52. Hypertension and Cardiac Failure Flashcards

Question

Describe the different parts of the medulla involved in the baroreflex. [EXTRA]

Answer 1

* Vasoactive drugs (e.g. NO) -\> These dilate the peripheral blood vessels, stimulating sympathetic activity to constrict the vessels * Blood loss * Neck suction * Change in posture * Lower body negative pressure These are all things that trigger the baroreflex, allowing it to be assessed.

Answer 2

Aside from dilating the peripheral blood vessels, thus stimulating the baroreflex, these also increase the heart rate, which is a confounding effect.

Answer 3

* The drop in blood pressure causes activation of the baroreflex * This leads to tachycardia and an increase in blood pressure * Experimentally, this can be demonstrated in animal models where there is denervation of the heart and the blood pressure drops very fast

Answer 4

When going from lying to standing: * When you stand, about 0.5L of blood pools in your legs, causing a drop in venous return * This causes a drop in atrial pressure (preload), so the cardiac output drops and so does the arterial blood pressure * The body's response involves activation of the sympathetic nervous system via the: * Cardiopulmonary reflex (first) -\> Leads to splanchnic vasoconstriction, increasing blood pressure and preserving blood for the vital organs * Baroreflex (second) -\> Leads to tachycardia and vasoconstriction When starting to walk: * Skeletal muscle pump -\> Moving of muscles causes blood to be pushed back to the heart (venous return) * Breathing also increases, which helps blood pressure to increase also

Answer 5

* Cardiopulmonary reflex (i.e. using low-pressure baroreceptors) * Baroreflex (i.e. using arterial baroreceptors)

Answer 6

ADD NOTES ON THIS - EXTRA?

Answer 7

* When accelerating, the astronauts experience lots of g's * This causes pooling of blood in the lower limbs, leading to hypotension * This can be combatted by: * Use of pressure suits that aid venous return * Placing the astronauts in a more lying-down position, so that the venous pooling is not as pronounced

Answer 8

* Fluid shifts towards the head due to lack of gravity * This causes an increase in puffiness of the face and cardiac engorgement * The CVP and therefore ABP are increased * The response includes a baroreceptor response, slowing down the heart, as well as urine loss * Eventually, after about 24hrs the body is acclimatised

Answer 9

It shifts to higher operating pressure, by inhibition of vagus activity by an unknown mechanism. This is important, or otherwise the increase in heart rate would immediately be counteracted.

Answer 10

* Coronary heart disease * Stroke

Answer 11

(Lipp, 2015)

Answer 12

Blood pressure = Cardiac output x Systemic vascular resistance

Answer 13

* Cardiac output * Systemic vascular resistance

Answer 14

This is equivalent to Ohm's law.

Answer 15

* The height of each tube shows the pressure in the arteries and veins * The width of each tube shows the compliance of the arteries and veins

Answer 16

* Stephen Hales in 1733 * He connected a vertical glass tube to the carotid artery of a horse lying down. Then he measured how high up the tube the blood moved up.

Answer 17

Mean circulatory filling pressure (P_mcf)

Answer 18

* It is the pressure throughout the circulatory system when there is no pump * Therefore the arterial and venous pressure can be considered as diverging from the P_mcf due to the heart pumping blood from the venous to arterial circuit

Answer 19

* Drugs that reduce cardiac output (e.g. beta-blockers) * Drugs that reduce systemic vascular resistance However, this neglects that circulation is an open system, so that pressure can also be regulated via: * Intake via the gut * Output via the urine

Answer 20

The urine production is proportional to the increase in blood pressure, so that the pressure is kept constant.

Answer 21

(Hall, 1980) * Several dogs were each assigned a diet with a different sodium intake, which came entirely from their solid feed * They were free to drink as much water as they wanted * No matter the salt intake, the blood pressure remained almost constant, showing that the kidneys filtered out fluid and salt proportionally to the arterial blood pressure Note: This graph is usually presented with the axes flipped.

Answer 22

(Hall, 1980) * Several dogs were each assigned a diet with a different sodium intake, which came entirely from their solid feed * They were free to drink as much water as they wanted * In the control group, the dogs had constant blood pressure over a range of sodium intakes * In the angiotensin II group, the dogs showed elevated blood pressure, most pronounced at high salt intakes * In the ACE inhibitor group, the dogs showed hypotension, most pronounced at low salt intakes Note: This graph is usually presented with the axes flipped.

Answer 23

* We can deduce that the kidney on its own will display a hyperbola-shaped curve on the ABP-sodium intake graph * It is the renin-angiotensin system that shifts the curve up or down depending on the salt intake, so that the blood pressure remains constant regardless of the salt intake * This results in the flat control line Note: This graph is usually presented with the axes flipped.

Answer 24

* The renin-angtiotensin system is responsible for ensuring that the kidney excretes more fluid when the arterial blood pressure rises -\> This means that the blood pressure is kept constant * Therefore, when it is blocked: * At high salt intakes, function is basically normal, since not much angiotensin II is required (since there is little need for lowering pressure). * At low salt intakes, the lack of angiotensin II means that the kidney's inherent filtering activity is too high, so that the blood pressure drops. * When there is an excess of angiotensin II: * At low salt intakes, function is basically normal, since the excess angiotensin II is required anyway to reduce salt and water loss. * At high salt intakes, the excess of angiotensin II means that the kidney's inherent filtering activity is too low, so that not enough salt and water are filtered, and blood pressure increases.

Answer 25

The inherent activity of the kidney means that it actually has a curved line with a gradient, showing that its filtration rate is not inherently proportional to the blood pressure. However, the renin-angiotensin system is used to ensure that no matter what the salt intake (and therefore the blood pressure), the curve shifts so that the filtration rate is proportional to the salt intake (and therefore blood volume), so that the blood pressure remains constant. [CHECK THIS]

Answer 26

* Certain vasodilators * Beta-blockers * Diuretics

Answer 27

* Vasodilators reduce systemic vascular resistance, so the blood pressure drops * However, as the arterial pressure drops, so does the loss of fluid in the kidneys (this is how the kidneys work) * Therefore, it is only a matter of time before intake of fluid exceeds loss, so that the circulation slowly fills back up to the previous pressure and the hypertension is renewed. * HOWEVER, if the afferent arteries supplying the kidney are targetted and vasodilate significantly, it may be possible to maintain sufficient renal perfusion at the decreased mean arterial pressure. Therefore, the loss of salt is maintained at a lower MAP. (Note: This might be a controversial view)

Answer 28

* Beta-blocker slows the heart down * This leads to a reduction in the arterial pressure and an increase in venous pressure * However, as the arterial pressure drops, so does the loss of fluid in the kidneys (this is how the kidneys work) * Therefore, it is only a matter of time before intake of fluid exceeds loss, so that the circulation slowly fills back up to the previous pressure and the hypertension is renewed. * HOWEVER, some beta-blockers also cause (1) afferent vasodilation of the arterioles supplying the kidney or (2) reduced salt reabsorption in the kidney. This therefore allows the loss of salt to be maintained at a lower MAP. (Note: This might be a controversial view)

Answer 29

* You must alter blood volume chronically, not just modify vasodilation and heart action. * With drugs like beta-blockers and vasodilators, by reducing the mean arterial pressure, you are also reducing renal perfusion such that salt and water excretion is reduced. This renews the hypertension. * Therefore, successful anti-hypertensive drugs (including some beta-blockers and vasodilators) have their useful action on the 'final common pathway' of the kidney. This includes: * Increasing renal perfusion via afferent vasodilation * Reducing salt reabsorption in the kidneys * Their effects elsewhere in the vasculature and on the heart are not the key to treating the hypertension (CHECK ALL THIS and note that it might be controversial)

Answer 30

* It is a graph of cardiac output against venous pressure, with a Frank-Starling curve superimposed on it * The gradient of the venous line is equal to -(1 + C_v/C_a)/R * The point where the lines cross is the flow in the system (since flow is conserved) * Therefore, this graph is useful since by changing one of the variables, such as cardiac output, compliance, resistance or pressure, we can predict the effects that this will have on the system (by looking at the intersect of the lines)

Answer 31

* Venous: -(1 + C_v/C_a)/R * Arterial: (1 + Ca/Cv)/R

Answer 32

* In the normal hypertensive state, the higher the sodium intake, the higher the MAP (and conversely the higher the sodium excretion). * The diuretics, ACE inhibitors and vasodilators act to lower the MAP at ever salt intake there is. * Diuretics are most effective at high salt intakes. * ACE inhibitors are most effective at low salt intakes. * Vasodilators are equally effective at all salt intakes.

Answer 33

Higher perfusion leads to higher salt excretion.

Answer 34

They make the kidneys work at a lower arterial pressure. (Note: This might be a controversial view)

Answer 35

(Gomez, 1951): * There is a 5 times higher resistance of the afferent arterioles, such that the MAP is increased and glomerular capillaries are decreased * This leads to decreased glomerular filtration rate

Answer 36

* Afferent vasodilators -\> These dilate the afferent arterioles supplying the kidney, so that perfusion is maintained as MAP drops * Inhibitors of Na⁺reabsorption in the kidney -\> These increase salt excretion, so that more water is lost via the kidneys as MAP drops * Afferent vasodilators + Inhibitors of Na⁺reabsorption in the kidney -\> These work by both mechanisms Most of these drugs also have an effect on heart action or systemic vasodilation, so they reduce MAP. (Check this is consistent with the later lecture)

Answer 37

(Crowley, 2006) produced 4 sets of mice and then infused them with a vasoconstriction, angiotensin II. The observed results: * Wild-type -\> The MAP increased and remained high the whole time. * Knockout of all angiotensin receptors except renal -\> The MAP increased gradually. * Knockout of only renal angiotensin receptors -\> The MAP increased acutely, but then it slowly decreased. * Total knockout -\> The MAP was relatively unaffected. This showed that, while systemic vasoconstriction can contribute to blood pressure in the short term, it is renal blood flow that ultimately controls blood pressure in the long-term.

