51. Electrolytes and Fluid Balance Flashcards

Question

What things can affect the extracellular concentration of potassium, [K⁺]_o by changing the action of the cell-surface Na⁺/K⁺-ATPase?

Answer 1

* Insulin * Catecholamines * Acid-base status * Hypoxia * Exercise

Answer 2

* Insulin -\> Decreases * Catecholamines -\> Increase/Decrease (depending on whether they are alpha or beta agonists) * Acid-base status -\> Increase/Decrease (acid leads to hyperkalemia) * Hypoxia -\> Increase * Exercise -\> Increase

Answer 3

* Pancreas -\> Secretes insulin * Adrenal glands -\> Secrete adrenaline and aldosterone

Answer 4

It decreases plasma potassium by moving potassium into cells: * When there is increased extracellular potassium, there is increased insulin secretion from beta cells of the pancreas * Stimulates Na⁺/K⁺-ATPase on cell membrane * This is due to second messenger which is not agreed upon, but it is probably a protein kinase that phosphorylates the ATPase * It also has an effect via stimulating Na⁺-glucose co-transport into the cell, which drives the ATPase

Answer 5

* α agonists increase plasma potassium * β₂agonists decrease plasma potassium

Answer 6

It decreases plasma potassium by moving potassium into cells: * Stimulates Na⁺/K⁺-ATPase on cell membrane

Answer 7

It decreases plasma potassium by moving potassium into cells: * Stimulates Na⁺/K⁺-ATPase on cell membrane

Answer 8

Causes a transient hyperkalemia followed by hypokalemia: * This is due to the fact that it is a non-selective adrenergic agonist * The hyperkalemia is due to it acting on alpha receptors * The hypokalemia is due to it acting on beta-2 receptors

Answer 9

In asthmatics who use salbutamol, overdose of salbutamol can result in hypokalemia.

Answer 10

* Insulin (+ Dextrose) -\> Slower * Beta-2 agonist (e.g. salbutamol) -\> Faster

Answer 11

* Metabolic acidosis leads to hyperkalemia * However, this is only the case with mineral acid (HCl) and not organic acid (lactic)

Answer 12

* Mineral acid (e.g. HCl) -\> Increase by 0.7mM * Organic acid (e.g. lactic acid) -\> No change

Answer 13

No, because it produces lactic acid, but lactic acid does not lead to hyperkalemia (like HCl does) since it is an organic acid. Therefore, it must be by a different mechanism.

Answer 14

* The acid responsible is HCl (not lactic acid). * H⁺ ions produced in cells are pumped into the blood in exchange for sodium. * High extracellular H⁺ decreases the gradient for this to happen. * This results in decreased intracellular sodium, so there less exchanged for potassium by the ATPase. * This leads to hyperkalemia. (In the diagram, consider everything outside of the cell to be blood.)

Answer 15

For every 0.1 drop in pH, potassium increases by 0.1mM. This is caused by hypercapnia causing the pH to drop.

Answer 16

* It leads to hypokalemia. * In respiratory alkalosis, potassium drops by around 0.3mM. * In metabolic alkalosis, potassium drops by around 0.2mM.

Answer 17

Hypoxia causes hyperkalemia.

Answer 18

* Hypoxia leads to hyperkalemia * This is thought be due to low oxygen causing a drop in ATP levels, which leads to K_ATP channels remaining open, so that potassium can flow out of the cell.

Answer 19

Exercise leads to hyperkalemia: * Potassium is lost from cells through delayed rectifier channels * Incomplete reuptake of the potassium by the Na⁺/K⁺-ATPase leads to hyperkalemia

Answer 20

Insulin and catecholamines increase the rate of potassium reuptake by the Na⁺/K⁺-ATPase.

Answer 21

* The initial rise is due to potassium expelled from cells during muscle contraction * The drop afterwards is due to catecholamines, which stimulate the Na⁺/K⁺-pump by the beta-2 pathway

Answer 22

It enhances the hyperkalemia caused by exercise. This is because propranolol is a β antagonist, so it promotes hyperkalemia since it slows down the Na⁺/K⁺-ATPase.

Answer 23

* In McArdle's disease, the patient is unable to produce lactic acid from glucose * However, if these patients exercise, there is still a normal rise in plasma potassium

Answer 24

* Skeletal muscle fatigue * Skeletal muscle hyperaemia (excess of blood in vessels supplying the muscle) * Blood pressure regulation * Hyperpnoea (increased breathing rate) * Myocardial stability

Answer 25

* Muscle weakness * Cardiac dysrythmias

Answer 26

* It has been proposed to be lactic acid, but this is controversial * Hydrogen ions (acid) are known to be negatively inotropic in muscle * Potassium can also cause depolarisation of nociceptive nerve fibres, leading to the feeling of burning

Answer 27

* At rest: 3.5-5.5mmol/L * During exercise there is an acute increase in potassium. [CHECK the normal range for exercise]

Answer 28

* Potassium released by muscles during exercise leads to hyperpolarisation of arterial muscle, so that blood flow to that muscle increases (hyperaemia) * (Knochel, 1972): * Blood flow through a muscle was correlated with the potassium released during exercise * Causation was shown by depletion of potassium from the system, which resulted in no change in blood flow

Answer 29

* The potassium released by the muscle during exercise causing depolarisation and therefore activation of the C-type pain fibres in the muscle * This triggers the muscle-pressor reflex, mediated by the brain: * Vasoconstriction in non-exercising vascular beds * Sympathetic activation of the heart * Hyperkalemia is detected by arterial chemoreceptors, particularly in the carotid body * The carotid body feeds back to the cardiorespiratory integrating centre via the glossopharyngeal nerve (IX) * The response triggered involves stimulation of the diaphragm and intercostal muscles, so that the breathing rate is increased

Answer 30

This allows them to detect hyperkalemia and respond to it.

Answer 31

The catecholamines and potassium cancel out each others deleterious effects (mutual antagonism). The angiotensin pathway is also involved. The increased calcium entry due to catecholamines and angiotensin cancels out the negative inotropic effect of potassium.

Answer 32

* Insulin, dextrose and beta-2 agonists are used. * In renal failure, dialysis is used. * If a very fast response is required, calcium injection can antagonise the negative inotropic effect of hyperkalemia -\> Allows time for clinical intervention

Answer 33

* (Band, 1985) * Injection of potassium chloride into a cat caused the ventilation to increase * When the carotid chemoreceptor nerves were cut, this effect was lost

Answer 34

No, only peripheral ones, because it cannot cross the blood-brain barrier easily.

Answer 35

* Hypokalemia -\> Vomiting + Diarrhoea * Hyperkalemia -\> Renal failure

Answer 36

Intracellular calcium levels are 10,000 fold lower than extracellular levels.

Answer 37

* Extracellular -\> 2.4mM * Intracellular -\> 0.1 micromolar

Answer 38

2.4mM, but only half of this (1.2mM) is free calcium: * 50% = Free, biologically active * 40% = Reversibly bound to protein * 10% = Bound to citrate or phosphate

Answer 39

* Cell division (mitotic spindle) * Muscle contraction (cross bridge cycling) * Cell motility * Membrane trafficking * Exocytosis via Ca2+ dependent activation of SNARE proteins

Answer 40

No, because there is a calcium pump that maintains the concentration gradient.

Answer 41

It tries to maintain free plasma calcium at 1.2mM, because this is the biologically active form.

Answer 42

* 1kg (25 moles) * 99% of this is in bones as hydroxyapatite, 1% is in the ECF

Answer 43

* 1% is freely exchangeable * 99% is hydroxyapatite bound to collagen (slowly-exchangeable)

Answer 44

* Important effects on excitable tissues and blood clotting * Essential component of bone There is, therefore, a conflict between ensuring that plasma calcium does not fall, and conserving calcium in the bone. In normal physiology the demands of plasma calcium are stronger, and the bones contains huge reserves of calcium that can be drawn on for some time before there is any appreciable weakening of the bones.

