Case 7 Flashcards

Question

describe bulk sodium reabsorption | - where does this take place

Answer 1

Proximal convoluted tubule: 1. The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell. 2. This allows the Na+-H+ exchanger on the apical membrane to take up Na+ ions from the urine. 3. The anion-Cl- exchanger allows the uptake of HCO3- ions in exchange for Cl- ions.  Therefore, both Na+ ions and HCO3- ions are reabsorbed.

Answer 2

Distal convoluted tubule & collecting duct: 1. The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell. 2. Aldosterone combines with a cytoplasmic receptor. 3. Hormone-receptor complex initiates transcription in the nucleus. 4. New protein channels (ENaC – epithelium sodium channel) and pumps are made. 5. Aldosterone-induced proteins modify existing proteins. 6. Result is increased Na+ reabsorption and K+ secretion.

Answer 3

``` 1. SLC – solute carrier family  SLC5: sodium-linked cotransporters 2. SGLT  SGLT1 - transports 1 glucose: 2 Na  SGLT2 – transports 1 glucose: 1 Na 3. GLUT  GLUT1 and GLUT2 (between these two glucose transporters, you can take up glucose from the fluid and get it back into the blood) - GLUT gene family - Facilitated diffusion ```

Answer 4

 The early proximal convoluted tubule is involved in the mass reabsorption of glucose.  The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.  This allows the Na+-glucose SGLT2 cotransporter on the apical membrane to take up Na+ and sodium from the urine.  Next, the GLUT2 protein allows passage of glucose from inside the cell into the blood.  These have a low-affinity but high capacity because there is a lot of glucose available and these transport proteins allow for mass reabsorption of glucose. - SGLT2 (take glucose and sodium in from tubule) - GLUT2 (glucose moves out into blood) = both low-affinity but high-capacity – grabs all glucose passing by and chucks it back into blood

Answer 5

 The late proximal convoluted tubule is involved in the fine reabsorption of glucose.  The Na+-K+ pump on the basolateral membrane pumps Na+ ions into the blood, thus lowering the Na+ concentration in the cell.  This allows the Na+-glucose SGLT1 cotransporter on the apical membrane to take up Na+ and sodium from the urine.  Next, the GLUT1 protein allows passage of glucose from inside the cell into the blood.  These have a high-affinity but low capacity because glucose has already been mass absorbed and so there is less glucose left in the tubular fluid. These transport proteins allow for fine-tuning reabsorption of glucose. - SGLT1 (take glucose and sodium in from tubule) - GLUT 1 (glucose moves out into blood) = both high-affinity but low-capacity – a lot less glucose present but they are able to mop up remaining amount of glucose because they have a high affinity for it - So, by the time the fluid leaves the proximal tubule there should be no glucose left in the fluid – it reabsorbs all of filtered glucose under normal circumstances

Answer 6

* Fasting glucose ~ 5 mmol/L and GFR = 125 ml/min * Filtered glucose = 5 x 0.125 = 0.63 mmol/min * Transport maximum (Tm) ~ 1.25 mmol/min Plasma glucose ~ 10 mmol/L * This graph shows that once the Tm is reached, no more glucose can be reabsorbed. * The excess glucose must be excreted (the point of intersection of the lines). - So, you can normally reabsorb all the glucose that you filter - But there is a limit to how much glucose they can transport (this is known as transport maximum) – problem in people with diabetes - Not until you get to a plasma glucose of about 10 mmol/L or higher that you are filtering more than you can reabsorb - Under normal circumstances, the amount of glucose filtered matches the amount reabsorbed - Only when exceeds the amount that you can reabsorb that you get excretion - Relationship not perfectly linear because not every nephron has the same transporting capacity

Answer 7

• The kidney itself is a source of glucose via gluconeogenesis. • The kidney makes around 20% of all glucose in the body, but it then breaks it back down. - 300% increase in diabetes

Answer 8

in the descending loop of Henle | • The longer the loop of Henle, the greater the amount of water that is reabsorbed.

Answer 9

the effect of ADH/ Vasopressin

Answer 10

• ADH inserts aquaporins (AQP2) in the apical membrane of the cells in the late distal convoluted tubule and the cells of the collecting tubule.  This allows water to be reabsorbed from the cells back into the body.  The water will only flow through these channels in the presence of an osmotic gradient caused by Na+ ions.

Answer 11

allows reabsorption of water via ENaC

Answer 12

- thin descending limb is permeable to water; impermeable to solutes - thick ascending limb is impermeable to water; active solute transport

Answer 13

PCT = 300 mOsm/kg bottom of loop of Henle = 1200 mOsm/kg DCT = 100 mOsm/kg leaving the CD = 1200 mOsm/kg (maximum gradient in ascending limb = 200 mOsm/kg)

Answer 14

• PCT & Loop of Henlé  91% Ca2+ reabsorbed – paracellular route (passive reabsorption)  89% Mg2+ reabsorbed – paracellular route (passive reabsorption) • DCT  3-7% Ca2+ reabsorption  5-6% Mg2+ reabsorption

Answer 15

passively reabsorbed (paracellular route)

Answer 16

using transport proteins using transport proteins • Ca2+ ions enter the cell via TRPV5 transport protein channels. • Because Ca2+ is an intracellular signalling molecule, we can’t have free Ca2+ in the cell as it would trigger other signalling pathways. • Therefore, Ca2+ needs to be chaperoned from the apical membrane to the basolateral membrane where they would then enter blood. • Ca2+ ions bind to an intracellular protein called Calbindin-D28K. • This allows Ca2+ ions to move to the basolateral membrane. • Once at the basolateral membrane, these ions can exit the cell into the bloodstream via two transport proteins: (1) Na+/Ca2+ exchanger [NCX1] and (2) plasma-membrane-calcium-ATPase-pump [PMCA1b]. - Calcium channel (TRPV5) in apical membrane – bring calcium in - Calbindin-D28K – binding protein in cell - Calcium pump – PMCA1b – principal route of calcium moving into blood – energy requiring – pumping out against a gradient - Ca2+/Na+ exchanger – NCX1 – calcium out into blood and sodium in

Answer 17