Answer 38

There are a number of causes that might act together and there may be more than this: * Increased sympathetic activity * Abnormal renal sodium handling * "Metabolic Syndrome" (a syndrome of uncertain cause that includes obesity, type 2 diabetes mellitus and hypertension) * Abnormal renin-angiotensin ratio -\> A variant mild form of Conn's syndrome (primary hyperaldosteronism) * Increased salt intake Keith Dorrington makes the case that any cause of chronic hypertension must somehow cause dysfunction of water excretion by the kidneys. This is because the kidneys are the organs that are ultimately responsible for blood volume control, and any changes in vasoconstriction, etc. should in theory be counteracted by changes in blood volume. (Check whether this is controversial or not!)

Answer 39

A reasonable approximation is: * Healthy systolic pressure increases linearly with age * Healthy diastolic pressure rises between the age of 20 and 50 and then progressively declines.

Answer 40

* White coat hypertension is the slightly elevated blood pressure seen in some patients when measured in a clinical setting, due to stress or similar reasons * It can be reduced by taking three measurements of the blood pressure at different times and averaging them

Answer 41

* It is usually argued that the values should be averaged * However, there is also an argument in some quarters that the damage done by hypertension is related to the volatility of the blood pressure more than the absolute level. If this hypothesis turns out to be true, then we ought not to be averaging the three measurements but rather we should be observing the variation in blood pressure over time. Portable monitors, which the patient can wear without discomfort and which are now fairly freely available, should help to resolve this question.

Answer 42

* There isn't a normal distribution * The population's blood pressure is skewed, with a thick and long tail at the upper end

Answer 43

According to NICE, hypertension is confirmed when a patient has: * Clinic blood pressure of 140/90 mmHg or higher **and** * ABPM daytime average or HBPM average of 135/85 mmHg or higher (these are measures of blood pressure throughout the day)

Answer 44

The benefits of treatment are due to the fact that hypertension is associated with other diseases: * Stroke (both haemorrhagic and embolic) * Heart attack * Heart failure * Renal disease * Retinal disease The disadvantages are that hypertension itself is usually asymptomatic and treatment often has side effects.

Answer 45

* Remember: BP = SVR x CO * It has been observed that patients with pre-hypertension typically have a high cardiac output but normal systemic resistance * However, in patients with hypertension, there is usually normal cardiac output but increased systemic resistance * Thus, it has been suggested that the first event in the pathophysiology is usually an increase in cardiac output * This results in an increased ratio of wall : lumen in systemic blood vessels, to combat the change in wall stress * This leads to an increase in systemic vascular resistance (Note: This might be controversial)

Answer 46

* Obesity * High salt intake * Sedentary lifestyle * Alcohol and coffee consumption * Smoke * Lack of sleep * Age over 65 * Have a relative with high blood pressure * Black African or black Caribbean descent * Live in a deprived area

Answer 47

Hypertension can affect: * Left ventricle * Arteries * Risk of stroke and TIA * Kidney and retina

Answer 48

* The left ventricle has a thick wall, and so it is dependent on the coronary arteries and their transmural branches for its oxygen supply. * The blood flow in these vessels is at its greatest during diastole, when the ventricular wall is relaxed and not compressing the coronary arteries. * In hypertension, the left ventricle hypertrophies to overcome the increased resistance. * This increases the risk of myocardial ischaemia for two reasons: * Decreased perfusion of the left ventricle since the wall compresses the coronary arteries * Increased metabolic demand of the heart to overcome the systemic resistance (Note that this ventricular hypertrophy is not the same as ventricular dilation, which occurs when the ventricle cannot clear all of its blood in systole, so that it remains partly filled. If the ventricular hypertrophy leads to ischaemia, both may occur simultaneously.)

Answer 49

* There is a bidirectional causal relationship between hypertension and atherosclerosis: * Hypertension increases the risk of atherosclerosis (due to increased turbulence of blood flow) * Atherosclerosis increases the risk of hypertension (due to reduced elasticity of the wall) * There is a similar bidirectional relationship between hypertension and arterial wall thickening, where the muscular arterial wall thickens to sustain the increased pressure, which in turn leads to increased blood pressure due to reduced elasticity

Answer 50

It is a self-exacerbating process, so early treatment is required to stop it spiralling out of control.

Answer 51

* Hypertension is associated with atherosclerosis, which can lead to embolic strokes, where a thrombus detaches from (usually) an atherosclerotic plaque on an arterial wall and is carried in the circulation to the brain, where it blocks an artery * Hypertension also encourages the formation of aneurysms in cerebral, which occur at points of weakness in the wall and can result in haemorrhagic stroke * Thus, the risk of stroke is reduced by lowering the blood pressure.

Answer 52

* The thickening of arterial walls already noted in the context of systemic arteries is conspicuous in the kidney * Some smaller arterioles seem to become almost obstructed by the changes, leading to slow flow in some areas. * Associated with these changes is a process that looks like chronic inflammation, with deposition of fibrous tissue and amyloid, and the progressive loss of functional nephrons. * In addition, glomerular damage is usually evident after years of elevated blood pressure -\> Proteinuria is the usual first indicator of this

Answer 53

The mechanisms that cause kidney damage in hypertensive patients also damage the retina over a long period: haemorrhages and exudates from retinal vessels may compromise the function of the eye, usually over a period of one or more decades.

Answer 54

* Statins -\> For prevention of atherosclerosis * Exercise and dietary planning are often useful alternatives to drugs in the drive to lower blood pressure, and both of these interventions can also reduce serum lipid levels.

Answer 55

* Beta-blockers * RAA antagonists can reduced the degree of left ventricular hypertrophy

Answer 56

* A persistent theme in discussions about hypertension and anti-hypertensive therapy has been that hypertension is not a disease in itself but is simply an indication of an underlying disease. * This argument points to a reason for the continuing difficulty in identifying an ideal anti-hypertensive drug that works in all situations: we cannot use a single drug to treat several different diseases. * This is also important because drugs that treat the underlying cause of symptoms tend to have fewer side effects than drugs that treat symptoms.

Answer 57

* Exercise * Low salt intake * Increased potassium intake (potentially)

Answer 58

There is debate surrounding this because: * Most "anti-hypertensive" treatment is not unambiguously targeted at an underlying disease: "anti-hypertensive" drugs are really "hypotensive drugs" – that is, drugs that lower blood pressure by means that are not necessarily related to the cause of the hypertension (which is often unknown) * Hypertension is usually asymptomatic for many years before it starts to cause obvious problems, whereas most drugs cause symptomatic side-effects, so the patient feels less well with the drug than without it; this problem is likely to have arisen because we are not often treating the cause of the hypertension, but are arguably imposing a hypotensive influence (the drugs) upon an unknown disease which has hypertension as one of its effects. However, we usually treat hypertension early because it is a self-exacerbating problem and therefore treating it early produces better results.

Answer 59

Black, non-Hispanics

Answer 60

* Isolated systolic hypertension -\> This is where the systolic pressure is classed as high, but diastolic is normal or even low. * This is commonly seen among the elderly as there is increased deposition of calcium and collagen to the arterial wall, which reduces the compliance of the arterial vessels, decreased lumen-to-wall ratio, and increased thickening and fibrotic remodeling of the vascular intima and media.

Answer 61

No, it remains relatively constant. It can be seen as a reservoir of driving force, which can be distributed locally to different tissues by local regulation.

Answer 62

* Primary hypertension (a.k.a. 'essential hypertension') -\> Hypertension with an unknown underlying cause * Secondary hypertension -\> Hypertension with a known disease causing it

Answer 63

* ‘Essential hypertension’ -\> Unknown cause * Renal disease * Phaeochromocytoma -\> Rare tumor of adrenal gland tissue. It results in the release of too much epinephrine and norepinephrine.

Answer 64

R ∝ 1/r⁴

Answer 65

To achieve: * Diastolic pressure of \<90mmHg * Systolic pressure of \<140mmHg

Answer 66

Diuretics: * Thiazide, loop and potassium-sparing diuretics Vasodilators: * Alpha-adrenoceptor antagonists * ACE inhibitors * Angiotensin receptor blockers * Ganglionic blockers * Nitic oxide donors * Ion channel modulators: Ca²⁺-channel blockers and K⁺-channel openers. * Renin inhibitors Cardio-inhibitory drugs: * Beta-blockers. * Ca²⁺-channel blockers. Centrally acting sympatholytic drugs.

Answer 67

* Drugs that modify the RAA axis (A) * Calcium antagonists (C) * Thiazide diuretics (D) * Beta blockers (B) Remember: A (ACE Inhibitors), B (Beta blockers), C (Calcium antagonists), D (Diuretics)

Answer 68

Note how beta-blockers are only used here after everything else has failed.

Answer 69

Drugs that modulate the RAA axis (such as ACE inhibitors)

Answer 70

Calcium channel blockers or diuretics

Answer 71

(Brown, 2006) proposes... Type 1: * More common in young people * 'Vasoconstrictor hypertension' due to increased renin * Best treated with RAA axis modulators and beta blockers Type 2: * More common in older people * 'Volume hypertension' due to high sodium intake and volume retention * Best treated with diuretics and calcium channel blockers This difference in ages is seen because renin secretion decreases with age.

Answer 72

* Black patients with hypertension tend to have low-renin hypertension (type 2), which means they are usually first treated with diuretics and calcium channel blockers * This is for two proposed reasons: * Commonly have a threonine to methionine substitution in the ENaC of the kidney -\> This is a gainer mutation, so the function of the channel is increased and there is more salt retention * Lower nephron mass

Answer 73

Juxtaglomerular cells (which surround the afferent arteriole)

Answer 74

* The macula densa are the specialised Na⁺-sensing cells in the distal tubule that come into close contact with the afferent arteriole * Renin is secreted by the juxtaglomerular cells that surround the afferent arteriole * They receive input from the macula densa (via the mesangial cells) and sympathetic innervation, as well as pressure in the afferent arteriole and angiotensin II negative feedback

Answer 75

Smooth muscle

Answer 76

Smooth muscle cells that surround the afferent arteriole can be recruited to become renin-secreting juxtaglomerular cells when there is, for example, there is renal hypoperfusion.