Answer 45

Hypocalcaemia

Answer 46

* Changes to the electrical activity of the heart, including a long QT and heart failure * Muscle spasms -\> Closure of vocal cords can occur, leading to asphyxiation * In chronic hypocalcaemia, some of the symptoms are explained by the underlying problems that are causing the low calcium, including kidney disease, hypoparathyroidism and sepsis: * Calcification of parts of the brain and seizures are seen with hypoparathyroidism. * Epidermal changes are common, as are changes in muscle function, such as an abnormal gait.

Answer 47

Partial depolarisation of the membrane due to the charge of the calcium and also increases in sodium permeability (via action on the sodium channels) of the neuron membrane.

Answer 48

Acute: * Secondary hypocalcaemia can rapidly occur following hyperventilation, where the pH increases, meaning that proteins bind calcium and so free ionised calcium falls Chronic: * Kidney disease * Hypoparathyroidism * Sepsis

Answer 49

* Chvostek and Trousseau signs are indicators of hypocalcaemia. * The tests involve tapping the facial nerve (Chvostek) and constriction of the brachial artery (Trosseau), which induces tetany in the facial muscles and hand/wrist muscles respectively.

Answer 50

Acutely: * Intravenous calcium Chronic: * Treating the underlying cause, such as vitamin D supplementation

Answer 51

* Decreased muscle excitability -\> Hyperpolarisation due to calcium decreasing voltage-gated sodium channel activity * Short QT on ECG * Kidney stone formation

Answer 52

For example, primary hyperthyroidism resulting from multiple endocrine neoplasia.

Answer 53

Polyuria helps rid the body of the excess calcium, but it also concentrates the plasma, renewing the problem.

Answer 54

Limbus sign in the eyes.

Answer 55

Treatment involves hydration and forced diuresis to remove excess calcium, along with treatment of the underlying cause, such as calcitonin supplements.

Answer 56

It is important to factor in for abnormal albumin levels which may affect the fraction of free calcium.

Answer 57

* Hypercalcaemia -\> Multiple myeloma (tumour of the plasma cells in bone marrow) reduces free calcium by binding it to immunoglobulins * Hypocalcaemia -\> Nephrotic syndrome results in protein leaking into the urine, so that blood protein is low and therefore free calcium is high

Answer 58

* Alkalosis -\> Increases negative charge on plasma proteins -\> More calcium binds to proteins -\> Hypocalcaemia * Acidosis -\> Decreases negative charge on plasma proteins -\> Less calcium binds to proteins -\> Hypercalcaemia

Answer 59

In general, net intake (diet - faeces) equals the excretion in the urine. Most of the calcium that reaches the kidney is reabsorbed.

Answer 60

* Net intake (diet minus faeces) = 3-5 mmol/day * Loss in urine = 3-5 mmol/day

Answer 61

* Children, pregnant women and lactating women -\> Have a net accumulation of 3 mmoles of calcium per day * During pubertal growth spurt -\> Accumulation of 5-7 mmoles of calcium per day * Post-menopausal women and ageing males -\> Lose Ca²⁺and undergo osteoporosis, so need increased intake

Answer 62

No, protein-bound calcium is not filtered.

Answer 63

* Vitamin D (active form a.k.a. calcitriol) * Parathyroid hormone (PTH) * Calcitonin FGF-23 is technically involved in phopshate homeostasis, but it also regulated vitamin D and PTH levels, so it also impacts calcium.

Answer 64

* Mostly as hydroxyapatite, Ca₁₀(PO₄)₆OH₂, which is not exchangeable * But also as exchangeable, non-crystalline salts and as calcium bone fluid, which protect against hypocalcaemia

Answer 65

* Osteoblasts are activated by PTH, which leads to RANKL presentation on the osteoblast surface * Osteoclasts' RANK receptors bind this RANKL to get activated * This means that bone breakdown cannot occur without bone being laid down, which allows balance * OPG (osteoprotegerin) is a naturally occuring RANKL decoy, decreasing activation of RANK receptors -\> PTH downregulates this

Answer 66

* Oestrogen and testosterone stimulate osteoblasts and precursors * Therefore, deficits lead to osteoporosis, especially in post-menopausal women.

Answer 67

* Need for bone remodelling is somehow sensed by osteocytes trapped in the bone * They secrete soluble RANKL, which along with RANKL on osteoblasts, binds to RANK receptors on osteoclast surface * This leads to activation of the osteoclasts * In turns, osteoclastic activity leads to release of TGF-β1 and IGF-1 from the bone matrix, which lead to the maturation of osteoblast progenitors * Osteoclasts also release sema4D, which prevents excessive activation of osteoblasts

Answer 68

Sema4D antagonists can be used, which decreases the inhibition of osteoblast activation.

Answer 69

* Parathyroid hormone (PTH) -\> Responds to low extracellular calcium in the short-term by mobilisation of Ca²⁺ from stores in the bone * Calcitriol -\> Responds to a chronic lack of calcium in the plasma, leading to an increase in net uptake of calcium. * This allows rapid maintenance of a constant plasma calcium, while simultaneously ensuring that there is a net maintenance of calcium stores for structural functions. * Calcitonin -\> Responds to high extracellular calcium.

Answer 70

* PTH is produced in the parathyroid glands and is the major hormone acting in response to low plasma calcium. * Low calcium is detected via calcium-sensing receptors (CaSR), which are GPCRs that act via Gq and Gi actions. * When calcium is low, IP₃ is low and cAMP is increased, leading to release of PTH.

Answer 71

(Brown, 1993): * The parathyroid CaSR was cloned to produce BoPCaR, which had similar properties and helped determine that other divalent ions have a similar effect as calcium on the receptor

Answer 72

* In bone: * PTH acts on PTH1R, found on osteoblasts. * This in turn triggers RANKL release, which binds to RANK receptors on osteoclasts, completing their differentiation and activation. * PTH also inhibits osteoprotegerin, which is a decoy receptor for RANKL. * Chronically raised PTH leads to bone breakdown, thus increasing extracellular calcium. * Also stimulates the PTH calcium pump in bone, quickly mobilising calcium. * In the kidney proximal tubule: * PTH binds to PTH1R * Stimulates production (in the proximal tubule) and action of 1 alpha-hydroxylase, which catalyses the production of calcitriol (an active form of vitamin D) by hydroxylation of vitamin D * In the kidney distal tubule: * PTH binds to PTH1R * Stimulates active calcium reabsorption from the distal tubule and collecting duct [CHECK IF THIS IS AN INDIRECT EFFECT VIA CALCITRIOL] * It also decreases phosphate reabsorption from the proximal tubule, which is significant because phosphate usually forms insoluble salts with calcium, reducing free ionized calcium in the blood. Summary: Stimulates osteoclasts, calcium efflux from bone, kidney calcium reabsorption, and vitamin D activation.

Answer 73

* Deficiency of PTH (hypoparathyroidism) -\> Leads to low plasma Ca²⁺ and tetany * Pseudohypoparathyroidism -\> Resistance to PTH due to receptor defect. * Excess hyperparathyroidism (tumours, such as MEN-1) -\> Leads to raised plasma Ca²⁺, bone destruction, urinary stones and sluggish CNS.

Answer 74

PTH1R and PTH2R

Answer 75

* PTH acts on PTH1R, found on osteoblasts. * This in turn triggers RANKL release, which binds to RANK receptors on osteoclasts, completing their differentiation and activation. * PTH also inhibits osteoprotegerin, which is a decoy receptor for RANKL. * Also stimulates the PTH calcium pump in bone, quickly mobilising calcium. * Chronically raised PTH leads to net bone breakdown, thus increasing extracellular calcium.

Answer 76

Proximal tubule

Answer 77

* Diuretics that work on the thick ascending limb such as furosemide (loop diuretic) decrease calcium absorption. * Diuretics acting on the distal tubule such as amiloride & thiazides increase calcium uptake.