 Parathyroid hormone (PTH)  Vitamin D – the kidneys activate vitamin D which stimulates TRPV5 in the DCT  Sex hormones  Klotho (higher up in tubule) – this is a protein that’s associated with longevity. - Channel in apical membrane is opened by the above

Answer 18

• Mg2+ reabsorption is less known. • There is a ROMK potassium channel on the apical membrane of these cells. • This causes the movement of K+ ions out of the cell and into the tubular fluid. • This makes the tubular fluid positively charged. • This favours the movement of Mg2+ ions into the cell via TRPM6 transport protein channels.  This is activated by epidermal growth factor. • There is a Mg2+ exchanger on the apical membrane but we don’t know what Mg2+ is exchanged for. - Lot less known about this - Magnesium channel – TRPM6 – apical - Buffer protein? - Mg2+ exchanger in basolateral? - Potassium leaks out in potassium channel in apical - This makes tubular fluid more positive - Which makes Mg2+ ions move from tubule into cell - Magnesium channel (TRPM6) can be opened by epidermal growth factor

Answer 19

* It enters the ECF. | * It is taken up by cells by a Na+-K+ pump.

Answer 20

98% of the potassium ions is taken up by the cells and 2% remains in the ECF.

Answer 21

* Proximal Convoluted Tubule takes up 65% of K+ ions. * Loop of Henlé takes up 25% of K+ ions. * Distal Convoluted Tubule & collecting duct have variable K+ reabsorption and secretion. Here, you either get net reabsorption or net secretion.

Answer 22

* 92% of the potassium is excreted by the kidneys. | * 8% of the potassium is excreted by the colon.

Answer 23

* Potassium needs to be carefully regulated because both hypokalaemia and hyperkalaemia can be fatal. * Hypolkalaemia causes excess hyperpolarisation which leads to paralysis and so death. * Hyperkalaemia causes excess depolarisation which also leads to paralysis and so death. - Hypokalaemia -> hyperpolarisation -> paralysis -> death - Hyperkalaemia -> depolarisation -> paralysis -> death

Answer 24

• On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions. (from blood) - high blood glucose concentration in glomerulus - Glucose Tm exceeded - Glucose present in tubular fluid in collecting duct - > 1200 mOsm/kg - = osmotic diuresis -> thirst * These can leave via a K+ channel on the basolateral membrane. * The net effect is the recycling of K+ ions. * On the apical membrane there is a K+ channel. * This allows the outflow of K+ ions, into the urine. * As the tubular fluid continues through the PCT, there is a gain in the charge of the fluid because of the secretion of positively charged ions into the tubular fluid. * This causes K+ ions to diffuse through the tight junctions between cells, back into the blood (down an electrochemical gradient). * This is unregulated. * In this way, most of the K+ ions are secreted into the tubular fluid, however, some diffuse back into blood. - Na+/K+-ATPase pump in basolateral side (blood) - Potassium ion channel in apical side going into lumen of proximal tubule - K+ ions makes the fluid go from negative to positive charge - This then favours the movement of potassium through a paracellular route -> into extracellular fluid where it is reabsorbed into the blood - Pretty much passive reabsorption – due to build up of positive charge – pushes the ions out

Answer 25

* On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions. * These can leave via a K+ channel on the basolateral membrane. * The net effect is the recycling of K+ ions. * On the apical membrane there are two K+ transport proteins. * The NKCC2 is a sodium-potassium- 2 chlorine cotransporter. * It allows the entry of potassium ions into the cell. * The ROMK2 potassium channel causes an outflow of K+ ions. * This causes recycling of K+ ions on the apical membrane, similar to that on the basolateral membrane. * The net movement of potassium ions favours the influx via NKCC2. - Na+/K+-ATPase transporter in basolateral side (lowers intracellular sodium which causes sodium to move in through the next transporter) - NKCC2/SLC12A1 (K+/Na+/2Cl- transporter – all moving into cell across apical membrane) – sodium and potassium reabsorption (potassium hitches a ride) - ROMK2 – apical membrane potassium channel (potassium recycling) (potassium into lumen) - Potassium channel on basolateral membrane (potassium can then be reabsorbed into blood) - Both potassium channels (basolateral and apical membranes – both potassium cell leaving cell) help reabsorption of potassium through NKCC2

Answer 26

1. principal (vast majority is this) | 2. intercalated

Answer 27

the secretion of K+ ions into urine

Answer 28

the reabsorption of K+ ions from the urine

Answer 29

 On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.  There is another K+ channel that allows the uptake of K+ ions form the blood into the cell.  On the apical membrane, there is a K+/Cl- cotransporter which causes the secretion of both K+ and Cl- ions into the urine.  There is also a K+ channel (ROMK1) that allows secretion of K+ ions. Principal cells: - Na+/K+-ATPase (K+ in) and K+ (out but can do either direction) channel in basolateral membrane - Na+ channel (sodium in) and K+ channel (potassium out) (ROMk1 and 3) and Cl-/K+ cotransporter (both out) in the apical membrane - Due to potassium channel on both apical and basolateral side we have a route for getting rid of (apical) and a route for retaining potassium (basolateral) - Aldosterone can be activated: opens sodium channel, activate potassium channel on apical membrane, and reverse the direction the potassium is going in on basolateral membrane (so the channel brings potassium into the cell instead of going into blood) - Hyperkalaemia can stimulate aldosterone release

Answer 30

by aldosterone or high plasma K+ (hyperkalaemia)

Answer 31

 On the basolateral membrane, the Na+/K+ pump allows intake of K+ ions.  On the apical membrane, there is a K+/H+ exchanger which causes the reabsorption of K+ ions.  There is also another H+ channel which causes the outflow of H+ ions. Intercalated cells: - K+/H+ cotransporter in apical membrane (potassium in, hydrogen out) - H+ pump in apical membrane (channel) (out) - If we have acidosis or low plasma K+ conc., the cotransporter kicks in – the system in the principal cell that loses potassium becomes less dominant - Na+/K+-ATPase in basolateral membrane