Answer 77

This is unusual because the calcium is an inhibitor of release.

Answer 78

* When there is reduced sodium detected by the macula densa, renin secretion is stimulated. * Prostaglandins are used to stimulate release * Adenosine is used to inhibit release

Answer 79

* ACE inhibitors * Angiotensin receptor blockers * Renin inhibitors

Answer 80

* Captopril was the first * Lisinopril, ramapril, enalapril, benazepril, cilazapril, fosinopril all have a slower onset of action that captopril * Some are pro-drugs converted in the body: ramipril to ramiprilat, enalapril to enalaprilat

Answer 81

* Block conversion of angiotensin I to angiotensin II (so that aldosterone is also not secreted) * This reduce peripheral resistance (passive dilatation) and sodium retention. * No direct effect on the heart.

Answer 82

They can also be used to treat congestive heart failure.

Answer 83

* They block the AT₁ receptors that bind angiotensin II. * Angiotensin II usually causes vasoconstriction and aldosterone release (which leads to salt retention).

Answer 84

* They block the enzymatic activity of renin in converting angiotensinogen to angiotensin I. * Thus, they reduce peripheral resistance (passive dilatation) and sodium retention (thus reduce blood volume).

Answer 85

* Dihydropyridine calcium channel blockers, a group that includes amlodipine, felodipine and lacidipine, are a common choice for treatment. * Verapamil (more cardiac-specific tbf)

Answer 86

* Block calcium entry into cells * This prevent contraction of smooth muscles, which leads to vasodilation * They also inhibit cardiac contraction, which lowers cardiac ouput * In the kidney, the afferent arteriole appears to be more affected than the efferent, so that GFR is maintained despite the falling blood pressure

Answer 87

* Inhibit the Na⁺-Cl^- co-transporter in the distal convoluted tubule. * This leads to greater excretion of salt and therefore less water retention, lowering blood pressure.

Answer 88

* Bendroflumethiazide * Chlorothiazide * Structurally unrelated drugs e.g. metolazone

Answer 89

It is weaker than with loop diuretics, but this is usually sufficient for treatment.

Answer 90

Inhibit the NKCC (Na/K/2Cl transporter) in the thick ascending limb of the loop of Henle. Additional effects include that they are vasodilators of: * Systemic resistance arterioles -\> Useful in lowering arterial pressure in hypertension and in reducing peripheral resistance in cardiac failure * Renal resistance arterioles -\> Useful in increasing GFR and so potentially increasing diuresis * Vasa recta of the renal medulla -\> Resulting in a "washout" of the accumulated osmotically active substances of the medullary interstitium, and so further reducing the osmotic potential there and increasing the potency of the diuresis

Answer 91

Furosemide

Answer 92

* Loop diuretics increase calcium excretion * Thiazide diuretics reduce calcium excretion -\> This can be used in treatment of conditions such as stone formation in the urinary tract

Answer 93

* Metabolic alkalosis and hypokalemia * Hypovolemia * Hypercalcaemia (thiazides) or hypocalcaemia (loop)

Answer 94

There are two main classes: * Aldosterone antagonists * Inhibitors of the epithelial Na+ channel in the collecting duct

Answer 95

* Aldosterone antagonists -\> Spironolactone * Inhibitors of the epithelial Na+ channel in the collecting duct -\> Amiloride

Answer 96

They are used when: * Aldosterone levels are too high in disease, such as: * Cardiac failure * Hypertension * Aldosterone levels are too high as a natural response to diuretic therapy (sinc aldosterone conserves water indirectly by conserving salt)

Answer 97

* Diuresis activates the juxtaglomerular apparatus, which releases renin and causes the production of aldosterone. * Potassium-sparing diuretics may be used in these cases.

Answer 98

During diuretic action: * Downstream nephron segments increase NaCl reabsorption as delivered NaCl load increases. Post-diuretic NaCl retention (short term): * As diuretic concentrations in the tubule decline, Na+ retention increases until the next dose of diuretic is administered. Chronic increase in Na+ retention (the 'braking phenomenon'): * Ability to increase renal NaCl excretion declines over time. Due to both depletion of the extracellular fluid volume and structural (hyperplasia, hypertrophy) and functional (include increase in Na/K ATPase in basolateral membrane) changes in the kidney tubules.

Answer 99

* Block of β₁-adrenergic receptors in the kidney, reducing renin release (remember that the juxtaglomerular cells receive sympathetic innervation) * May also have a CNS effect to reduce sympathetic outflow to the heart and reduce cardiac output

Answer 100

‘Cardioselective’ β blockers -\> e.g. Atenolol

Answer 101

They block alpha-1 receptors in the vasculature, causing vasodilation.

Answer 102

Sympathetic innervation of the vasculature is important in everyday life, such as when standing up.

Answer 103

* Prazosin * Terazosin

Answer 104

* They open K_ATP channels on smooth muscle cells in the arteries * This leads to hyperpolarisation and therefore vasodilation of the vessels

Answer 105

* Diazoxide * Minoxidil * Hydralazine (maybe)

Answer 106

* They are drugs that lead to the production or release of NO * This NO is responsible for the dilation of blood vessels, especially the venous system

Answer 107

Nitroprusside

Answer 108

* They lead to decreased activity of post-ganglionic nerves * Therefore, in theory, they should reduce both sympathetic and parasympathetic activity * However, since arteries receive only sympathetic innervation, this means that vasodilation is favoured

Answer 109

Pentamethonium (C5) and hexamethonium (C6) found to be selective, non-depolarising ganglion blockers.

Answer 110

* Ganglionic blockers * Nitric oxide donors

Answer 111

Drugs that block the sympathetic nervous system at different points: * Peripheral sympatholytic drugs (e.g. alpha-adrenoceptor and beta-adrenoceptor antagonists) block the influence of noradrenaline at the effector organ * Ganglionic blockers block impulse transmission at the sympathetic ganglia * Centrally acting sympatholytic drugs block sympathetic activity within the brain

Answer 112

* They are agonists of α₂-adrenoceptors primarily in the brainstem. * This reduces sympathetic outflow to the heart and vasculature.

Answer 113

* Clonidine * Methyldopa

Answer 114

* There is the argument that all anti-hypertensive drugs must also exert an effect on the kidney, making it filter salt and water out more quickly (as Keith Dorrington argues). * This is because any systemic changes caused by anti-hypertensives, such as vasodilation, should in theory be counteracted by the decreased blood pressure reduced GFR, so that the volume of the system gradually increases again * This is controversial though?

Answer 115

A potentially fatal, pathophysiological disorder characterised by acute failure of the cardiovascular system to perfuse the tissues of the body adequately.

Answer 116

* Rapid and weak pulse (tachycardia with reduced stroke volume) -\> Unless the cardiac failure is due to bradycardia * Mean arterial pressure may be reduced or normal, but pulse pressure reduced * Shallow and rapid breathing * Reduced urine output is reduced * Reduced mental awareness or confusion

Answer 117

* Hypovolaemic * Cardiogenic * Distributive (vasodilatory) * Obstructive

Answer 118

* Lack of perfusion of tissues caused by loss of fluid volume. * Causes: * Hemorrhage * Diarrhoea/vomiting * Third space losses (pancreatitis, burns) -\> Fluid losses into spaces that are not visible

Answer 119

* Lack of perfusion of tissues caused by decreased effectiveness of heart pumping. * Causes: * Reduced stroke volume in MI or myocarditis * Bradycardia * Tachyarrhythmias (when the heart rate is too fast for the heart to refill between strokes) * Acute valve rupture

Answer 120

* Lack of perfusion of tissues caused by systemic vasodilation. * Causes: * Sepsis * Anaphylaxis * Neurogenic causes (epidural anaesthesia/spinal injury)

Answer 121

* Lack of perfusion of tissues caused by mechanical obstruction of inflow or outflow from the heart. * Causes: * Cardiac tamponade * Pulmonary embolism * IVC obstruction (e.g. thrombus)

Answer 122

There is an overall loss of fluid volume leading to decreased pressure, but the mechanism can also be understood in terms of Frank-Starling, where reduced filling of the heart leads to reduced cardiac output.

Answer 123

* CVP and ABP both fall, although ABP may be maintained by compensatory mechanisms -\> Pulse pressure is greatly reduced though * Heart rate and TPR resistance increase due to increased sympathetic activity (via baroreflex) and increases in circulating catecholamines/RAA axis * Limb blood flow is reduced and the limb volume is decreased as venoconstriction occurs -\> There is also transfer of fluid from the interstitial fluid into the blood * Blood pH drops and lactate levels increase due to anaerobic respiration in underperfused tissues

Answer 124

* The drop in blood pressure detects to decreased firing of arterial and cardiopulmonary baroreceptors -\> This is the baroreflex * There is also increased firing of arterial chemoreceptors due to metabolic acidosis * These increase brainstem sympathetic stimulation of the vasculature and heart * Arterial vasoconstriction and increased cardiac output lead to maintained blood pressure * Venous vasconstriction increases cardiac filling pressure

Answer 125

Activation of the RAA axis: * The RAA axis is activated by the decreased perfusion of kidney, decreased flow of NaCl and increased sympathetic stimulation * Angiotensin leads to vasoconstriction, central effects (e.g. stimulating thirst) and aldosterone release * The aldosterone leads to increased salt and water retention ADH release: * Severe water loss (10-15% loss of fluid volume) leads to a shift of the vassopressin-osmolarity release curves * This means there is more ADH release * This is due to baroreceptors and arterial receptors detecting the drop in blood pressure, which via the brainstem leads to stimulation of ADH release from the posterior pituitary * This ADH leads to vasoconstriction (via V1 receptors) and antidiuresis (via V2 receptors)

Answer 126

* In shock, the capillary pressure is decreased * According to Starling forces, by the end of the capillary, there is a net inward force that causes fluid to enter the capillary from the interstitial fluid * This helps maintain blood pressure * It is observed at a time scale of minutes to hours

Answer 127

Landis-Michel red cell method: * A capillary is blocked * The capillary pressure is then changed * The movement of red cells within the capillary is used to assess whether there is absorption or filtration occurring

Answer 128

On a time scale of hours to days: * Reduction in GFR * Thirst * Red cell synthesis * Hepatic alobumin synthesis -\> This increases oncotic pressure, helping retain water

Answer 129

* Type II Myocardial infarction -\> Due to hypoperfusion, anaemia, increased coagulability and increased metabolic demand of the heart as it tries to compensate. * Acute tubular necrosis * Multi-organ failure Shock is a downwards spiral since the effects and some compensatory mechanisms reinforce the problem of decreased oxygen delivery to tissues.