Answer 78

It increases whole body calcium, via stimulating uptake.

Answer 79

* In the skin, UV light converts a cholesterol derivative to cholecalciferol (pre-vitamin D3) * In the liver, this is hydroxylated at the 25th position, leading to an inactive form. * In the kidney, this is hydroxylated at the 1st position, which activates the vitamin D. This is under the control of PTH. There is also some dietary intake of D3.

Answer 80

Calcitriol

Answer 81

PTH, which occurs most when PTH is raised chronically. This suggests that PTH responds to acute drops in calcium, while chronically low calcium levels are responded to by calcitriol.

Answer 82

PTH is a peptide hormone, while calcitriol is a steroid hormone, meaning that PTH has a shorter duration of action than calcitriol.

Answer 83

They are intracellular receptors, since calcitriol is a steroid hormone.

Answer 84

* In the intestine: * Increases transcellular calcium uptake from the diet * By synthesis of calbindin, an intracellular Ca²⁺-binding protein, as well as stimulating paracellular uptake. * In the kidney: * Reduces excretion of calcium and phosphate * In bone: * Supports the action of PTH * Inhibits synthesis of collagen by osteoblasts and increases osteoclast action In other words, it supports the action of PTH along with stimulating uptake of calcium from the diet.

Answer 85

* Rickets (in children) * Osteomalacia (adults) [IMPORTANT] * Vitamin D poisoning

Answer 86

* Rickets is a condition that results in weak/soft bones in children * This is due to vitamin D deficiency or mutations in the calcitriol receptor * This may be counter-intuitive since calcitriol is involved in breakdown of bone to mobilise calcium, but the reason why this happens is because low levels of vitamin D (calcitriol) lead to increased secretion of PTH that breakdown bone and also because vitamin D is required for absorption of calcium

Answer 87

* Osteomalacia is a condition that results in weak/soft bones in adults * This is usually due to vitamin D deficiency * This may be counter-intuitive since calcitriol is involved in breakdown of bone to mobilise calcium, but the reason why this happens is because low levels of vitamin D (calcitriol) lead to increased secretion of PTH that breakdown bone and also because vitamin D is required for absorption of calcium

Answer 88

Pathologies of vitamin D are not usually marked by abnormal extracellular calcium, which demonstrates its role is primarily in controlling net flux of calcium through the body, rather than plasma calcium homeostasis.

Answer 89

* PTH, involved in acute response to hypocalcaemia, is required for activation of vitamin D (when PTH is chronically activated) * Vitamin D inhibits PTH (negative feedback) * This demonstrates how PTH is mostly involved in acute control, while vitamin D is involved in chronic control * It also explains why vitamin D deficiency leads to rickets (since there is decreased inhibition of PTH)

Answer 90

Calcitriol ends in 'ol' so it is a steroid (cholesterol) hormone, which means it is the activated form of vitamin D. Calcitonin is calcitonin.

Answer 91

It has a calcium-sensing receptor (CaSR) that detects low plasma calcium.

Answer 92

* Parathyroid gland -\> Controls release of PTH * Renal tubules of the kidney -\> Controls reabsorption of calcium * Brain * Gut enterocytes * Osteoblasts

Answer 93

* Low calcium is detected via calcium-sensing receptors (CaSR), which are GPCRs that act via Gq and Gi actions. * When calcium is low, IP3 is low and cAMP is increased, leading to release of PTH.

Answer 94

* Calcimimetics are drugs that mimic or sensitise the stimulation of CaSR by calcium. * Therefore, they lead to lower release of PTH. * Thus, they can be used to treat hyperthyroidism.

Answer 95

It is the only hormone that actively decreases plasma calcium levels.

Answer 96

Peptide (so it has a short duration of action)

Answer 97

C cells in the thyroid

Answer 98

* In bone: * Inhibits osteoclasts activity, most of all in children. * In the intestines: * Helps control uptake of calcium after a meal by inhibiting uptake * In the kidney: * Pharmacological doses affect calcium fluxes

Answer 99

Gs-coupled

Answer 100

During pregnancy and the lactation period, calcitonin is increased, which primarily acts to ensure that sufficient calcium is preserved for the mother (since it promotes storage in bone).

Answer 101

* Deficiency -\> Compensation by changes in PTH. * Excess -\> Uncontrolled secretion from ‘medullary’ carcinoma of thyroid. In both these situations, serum calcium is maintained at approximately normal levels.

Answer 102

They have an inverse relationship.

Answer 103

FGF23: * Released by osteocytes when they sense high phosphate levels * FGF23 has these effects: * Promotes phosphate and calcium excretion * Downregulates PTH formation * Downregulates vitamin D activation * Therefore, calcium levels and phosphate levels drop

Answer 104

* PTH and calcitriol overlap to a large degree but keep in mind that the primary function of these two hormones are very different. * The main role of active calcitriol is to promote mineralization of new bone (mainly through indirect mechanisms) and as a result, increase the absorption of both calcium and phosphate. * On the contrary, PTH acts as guardian against hypocalcaemia and therefore this hormone therefore promotes the loss of phopshate (in addition to the increased absorption of calcium) in order to increase free plasma calcium.

Answer 105

* Hyperplasia of the parathyroid gland in response to perceived low plasma calcium levels. * Primary hyperparathyroidism -\> Usually due to tumours of the parathyroid gland. The phenotype shows an osteoporosis-like phenotype (due to excess osteoclast activity) along with HYPERcalcaemia. * Secondary hyperparathyroidism -\> Usually due to kidney failure, which means that calcitriol cannot be produced. The phenotype shows an osteoporosis-like phenotype (due to excess osteoclast activity) along with HYPOcalcaemia, since there is insufficient calcitriol to promote calcium absorption from the diet.

Answer 106

Green is normal bone, while yellow is actively exchanged bone.

Answer 107

* PTH -\> Increasing reabsorption of calcium from the kidney and osteoblast/osteoclast activity * Calcitriol -\> Increasing dietary absorption of calcium * Calcitonin -\> Decreasing osteoclast activity and aborption of dietary calcium, Increasing calcium excretion in urine

Answer 108

Primary regulators: * RAA axis * ADH (vasopressin) * ANP / BNP (natriuretic factors) Secondary regulators: * ACTH - cortisol axis

Answer 109

The CVP increases first because of the high compliance of the venous system.

Answer 110

* Carotid and aortic baroreceptors -\> High pressure, for arterial pressure * Renal baroreceptors -\> Medium pressure, for renal perfusion * Atrial stretch receptors -\> Low pressure baroreceptors, for blood volume and CVP Also: * Left ventricular stretch receptors -\> Related to secretion of BNP * Macula densa -\> Flow detectors, related to distal convoluted tubule

Answer 111

* Osmolarity -\> Alterations in water balance * Volume -\> Alterations in Na⁺ balance.

Answer 112

* Renin is released from juxtaglomerular cells surrounding the afferent arteriole due to: * Renal baroreceptors (low pressure) detecting drops in pressure * Macula densa detecting decreased salt or water flow * Sympathetic stimulation * (Release is also decreased by negative feedback of angiotensin II) * Renin cleaves angiotensinogen (made in the liver) to form angiotensin I * In the lungs, ACE cleaves angiotensin I to angiotensin II * Angiotensin II: * Stimulates sympathetic activity * Stimulates NaCl reabsorption in the proximal tubule * Stimulates arterial vasoconstriction (except renal afferent arterioles) * Stimulates ADH secretion * Stimulates aldosterone release from the adrenal cortex * Aldosterone: * Stimulates sodium and water retention in the distal tubule, with potassium and proton loss

Answer 113

* Causes vasoconstriction * Causes release of aldosterone Other actions: * Stimulates sodium reabsorption at several renal tubular sites * Stimulates ADH release from the posterior pituitary * Stimulates thirst centers within the brain * Enhaces sympathetic activity * Stimulates cardiac hypertrophy and vascular hypertrophy

Answer 114

* Stimulates Na⁺/H⁺ exchangers located on the apical membranes of cells in the proximal tubule and thick ascending limb of the loop of Henle * Stimulates apical Na⁺ channels in the collecting duct

Answer 115

In approximate descending order of potency: * Plasma potassium concentration * Angiotensin II * Plasma acidosis * Low atrial pressure (detected by atrial baroreceptors) * ACTH

Answer 116

* Increase the number of sodium channels (ENaC) in the luminal membrane * Increase the activity and number of Na⁺/K⁺-ATPase pumps on the basolateral membrane, increasing sodium reabsorption in exchange for K and H (principal cells) * Increase the activity and number of sodium-chloride symporters (NCC) in the distal convoluted tubule * Increase H⁺-ATPase pumps (intercalated cells), leading to further loss of protons * Increases sodium and water absorption from the gut, in exchange for K⁺ and H⁺.

