plasma levels of potassium are increased.
90
Which hormones regulate calcium?
In plasma, 40% of calcium is bound to protein.
Reabsorption is stimulated in parathyroid hormones, which upregulates calcium channels in the apical membrane of tubular cells and via the active form of vitamin D.
91
How does equine urine composition differ from other species?
Nothing is added to the composition of urine from the renal pelvis, except from in horses, where some proteins may be added, which is what give shores urine its cloudy appearance.
92
Describe the filling phase of micturition.
1. As the bladder is filling, bladder wall is relaxes. There is inhibition of parasympathetic activity to the smooth muscle of the bladder wall.
2. Tonic sympathetic nerve activity to the internal sphincter that causes the smooth muscle at the neck of the bladder to be closed.
3. Tonic somatic activity to the external sphincter that causes the skeletal muscle to keep the outer urethral sphincter closed.
4. As the bladder fills, the volume increases without causing the pressure to increase due to structural adaptations, such as rugae and transitional epithelium.
93
Describe the voiding phase of micturition.
1. When the bladder is full, this does cause an increase in pressure.
2. This stimulates sensory neurones within the wall of the bladder.
3. Increased parasympathetic nerve activity that allows for reflex emptying and bladder contraction.
4. Decreased somatic activity to the external sphincter that allows is to be opened so that urine can pass.
5. High pressure within the bladder opens the inner urethra sphincter passively.
94
What is voluntary micturition?
This reflex can be inhibited by activity in higher centres, which allows voluntary micturition. Useful for animals that mark their territory with their urine.
95
Define diuretics.
Drugs that act to increase urine output and reduce body fluid volume. May be prescribed for pulmonary oedema.
96
Which diuretics affect the proximal convoluted tubule?
Osmotic diuretics - increase osmolarity of the tubule fluid
Carbonic anhydrase inhibitors
97
How do diuretics affect the Loop of Henle?
Inhibit sodium reabsorption in the thick ascending limb, decreasing solute in the medulla and decreasing the osmolarity of urine.
98
Which diuretics affect the distal convoluted tubule?
Thiazide diuretics block sodium transporters here, increasing osmolarity of the tubular fluid.
99
Which diuretics affect the collecting duct?
Potassium sparing diuretics are aldosterone antagonists that decrease reabsorption of sodium and secretion of potassium from principle cells.
Sodium channel blockers decrease sodium entry across the apical membrane.
100
What are the 4 main causes of diarrhoea?
Secretory
Osmotic
Hypermotility
Malabsorption
101
What are the clinical signs of dehydration?
- Skin turgor = fullness or rigidity. So loss of turgor is related to the loss of volume from the cells and ECM
- Dry mucous membranes
- Lack of tears
- Hypotension
- Oliguria = low urine volume = low production
- Cooling of extremities
102
What are the sodium concentrations and osmolarities in isotonic, hypotonic and hypertonic dehydration?
Isotonic: sodium concentration 130-150mmol/l and serum osmolarity 275-295 mOsmol/l
Hypotonic/hyponatraemic: sodium concentration less than 130mmol/l and serum osmolarity less than 275mOsmol/l
Hypertonic/hypernatraemic: sodium concentration more than 150mmol/l and serum osmolarity more than 295mOsmol/l
103
What are the clinical stages of dehydration?
* 4%-5% dehydration - Semidry oral mucous membranes, normal skin turgor, and eyes maintaining normal moisture.
* 6%-7% dehydration - Dry oral mucous membranes, mild loss of skin turgor, and eyes still moist.
* 8%-10% dehydration - Dry mucous membranes, considerable loss of skin turgor, retracted eyes, acute weight loss, and weak rapid pulses (concurrent intravascular deficit).
* ≥12% dehydration - Very dry oral mucous membranes, complete loss of skin turgor, severe retraction of the eyes, dull eyes, possible alteration of consciousness, acute weight loss, and thready, weak pulses.
104
What are the compensations of the GI tract in diarrhoea?
Increased sodium absorption from gut lumen and increased potassium secretion into the gut lumen. Resulted from:
- Increased aldosterone that results in an increase in the permeability of the apical membrane of enterocytes to sodium
- An increase in the number and or activity of apical sodium channels.
105
What are the compensations of the CVS system in diarrhoea?
- Increased peripheral resistance – increased symp, ADH and Ang II
- Reduced peripheral blood flow – consequence of increased resistance
- Constriction of capacitance vessels
- Increased heart rate
106
What are the mechanisms behind CVS compensations in diarrhoea?
- Increased sympathetic activity to most vascular beds (e.g. skeletal muscle, skin, splanchnic) resulting in constriction of arterioles => increased resistance)
- Increased stimulation of renal sympathetic nerve => release of renin from juxtaglomerular cells and, as a consequence, increased Ang II.
- Increased sympathetic stimulation of heart => increased rate and strength of contraction
- Increased rate of release of anti-diuretic hormone (ADH).
- Reduced release of atrial naturetic peptide
107
What are the compensations made by the renal system in diarrhoea?
Increased reabsorption of sodium
Decreased urine volume (reduced water loss) and increased thirst
Acid-base: Increased tubular secretion (=excretion) of H+(potassium?), Increased reabsorption of bicarbonate and Increased production of new bicarbonate
108
What are the mechanisms behind the compensations of the renal system?
- Increased aldosterone from the adrenal cortex (Sodium reabsorption)
- Aldosterone stimulates Na reabsorption of Na by stimulating the activity of the Na-K-ATPase pump and increasing the permeability of the apical membrane to sodium
- Aldosterone stimulates an apical H-K-ATPase (in intercalated cells) resulting in acidification of the tubular lumen and absorption of potassium.
- Increased ADH from the posterior pituitary
- ADH acts on principal cells of distal tubule and collecting duct resulting in insertion of aquaporins that increase the water permeability of apical membrane
- Activation of thirst centre in hypothalamus leading to increased intake
109
What are the compensations of the respiratory system in diarrhoea and what are the mechanisms behind these?
Hyperventilation > reduced PCO2 > reduced [H+]
- Increased depth and frequency of respiratory movements > increased minute volume.
- Reduced alveolar PCO2 increases gradient favouring CO2 from blood to alveolar air and so lowers PCO2 of arterial blood
Elevated [H+] that is detected by the peripheral chemoreceptors.
110
How could peripheral tissue temperature be useful clinically?
Peripheral vasoconstriction due to baroreflex. As blood volume decreases in dehydration, CO falls, decreasing blood pressure and stimulating baroreceptors to cause effects such as vasoconstriction to peripheral tissues, which can go periods of lesser perfusion.
111
Describe the sodium and lactate levels in a calf with diarrhoea.
Decreasing sodium concentration. So both water and sodium are being lots in hypotonic/hyponatraemic dehydration.
Increase in lactate due to anaerobic respiration in peripheral tissues, as they have less perfusion due to peripheral vasoconstriction.
112
How does pH change in diarrhoea? How would it change in vomiting?
pH is decreasing/becoming more acidic, as the amount of lactic acid increases due to the anaerobic respiration occurring at peripheral tissues due to peripheral constriction. Increased loss of bicarbonate and gain of protons.
If fluid loss was due to vomiting, alkalaemia is caused due to the expulsion of acidic contents of the stomach.