Answer 130

* Identify early * Rapidly stabilise the patient * Treat the underlying cause * ITU/CCU monitoring/support

Answer 131

National Early Warning Score (NEWS2) is a system used to assign a score to a patient based off several parameters.

Answer 132

* A: Airway * B: Breathing * C: Circulation * D: Disability * E: Exposure

Answer 133

* The way the fluid distributes within the body compartments determines how effective it is. * 1L of glucose solution only increases plasma volume by 1/12L since it can enter intracellular compartments too * 1L of saline solution increases plasma volume by 1/4L since it is distributed between all the extracellular compartments. * 1L of blood will increase plasma volume by 1L due to the oncotic pressure it exerts * Thus, blood is best, especially in stage 3 hypovolaemia and beyond * Colloid (e.g. albumin) or crystalline (e.g. saline) solution are best used

Answer 134

(Annane, 2013) CRISTAL trial: * Found no significant difference in 28 day mortality in hypovolaemic patients between use of colloids or crystalloids * 90 day mortality was lower in patients treated using colloids, but this is a tentative finding and it requires more research

Answer 135

It is difficult to know how much blood to give the patient (i.e. do we bring them back to 'normal' or just to a safe point) -\> This will vary on a case-by-case basis (e.g. a patient with poor cardiac function may struggle with pulmonary oedema if too much fluid is given)

Answer 136

* Treat underlying cause * Fluid resuscitation * Colloid or crystalloid solution is usually sufficient if mild shock * Blood infusion required if severe shock * Major haemorrhage protocols (used if more than 50% blood lost in 3 hours) * Guided administration of RBC, plasma and platelets in the correct ratio * Bleeding control techniques

Answer 137

* Drive clotting: * Account for underlying cause (e.g. supplement vitamin K if patient takes warfarin) * Anti-fibrinolytics: Tranexamic acid if within 3 hours * Mechanical intervention * Tourniquets * Sengstaken–Blakemore tubes (device with a balloon that inflates to stop bleeding in the stomach and oesophagus) * Cell salvage (recovery of blood that the patient has lost, such as during surgery) * Endovascular repair * Embolization * Stents * Surgical repair * Clamps * Suturing/ligation * Grafting * By-pass * RAPTOR units -\> Specialised units that use a combinations of all of the above

Answer 138

* Surgery requires general anaesthesia, which tends to depress the cardiovascular system, exacerbating the shock. * Therefore, the patient usually needs to be stabilised before surgical intervention.

Answer 139

* Acute = 40% * Chronic mortality is higher at lower ejection fractions

Answer 140

* The response is similar to in hypovolaemic shock, since the arterial baroreceptors detect the low pressure and there is the baroreflex * The RAAS and sympathetic nervous system lead to vasoconstriction, fluid retention (at the kidneys) and cardiovascular remodelling in the long term * This helps to increase cardiac output due to increased cardiac filling, but it causes the heart to have to work more against the increased fluid, which can exacerbate the problem * However, natriuretic peptide release is triggered by stretch of the atria -\> This leads to countering of the damaging effects of the shock

Answer 141

* Left sided -\> Pulmonary oedema * Right sided (or both sides) -\> Jugular vein distension

Answer 142

* Treat underlying cause (frequently a heart attack) * Improve oxygenation * High flow O₂ * Continuous positive airway pressure * Invasive ventilation via endotracheal tube * Either: * Reduce fluid retention if the patient is 'falling off' the Frank-Starling curve -\> Increases cardiac output * Loop diuretics (furosemide) * Infuse fluid if hypovolaemic -\> Increases preload and therefore cardiac output * Either: * Reduce afterload (if there is sufficient blood pressure to sacrifice) -\> This increases cardiac output by shifting the Frank-Starling curve upwards * Nitrates (as blood pressure allows) * ACE inhibitors or angiotensin receptor blockers * Use vasoconstrictors (if hypotensive) -\> This maintains pressure * Improve cardiac contractility * Inotropes: Dobutamine, Milrinone, Levosimendan * Mechanical haemodynamic support (i.e. mechanically supporting the heart) * Intra-aortic balloon pump use * Others: Impella, Tandem Heart, Extracorporeal membrane oxygenation (ECMO) (CHECK when fluid infusion/retention and vasoconstriction/dilation are used)

Answer 143

Fluid management: * Fluid infusion * Most of the fluid enters the venous circulation and therefore increases preload * This increases cardiac output * Reducing fluid retention (loop diuretics) * This is used if the patient is 'falling off' the Frank-Starling curve * In these situation, further increases in preload decrease cardiac output because the heart cannot mobilise all of the blood supplied to it Vascular control: * Vasodilation (nitrates, ACE inhibitors, ARBs) * Reduces afterload, which increases cardiac output by shifting the Frank-Starling curve upwards * This is useful, but can only be done if there is sufficient arterial blood pressure to sacrifice * Vasoconstriction * Increases arterial blood pressure * But also increases afterload, which reduces cardiac output

Answer 144

* Fluid infusion (which mostly enters the veins) or venous vasoconstriction (i.e. decreased capacitance) lead to a shift to the right of the Pmcf, which consequently shifts the venous and arterial lines * Arterial vasoconstriction leads to increases in TPR, which decreases the gradient of the arterial and venous lines (no change in Pmcf though) * When both happen at the same time (i.e. both arterial and venous vasoconstriction), the two effects are combined and so the lines shift to the right but the gradient decreases * Decreased afterload (e.g. due to arterial vasodilation) shifts the Frank-Starling curve upwards

Answer 145

Diagnosis: * ABCDE * Blood cultures Treatments: * Oxygen supply * IV fluids * Broad spectrum antibiotics * Vasopressors * Steroid -\> Support vasoconstriction, but weaken the immune response against the infection * Manage coagulation

Answer 146

* Remove trigger * Lay down * Adrenaline (“epipen”) * Oxygen delivery * IV fluids * Chlorphenirame * Hydrocortisone

Answer 147

* Tiredness and lethargy (caused by reduced perfusion of tissues, and by acidaemia) * Breathlessness, particularly on exertion and (in the case of left ventricular failure) on lying flat * In the case of right ventricular failure, dependent oedema (i.e., usually ankle oedema)

Answer 148

* Reduced systemic arterial pressure * Increased heart rate * Apex beat displaced to the left (left ventricular dilation) * Pulmonary oedema And if there is right ventricular failure: * Raised jugular venous pressure * Dependent oedema (venous congestion in dependent areas, plus reduced oncotic pressure as resulting from fluid retention by the kidneys)

Answer 149

* Chronic ischaemic failure may occur in isolation, or may be an end point of other diseases, such as hypertension. * When it apparently occurs in isolation, the underlying pathology is usually some form of obstruction to the blood supply of the myocardium.

Answer 150

* Coronary atherosclerosis * Small vessel disease (occlusion of small and medium arteries supplying the myocardium) * Ventricular hypertrophy (in response to hypertension or valve disease, but increasing metabolic demand) * Atrial fibrillation (there is a correlation between atrial fibrillation an heart failure, but it is not certain which is the primary event) * Anaemia (decreased oxygen delivery)

Answer 151

Physical: * Ventricular dilation -\> The failing ventricle does not clear the venous return that is presented to it and so begins to dilate. This is usually useful but it is a problem when the hump of the Frank-Starling curve is passed and cardiac contractility is decreased. Neuroendocrine: * Sympathetic activity -\> Decreased cardiac output triggers the baroreflex, which leads to increased heart rate, but also increased the metabolic demand of the heart. * RAA axis -\> Triggered by decreased renal blood flow and sympathetic stimulation. Leads to increased fluid retention and vasoconstriction, increasing the work the heart must do. * ADH -\> Release triggered by angiotensin and sympathetic stimulation. Leads to increased fluid retention and vasoconstriction, increasing the work the heart must do.

Answer 152

* Atrial natriuretic peptide (ANP, released mainly from the atria) and B-type natriuretic peptide (BNP, released mainly from the ventricles) are released in response to myocardial stretch. * Blood levels of both are elevated in chronic failure, and BNP is used clinically as a measure of the severity of the failure. * Both are weak angiotensin antagonists so they should be capable of counteracting the progression of heart failure. It is a mystery why this effect is so small.

Answer 153

* Around 40% * The cause of death is usually cardiac dysrhythmia, probably from ischaemia and/or cellular uncoupling as a result of ventricular dilation.

Answer 154

* It is usually difficult to treat the underlying cause of chronic ischaemic heart failure. * The exceptions are treating anaemia or surgical interventions (for valve disease or large-vessel coronary atherosclerosis) * In the majority of cases the aim of medical therapy is to relive the symptoms and, where possible, to slow the progression of the disease.

Answer 155

* Should increase cardiac contractility without increasing oxygen demand (or, alternatively, it should increase oxygen delivery through obstructed blood vessels) * Should maintain systemic arterial pressure without increasing peripheral resistance * Should reduce ventricular dilation without reducing arterial pressure and without reducing venous return too much * Should reduce oedema without dehydrating the patient, and without triggering the RAA axis However, these are all very difficult to achieve, so the drugs tend to have significant side effects.