Answer 117

* When there is increased intake of sodium, there is increased concentration and osmolarity of body fluid * ADH increases water retention, so concentration falls but volume increases * ANP increases salt excretion (while angiotensin-aldosterone system increases sodium retention, so it is downregulated) * Increased salt excretion leads to lower osmolarity, so ADH is down-regulated and water is not retained * This means that the volume also falls back to normal In this way, the two mechanisms allow maintenance of osmolarity and volume.

Answer 118

Mostly triggered by: * Rising plasma osmolarity * Detected by the hypothalamic osmoreceptors And to a lesser extent: * Hypovolaemia * Detected as fall in CVP by the atrial baroreceptors (low-pressure) * Signal to the nucleus tractus solitarii and lead to ADH production in the hypothalamus * Hypotension * Detected by carotid and aortic arch baroreceptors * Leads to activation of the sympathetic nervous system, which triggers ADH synthesis and release * Angiotensin II * Acts directly on the hypothalamus.

Answer 119

* Insertion of aquaporins II in collecting duct principle cells * Activation of NKCC in thick ascending loop of Henle * Activation of urea transporters in the inner medullary collecting duct principle cells * Slowing of the blood flow through the vasa recta This is via binding of V2 receptors in the collecting duct. ADH also stimulates vasoconstriction and pituitary release of ACTH via V1 receptors.

Answer 120

* Atrial natriuretic peptide (ANP) -\> From the atria * B-type natriuretic peptide (BNP) -\> From the (left) ventricles

Answer 121

They signal blood volume expansion, since their release is triggered by stretch of the atria.

Answer 122

* Natriuretic and diuretic effects at the kidney * Vasodilation * Inhibition of the RAA axis * Inhibition of sympathetic nervous activity systemically, but especially to the kidney

Answer 123

It is like the 'brake' to RAA axis, inhibiting it and counteracting it.

Answer 124

BNP, and especially the "inactive" part of pro-BNP (known as NT-proBNP, for N-terminal pro-BNP), are widely used clinically as markers of cardiac failure. Blood concentrations of these compounds can provide an easy and relatively objective measure of the severity and progression of cardiac failure.

Answer 125

* They are not directly concerned with direct regulation of fluid volume in normal circumstances, but they can influence it, especially when secreted at high levels. * Cortisol at high levels, like aldosterone, causes sodium retention and potassium loss. * This effect is seen in Cushing's disease, which involves high levels of cortisol secretion. Unlike aldosterone, cortisol excess usually produces a moderate degree of peripheral oedema. There is usually also a modest degree of arterial hypertension, though usually less than that seen with aldosterone excess.

Answer 126

* Shock * Dehydration * Heart failure * Hypertension Note: These will be discussed more in-depth in their respective lectures.

Answer 127

* The formal definition of shock is concerned with tissue hypoxia, which can include biochemical abnormalities (failure to utilize oxygen effectively) as well as cardiovascular problems. * But usually when people talk about shock they mean "distributive shock", named after a failure of distribution of blood, which implies under-perfusion of tissues (i.e., tissue ischaemia because of a failure of the blood supply). * The three most common types: * Septic shock * Cardiogenic shock * Hypovolaemic shock

Answer 128

* When an infection results in a widespread systemic acute inflammatory response, causing widespread arteriolar dilation and an increase in the permeability of the post-capillary venules. * Thus there may be a reduction in absolute blood volume (because of loss of plasma into the tissues) as well as a significant increase in vascular volume (because of the vasodilation), meaning a substantial fall in arterial pressure.

Answer 129

* Under-perfusion of the kidneys activates the RAA axis. * Sympathetic nervous system is activated by the fall in blood pressure, RAA axis and the inflammatory response directly. * ADH is released in response to the fall in blood pressure and the activation of the RAA axis. * Acidaemia, which is a characteristic feature of this type of shock (because the under-perfused tissues resort to anaerobic metabolism), further activates the RAA axis.

Answer 130

* Fluids * Vasoconstriction * Treating the underlying cause

Answer 131

Shock (it is just a more mild version)

Answer 132

Most patients with heart failure present with oedema of some kind: * Pulmonary oedema -\> In the case of left ventricular failure * Peripheral oedema (sacral or ankle) -\> In the case of right ventricular failure The oedema results from a combination of increased venous pressure from venous congestion behind the failing chamber, and dilution of plasma proteins by the kidney's retention of water and sodium.

Answer 133

* Retention is due to hypotension (because of the fall in output from the failing ventricle) and thus a fall in renal perfusion. * The hypotension also triggers the baroreceptor reflex and so the sympathetic nervous system is activated. Sympathetic innervation "primes" the kidney to increase secretion of renin. * Since no additional proteins are produced, the nlood is diluted and therefore water moves out of the blood, causing oedema.

Answer 134

* The stretch of the atria and ventricles in heart failure triggers ANP and BNP * You might think that this would counteract the retention of salt and water by inhibiting the RAA axis, but the RAA axis appears to predominate still

Answer 135

* Diuretics (risk of electrolyte disturbance and also of hypotension that can exacerbate the disease process) * RAA antagonists * Vaptans (ADH antagonisis, relatively weak action but perhaps useful as adjuncts to other therapies) This is covered in more detail in another lecture.

Answer 136

* Conn's syndrome (primary hyperaldosteronism) * Addison's disease (hypoadrenalism) [EXTRA]

Answer 137

* It is primary hyperaldosteronism, which means that there is a tumour (or other cause) in the zona glomerulosa of the adrenal cortex causing excess secretion of aldosterone * Symptoms: * Hypokalaemia * Increased systemic arterial blood pressure (due to sodium retention) * Potentially a metabolic alkalosis (but usually not significant) * In practice, patients usually complain of weakness and fatigue (because of the hypokalaemia) and intermittent throbbing headaches. * Treatment: * Aldosterone antagonist (e.g. spironolactone). * Remove the adenoma, if there is one

Answer 138

* It is hypoadrenalism, which is the deficiency of steroid secretion from the adrenal cortex, including both aldosterone and the glucocorticoids such as cortisol. * Most often due to an autoimmune reaction but sometimes secondary to infection * Symptoms include a failure to maintain an adequate arterial blood pressure (because of the lack of aldosterone) and metabolic disturbances (because of the lack of glucocorticoids).

Answer 139

* Neurogenic diabetes insipidus -\> Failure of secretion of ADH, usually following injury to pituitary stalk (e.g., whiplash). Supplement ADH. * Nephrogenic diabetes insipidus -\> Autoimmune attack on renal ADH receptors. Give immune suppression. * SIADH -\> Excess ADH secretion due to tumours, etc. Give ADH antagonists if the primary condition is not treatable.

Answer 140

pH = -log₁₀[H⁺]

Answer 141

The structure and function of many large organic molecules is very sensitive to [H⁺].

Answer 142

* Acids (symbolised AH) are taken in from the diet * These are buffered and taken out of solution by buffers (symbolised B^-) in the body, such as proteins and bicarbonate The problem with this is that substances such as water make defining acids, bases, buffers, etc. very difficult. For example, water is in theory an endless supply of H⁺.