Answer 32

acidosis or hypokalaemia

Answer 33

• Normally, there is around 15,000mmol of CO2 produced per day. This is ‘potential acid’, but it usually isn’t a problem as it is efficiently excreted by the lungs. • Metabolism also produces ~40 mmol H+ per day (‘non-volatile acids’: sulphuric, phosphoric, organic acids). • There is also a net uptake of ~30 mmol H+ per day by GI tract • So the kidney has to:  Excrete ~70 mmol H+ per day  Reabsorb all the filtered HCO3 -

Answer 34

* Excess H+ ions in the urine can cause the urine to become very acidic (pH = 1.3), thus painful. * Therefore, in the urine, the H+ ions needs to be buffered.

Answer 35

• These are enzymes that contain Zn. • There are at least 16 isoforms, but two important isoforms reside in the kidneys:  CA II – soluble cytoplasmic (found freely dispersed in the cytoplasm)  CA IV – extracellular, linked to cell membrane (by a GPI anchor) • They catalyse the hydration of CO2. But, this is what actually happens… • Carbonic anhydrase (CA) catalyses the second reaction (CO2 + OH-…) H2O H+ + OH- CO2 + OH- HCO3- (this reaction) May see this shorted as H2O + CO2 -> H2CO3 -> H+ + HCO3- (but this isn’t really what’s happening)

Answer 36

* HCO3- in the tubular fluid is converted to CO2 and OH- ions as a result of CA IV. * The CO2 diffuses into the cell. * The OH- ions combine with the H+ ions in the tubular fluid to form water. * This water diffuses into the cell via osmosis. * Once in the cell, the water breaks down again into H+ and OH- ions. * The CO2 combines with the OH- (via CA II) ions to from HCO3- ions. * At the basolateral membrane, the HCO3- ions exit the cell and enter the blood. * The net movement of HCO3- ions is from the tubular fluid into the blood. * This process uses a lot of ATP. - H+ secretion at apical membrane reclaims HCO3- -> CO2 + H2O (carbonic anhydrase IV (CAIV) – apical membrane) - CO2 can freely diffuse across apical cell membrane - In cell, CO2 + H2O -> H+ + HCO3- (CAII) - H+ recycled and resecreted into lumen - HCO3- extruded at basolateral membrane - Net transfer of HCO3- from lumen to interstitium/blood

Answer 37

• HCO3- ions are reabsorbed throughout the nephron:  PCT = 80% (same as reabsorption of NaCl and water)  Thick ascending loop of Henle (TAL) = 10%  DCT = 6%  Collecting duct = 4%

Answer 38

Less than 0.01% is excreted.

Answer 39

* HCO3- in the tubular fluid is converted to CO2 and OH- ions as a result of CA IV. * The CO2 diffuses into the cell. * The OH- ions combine with the H+ ions in the tubular fluid to form water. * This water diffuses into the cell via osmosis. * Once in the cell, the water breaks down again into H+ and OH- ions. * The CO2 combines with the OH- (via CA II) ions to from HCO3- ions. * At the basolateral membrane, the HCO3- ions exit the cell via a ‘kidney variant of Na+/ HCO3- cotransporter’ (kNBCe1) and enter the blood. * The H+ ions are secreted from the cell via a H+-ATPase pump and via a Na+/H+ exchanger (NHE3). * The net movement of HCO3- ions is from the tubular fluid into the blood. * This process uses a lot of ATP. - Acid secreted across apical membrane into lumen - NHE3 (sodium-hydrogen exchanger) (very common to have exchangers using sodium) (sodium is moving along its concentration gradient and hydrogen ions moving against concentration gradient (secondary active transport?)) - H+-ATPase – primary active transport into lumen - H+ ions combine with bicarbonate (CAIV) -> CO2 + H2O - CO2 -> diffuse into cell -> break back down into H+ and bicarbonate - In PCT, transporter that’s responsible for transporting HCO3- across basolateral membrane = kNBCe1 (kidney sodium-bicarbonate cotransporter) – 3HCO3- and 1Na+ -> both transporter out of cell (unusual for having Na+ moving out of cell in cotransport because that’s against sodium’s natural gradient) (however it is able to function like this due to its unusual stoichiometry – moving three negative charges and one positive charge in the same direction – net movement of charge = 2 negative = transporter is electrogenic – this net movement of charge allows sodium to move in unusual direction) • NHE3 is dominant in proximal tubule (majority of H+ secreted is by NHE3 rather than H+-ATPase) • large capacity (the transporter – trying to reabsorb 80% of bicarbonate and to do this we need to secrete acid) but limited gradient generation (only down to pH 6-ish in the lumen (if we just had the NHE3 transporter)) • V-type (vacuolar) H+-ATPase can generate a bigger gradient (down to pH 4 or 5) (this becomes really important in the collecting duct) • more important later in the tubule where lumen is more acidic • 1:3 stoichiometry of kNBCe1 makes it electrogenic • allows HCO3- efflux from the cell because of extra drive from membrane potential • unusual to have Na+ leaving the cell on a cotransporter NHE3 = apical membrane kNBCe1 = basolateral membrane

Answer 40

in PCT (Na+/H+ exchanger) * The NHE3 is dominant in proximal tubule. It has a large capacity but limited gradient generation (from 7.35 to 6 pH). This is because the Na+ ions move over a small gradient and so only small amounts of H+ are exchanged (secreted), therefore the pH only decreases by a small amount. * V-type (vacuolar) H+-ATPase can generate a bigger gradient (from 7.35 to 4/5 pH).

Answer 41

• 1:3 stoichiometry of kNBCe1 makes it electrogenic.  It allows HCO3 - efflux from the cell because of extra drive from membrane potential.  This is because there is a net efflux of 2- charge. This gives the protein the extra drive.

Answer 42

* Rare autosomal-recessive disease * Impaired HCO3- reabsorption in PCT * Severe metabolic acidosis (PCT responsible for absorbing 80% of bicarbonate) * Not treatable by HCO3- supplementation (80% of bicarbonate is reabsorbed in PCT) * Attributed to mutations in kNBCe1 (reabsorbing 3 bicarbonate ions) * Ocular abnormalities too because of kNBCe1 and pBNCe1 expression there too

Answer 43

* The transport protein for HCO3- ions at the basolateral membrane differs to that in the PCT. * Here, it is an anion-exchanger (AE2). * It exchanges HCO3- ions for Cl- ions. - same processes but slightly different combination of transporters - H+ generated from CO2 + H2O as usual (CAII) - Luminal CAIV less important (slower here) - Still have Na-H exchanger (NHE3) and H+-ATPase but there is a different transporter on the basolateral membrane - No kNBCe1 here, just AE2 (carbonate-chloride exchanger) for HCO3- exit at the basolateral membrane - 1 bicarbonate ion out of cell for 1 chloride ion into cell