Answer 156

* Diuretics * Thiazide * Loop * Potassium-sparing * Vasodilators * ACE inhibitors * Angiotensin receptor blockers (ARBs) * Nitric oxide donors * Natriuretic peptides * Phosphodiesterase inhibitors * Cardio-stimulatory (inotropic) drugs * Digitalis * Sympathomimetic drugs (beta agonists) * Phosphodiesterase inhibitors * Cardio-inhibitory drugs * Beta blockers * Calcium channel blockers

Answer 157

ACE inhibitors or angiotensin receptor blockers: * Reduces vasoconstriction, which reduces cardiac work and increases cardiac output * Reduces the sodium-retaining effects of angiotensin and aldosterone, which reduces oedema and also slightly reduces the effective circulating volume, so reducing ventricular dilation * Reduces the activation of the sympathetic nervous system (so reducing cardiac oxygen demand) and of ADH (so further reducing vasoconstriction and fluid retention) Spironolactone: * Reduces the sodium-retaining effects of aldosterone, which reduces oedema and also slightly reduces the effective circulating volume, so reducing ventricular dilation Side effects: * Postural hypotension (due to reduced vasoconstriction and plasma volume) * Electrolyte disturbances (due to reduced renal perfusion) * Cardiac problems (mostly related to the reduced volume and the electrolyte disturbances), including angina, palpitation and other rhythm disturbances

Answer 158

Not always suitable for patients with renal disease, which is an increasingly common problem in this age group.

Answer 159

* Ramipril (ACE inhibitor) * Losartan (angiotensin-receptor blocker)

Answer 160

Beta blockers work by: * Reducing vasocontriction, which reduces the workload on the heart, but also reduces blood pressure * Reducing cardiac contractility, which reduces the metabolic demand on the heart, but also reduces cardiac output * Reducing the release of renin and ADH Side effects: * Postural hypotension * Others Note that calcium channel blockers have similar effects to beta blockers.

Answer 161

* Spironolactone (aldosterone antagonist) produces much better results than other diuretics and also the other RAA axis antagonists. * Aldosterone is elevated in heart failure, which may explain why this is so effective, but it does raise the question about whether the spironolactone is acting by a different mechanism too.

Answer 162

Their use is relatively limited: * Sympathomimetics (beta agonists) -\> Increase contractility but also increase oxygen demand, so they are not widely used in chronic heart failure, only cardiogenic shock. * Glycosides (Na⁺/K⁺-ATPase inhibitors) -\> Increase contractility with little effect on oxygen demand, but they are highly toxic and clinical trials have shown mixed results. * Calcium sensitizers -\> None are used clinically yet but they show promise. Levosimendan is the drug closest to clinical use. * Phosphodiesterase inhibitors -\> Analogous to sympathomimetics.

Answer 163

* Digitalis * Works by inhibiting the Na⁺/K⁺-ATPase, which leads to increased intracellular sodium and thus increased extrusion in exchange for calcium. This leads to increased contractility.

Answer 164

* Diuretics used to be routinely used to treat chronic ischaemic heart failure, since they provided fast relief of symptoms, especially the breathlessness that follows left ventricular failure * They work by reducing the circulating volume, but many vasdilators also have a secondary effect as vasodilators -\> Evidence for this comes from the fact that furosemide provides rapid relief of breathlessness after a myocardial infarction before diuresis has had time to occur * Thus, they reduce left ventricular dilation, which is beneficial * However, the reduction is fluid volume also leads to: * Sympathetic stimulation (via the baroreflex) * Activation of RAA system * Increase myocardial oxygen demand (due to sympathetic stimulation) * Electrolyte disturbances that increase the risk of dysrhythmia. * So now diuretics are not normally used as first-line treatment for new patients with failure where there is a reduced ejection fraction.

Answer 165

* RAA inhibitors are more effective because they also act as diuretics and vasodilators (via their inhibition of angiotensin and aldosterone), just like diuretics, but they have fewer side effects * This is because they inhibit sympathetic tone (unlike the compensatory sympathetic stimulation in diuretic use), so they tend to reduce metabolic demand of the heart, rather than increase it * However, RAA antagonists leave the kidney relatively under-perfused and can lead to electrolyte disturbances

Answer 166

Based on the ejection fraction: * In classical heart failure, the LVEF is below 40% * In a normal heart, the LVEF is 50-70% It is possible to have symptoms of heart failure with a normal LVEF, which can occur when the left ventricle is stiff during diastole and thus the reduced stroke volume does not affect the LVEF. It is typical in cases of hypertension or diabetes.

Answer 167

Reduced ejection fraction: * First use RAA antagonist or beta-blocker -\> Combine the two as the heart failure worsens. The RAA antagonists currently recommended are ACE inhibitors, switching to angiotensin-receptor blockers (ARBs) if ACE-inhibitors are not well tolerated. * If symptoms worsen, use spironolactone. * Closely monitor renal function. Normal ejection fraction: * Use furosemide (loop diuretic) for symptomatic relief.

Answer 168

* Nitric oxide donors * Natriuretic peptides * Phosphodiesterase inhibitors

Answer 169

* One of the puzzles about the endocrine network in cardiac failure is the apparent silence of the ANP/BNP natriuretic peptides. * Blood levels of BNP are certainly elevated in cardiac failure, but they seem to be ineffective. By contrast, ANP levels are not elevated to the same extent, despite the common rise in central venous pressure. * Analogues of ANP are unsuccesful therapeutically, but attempts to inhibit the degradation of natriuretic peptides via inhibition of the enzyme neprilysin. The drug most commonly used for this now is called neprilysin. * Initial clinical trials suggested only a weak effect for secubitril, but combination with valsartan (an ARB) shows more promising results and is being used clinically.

Answer 170

Ivabradine: * Inhibits the funny current, reducing the activity of the pacemaker current. Vaptans: * ADH inhibitors used to releive oedema. Omecamtiv: * Modifies myosin, increasing contractility. Similar to calcium sensitizers. * Not yet in clinical use.

Answer 171

* Cardiac glycosides (purified from foxgloves) have historically been a major part of treatment of cardiac failure. * It has been found that these drugs act at remarkable low concentration relative to their effects, which has led to the idea that these glycosides may influence an endogenous regulator that leads to more profound effects. * Since glycosides tend to take 3-6 hours to work, this suggests the regulator they control may influence transcription. This is supported by their steroid structure. * Attempts to identify the endogenous regulator led to the discovery of some pregesterone-derived steroids that were present in the urine of hypertensive patients. It appears that these steroids can increase cardiac output and increase arterial blood pressure. * One suggestion is that heart failure might result from the failure of synthesis of these endogenous glycosides. * If this is the case, then replacement of these glycosidfes would be the best therapy for heart failure. This would involve discovery of a less-toxic version of digoxin.

Answer 172

* Fraction of the filtered load is reabsorbed * This fraction is different for different solutes and varies with regulation * Secretory processes also present to augment excretion of solutes (e.g. organic anions or acid) * Combination of both of the above allows maintainence of the body's fluid composition

Answer 173

1/5th of the blood volume per minute

Answer 174

* Endocrine target (e.g. for aldosterone or renin) * Endocrine sensor/organ for: * Fluids/minerals * Flow and blood pressure * O2 and blood composition

Answer 175

* Angiotensin II (both secreted by and acting on) * Aldosterone * Natriuretic peptides * ADH * Calcitriol and PTH

Answer 176

* Angiotensin II (both secreted by and acts on) * Calcitriol (Vit D3) * Erythropoietin (EPO)

Answer 177

* Peptidase: kallikrein * This protein itself is generated from a pre-protein synthesised in connecting tubule cells of the kidney

Answer 178

* Released from granular cells of the afferent arteriole wall (part of the juxtaglomerular apparatus) in response to signals from the macula dense * Catalyses the truncation of angiotensinogen (synth. in the liver) to yield angiotensin I * This is further truncated by ACE in the pulmonary circulation to produce angiotensin II * ACE expression and angiotensinogen synthesis has also been noted within the kidneys itself (therefore Ang II can be considered a hormone secreted by the kidneys, acting on the kidneys)

Answer 179

A drop blood pressure and fluid volume causes granular cells in the afferent arteriole walls in the kidney to release renin.

Answer 180

* The macula densa detects NaCl levels in the glomerular filtrate at the beginning of the distal tubule * Most significant trigger for the release of renin is a decrease in the delivery of NaCl to the macula densa * This occurs due to a decrease in GFR, as a result of decrease in BP/effective circulating volume

Answer 181

* Increase Na+ (and therefore H2O) retention and cause vasoconstriction * This aims to maintain blood pressure and restore effective circulating volume (ECV)

Answer 182

* ↑ Cl- efflux (through apical NKCC, anion channel on basolateral surface for efflux) -\> depolarisation -\> Ca2+ influx (via VGCCs) * ↑ [Ca2+] activates an anion channel * This allows ATP efflux * ATP release, adenosine production (by an ectoenzyme/extracellular nucleotidase) * ATP/adenosine increases [Ca2+] * In granular cells: **inhibition** of renin release * In afferent arteriole smooth muscle: contraction * The above effects cause a reduction in GFR

Answer 183

* Afferent arteriole * Efferent arteriole * Macula densa * Extraglomerular mesangial cells

Answer 184

* Bell *et al,* 2003 * Demonstrations of ATP release from macula densa cells * PC12 is a cell line that expresses P_2X ATP receptors * These cells are being used as a bioassay system to check for ATP release, and are **not** part of the JGA * PC12 cells are attached to a patch pipette and are brought close to the macula densa * B shows the effect of increased NaCl delivery to macula densa cells through changes in current across PC12 cell membranes * Can see that current is seen after increase of NaCl * This indicates ATP release by macula densa cells and its subsequent binding to P_2X receptors on the PC12 cells, causing the opening of Ca2+ channels * D shows the use of a calcium-sensitive fluorescent dye to measure intracellular Ca2+ levels * These readings confirm that Ca2+ influx occurs as a result of P_2X activation by ATP as it occurs after NaCl delivery to the macula densa has occurred

Answer 185

* Adenosine is generated from ATP using an enzyme/nucleotidase on the cell membrane of macula densa cells * ATP released via basolateral anion channels from macula densa cells * Adenosine acts at granular cells to suppress renin release and smooth muscle cells to induce vasoconstriction

Answer 186

* Use Ca2+ sensitive fluorescent dye * In diagram, warm colours = high concentration, cold colours = low concentration * Using this method, we can see a wave of elevated Ca2+ * Peti-Peterdi et al, 2006