Answer 143

* It accounts for the intake and excretion of ALL substances that affect [H⁺] in the body, rather than just the intake and excretion of H⁺ * This allows us to identify independent variables that determine body pH The problem with this is that the equations become way too complicated and there is no true independent variables, just a mess of inter-dependent variables.

Answer 144

* H⁺participates in 4 main reactions: * Reactions with proteins and other 'weak acids' * Reactions with OH^- * Reactions with HCO₃^- (leading to CO₂ formation) * Reactions with CO₃^2- * These can be represented in a cross diagram * The strong ion difference (SID) is the difference between the sum of the charges of all of the main positive ions minus the sum of the charges of all of the main negative ions -\> It is equal to around +40mM/L * Then, assuming the charges need to be balanced: * [H⁺] + SID = [OH^-] + [Protein^-] + 2[CO₃^2-] + [HCO₃^-] * Thus, by rearranging the equation, we find the [H⁺] is dependent on: * SID (controlled by the kidneys) * CO₂ (controlled by the lungs) -\> Since it affects bicarbonate and carbonate * Total protein

Answer 145

The final of these can be rearranged to give the Henderson-Hasselbalch equation.

Answer 146

* They are graphs produced by Stewart combining the 3 main determinants of [H⁺], which are SID, CO₂ and protein * They show how [H⁺] varies with P_CO2 and either SID or protein (the other is kept constant) * These allow us to see the effects of changing each of these variables to produce acidosis or alkalosis

Answer 147

* Metabolic acidosis/alkalosis is shown by a vertical change due to changes in SID or protein * Respiratory acidosis/alkalosis is shown by a change along the lines of the diagram due to changes in ventilation

Answer 148

* It is a diagram used to understand the different factors that determine [H⁺] * It uses the assumption that positive and negative charges are balanced * The SID is the difference between the strong ions at the bottom of each column, which do not change much * Protein, HCO₃^- and H⁺ are the variables that ensure that charges are balanced * A large SID means that there is not a lot of H⁺ required to balance out the protein and HCO₃^-and keep reactions in equilibirum, since the strong negative ions are doing part of the job * A large amount of protein means that there is a lot of H⁺ required to balance out the proteinand keep reactions in equilibirum

Answer 149

* In gastric acid, the SID is very negative, which is unusual * This means there is no protein or bicarbonate, but there are very high amounts of H⁺

Answer 150

* Plots of [HCO₃^-] against pH at different P_CO2 values * They allow us to see the effects of different metabolic disturbances

Answer 151

Think of it as a product of CO₂ reacting with water. It is the dependent variable.

Answer 152

* Proteins act as non-bicarbonate buffers * As P_CO2 is increased, the magnitude of the resulting change in pH (i.e. the gradient of the red line) is dependent on the buffering power of the non-bicarbonate buffers present in the solution. * If protein is present, then it will quickly absorb the vast majority of protons released by the formation of bicarbonate, and pH will change very little for a given rise in bicarbonate concentration -\> This will present as a steep slope. * If no protein is present, then a much larger change in pH will be observed for a given change in bicarbonate concentration -\> This will present as a shallow line. Think of it this way: If there is protein present then, as bicarbonate is produced, the H⁺is quickly mopped up by the protein, leading to small changes in pH per unit bicarbonate produced.

Answer 153

The higher the haemoglobin concentration, the steeper the gradient, due to the buffering power of the protein.

Answer 154

* Metabolic disturbances are corrected by respiratory changes -\> This is FAST * Respiratory disturbances are corrected by metabolic changes -\> This is SLOW

Answer 155

It leads to the retention of chloride, which reduces the SID (strong ion difference).

Answer 156

It is carbonic anhydrase inhibitor so it reduces retention of bicarbonate.

Answer 157

It increases excretion of chloride, increasing the strong ion difference (SID).

Answer 158

It leads to an increase in the SID (strong ion difference).

Answer 159

Bicarbonate (HCO₃^-)

Answer 160

* When H⁺and HCO₃^- produce H₂CO₃, it can dissociate into H₂O and CO₂. * This CO₂ can then be lost via the lungs, so it is an open system.

Answer 161

* 5mol * This is a very large amount compared to the 25mmol/L concentration of bicarbonate in the blood, implying that the kidneys must be reabsorbing a large amount of bicarbonate back into the blood.

Answer 162

The kidneys regulate HCO₃^- concentration by: 1. Reabsorption of filtered HCO₃^- (back from the tubular fluid) 2. Generation of new HCO₃^-(that has been used in buffering non-volatile acids) 3. Distal tubular secretion of HCO₃^-

Answer 163

H⁺ secretion into the tubular fluid

Answer 164

* Reabsorption of filtered HCO₃^- -\> Proximal tubule + Loop of Henle * Generation of new HCO₃^- -\> Distal tubule + Collecting duct * Distal tubular secretion of HCO₃^- -\> Distal tubule

Answer 165

Non-volatile acids (NVAs)

Answer 166

Volatile acids: * Carbon dioxide * Carried in blood as the potential acid H₂CO₃ * Volatile means it can be excreted via the lungs * Produced by the metabolism of carbohydrates and fats

Answer 167

* Acids produced by metabolism of amino acids and phopshate * They are essentially the blood acids that are not produced by CO₂

Answer 168

Produced by the metabolism of: * Amino acids -\> Cationic and sulphur containing * Phosphate Offset by HCO₃^- production by the metabolism of: * Amino acids -\> Anionic * Organic ions

Answer 169

* Sulphur-containing amino acids -\> H₂SO₄ * Cationic amino acids -\> HCl * Phosphate -\> H₂PO₄^-

Answer 170

* Cationic -\> Produce non-volatile acids * Anionic -\> Produce HCO₃^- (offsetting non-volatile acid production)

Answer 171

70mmol/day (or mEq/day -\> Milliequivalents)

Answer 172

* They must be buffered and then excreted * This is done by reacting them with HCO₃^-

Answer 173

* Salt * Carbon dioxide * Water For example: HCl + NaHCO₃ -\> NaCl + CO₂ + H₂O

Answer 174

* Kidneys -\> Vary the HCO₃^- concentration * Lungs -\> Excrete CO₂ from the system Since both HCO₃^- and CO₂ are in the Henderson-Hasselbalch equation for the HCO₃^-/CO₂ buffer system, these two organs control the blood pH.

Answer 175

* The blood becomes less acidic * But the HCO₃^- is gradually used up because the CO₂ produced can be lost at the lungs * Therefore, the kidneys need to regenerate HCO₃^-

Answer 176

* 4320mEq/day is needed to recovered filtered HCO₃^- * 70mEq/day is needed to regenerate HCO₃^- that was used in buffering NVAs So the total is 4390mEq/day (equal to 4390mmol/day).

Answer 177

* The body produces both volatile acids (H₂CO₃) through the metabolism of carbohydrates and fats, and non-volatile acids through the metabolism of cationic and sulphur-containing amino acids * The volatile acids can be dealt with by breathing out CO₂ in the lungs * The non-volatile acids must be buffered using HCO₃^- * The net amount of NVA that must be neutralised by HCO₃^- (after accounting for anionic acid metabolism, which offsets this) is 70mEq per day * Thus, the kidney needs to recover 4320mEq/day of HCO₃^- that is filtered by the kidney and it needs to regenerate 70mEq/day that was used in buffering NVAs * Since recovery and regeneration require H⁺ secretion into the renal tubule, this is how much H⁺ must be secreted

Answer 178

All along the renal tubule.

Answer 179

* Glomerulus * Involved in filtering out almost all HCO₃^- from the blood * Proximal tubule * Involved in 80% of HCO₃^- reabsorption into the blood * Not really involved in HCO₃^- regeneration * Ammoniagenesis (ammonia is used as a urinary buffer) * Loop of Henle * Involved in 15% of HCO₃^- reabsorption into the blood * Distal tubule and collecting duct * Residual HCO₃^- recovery * Involved in HCO₃^- regeneration

Answer 180

* CO₂ and H₂O react in epithelial cells, which is catalysed by carbonic anhydrase * HCO₃^- -\> Pass across basolateral membrane into interstitial fluid and then blood * H⁺-\> Pass across apical membrane into the lumen Depending on conditions in the renal tubule, this model can be used to both reabsorb bicarbonate ions, and to regenerate bicarbonate ions and excrete H⁺in the urine.