Answer 44

* The H+ pump at the apical membrane is electrogenic. * The H+/K+ -ATPase pump at the apical membrane is not electrogenic, therefore allowing transport of H+ ions up a steep gradient. * The kAE1 exchanger protein at the basolateral membrane exchanges HCO3- ions for Cl- ions. - Different isoform of the same transporter on the basolateral membrane - kAE1 rather than AE2 – slightly different protein structure - kAE1 has shorter N-terminus than eAE1 - Here is the main site of V-type H+-ATPase activity – bulk of hydrogen ion secretion here - Instead of NHE3, there is H+,K+-ATPase (hydrogen-potassium exchanger) – main role is in the reabsorption of K+ rather than secretion of H+ ions * V-type H+-ATPase in apical membrane of α-intercalated cells – transporter very cell-specific, even within the collecting duct * absent from principal cells

Answer 45

* Defective H+ excretion by distal segment of nephron • Inability to acidify urine (acid not secreted) – serious systemic consequences (metabolic acidosis) * May be incomplete (compensatory mechanisms of proximal tubule) * Treatable with HCO3- supplementation * Dominant and recessive patterns * Several transporter mutations – mainly affecting the α – intercalated cells: kAE1, V-type H+ -ATPase, CAII (proximal effects too)

Answer 46

* The water that diffused into the cell during reabsorption of HCO3- ions split into H+ and OH- ions. * These H+ is secreted back out of the apical membrane into the tubular fluid. * Once in the tubular fluid, the H+ ions are buffered by filtered phosphate (HPO42-) into H2PO4-. * At the same time, HCO3- enters the tubular fluid after being filtered by the glomerulus, which further neutralises it. - CO2 + H2O -> H+ + HCO3- (CAII) - H+ secreted from apical membrane - HPO42- + H+ -> H2PO4- in lumen - This acid is effectively buffered and we can excrete acid in the form of H2PO4- rather than excreting free H+ ions - Secreted H+ is mostly buffered by filtered phosphate – also creatinine, urate, etc. - ‘New’ HCO3 (essentially brings more acid into cell) exits across basolateral membrane -> enters circulation - HCO3- neutralises acidity HCO3- + H+ -> CO2 + H2O -> CO2 freely diffuses across basolateral membrane into cell (this means there’s a net movement of acid being moved from intersitium into filtrate) - The acid in the blood forms CO2 -> forms H+ in the cell -> buffered in filtrate -> urine

Answer 47

* An alternate way of secreting H+ ions is to utilise the ammonium (NH4+) ions synthesised in the cell during glutamine metabolism. * Glutamine metabolism produces NH4+ ions and OH- ions. * The OH- ions can combine with CO2 (via CA II) to form HCO3- ions that can enter the blood. * The NH4+ ions split into ammonia (NH3) and H+ ions. * NH3 and H+ ions are secreted into the tubular fluid where they both combine again to form NH4+ for excretion in urine. - Glutamine metabolism -> NH4+ + OH- (NH4+ is synthesised by the kidney) - NH4+ -> NH3 + H+ - H+ secretion across apical membrane - NH3 freely passes across apical membrane - Once in the filtrate, NH4+ is formed again -> acid excreted in this form - OH- + CO2 (diffuses into cell from interstitium) -> HCO3- (CAII) -> transported across basolateral membrane - ‘New’ HCO3- enters circulation and neutralises acidity - HCO3- + H+ -> CO2 (diffuses through basolateral membrane) + H2O

Answer 48

• Acid (H+ ions) is secreted throughout the nephron:  PCT = 40mmol NH4+ and 15mmol titratable acid (TA)  DCT = 5mmol TA  Collecting duct = 10mmol TA  Small amounts of this acid is recycled in the medulla of the kidneys.  Excreted = 40mmol NH4+ and 30mmol TA. - Most of the NH4+ is secreted in the proximal tubule (40 mmol NH4+) - Some NH4+ recycles in the medulla - Hyperosmotic gradient in medullary interstitium, created by the loop of Henle due to secretion of NaCl, urea and NH4+ - therefore some secretion and reabsorption of NH4+ in thick ascending limb - Re-secretion into collecting duct and excreted there - 50% of titratable acids are secreted in proximal tubule (15 mmol TA) - 5 mmol TA secreted in DCT - 10 mmol TA secreted in collecting duct  40 mmol NH4-  30 mmol TA = 70 mmol acid secreted by kidneys (based on someone that’s 70kg)

Answer 49

- most is secreted in PCT - some re-enters tDLH - partly reabsorbed in TAL - a bit lost to liver - most re-secreted in collecting duct

Answer 50

* On the apical membrane, there is a Na+/K+/Cl- cotransporter (NKCC1). * There is a lack of selectivity for the K+ ion and instead NH4+ can be selected for. * Also, there is a ROMK2 channel on the apical membrane. * This is a K+ channel but can also select for NH4+ ions. * Once in the cell, NH4+ splits into H+ ions and NH3. * NH3 can now diffuse into the blood. (reabsorption from the lumen into the interstitium) (due to NH4+ role in creating hyperosmotic gradient in medulla) - NH4+ in lumen can pass through potassium channels (ROMK2) into cell - NH4+ can also replace K+ in the NKCC1 (1Na+, 1K+, 2Cl-) transporter – transporter into cell - Cells will also be producing NH4+ through glutamate metabolism - NH4+ -> NH3 + H+ - NH3 -> diffusion across basolateral membrane (this membrane over apical membrane due to nature of plasma membrane – more permeable on basolateral membrane than apical membrane ) - NH3 + H+ -> NH4+ in interstitium • Via ROMK2 channel, and NKCC1 accepts NH4+ in place of K+ • Low NH3 permeability at apical membrane, so it leaves across basolateral membrane

Answer 51

- cause = hypoventilation/increased PCO2 | - compensation = increase HCO3- reabsorption (to react with excess H+), kidneys excrete additional H+

Answer 52

- cause = hyperventilation/decreased PCO2 | - compensation = decreased HCO3- reabsorption (to increase HCO3- levels in urine), and excrete less H+

Answer 53

- cause = decreased HCO3- reabsorption (causes a build-up of H+ ions in the blood as HCO3- can't react with it) - compensation = hyperventilation/decreased PCO2 (to get rid of excess H+ ions)

Answer 54

- increased HCO3- reabsorption

Answer 55