Answer 187

* These mice lack tubuloglomerular feedback (TGF) * These experiments confirm that it is adenosine (and not ATP) that controls TGF * Can indicate this using the stop-flow perfusion technique * Collection pipette placed in PCT * Pressure applied to stop flow of fluid out of the tubule/into the pipette * This stop-flow pressure is roughly equivalent to the hydrostatic pressure in the glomerular capillary driving filtration and fluid flowing along the PT * As afferent arteriole diameter changes, the hydrostatic pressure in the capillary does *not* change (?) * Pressure used to stop flow down and out of the tubule by the pipette will change * This provides a means of assessing SMC tone in afferent arteriole wall * Distal to the collection pipette, a 2nd pipette is inserted into the tubule to control the rate of perfusion of fluid past macula densa cells, therefore manipulating TGF * Increased perfusion resulted in subsequent reduced stop-flow pressure, indicated that the macula densa signalled to arteriolar SMCs to *contract* * In A1AR KO mice, there was no change in stop-flow pressure when perfusion was modified, indicating that the signal required was adenosine

Answer 188

Beta-1 adrenoceptors

Answer 189

* Angiotensin II * ADH * Stretch of granular cells

Answer 190

* Tubuloglomerular feedback needs to be attenuated for renin secretion to occur * When NaCl delivery to the macula densa is reduced (reflecting a contraction of the ECV and reduction in GFR), ATP release/adenosine production is attentuated * This causes the inhibition on renin secretion to be **relieved**

Answer 191

* Angiotensin II acts mostly on the proximal tubule * Aldosterone acts mostly on the collecting duct * The aims of angiotensin are: * Increase effective circulating volume * Increase blood pressure * ADH acts mostly on principal cells, causing AQP2 insertion

Answer 192

* Peptide hormone indirectly generated by the kidney * Acts on the kidney to promote sodium reabsorption * Predominantly acts on the proximal tubule

Answer 193

* Predominantly at the PT * Direct effects are through AngII-mediated activation of PLC and generation of IP3 * This stimulates the release of calcium from intracellular stores * Ca2+ release causes activation of kinases, which phosphorylate Na+/H+ exchangers in the apical membrane * These are involved in the reabsorption of Na+, HCO3- and Cl- ions * This action augments the NaCl absorbing capacity of the proximal tubule

Answer 194

* Induces efferent arteriole constriction * Preserves GFR (despite fall in ECV) * Reduces medullary blood flow * Reduces flow through the vasa recta * This augments urinary concentration as it prevents 'wasahout' of the hypertonic interstitium * Alters renal interstitial hydrostating pressure * Changing the balance of Starling forces dictates the movement of fluid between interstitium and peritubular capillaries * Therefore alters backflux/reabsorption of fluid back into renal tubule * Inhibits synthesis of PGE2, which normally inhibits Na+ pumps and so removes this inhibition * Potentiates TGF * Therefore greater effects of changes in flow on GFR and renin release

Answer 195

* Steroid hormone secreted by the adrenal cortex (zona glomerulosa) * Acts on the kidney through: * Classical steroidal pathway * Aldosterone binds to a cytoplasmic receptor which is then translocated to the nucleus for the transcription of proteins involved with Na+ reabsorption, including: ENaC, Na+/K+ ATPase, metabolic enzymes to generate more ATP to fuel the pump * Non steroidal pathway * Receptor activates PKC and PKD through increasing [Ca+] intracellularly, which increases the activity of a variety of transport proteins within epithelial cells * Aldosterone acts to promote Na+ retention (and therefore also K+ excretion)

Answer 196

* EMCs express adenosine A1 receptors * This induce increased intracellular [Ca2+] after binding to adenosine * These cells are coupled to other mesangial cells by gap junctions * These are ultimately connected to other vascular smooth muscle cells and granular cells * In this way, the wave of increased [Ca2+] passes from the EMCs to effector cells (SMCs and granular cells)

Answer 197

* This pathway increases activity of a variety of transporters within minutes * Non-steroidal actions are mediated by PKC and PKD, which are induced by elevation of [Ca2+] intracellularly as a result of epithelial cell exposure to aldosterone

Answer 198

* Through using calcium-sensitive fluorescent dyes, you can measure waves of calcium/intracellular calcium through observing fluorescence * Within 1 minute of exposure to aldosterone, significant increases in [Ca2+] are apparent * This can lead to altered activity of protein kinases and phosphorylation of pre-existing transport proteins in the apical and basolateral membranes to increase their activity

Answer 199

During volume expansion

Answer 200

* ANP * Main peptide hormone (17aa) * BNP * CNP

Answer 201

The heart and the brain

Answer 202

* ANPR-A * ANPR-B * These act on the kidney to promote natriuresis

Answer 203

* Act through cGMP and PKG * PKG (serine/threonine kinase) phosphorylates target proteins to result in the following effects * Tubular effects: * Inhibits renin release via macula densa mechanism * Inhibits transport of Na+ (through inhibition of a number of transport proteins in the renal tubule) * Haemodynamic effects: **vasodilation** * ****Increased GFR * Increased flow to medulla - this washes out the hypertonic interstitium and alters the renal interstitial hydrostatic pressure, causing balance of Starling forces to be tilted back towards backflux of fluid reabsorption across the epithelial cells and into the renal tubule

Answer 204

Involved in homeostasis of osmotic potential of body fluids

Answer 205

* Peptide hormone (9aa) * Released from the posterior pituitary

Answer 206

* Increased osmolarity * Decreased blood pressure

Answer 207

* Angiotensin II * This is in keeping with the increased H20 requirements when Na+ retention is increased (as is seen during action of AngII and aldosterone)

Answer 208

* Acts on the kidney to promote urinary concentration * Inserts AQPII into the apical membrane of principal cells in the collecting duct * Stimulates NKCC in the TALH * This potentiates the single effect that creates medullary hypertonicity, by which water is extracted from the collecting duct via aquaporins * Activates urea transporter A (UT_A) * This occurs in the inner medullary collecting duct and allows for urea efflux from the renal tubule into the interstitium * This potentiates the interstitial hypertonicity that allows for H20 reabsorption * Vasoconstriction * Reduces blood flow to the inner medulla, therefore minimising washout of the hypertonic interstiitium

Answer 209

* Calcium homeostasis requires the coordinated regulation of: * Assimilation of calcium into or the liberation of calcium from bone * Regulation of absorption by the GI tract * Regulation of fractional excretion of calcium excretion by the kidney * The kidney is the site of the final hydroxylation of vitamin D3, one of the essential hormones in calcium homeostasis

Answer 210

* Parathyroid hormone (PTH) * Calcitriol (Vitamin D3) * These two aim to **elevate** calcium levels when they are too **low** * Calcitonin * This hormone aims to **reduce** calcium plasma levels when **elevated**, but only really has physiological importance in children and breastfeeding mothers

Answer 211

* 1,25-dihydroxycholecalciferol * aka 1,25(OH)₂D₃ or calcitriol * This is a derivative of D3

Answer 212

* In absence of PTH, 25(OH)D3 is hydroxylated at the 24th postition at the kidneys * This produces an inactive molecule

Answer 213

* Aldosterone binds to a cytoplasmic receptor which is then translocated to the nucleus for the transcription of proteins involved with Na+ reabsorption * This includes the transcription of: * ENaC (apical protein) * Na+/K+ ATPase (basolateral protein) * Metabolic enzymes to generate more ATP to fuel the pump * This pathway takes hours to have a noticeable effect

Answer 214

* Calcitriol aims to increase Ca2+ reabsorption * This is achieved in a similar fashion to what is seen in the renal tubule

Answer 215

* Act to increase Ca2+ reabsorption through: * Increasing activity and/or number of transport proteins involved in Ca2+ reabsorption, including: * ECaC * Na2+/Ca2+ exchanger * Ca2+ ATPase * PTH also inhibits Pi reabsorption * NaPi cotransporter in the PT is inhibited * This elevates plasma calcium levels as calcium phosphate concentration is reduced

Answer 216

* General function is to induce transcription of regulators of RBC growth and maturation * This hormone is released from the kidneys in response to hypoxia

Answer 217

* Peptide hormone (165aa) * 34kDa, glycosylated

Answer 218

* Actions are achieved through tyrosine-kinase associated receptors (dimers) * EPO binding initiates Jak (Janus kinase) autophosphorylation * This is the cytoplasmic component of the receptor * Following this there is subsequent activation of MAP/Akt kinases * This proteins induce changes in gene transcription through interactions with transcription factors for regulators of RBC growth and maturation

Answer 219

Type 1 interstitial cells in the renal cortex and outer medulla

Answer 220

* High altitude * Due to associated fall in PaO2 * Pulmonary disease, e.g. emphysema * Compromised gas exchange at lungs, therefore hypoxia and EPO release * Right to left shunts, e.g. in the heart * Causes blood to bypass the alveoli in the pulmonary circulation, therefore are not oxygenated * Alkalosis * Affects affinity of Hb for O2 * Renal tumours * If secretory can increase production of EPO * Professional cycling lmao * Associated with elevated EPO levels

Answer 221

* Low local O2 triggers EPO synthesis through HIF signalling * HIF = hypoxia inducible factor, which translocates to the nucleus to promote transcription of the EPO gene in type 1 interstitial cells when present * Translocation of HIF to the nucleus in normoxic conditions is prevented by the enzyme prolylhydroxylase * In presence of O2 and Fe, this enzyme hydroxylates HIF, causing it to adopt a conformation that can then be bound by 2 proteins: * Von Hippel-Lindau protein (VHL) * Ubiquitin * Together, these proteins chaperone HIF for destruction/proteosome degredation

Answer 222

* 150 litres per day * Useful molecules such as: glucose, amino acids, water, bicarbonate * Waste products such as: urea, ammonium, creatinine

Answer 223

* In the tubules (majority in the proximal tubule, balancing and smaller modifications are achieved in the tighter epithelium of the distal tubule and collecting duct) * Useful products are reclaimed and waste products are also secreted to increase their excretion