Answer 181

There are transporters on each membrane that move H⁺ or HCO₃^-.

Answer 182

* If the H⁺ reacts with filtered HCO₃^-, the bicarbonate is reabsorbed (4.3mol day-1) * If the H+ reacts with a urinary buffer, it is excreted. This is used in regenerating bicarbonate. (70mmol day-1)

Answer 183

Individual cells along the renal tubule need to maintain their own pH too, so they have transporters on their membranes that pump H⁺ and HCO₃^- in the opposite direction to what is expected (H⁺ out across the basolateral membrane or HCO₃^- across the apical membrane).

Answer 184

On basolateral membrane: * NHE (sodium-hydrogen exchange) * NDAE (sodium-dependent anion exchange) * NBC (sodium-bicarbonate co-transporter) * AE (anion exchanger)

Answer 185

Apical membrane: * NHE3 -\> In proximal tubule * V H⁺-ATPase -\> In type A intercalated cells of the collecting duct * P H⁺/K⁺-ATPase -\> In collecting duct cells Basolateral membrane: * NBC -\> In proximal tubule * AE -\> Type A intercalated cells of the collecting duct * NHE1 -\> Cell pH regulation * NDAE (4 ion) -\> Cell pH regulation

Answer 186

* NHE3 -\> On apical membrane in proximal tubule * NHE1 -\> On basolateral membrane

Answer 187

* CO₂ and H₂O react in epithelial cells, which is catalysed by carbonic anhydrase * HCO₃^- -\> Pass across basolateral membrane into interstitial fluid and then blood * H⁺-\> Pass across apical membrane into the lumen Depending on conditions in the renal tubule, this model can be used to both reabsorb bicarbonate ions, and to regenerate bicarbonate ions and excrete H⁺in the urine.

Answer 188

In the proximal tubule mostly and loop of Henle (and somewhat in the distal tubule and collecting duct): * H⁺ ions are secreted into the tubular fluid by Na⁺/H⁺exchange (due to large sodium gradient) and H⁺-ATPase * The H⁺ ions combine with HCO₃^- in the lumen to form carbonic acid * Carbonic acid (H₂CO₃) can dissociate into carbon dioxide and water under the action of carbonic anhydrase on the apical membrane * The CO₂ can diffuse into the cell and react with water to reform H₂CO₃ * Cytosolic carbonic anhydrase can reform HCO₃^- and H⁺ * H⁺can be returned to the lumen, restarting the process * HCO₃^- can move across the basolateral membrane into the interstitial fluid by: * HCO₃^-/Cl^- exchanger * Na⁺/3HCO₃^- symporter (more important)

Answer 189

* HCO₃^-/Cl^- exchanger * Na⁺/3HCO₃^-symporter (more important) This is unusual because the symporter is moving sodium ions against their concentration gradient, which is why 3 bicarbonate ions are required per sodium.

Answer 190

This happens mostly in the collecting duct and distal tubule. The mechanism is essentially the same as for HCO₃^- reabsorption, except no HCO₃^- is reabsorbed and there is no sodium-dependent processes: * H⁺ is secreted into the tubule by a H⁺-ATPase (with no help from the Na⁺/H⁺ exchanger since no sodium reabsorption is occuring at this point in the tubule) * In this case, however, H⁺ does not combine with HCO₃^-, since very little is present at this late point in the renal tubule * Instead, H⁺ is buffered by PO₄^3- or by NH₃ (or it acidifies the tubule fluid) * Inside the intercalated epithelial cells, cytosolic carbonic anhydrase forms HCO₃^- and H⁺ from water and CO₂ * This newly generated HCO₃^-can move across the basolateral membrane into the interstitial fluid by an HCO3^-/Cl^- exchanger * Na⁺/3HCO₃^-symporter is not involved because no sodium reabsorption is occuring at this point in the renal tubule Note: The hydrogen isn't really doing anything here, it is just being buffered.

Answer 191

* Mostly by the Na⁺/H⁺exchanger, driven by a sodium gradient * Also by a H⁺-ATPase

Answer 192

* Firstly, HCO₃^- is all reabsorbed in the early renal tubule, so there is none left in the late tubule * Secondly, there is no sodium gradient across the epithelium in the late distal tubule (which is because there is no reabsorption of sodium here) and so the sodium-dependent processes do not occur. Note: Ignore the middle part of the diagram.

Answer 193

The same amount as was formed by the original reaction of the HCO₃^- with an NVA.

Answer 194

Type A intercalated cells of the collecting duct (and distal tubule?)

Answer 195

Renal tubular acidosis -\> This is acidosis of the plasma, NOT the tubular fluid

Answer 196

Equivalent to the amount of NVA buffered by HCO₃^- in the plasma.

Answer 197

Occurs in the cells of the proximal tubule: * Glutamine is converted to glutamic acid by glutaminase * Glutamic acid is converted to α-ketoglutaric acid by glutamate dehydrogenase * Both of these steps yield: 1 NH₃ and 1 HCO₃^-

Answer 198

* Buffers other than HCO₃^- that are found in the renal tubule * They react with the H⁺that is secreted into the renal tubule lumen at the collecting duct and distal tubule * They are used to allow large amounts of free H⁺secretion into the tubular fluid without unsustainable drops in urinary pH

Answer 199

* Phosphate * Ammonia

Answer 200

* Dietary in origin * So amount available is amount filtered minus that reabsorbed earlier in the tubule * Work by a two-step process: * H⁺ + PO₄^3- -\> HPO₄^2- * H⁺ + HPO₄^2- -\> H₂PO₄^-

Answer 201

* Synthesised within tubular cells from glutamine * Synthesis altered to reflect acid-base status: one of the main ways kidney responds to an acid load * H⁺ + NH₃ -\> NH₄⁺

Answer 202

* Ammoniagenesis is upregulated when plasma pH is acidic * It occurs in proximal tubule cells

Answer 203

* After NH₃ is synthesised in the epithelial cells of the proximal tubule, it diffuses into the lumen * The NH₃ is converted to charged NH₄⁺ using secreted H⁺ * The pK is around 9, so at physiological pH the reaction is strongly to the right and there is lots of NH₄⁺ * This traps the ammonium in the lumen * As the luminal pH falls along the nephron, NH₄⁺ is increasingly trapped Some other points: * NH₄⁺ may be generated from NH₃ and H⁺ WITHIN tubule cells, then secreted by the Na⁺/H⁺ exchanger

Answer 204

* Because the reabsorption is a carrier mediated process, meaning that there is a maximum rate of reabsorption possible * The maximum rate of reabsorption is the transport maxmimum (Tm)

Answer 205

H⁺secretion is stimulated by: * Decreased plasma pH * Increased blood P_CO2 This is due to: * In proximal tubule and TALH -\> Upregulation of Na⁺/H⁺ exchanger * In collecting duct -\> Insertion of H⁺-ATPase from vesicles The result is that the Tm is changed and full reabsorption of bicarbonate is possible over a wider range of bicarbonate concentrations.