``` damage to the glomerular filtrate this can be damage to the:  Endothelium (pre-eclampsia)  Glomerular basement membrane  Podocytes – this is due to genetic mutations. The podocytes ‘drop off’ the basement membrane and flow in the blood until they are removed from the system. ``` * This damage leads to a faulty barrier, which allows larger molecules such as albumin and glucose to pass through into the kidneys. * Chronic damage to the glomerular filter leads to kidney dysfunction.

Answer 56

this is a disease where there is loss of protein (e.g. proteinurea, hypoalbuminaemia)

Answer 57

presence of protein in the urine

Answer 58

 <20mg/mmol (normal) |  200mg/mmol (nephrotic range)

Answer 59

this is a disease where there is loss of blood (e.g. haematourea etc)

Answer 60

 <30 μg/mg (normal)  30-300 μg/mg (microalbuminuria)  >300 μg/mg (albuminuria)

Answer 61

 2025: 300 million with diabetes (WHO)  40% develop nephropathy – Genetic susceptibility  Commonest cause of kidney failure worldwide

Answer 62

both share same pattern

Answer 63

developing a heart attack

Answer 64

```  Hyperfiltration  Microalbuminuria  Macroalbuminuria  Proteinuria  Declining renal function ```

Answer 65

```  Endothelial cells  Glomerular basement membrane  Podocytes  Mesangial cells  Mesangial cell deposit ```

Answer 66

 GBM thickening  Mesangial expansion  Nodular sclerosis  Advanced renal sclerosis

Answer 67

• Aims of treating Diabetic Nephropathy:  Glycaemic control  Blood pressure control – these drugs help to delay the progression of kidney diseases by blocking the renin-angiotensin aldosterone system(RAAS): o ACE inhibitors o Angiotensin-2 receptor blockers (ARB) - Losartan o Renin-inhibitors – Aliskiren  These drugs delay the progression because they lower the blood pressure which in turn lowers the GFR. • Secondary treatments:  Lipid lowering  Reduce other CV risks

Answer 68

• Reduce extracellular fluid volume • Lower blood pressure • Augment effects of RAAS inhibitors • Choice of diuretic agents depends on renal function: 1) Osmotic Diuretics (e.g. mannitol) – these work on the late PCT and the Descending loop of Henle. 2) Loop diuretics (e.g. furosemide) – these work on the ascending Loop of Henle 3) Thiazide diuretics (e.g. bendroflumethiazide) – these work on the DCT 4) Potassium-sparing – these work on the late DCT and early collecting tubule.

Answer 69

* Waste, excess fluids and salts are removed from the body by passing the blood over a dialysis membrane. * This allows the exchange of substances between the blood and the dialysis fluid, which has the same concentration of substances as blood plasma. * Substances diffuse from both sides to create the correct concentration of substances.

Answer 70

* Immediate use reduces fluid overload. * No anticoagulation. * Cheaper and can be used at home. * Continuous * Least likely to cause fluid shifts and hypotension.

Answer 71

* Specialist nursing care * Tertiary units * Need for good central venous access * High and efficient solute clearance * Anticoagulation (heparin) required. * Intermittent: not tolerated when haemodynamically unstable. * Continuous Hemofiltration

Answer 72

* Kidney * Combined kidney and pancreas – in the case of severe diabetes * Islet cell

Answer 73

In 2012:  25% of adults (>16) in England were obese - an overall increase from 15% in 1993.  19% of children (yr 6) were obese

Answer 74

 Subcutaneous fat – storage |  Visceral/omental fat – endocrine tissue

Answer 75

energy balance and for monitoring appetite

Answer 76

1. Inflammatory mediators:  TNFa – induces insulin resistance by promoting serine-phosphorylation of IRS-1, which impairs insulin signalling  Resistin – neutralising antibodies reduces insulin resistance  IL-6 – direct correlation between IL-6 and insulin resistance/ visceral fat secrets 2x more IL-6 than subcutaneous fat 2. Adiponectin (Acrp30) – this stimulates adipose tissue to function correctly. Obesity reduces Acrp30. 3. Leptin  This signals the adipose tissue mass size to the CNS (hypothalamus).  Increased leptin = reduces food intake + increases energy expenditure.  Obesity increases adipose tissue mass.

Answer 77

Brain: • Leptin secretion sends signals to the hypothalamus. • This causes inhibition of feeding and increased sympathetic output. • The increase of sympathetic output causes B-cells to decrease insulin synthesis and secretion. • This leads to increased lipolysis and decreased lipogenesis. Liver: • Leptin decreases gluconeogenesis. • Leptin increases glycogenolysis. • Leptin increases B-oxidation. Muscle: • Leptin increases glucose uptake. • Leptin increases glycogenolysis.

Answer 78

Obese people are leptin resistant. This means that they have an increased appetite and they don’t expend much energy. This means that they get fatter and secrete more TNF-a and so more insulin resistance manifests, increasing the risk of insulin resistance.

Answer 79

• High doses of salicylates (aspirin)  Reverse insulin resistance and diabetes  Preserve β-cell function • High-fat diets or obesity activate NF-κB and increase production of IL- 6, IL- 1β and TNFα.  When these reach their targets (e.g. liver) they cause a further increase in NK-KB. • Activation of NF-κB in liver results in liver and muscle insulin resistance and diabetes. • Antibody-mediated neutralization of IL- 6 in high-fat fed animals partially restores insulin sensitivity.

Answer 80

a protein that controls transcription of DNA. It plays a key role in regulating the immune response to infection. Incorrect regulation of NF-kB has been linked to inflammatory diseases. NF-kB is the protein responsible for cytokine production and cell survival.