Answer 224

* Blocks the entry of proteins and other large structures into the ultrafiltrate/Bowman's space

Answer 225

* Presence of proteins from the blood in the ultrafiltrate * This is **nephrotic syndrome**

Answer 226

* Idiopathic (unknown cause/spontaneously) * Immunological * Abs binding to components of the barrier, or immune complexes formed elsewhere end up deposited within the barrier * How the latter process results in loss of the barrier is not yet completely clear * Structural/genetic * See diagram for the proteins involved in this barrier * Particular mutations that can result in nephrotic syndrome include podocin and nephrin

Answer 227

As a triad of: * Proteinuria (\>3.5 g/day) * Hypoalbuminaemia (\<30g/dL) * Oedema Other associated features: * Hyperlipidaemia * Hypercoagulability * Various histopathologies * Often perform renal biopsy to elucidate cause, wide variety of histopathologies can be seen but all result in the same pathophysiological response

Answer 228

* Patient shows acute onset * Frothy urine is due to the increased protein content of the urine - this causes bubbles to form

Answer 229

* Protein loss at kidneys (proteinuria and catabolism) leads to * Reduced oncotic pressure in the blood, and so this causes a reduced oncotic gradient leading to * Oedema formation and (as fluid is leaving the blood) reduced circulating volume, leading to * Activation of the RAAS (IMPORTANT), leading to * Sodium and water retention (this refills the intravascular space but supplies more water and salt for oedema formation)

Answer 230

Predictions in nephrotic syndrome: * Plasma oncotic pressure will fall * Circulating volume will be reduced * Renin levels will rise/RAAS activation will occur Reality: * Literature from the 70s suggests that the oncotic pressure does not really show much change, ECV is neither always reduced nor always raised, renin levels can be medium, low or high * This therefore provides some uncertainty over what the actual underlying pathology of nephrotic syndrome is

Answer 231

* Dip test * Dip a tes stick into a urine sample to analyse it and estimate a value for glucose levels * In health, urine should contain no glucose, but may do so in pathology * This test is **not** quantitative

Answer 232

* Glucose is taken up from the renal tubule via transporters (GLUT transporters), which can therefore become saturated * If filtered load exceeds the concentration at which the transporters become saturated, then glucose will start appearing in the urine * As filtered load increases from this point, so will the concentration of glucose in the urine * Below the concentration at which saturation occurs, there should be no glucose in the urine, making glycosuria an indication of potential pathology

Answer 233

* Excess glucose in blood * E.g. in diabetes mellitus * Black line on graph * Excess glucose filtered * E.g. during pregnancy * Increased BP results in increased GFR, therefore even at normal blood glucose levels, filtered load can reach concentrations that exceed the tubular filtration maximum and so glucose is seen in the urine * Blue line on graph * Failure of tubular reabsorption * E.g. after tubular damage * For example after extended periods of hypotension * Until the tubule recovers, there will transiently be a period where there is a reduced maximum capacity for glucose reabsorption in the tubule * E..g SGLT2 inhibitor treatment * These drugs were used (initially) to treat diabetes but are now also used to generally improve kidney function * This reduces tubular maximum for glucose reabsorption and therefore glycosuria occurs at 'normal' blood levels

Answer 234

* Osmotic diuresis * This is a common presentation of diabetes, as results in polyuria and excessive thirst

Answer 235

* Arterial blood gases frequently taken upon arrival if patient presents as unwell * pH: low * pCO2: low * pO2: adequate * HCO3: low * Therefore acid-base status is: * Acidotic (low pH) * Metabolic acidosis (therefore driver for low pH is the absence of alkali) * Low pCO2 due to sensing of acidaemia by carotic bodies and subsequent increase in respiratory drive/hyperventilation (**respiratory compensation**) * These are common findings in diabetic patients with ketoacidosis *

Answer 236

* Reaching chronic respiratory acidosis or alkalosis is through the action of/compensation by the kidneys (cause the shift) * In metabolic acidosis, respiratory compensation occurs almost immediately, therefore it is very rare that metabolic acidosis occurs without some change in pCO2, unless the patient has very severe lung disease

Answer 237

* Low urinary pH * Normal function of the kidneys, therefore urinary pH will mirror that of the blood pH (increased [H+], lower pH) * This normal response might not be seen in renal tubular acidoses (this is where kidneys fail to secrete protons into the urine, so the blood remains too acidic)

Answer 238

* Reduced bicarbonate reabsorption in PCT delivers a high amount of bicarbonate to DCT * DCT has a limited ability to reabsorb bicarbonate * Leads to massive bicarbonate loss in urine, causing acidosis due to the massive alkali loss * This causes a decrease in bicarbonate concentration * Therefore glomerular filtrate bicarbonate concentration falls * This cycle continues until filtered bicarbonate concentration falls low enough for full bicarbonate reabsorption in the DCT (limits the extent of bicarbonate loss) * Acid urine CAN then be excreted, meaning that severe acidosis does not occur

Answer 239

* Can be associated with isolated effects, e.g. mutation in one of the proteins involved in H+ excretion or HCO3- reabsorption in the PCT * Sometimes associated with a more generalised PCT disorder, however, e.g. Faconi's syndrome

Answer 240

Distal renal tubular acidosis

Answer 241

* Renal tubular acidosis + generalised proximal tubular dysfunction * Associated features: * Aminoaciduria * Glycosuria * Phosphaturia * Impaired vitamin D activation * Raised urinary calcium and citrate levels * Uricosuria (uric acid in the urine) * Hypokalaemia * Can be caused by some toxins causing generalised damage to the proximal tubule (also some antibiotics), but can also be due to genetic defects * Genetic defects have recently been found to include molecules involved in the energetics of the tubule, as the PCT has a high ATP demand * Condition can also occur as a result of kidney transplant

Answer 242

* H+ excretion impaired in the DCT and CD * Typically causes more severe metabolic acidosis than proximal RTA * Diagnosis made by failure to produce acidic urine even in response to acid load with NH4CL * Associated features: * Acidosis mobilises bone calcium: * Osteomalacia (thinning of bones) * Nephrocalcinosis * Renal stones * Above two are due to increased deposition of calcium in the kidneys, and will increase in prevalence * Hypokalaemia

Answer 243

* Osmotic gradient is generated in the renal medulla by the countercurrent mechanism * Urinary filtrate in the collecting ducts runs through this osmotic gradient * In the presence of ADH/vasopressin (from the hypothalamus/posterior pituitary), AQPs are inserted to allow the movement of water out of the filtrate, resulting in the concentration of and a reduced volume of urine

Answer 244

* Specific receptor is a V2 receptor (also V1(a) and V3(or 1b) receptors elsewhere in the body) * AQP4 is constitutively present on the basolateral membrane * Insertion of AQP2 apically increases permeability to H2O * Receptors are coupled to Gs proteins

Answer 245

* AQP4 is constitutively active (basolateral) * AQP2 is inserted in response to ADH (apical)

Answer 246

* Compulsion to drink * Failure of ADH production from the hypothalamus/posterior pituitary * Failure of kidneys to respond to ADH

Answer 247

* Plasma osmolarity is normal, but urine is dilute (for urine) with no real change * Plasma osmolarity rises, indicating concentration of the plasma and therefore should have triggered ADH release and stimulated the concentration of urine by up to ~1000 * Weighing allows the clinician to know whether H2O intake is being restricted as instructed * Can see that the patient has dropped 2.6kg over the time period due to polyuria * These results indicate a failure of the renal response to hyperosmolar blood * Next step is to determine whether this is a renal or pituitary issue * Administer synthetic ADH (DDAVP) - if a normal response is then seen/urine concentrated, then the issue is in the pituitary, whereas if the same response is observed then the issue can be localised to the kidneys

Answer 248

* Increase in weight is due to free access to water * Should have seen an increase in urine osmolarity in response to DDAVP, but as this is not seen then the issue can be located to the kidneys * The diagnosis is therefore: **nephrogenic diabetes insipidus** (kidney cannot respond to ADH)

Answer 249

* Osmotic diuretic causes the osmotic gradient to be less/the lumen to not be as hypoosmolar * Tolvaptan is a V2R antagonist * Can also have failure of ADH action at V2R via mutation * Inflammation in the kidneys stops the tubules from functioning normally, therefore can result in a hopefully transient form of diabetes insipidus

Answer 250

* Interstitial nephritis * Can see eosinophils and other inflammatory cells amongst the tubule cells * This prevents/limits normal tubular function * This causes failure of normal urinary concentration mechanisms and presents initially as thirst and polyuria

Answer 251

* Drugs (idiosyncratic) * Penicillins * Proton pump inhibitors * NSAIDs * Autoimmunity * Sarcoid and Sjogren's commonly present with interstitial nephritis * Injections * CMV * EBV * Toxoplasmosis * Initially present with thirst and polyuria but if they get dehydrated or inflammation is not reversed then the condition can progress to kidney failure

Answer 252

* Macula densa signalling (needs to be attentuated for renin secretion, this occurs when NaCl load is decreased) * SNS innervation

Answer 253

* NB as less NaCl is filtered (indicating decreased delivery/GFR) PCT reabsorption is able to take up more of the NaCl, causing the decreased load to the macula densa * NB Angiotensin II acts as a vasoconstrictor

Answer 254

* Sodium - normal * Potassium - low * Bicarb - slightly alkalotic/high * ACE inhibitors are not affecting blood pressure indicating that the cause of hypertension lies downstream in RAAS * One of the more common causes of this is increased aldosterone secretion * See diagram

Answer 255

* Renal hypoperfusion, e.g. due to renal artery stenosis (atheromatous change in the artery causing it to be narrowed) * Risk factors: older, smoker, male * Fibromuscular hyperplasia (change in the muscle of the renal artery, causing a characteristic series of stenoses along the length of the artery) * Risk factors: Young/middle aged females * Not a common diagnosis, but should be considered in those presenting with hypokalaemia, hypertension and alkalosis * Treatment of stenoses can be achieved through performing angioplasty to open up the vessel and improve renal blood supply (which should also decrease renin secretion) * Top image: renal artery stenosis * Bottom image: Fibromuscular hyperplasia