Answer 206

In the Type B intercalated cells of the collecting duct: * The same system is used as for regeneration of bicarbonate, except that the membrane proteins are reversed * The HCO₃^-/Cl^- exchanger is on the apical membrane, while the H⁺-ATPase is on the basolateral membrane * Carbonic anhydrase converts water and CO₂ into HCO₃^- and H⁺ * However, this time the HCO₃^- moves into the tubule lumen, while H⁺ goes into the interstitial fluid (this is due to reversal of the membrane proteins)

Answer 207

Type B intercalated cells of the colleting duct

Answer 208

Bicarbonate reabsorption: * Occurs most in the earliest part of the tubule -\> PT, LOH * This is because there is enough bicarbonate in the lumen for this to happen, although the amount decreases along the tubule Bicarbonate regeneration: * Occurs in the late parts of the tubule -\> DT, CD * In type A intercalated cells * This happens because there is no bicarbonate left in the lumen, so it has to be generated by carbonic anhydrase in the epithelial cell * Allows response to acidosis Bicarbonate regeneration: * Occurs in the late parts of the tubule -\> DT, CD * In type B intercalated cells * This happens by the same process as bicarbonate regeneration, BUT the membrane proteins are on the opposite membranes, so bicarbonate is secreted into the tubule instead of the interstitial fluid * Allows response to alkalosis

Answer 209

You can think of it as the side on which the H⁺-ATPase (the driving force behind acid-base balance) is found: * Type A -\> On the Apical side * Type B -\> On the Basolateral side

Answer 210

Hyperkalemia inhibits NH₃ production, and so H⁺ excretion (since it is a urinary buffer that increases H⁺ excretion).

Answer 211

* They can be identified using differently coloured fluorescently-labelled antibodies for the apical and basolateral H⁺-ATPase * The outer medullary collecting duct has only type A cells (with the apical ATPase), while the inner medullary collecting duct has both type A (with the apical ATPase) and type B cells (with the basolateral ATPase). (Brown, 1992)

Answer 212

No, there may also be intermediate cells which are yet to differentiate based on acid-base balance, so they express the H⁺-ATPase on both the apical and basolateral membranes.

Answer 213

* H⁺-ATPase -\> Acid-base balance * H⁺/K⁺-ATPase -\> Potassium balance The evidence for this is done via acidification of a test model and then inhibiting one of the two ATPase types. H⁺-ATPase inhibition leads to slow recovery from acidosis, while H⁺/K⁺-ATPase inhibition leads to only slightly impaired recovery from acidosis (Schwartz, 1995).

Answer 214

* Acidosis leads to insertion of H⁺-ATPase into the apical membrane of the renal tubule cells, leading to increased H⁺secretion into the tubule. * This is done by cytoskeletal-driven fusion of subapical vesicles.

Answer 215

ATPase activity in the apical membrane was markedly reduced by colchicine, which is a cytoskeletal disrupted (so it prevents fusion of ATPase-containing vesicles with the apical membrane). (Brown, 1992)

Answer 216

Stewart model: * pH is controlled by SID, P_CO₂ and weak acid (A_tot) * Increases in the SID lead to falls in [H⁺], leading to alkalinsation * Argues that it is the movement of strong ions ASSOCIATED with the action of transporters that move H⁺ and HCO₃^- that controls pH. The movement of H⁺ and HCO₃^- is simply coincidental. Henderson-Hasselbalch model: * pH is controlled by P_CO2 and actions of the kidneys on HCO₃^- and H⁺ * Increased H⁺ secretion into the renal tubule leads to increased HCO₃^- regeneration and alkalinisation. * Argues that it is this movement of H⁺ and HCO₃^- that determines pH.

Answer 217

Henderson-Hasselbalch: * Decreased production and secretion of H⁺ into the lumen of the tubule * This leads to impairment of H⁺ and HCO₃^- reacting in the lumen, so that reabsorption of HCO₃^- is decreased * This causes acidosis Stewart model: * Decreased production of H⁺ and HCO₃^- in the cell, which are substrates for the NBC and NHE transporters * This means there is decreased reabsorption of sodium * This decreases the SID * This causes acidosis

Answer 218

* Hyperkalaemia leads to acidosis * Acidosis also leads to hyperkalaemia

Answer 219

* Raised [H+] inhibits the basolateral Na⁺/K⁺-ATPase in the collecting duct and the apical membrane permeability to K⁺ * This in turn reduces K⁺ secretion in the collecting duct

Answer 220

Hyperkalaemia inhibits NH₃ production and therefore H⁺ excretion (since NH₃ is a urinary buffer that stops the urine becoming too acidic - CHECK THIS)

Answer 221

* Buffers * Ventilatory mechanisms * Renal mechanisms

Answer 222

* Haemoproteins * Iron-sulphur proteins * Co-factor for enzymes This is due to it redox properties, since it can exist in the ferrous (Fe²⁺) and ferric (Fe³⁺) forms.

Answer 223

It can be very toxic in excess, since it participates in intracellular 'Fenton reactions' (e.g. Fe²⁺ + H₂O₂ -\> Fe³⁺ + OH· + OH^-) that can generate harmful free-radicals compounds.

Answer 224

Homeostatic mechanisms must balance the requirement of the body for sufficient iron against the risk of cellular iron overload.

Answer 225

Around 4000mg

Answer 226

* RBCs -\> 1800mg * Liver -\> 1000mg * Reticuloendothelial macrophages -\> 600mg * Bone marrow -\> 300mg * Other tissues -\> 400mg * Blood -\> 3mg

Answer 227

* 3mg * Transferrin

Answer 228

In the erythropoietic pathway

Answer 229

* Blood contains iron bound to tranferrin (3mg iron) * Iron is taken up from the blood into the bone marrow (300mg iron) * Iron is incorporated into RBCs (1800mg iron) * Senescent RBCs are broken down by reticuloendothelial macrophages (600mg iron) and released back into the blood

Answer 230

* Enters via the duodenum * 1-2mg/day

Answer 231

* Only 1-2mg are taken up per day, which is a very small amount compared to body stores. * Therefore, it is very easy to become anaemic if there is blood loss. * So if there is a patient with anaemia, it is very important to make sure there is not any unnoticed bleeding, such as in small amounts in the bowels.

Answer 232

* It happens via shedding of skin cells and gut cells, etc. * This is unregulated, which means that all regulation of body iron must be via intake of iron

Answer 233

* Meat and fish -\> Contain haem iron. * Green vegetables, tofu, beans and pulses -\> Contain non-haem iron.

Answer 234

Most dietary iron found as Fe(III), but converted to Fe(II) in the gut.

Answer 235

It is promoted by vitamin C.

Answer 236

* **Fe²⁺crosses the apical membrane by the divalent cation transporter DCT1** (dependent on the H⁺ gradient generated by the acidity of the duodenum lumen) * Any Fe³⁺ in the lumen is reduced to Fe²⁺ by iron reductase on the apical membrane, so it can be taken up by DCT1 * Haem can also be taken up by a haem transporter on the apical membrane, after which it is converted to Fe²⁺ by haem oxidase * Fe²⁺can now enter one of two pathways: * Absorptive pathway * **A complex of two proteins (hephaestin and ferroportin) transports the Fe²⁺ into the blood -\> The hephaestin converts the Fe²⁺ into Fe³⁺** * In the blood, the Fe³⁺ is bound to transferrin for transport * Storage pathway * **Fe²⁺ binds to ferritin in the cytoplasm, where it is stored** * When needed, the Fe²⁺ can be mobilised and taken to the hephaestin/ferroportin complex for transport into the blood

Answer 237

It means that it has not yet technically been absorbed, which is advantageous because it means that this iron can either be fully absorbed or shed with the enterocytes (depending on the iron levels in the body).

Answer 238

DCT1 (divalent cation transporter 1)

Answer 239

* It is reduced to Fe²⁺ by iron reductase on the apical membrane * Then it is taken up by DCT1

Answer 240

* It is taken up by a haem transporter on the apical membrane * Then it is converted to Fe²⁺ by haem oxidase.

Answer 241

A complex of two proteins (hephaestin and ferroportin). (Ferroportin is the one mentioned in the spec, while hephaestin is responsible for converting Fe²⁺ into Fe³⁺)

Answer 242

* Ferritin -\> Storage of iron in enterocytes * Tranferrin -\> Transport of iron in the blood around the body

Answer 243

Ferroportin

Answer 244

Glycoprotein

Answer 245

* Fe³⁺ * It binds two irons

Answer 246

Serum transferrin concentration rises in response to iron deficiency, and is often quantified as 'total iron-binding capacity'.