Answer 81

• These are a form of drug used to treat type 2 diabetes. • They work by increasing the sensitivity of cells to insulin (that are insulin resistant). • These provide:  Improvement of fasting plasma glucose.  Improvement of lipid profile – lower NEFA/ TG/ cholesterol  Improvement of B-cell function

Answer 82

* These drugs are PPARϒ agonists. * PPARϒ are nuclear hormone receptors that cause an increase in adipogenesis in fat cells. * This causes an increase in glucose uptake for adipogenesis, thus reducing the blood glucose level, without the need of insulin secretion. * These drugs also activate AMP-Kinase. * Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation.

Answer 83

* AGEs are substances that can be a factor in the development or worsening many degenerative diseases, such as diabetes. * These compounds can affect nearly all types of cells and molecules in the body. * They are thought to play a causative role in the blood vessel complications of diabetes. * AGEs are seen as speeding up oxidative damage to cells and in altering their normal behaviour.

Answer 84

* Normally, AGE is produced in the body due to the combination of proteins and glucose. * In type II diabetes, a state of hyperglycaemia develops intracellularly because on increased uptake of glucose (due to the increased levels of insulin), even though the intracellular mechanisms are abnormal (insulin resistance). * This leads to increased levels of NADH and FADH. * This increases the proton gradient in the oxidative phosphorylation. * This results in mitochondrial production of reactive oxygen species which damage the DNA. * These reactive oxygen species also cause accumulation of metabolites, which activate multiple pathogenic mechanisms. * One of these mechanisms includes increased production of AGEs.

Answer 85

* Causes activation of NF-kB, which results in the production of cytokines, and therefore is proinflammatory. * Main targets are endothelial cells and smooth muscle.

Answer 86

• Crosslinking key basement membrane molecules. • Targets:  collagen I and IV, vitronectin, laminin, elastin  Lipid linked LDL • Consequences:  Increased vascular stiffness  Increased synthesis of several ECM components  Reduced endothelial cell adhesion  Reduced NO (muscle relaxant) production and clearance of LDL

Answer 87

* Basement membrane AGEs inhibit monocyte migration - “apoptaxis.” * Soluble AGEs activate monocytes. * AGE binds to receptors on monocytes. * This causes increased expression of macrophage scavenger receptor (MSR) class A receptors and CD36 receptors on the monocyte cell membrane. * As a result more Oxidised LDL (OxLDL) is taken up, thus increasing the concentration of LDL inside the cell. * This leads to foam cell formation.

Answer 88

• AGE generation by hyperglycaemia underpins development of diabetic complications, such as kidney disease and atherosclerosis. • Glucose forms adducts, causes protein crosslinking and changes in structure. • AGE will:  Target vascular tissue and beta cells  Trigger inflammatory reactions  Trigger atherosclerosis  Induce apoptosis  Change cell adhesion properties  Cause vascular stiffness and vasoconstriction  Change basement membrane properties – kidney function • Overall, in diabetes, AGE is responsible for the chronic effects:  Vascular damage  Kidney dysfunction  B-cell damage

Answer 89

where the nephrons come together to drain into the pelvis

Answer 90

- There’s a range of 600,000 to 2.5 million nephrons per kidney - The fewer nephrons you have, the more likely you are to have raised blood pressure in later life - So, link between number of nephrons and risk of cardiovascular disease

Answer 91

in the cortex, so filtration takes place in cortex

Answer 92

- On glomerular capillaries – podocyte cells – they have foot processes – sat on outside of endothelium – but they move around on the surface of capillaries - Filtration slits between the foot processes of the cells let and prevent stuff moving through – e.g. red blood cells are too big to get through

Answer 93

they break off

Answer 94

- Epithelial cells in the Bowman’s capsule | - Endothelial cells in the capillaries

Answer 95

About 20% of plasma that enters the capillary is filtered, the remaining 80% remains in the blood

Answer 96

will be more viscous because it’s lost 20% of plasma – so higher concentration of red blood cells

Answer 97

- Net pressure favouring filtration is only 10 mmHg (pressure small really) - But it’s enough to cause significant volumes of fluid to be filtered

Answer 98

- Net pressure favouring filtration is only 10 mmHg (pressure small really) - But it’s enough to cause significant volumes of fluid to be filtered GFR = 20% RPF (renal plasma flow?) = 125 ml/min = 180 L/day = 60 times plasma volume!! - Under normal circumstances, your GFR doesn’t change – it remains constant (so if you drink more water or something it doesn’t change it?) (IMPORTANT) - This is because even a slight change in GFR could mean huge changes in volume, so you could potentially become dehydrated very quickly if there weren’t compensatory mechanisms

Answer 99

- Sleep - Exercise - Chronic disease e.g. hypertension, renal, artery stenosis Even through changes due to this, GFR does not change due to autoregulation

Answer 100

- Na+/K+-ATPase pump (basolateral side) - sodium out into blood and potassium in - this is what requires the energy - Na+/H+ exchanger - sodium taken up from tubular fluid in proximal tubule (due to lower Na+ gradient inside cell now) - H+ into proximal tubule which goes to urine - exchanger = NHE-3/SLC9A3 - Cl-/anion exchanger - Cl- taken in from proximal tubule - anion given out - Chloride ion channel - chloride out into blood - Na+/H+ exchanger - sodium taken in from blood - H+ given out into blood - NHE-1/SLC9A1 (this is to do with acid regulation of cell itself – not to do with sodium reabsorption, but to do with cell’s own volume and pH)

Answer 101

Na+/K+-ATPase

Answer 102

- Fine regulation - Mediated by aldosterone – from adrenal gland - Na+/K+-ATPase in basolateral membrane - Na+ channel (ENaC (epithelium sodium channel)) taking in Na+ from urine - K+ channel giving out K+ to urine - Both channels present normally but aldosterone increases the production and the open probability of these channels – making the membrane much more leaky – allows a lot more sodium to come in if we need it - Slow process – 24-48hrs – genomic effect - However, it’s generally not an emergency because the amount of sodium we eat doesn’t vary that much

Answer 103

potassium loss

Answer 104

- Loss of considerable nephron function – global GFR was 22 but a considerable proportion of her nephrons would not have been functioning, so GFR of each individual nephron would have been higher - Splay – uraemic toxins – she was beginning to develop uraemia (retaining urea in blood) – toxins damaging the function of the remaining filtering nephrons – so their capacity to filter and reabsorb glucose would also be diminished