Answer 256

* Sodium - normal * Potassium - low * Bicarb - slightly alkalotic/high * ACE inhibitors are not affecting blood pressure indicating that the cause of hypertension lies downstream in RAAS * One of the more common causes of this is increased aldosterone secretion * See diagram

Answer 257

* Measure renin and aldosterone levels * If aldosterone is high (and renin is suppressed, as would be expected due to the negative feedback loop), try to identify where the source of secretion is * This presentation indicates a source of excess aldosterone production, for example: * Benign adrenal adenomas (these can sometimes have high secretion despite small size) * Could identify this through imaging - indication would be an enlarged adrenal gland * This can occur for a number of reasons, however, so first would use radiology to insert catheters into the adrenal veins on both sides and confirm from which gland the elevated blood aldosterone levels were coming from

Answer 258

* Underweight and young age raises concerns over accompanying psychiactric disorders (e.g. eating disorder) * Potassium levels are very low * Potential causes of hypokalaemia: * Diarrhoea * Including purgative abuse and malabsorption * Renal artery stenosis * **Conn's syndrome (hyperaldosteronism, on spec)** * Liddle's syndrome * Autosomal dominant condition, gain of function mutation in ENaC * Renal tubular acidosis * Diuretic (ab)use * Bartter's syndrome * Gitelman's syndrome * The two syndromes above are rare genetic conditions, resulting in abnormal K+, Na+ or Cl- handling in the renal tubule

Answer 259

* Potential causes of hypokalaemia: * Diarrhoea * Including purgative abuse and malabsorption * Renal artery stenosis * **Conn's syndrome (hyperaldosteronism, on spec)** * Liddle's syndrome * Autosomal dominant condition, gain of function mutation in ENaC * Renal tubular acidosis * Diuretic (ab)use * Bartter's syndrome * Gitelman's syndrome * The two syndromes above are rare genetic conditions, resulting in abnormal K+, Na+ or Cl- handling in the renal tubule

Answer 260

* If urinary potassium conc is low, can discern that the issue is not likely to be within the kidneys so can then investigate GI causes such as diarrhoea * If GI issue, normal kidney responses should be seen, so in hypokalaemia the normal response is to retain as much potassium as possible * This results in low K+ losses in the urine

Answer 261

* High [K+] in urine indicates that the hypokalaemia is caused by renal losses in some form * This could either be intrinsic within the kidney or driven by hormonal mechanisms * If the latter is true, imbalances in renin or aldosterone will be seen in the blood, and this could be for a number of reasons * There is also likely to be hypertension if RAAS is the reason for potassium imbalance

Answer 262

* Next step is to check plasma bicarbonate levels * If low, this could be due to renal tubular acidosis and so further tests are required to check whether this is distal or proximal * If high, need to check urinary concentration of Cl- * If alkalotic, high plasma bicarbonate and high urinary Cl-, we consider: * Gitelman syndrome * Bartter syndrome * Magnesium deficiency * Diuretic (ab)use * If urinary concentration of Cl- is low, we condsider: * Gastric loss: vomiting (loss of HCl from stomach, kidneys compensate for this loss by reabsorbing as much Cl- as poss. at the expense of K+) * Nonreabsorbable ion

Answer 263

* Caused by loss of function in the thick ascending limb of the loop of Henle * Can compare mechanism with the action of furosemide (targets NKCC), but as action of the channels in the TALH are all integrated, genetic mutations in any of the channels can all alter uptake of NaCl * Bartter syndrome can be caused by mutations in at least five genes. * Mutations in the SLC12A1 gene cause type I. * Type II results from mutations in the KCNJ1 gene. * Mutations in the CLCNKB gene are responsible for type III. * Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes. * Presentation can occur either as a neonate or at a slightly older age (classical presentation) * Symptoms: * Autosomal recessive * Salt and water wasting * Hypokalaemia * Alkalosis * Increased renin and aldosterone

Answer 264

* Caused by loss of function mutations in the thiazide sensitive channel (NCCT) in the distal convoluted tubule * Can be compared to thiazide usage * Less commonly seen is a causative mutation in the CLC-Kb channel, occurs due to the integration of channels in epithelia * Later presentation – often in adulthood * This is due to the milder presentation of this syndrome (much less severe than Bartter's) so is only picked up fairly late * Autosomal recessive * Symptoms * Normotensive, muscle cramps / weakness * No polyuria * Hypokalaemia * Hypocalciuria * Hypomagnesmia * Metabolic alkalosis

Answer 265

* Very rare * Due to GAIN of function mutations in ENaC resulting in hypertension * Can be treated with amiloride

Answer 266

* EARLY EFFECTS may relate to site of damage * E.g. Nephrotic syndrome * Glomerulonephritis * Tubulo-interstitial nephritis * END RESULT is nephron loss with consequent loss of * EXCRETORY FUNCTION * CONTROL OF BODY WATER * CONTROL OF BLOOD PRESSURE * Many patients become hypertensive, which can then lead to further kidney damage * CONTROL OF pH * CONTROL OF HAEMATOCRIT * Patients can become anaemic * CONTROL OF BONE METABOLISM * This is due to the role of the kidney in phosphate excretion and VitD3 activation

Answer 267

* Patient has chronic kidney disease * Creatinine levels show significant elevation due to decreased GFR and therefore a failure to properly excrete waste products * Corrected calcium (e.g. corrected for proteins) are low due to increased phosphate concentrations in the blood and decreased production of VitD3 in the kidney * Phosphate is significantly incresaed due to lack of phosphate excretion/over secretion of PTH * Alkaline phosphatase is elevated due to increased bone turnover as the body attempts to correct the altered biochemistry/lack of calcium * Also driven by increase in PTH levels, which is increased in response to hypocalcaemia * Patients become anaemic in chronic renal failure (decreased EPO secretion)

Answer 268

* Renal failure means that VitD3 cannot be activated, and a decreased GFR also occurs therefore limiting Pi excretion * Decreased plasma calcium concentration (due to inactivity of VitD3) is sensed in the parathyroid gland, causing increased secretion of PTH * This leads to increased bone breakdown, which in turn increases alkaline phosphatase and release of Ca and Pi * As ingestion of Pi continues as normal and excretion is impaired, plasma Pi rapidly rises * This exacerbates the decreased Ca2+ levels as Ca3(PO4)2 is insoluble * Therefore, if Pi increases, Ca2+ decreases, and if Ca2+ decreases, Pi again increases * Decreased Ca2+ will also cause PTH release and breakdown of bone, releasing more Pi alongside Ca2+ * This means that PTH contributions to restore plasma Ca2+ through bone breakdown can never fully restore blood calcium levels, partly due to its interactions with Pi * Calcium also moves into tissues, meaning that patients have a lot of calcification (particularly in blood vessels)

Answer 269

* Can replace active Vitamin D3 with drugs such as ergocalciferol * Reducing intake and absorption of phosphate can be done through changing the diet or through giving phosphate-binding drugs so that not all of the Pi in the diet is absorbed * Calcimimetics sensitise Ca2+ sensing receptors on parathyroid gland, making them **more** sensitive than usual * This suppresses PTH secretion (as CaSR activation **inhibits** release of PTH) * If the above treatments fail, hyperparathyroidism will occur in which the best treatment is some form of surgical excision

Answer 270

* In health, kidneys are the main source of EPO * EPO acts as a survival factor for RBC precursors in the bone marrow * If EPO levels increase, so do the survival rates of RBC precursors, increasing RBC production which in turn improves/increases the haematocrit * This should ideally increase the oxygen-carrying capacity of the blood, therefore turning off the hypoxic signal for EPO release

Answer 271

* Upper/diagonal bar is normal physiology * Lower bar is renal failure * In anaemia, plasma levels of EPO increase massively * As long as Fe is available and the bone marrow is functioning, more RBCs are produced to restore blood [Hb] and O2 saturation * Patients with chronic kidney disease can normally not secrete EPO, so as Hb falls an adequate response cannot be mounted * This causes them to equilibrate at a lower [Hb] * In untreated patients, [Hb] = as low as ~6-8g/L * In health, as haemoglobin levels fall erythropoietin is produced by renal interstitial fibroblasts in response to elevated levels and activity of HIF-2alpha resulting from oxygen-regulated inhibition of HIF-hydroxylase activity.

Answer 272

* Haemodialysis * Allows clearance of waste products from the blood * Often needed fairly frequently (3x a week) * CAPD/APD * Continuous ambulatory peritoneal dialysis, replace kidney function through using the fine capillaries in the peritoneum, put a certain amount of fluid in the peritoneal space and drain/replace frequently to continue dialysis * Automated peritoneal dialysis (APD) is similar to CAPD, except a machine is used to control the exchange of fluid during sleep - bag is attached (filled with dialysate fluid) and connected to the APD machine before going to bed. During sleep, the machine automatically performs a number of fluid exchanges. * Transplantation * Palliative care (especially in older patients with comorbidities) * Diet and fluid restriction * Drugs to treat complications * Blood pressure * Anaemia * Mineral bone disease

Answer 273

* Renal function -\> Increases sodium reabsorption and potassium excretion * Vascular tone -\> Increases vascular tone due to endothelial dysfunction and enhances the pressor response to catecholamines and up‐regulation of angiotensin II receptors * Circulating volume -\> Increases circulating volume

Answer 274

* Renal function -\> Increases GFR by increasing glomerular blood flow and increases phosphate excretion by decreasing its reabsorption in the proximal tubules. In excess, cortisol has aldosterone-like effects in the kidney causing salt and water retention. * Vascular tone -\> Increases vascular tone * Circulating volume -\> Increases circulating volume [CHECK THESE]

Answer 275

* Renal function -\> Decreases flow to kidneys by increasing the resistance in all renal vascular segments, leading to antidiuresis * Vascular tone -\> Decreases vascular tone * Circulating volume -\> Increases circulating volume [CHECK THESE]

52. Hypertension and Cardiac Failure Flashcards

(328 cards)