Answer 247

Transferrin saturation (serum iron/TIBC x 100) is usually around 20-30%, and is often used as index of iron availability.

Answer 248

* Target cells (e.g. erythroid cells) express the cell surface transferrin receptors TfR1 * These bind the Fe³⁺-transferrin complex and lead to the formation of a clathrin-coated pit. * An endosome is then formed, which is acidified to release the iron. * The iron is stored using ferritin or converted into haemoglobin

Answer 249

* Liver cells also express TfR2 (tranferrin receptor 2). * This allows the liver to regulate iron homeostasis via hepcidin.

Answer 250

Ferritin is a capsule that stores iron in the centre.

Answer 251

* Plasma ferritin levels are an indicator of total body stores of iron (even though we don't know why it finds its way into the plasma). * However, it is also an acute phase protein, so its levels rise with inflammation or infection.

Answer 252

* Hepcidin is produced when the liver senses elevated iron levels (via sensing transferrin-iron complexes) * It opposes the release of iron from macrophages and enterocytes (You can think of hepcidin as an equivalent of insulin, but for iron)

Answer 253

* Hepcidin inactivates ferroportin by binding to it, so that it is internalised and degraded by lysosomes. * Thus, it prevents the release of iron from macrophages and enterocytes.

Answer 254

* Erythropoiesis [EXTRA] -\> Reduces hepcidin production. This can cause problems in patients with excessive but ineffective erythrocytosis (e.g. thalassaemia), in whom profound hepcidin suppression can produce tissue iron overload. * Hypoxia [IMPORTANT] -\> Reduces hepcidin production. This is partly by stimulating erythropoiesis and causing iron deficiency, but also directly via HIF. * Inflammation [EXTRA] -\> Inflammatory cytokines (esp. IL-6) stimulate hepcidin production. This may reflect a desire to deprive invading microbes of iron.

Answer 255

* It reduces hepcidin secretion * This is partly by stimulating erythropoiesis and causing iron deficiency, but also directly via HIF.

Answer 256

IRPs (iron-regulatory proteins)

Answer 257

When cellular iron levels are low, IRPs: * Inhibit translation of ferritin * Stabilise transferrin receptor mRNA Thus, they encourage iron uptake.

Answer 258

When cellular iron levels are high, IRPs are degraded, so that: * Ferritin translation is no longer inhibited * Transferrin receptor mRNA is no longer stabilised, so it is degraded Thus, they inhibit iron uptake.

Answer 259

* Haemoglobin and mean cell volume * Serum ferritin * Serum iron and transferrin * Serum transferrin saturation * Soluble transferrin receptor

Answer 260

Hypochromic microcytic anaemia (Hypochromic = Lacking colour, Microcytic = Small RBCs)

Answer 261

* Inadequate dietary intake * Malabsorption (e.g. coeliac disease) * Excessive use of iron (e.g. pregnancy, growth) * Hookworm infection (common worldwide) * Blood loss: * Blood donation * Menstrual loss in young women * Gastrointestinal bleeding

Answer 262

* Primary genetic disease (haemochromatosis) * Alcoholic cirrhosis * Excessive oral intake of iron * Repeated blood transfusions * Excessive (ineffective) erythropoiesis

Answer 263

* Relatively common group of genetic diseases characterised by excessive dietary iron absorption or cellular iron retention. * Most are due to inadequate hepcidin expression.

Answer 264

Due to iron deposition in parenchymal tissues: * Liver (cirrhosis) * Pituitary (hypogonadism) * Pancreas (diabetes) * Joints (arthropathy) * Heart (cardiomyopathy) * Skin (hyperpigmentation)

Answer 265

* Diagnosis involves blood tests (e.g. transferrin saturation and ferritin), genetic testing and sometimes liver biopsy * Treatment may include therapeutic phlebotomy or iron chelation

Answer 266

It depolarises skeletal muscle, causing it to become refractory since the sodium channels remain in an inactivated state.

Answer 267

1. Check the pH to see if it is acidosis or alkalosis 2. Check to see if this can be explained by the pCO₂ level * If yes, then it is respiratory acidosis/alkalosis * If not, then it is metabolic acidosis/alkalosis

Answer 268

If there is metabolic acidosis, then there is likely to be compensatory hyperventilation.

Answer 269

* There may be situations where there is both a respiratory acidosis AND metabolic acidosis simultaneously * In these situations, the metabolic acidosis will only be revealed once the respiratory acidosis is corrected * In these situations, the base excess is a way of identifying this right at the start * How it is done: * "Ventilate" a sample of blood * Titrate to assess the acidity * Base excess is a measure of this

Answer 270

Not really, because there are very many complications in its interpretation.

Answer 271

Siggaard-Andersen Acid-Base Chart

Answer 272

* The Stewart model is like a more complicated version of the Henderson Hasselbalch equation * It explains acid-base balance using a wider range of causes. * For example, it explains the mechanism of oddities like saline-induced acidosis. * Note that Henderson-Hasselbalch also MEASURES this saline-induced acidosis, it just cannot explain it mechanistically. * Thus, there have been discussions about which is more clinically useful and accurate. * A major advantage of Henderson-Hasselbalch is simply that it is easier to understand and arguably more intuitive.

Answer 273

Chronic acidosis: * Loss of bone density -\> Due to acid buffering * Muscle wastage -\> Due to increased protein catabolism Acid buffering leads to loss of bone density, resulting in an increased risk of bone fractures Chronic alkalosis: * Neuromuscular irritability + Tetany * Abnormal heart rhythms (usually due to accompanying electrolyte abnormalities such as low levels of potassium in the blood)

Answer 274

* Potassium is freely filtered by the glomerulus. * In the proximal tubule: * K⁺ reabsorption is mostly passive via the paracellular route. It is proportional to Na⁺ absorption since water follows the sodium and carries potassium with it (solvent drag). * In the thick ascending loop of Henle: * K⁺ reabsorption in the thick ascending limb of Henle occurs through both transcellular (via NKCC) and paracellular pathways. * In distal convoluted tubule and collecting duct: * Principal cells (in the collecting duct): * Actively secrete K⁺ using K⁺transporters and K⁺/Cl⁻ cotransporters on the apical membrane * Type A intercalated cells * Can insert H⁺/K⁺-ATPase into the apical membrane to increase K⁺ reabsorption

Answer 275

In the distal nephron. Delivery to the distal nephron is approximately constant, but secretion of potassium into the renal tubule (by principal cells and type A intercalated cells) varies according to physiological needs.

Answer 276

The main determinants of secretion of potassium in the principal cells include: * Intracellular K+ concentration * Luminal K+ concentration * Potential difference across the luminal membrane (i.e. electronegativity of the lumen) * Permeability of the luminal membrane for K+ Thus, the two main determinants are: * Mineralocorticois * Distal delivery of Na⁺ and water

Answer 277

* There is reciprocity between K⁺ and H⁺ fluxes. * This is due to the H⁺/K⁺-ATPase on principal cells of the collecting duct.

Answer 278

* Increases the activity and number of Na⁺/K⁺-ATPase pumps on the basolateral membrane of principal cells -\> This increases intracellular potassium concentration, meaning more is secreted via the H⁺/K⁺-ATPase * Increases sodium absorption by increasing the activity and number of sodium-chloride symporters (NCC) in the distal convoluted tubule as well as ENaC channels -\> This increases luminal electronegativity, so more potassium is secreted into the lumen * Increase apical membrane permeability to potassium

Answer 279

* Increased distal delivery of Na⁺ stimulates distal Na⁺ absorption, which will make the luminal potential more negative -\> This increases K⁺ secretion * Increased flow rates also increase K+ secretion by diluting the lumen and thus maintaining potassium gradients

51. Electrolytes and Fluid Balance Flashcards

(340 cards)