Answer 105

- Takes place in cortex? Lactate pyruvate -> oxaloacetate -> phosphoenol pyruvate -> triose phosphatases -> glucose - Glycolysis in medulla? Lactate pyruvate

Answer 106

loop of Henle

Answer 107

vasa recta (capillary network surrounding tubule)

Answer 108

just dip into medulla

Answer 109

Juxtamedullary nephrons are much longer – they go virtually all the way to the ends of the pyramids – these are the ones that are important in your ability to concentrate urine (called that because the glomerulus is juxtaposed/close to the boundary with the medulla)

Answer 110

- Active transport of NaCl along the ascending thick limb results in the movement of water from the descending limb (due to high concentration of sodium and urea) - As fluid moves down descending limb it gets more concentrated as water is leaving - As passes up ascending limb, sodium removed, which reduces osmolality of fluid to point where it’s more dilute than it was when it started (100 mOsm/l compared with 300 mOsm/l) - Maximum concentration gradient that Na+Cl- pumps can maintain between fluid inside and fluid in the extracellular space is 200 mOsm/kg (concentration higher in the extracellular fluid) (this is in the ascending limb) - The outside will be 200 mOsm/kg higher than it is on the inside – that’s the most that those pumps can maintain - Therefore, can be any lower than 100 mOsm/kg on the inside at the top of the ascending limb

Answer 111

- Na+ concentration in the fluid in tubule higher than in the cell so it will go down concentration gradient - Na+/Cl-/K+ cotransporter on apical side takes the sodium into the cell - Na+/K+-ATPase on basolateral side will pump it out into extracellular fluid against concentration gradient

Answer 112

- In the proximal tubule, water and sodium are reabsorbed in proportion - So, the concentration of fluid that enters your loop of Henle is the same as plasma = 300 mOsm/kg - Because as it goes down water can leave down water potential gradient, when you get to bottom of loop concentration is 1200 mOsm/kg - As you go up loop, sodium transported out, lowering osmolality - At distal tubule osmolality is 100 mOsm/kg - So, by passing fluid through the loop we have diluted the fluid – large volume of diluted urine - But often we need to concentrate urine, if we need to retain fluid - This depends upon hormone ADH/vasopressin - Under normal circumstances, collecting duct is not permeable to water - The only way you can get water back and concentrate urine is to make collecting duct permeable to water - When this happens, you can maximally concentrate your urine to 1200 mOsm/kg = MAXIMUM – determined by length of loop of Henle

Answer 113

LATE DISTAL/COLLECTING DUCT - Aldosterone acts on collecting duct cells to open sodium channels on apical side - There’s a Na+/K+-ATPase pump on basolateral membrane, pumping sodium out and so gradient for Na+ to come into cell down channel from tubule - So, aldosterone allows sodium to enter the cell and be pumped out - What you also need is ADH to bind to receptor on basolateral side, and stimulate the insertion of water channels – aquaporins (AQP2) - When these are inserted into the apical membrane, the collecting duct cells become permeable and water can enter from the fluid in tubule - So, aldosterone promotes sodium reabsorption and ADH promotes water reabsorption – aldosterone on its own doesn’t cause any water reabsorption - Water than enters the cell can leave into extracellular fluid through AQP3/4 – allows it to get back into blood

Answer 114

Blood in vasa recta (from the efferent arteriole) is moving in the opposite direction to the direction of flow through the nephron (so blood moving down when fluid moving up ascending limb)

Answer 115

- High blood glucose concentration in glomerulus - Glucose Tm exceeded - Glucose present in tubular fluid in collecting duct - > 1200 mOsm/kg - = osmotic diuresis -> thirst

Answer 116

- Proximal - 65% K+ reabsorbed - Loop of Henle - 25% K+ reabsorbed - Distal & collecting duct - variable K+ reabsorption or secretion

Answer 117

- The way insulin is being used here is to stimulate the Na+/H+ exchanger in basolateral side - So, more sodium pumped into cell, providing a gradient for the Na+/K+-ATPase, so potassium pumped into cell – reducing plasma levels - This isn’t in kidney

Answer 118

Ca2+ & Mg2+ | because an inability to regulate particularly calcium properly -> bone mineral wasting

Answer 119

- Calcium – 99% in bone, 1% in extracellular fluid | - Magnesium – 50% in bone, 50% in extracellular fluid

Answer 120

- Osteoblast cells = take up calcium and magnesium from ECF into bone - Osteoclast cells = take calcium and magnesium out of the bone and into ECF

Answer 121

- 40% of calcium is absorbed by the gut from food we eat - 10-65% of magnesium is absorbed in the gut from food we eat - The above enters the extracellular space through a paracellular route - Then we lose 1-2% calcium and 3-5% magnesium in our urine

Answer 122

lower/raise depolarisation threshold

Answer 123

raise/lower heart rate

Answer 124

- Water excretion - dependent on osmotic gradient in medulla - regulated by aldosterone (Na+) and ADH/vasopressin (aquaporins) - Potassium - critical for excitable cells - reabsorbed & secreted by the tubule - Calcium & magnesium - fine control of reabsorption in distal tubule I MAY HAVE CALLED SOME OF THE PUMPS CHANNELS – MAYBE CHECK THAT WHAT I CALLED CHANNELS ARE ACTUALLY CHANNELS AND NOT PUMPS – CHANNELS ARE THE RECTANGES, PUMPS ARE CIRCLES

Answer 125

mineralocorticoid – produced by the zona glomerulosa of adrenal cortex in adrenal gland – essential for sodium conservation in the kidney, salivary glands, sweat glands and colon

Answer 126

- Permits donation post mortem – opt-in - Allows family members to refuse if you have not registered on the Organ Donor Register (and occasionally even if you have) - Permits (some) live organ donation to be targeted to specific individuals - Makes paid donation illegal - Allow 12-year-old + to make their own decisions

Answer 127

Amends Human Tissue Act 2004 on the issue of consent: The person concerned is to be deemed, for the purposes of …(transplantation).. to have consented to the activity unless a person who stood in a qualifying relationship to the person concerned immediately before death provides information that would lead a reasonable person to conclude that the person concerned would not have consented.

Answer 128

7.4 in arterial blood

Answer 129

- regulation is dominated by the HCO3-/CO2 buffering system CO2 + H2O H+ + HCO3- (catalysed by carbonic anhydrases) - CO2 = potential acid – because if you increase concentration of CO2, that pushes equilibrium to other side, increasing H+ concentration – so CO2 has potential to become acidic load to our body - Metabolism -> CO2 -> excretion by lung - Metabolism & diet -> H+ -> excretion by kidney - HCO3- - retained by kidney – freely filtered into glomerulus – all absorbed by kidneys in order to buffer acid in body fluids - Urine is always slightly acidic

Answer 130

pH = pK + log10 [HCO3-]/[CO2] - we want to maintain pH at 7.4 - pK = 6.1 (constant) - therefore, log1- [HCO3-]/[CO2] = 1.3 - log20 = 1.3, therefore, [HCO3-][CO2] ratio needs to = 20 so that we maintain pH at 7.4 - we get this ratio by having [HCO3-] = 24 mM (regulated by kidneys) and [CO2] = 1.2 mM (regulated by respiratory system)

Answer 131

- 15,000 mmol CO2 produced per day - ‘potential acid’ – not a problem – excreted by lungs - Metabolism also produces about 40 mmol H+ per day - ‘non-volatile acids’: sulphuric, phosphoric, organic acids - Net uptake of about 30 mmol H+ per day by GI tract (some bicarbonate also absorbed but overall a lot more acid) - So, the kidney has to: a) Excrete about 70 mmol H+ per day b) Reabsorb all the filtered HCO3- (equivalent to about 4,000 mmol H+ per day!! If we didn’t reabsorb the bicarbonate in order to buffer the acid – bodies wouldn’t be able to deal with this)

Answer 132

- Typical daily urine output: 1.5 litres - 70 mmol H+ in 1.5 litres is 47 mM - Without any buggering that would be pH 1.3 - Ouch! – very acidic - And, renal epithelia can only secrete H+ to a concentration of about pH 4.4. (i.e. a 1000-fold concentration gradient) - Excreted H+ needs to be buffered!

Answer 133

- H+ secreted across apical membrane | - HCO3- absorbed across basolateral membrane (using various different transporters)

Answer 134

- What happens when HCO3- reabsorption and H+ excretion go wrong Four types - Type 1 – Distal RTA - Type 2 – Proximal RTA - Type 3 RTA (combination of type 1 and 2) - Type 4 – Hyperkalaemia RTA (Hypoaldosteronism) (this type of acidosis due to having an aldosterone insufficiency or inability to respond to aldosterone in kidneys)

Answer 135

- NH4+ produced by glutamine metabolism (occurs in mitochondria of proximal tubule cells) - NH4+ -> NH3 + H+ - NH3 freely diffused into lumen - H+ ions transported into lumen – either via H+-ATPase or NHE3 - NH4+ ions reformed and excreted in this form - On basolateral membrane, NBC (sodium-bicarbonate cotransporter), secreting ‘new’ HCO3- across membrane

Answer 136

(NH4+ contributing to medullary gradient which is quite important but overall we want to be excreting acid in the form of NH4+, so we get some re-secretion of NH4+ in the collecting duct – so now we’re getting NH4+ moving back the other way) - NH4+ can replace K+, which is thought to be in the Na+,K+-ATPase on basolateral membrane (2NH4+ in cell, 3Na+ out cell) - Majority of ammonium will come from NH3 diffusing back into cell across basolateral membrane which will then pass through apical membrane - NH4+ -> NH3 + H+ - H+-ATPase will secrete H+ - NH3 + H+ -> NH4+ in lumen • Most crosses epithelium as NH3 • Maybe some NH4+ is carried by Na+,K+-ATPase

Answer 137

* PCO2 (resp.) or [HCO3-] (metab.) * (after being detected by kidneys) both directly stimulate H+ secretion and NH4+ synthesis by proximal tubule * chronic leads to expression of NHE3 and kNBCe1 (so can be excreting more acid and be reabsorbing more bicarbonates)

Answer 138

* opposite changes in proximal tubule – excrete less H+ ions * chronic leads to more β-intercalated cells (HCO3- secreting) in collecting tubule (doesn’t occur under normal conditions)

Answer 139

* Kidney reabsorbs all of the filtered HCO3- * Excretes additional H+ as titratable acid (using filtered buffers) and NH4+ (synthesized) * All achieved by apical H+ secretion via NHE3, V-type H+-ATPase and H+,K+-ATPase * Basolateral HCO3- exit via kNBCe1 and AE2 replenishes plasma HCO3- * Dependent on carbonic anhydrases II & IV

Answer 140

- A skillful clinical style for eliciting from patients their own good motivations for making healthy behaviour changes by exploring and resolving ambivalence - Not for tricking people into doing what they don’t want to! - In general, growing evidence for the effectiveness of MI - MI out outperformed traditional lifestyle advice in 80% of studies and was no more time consuming ‘We are generally better persuaded by the reasons we discover ourselves than by those given to us by others’

Answer 141

Collaborative: conversation between equals working together, using our empathy skills Evoking: asking the person about their motives, ideas and resources – guiding and listening not telling Supporting autonomy: respectful of their choice and control, so as not to create resistance

Answer 142

- Engaging - Focusing - Evoking - Planning (i.e. the general path across one consultation, or several) Engaging: settle into a helpful conversation Focusing: find a useful direction Evoking: draw out person’s good reasons for change Planning: if they want to, help them plan how to change

Answer 143

Sustain talk: - Talk from the patient about staying the same - Listen out for it - Can identify obstacles the person needs to problem solve or lack of confidence Change talk: - Talk from the patient about changing - Listen out for it - Can identify motivation and confidence - Helping people voice ‘change talk’ and explore it further helps them move towards change

Answer 144

OARS - Open questions - Affirmation of strengths/progress – ‘that’s great that you’ve come along to appointment’ - Reflections – ‘wow it sounds like you’re struggling/doing great’ – shows that you’re listening – better than always asking questions - Summarising

Answer 145

ELICIT – PROVIDE – ELICIT (EPE) FRAMEWORK Elicit: - What do they already know? - What do they want to know? - Do you have their permission to give information? Provide: - One tailored chunk of information Elicit: - What do they think of your information?

Case 7 Flashcards

(175 cards)