Esa 3 - Urinary System - Session 6

Front 1

State the normal plasma ranges for pH, PO2, PCO2, potassium and hydrogen carbonate.

Back 1

Ph – 7.38 – 7.42,
PCO2 – 4.8-6.1KPA
PO2 – 10-13.3KPA
[HCO3-] – 22-26mmol/l
[K+] – 3.5-5mmol/l

Front 2

Describe the clinical effects of acidaemia and alkalaemia.

Back 2

Acidaemia: If pH is below 7.38 this indicates high concentration of H ions in the blood. Acidosis affects enzyme function, affecting hydrogen bonds within domains and eventually denaturing enzymes.
• Reduced cardiac & skeletal muscle contractility
• Reduced glycolysis in many tissues
• Reduced hepatic function
• Increased plasma K - hyperkalaemia due to cells pumping out potassium ions into plasma in exchange for H ions. This cause dysrrhymias as potassium is necessary to establish resting potential across cardiac membranes.
Effects severe below pH 7.1 & life threatening below pH 7.0

Alkaleamia : if pH is above 7.42 this indicates high concentration of HCO3 in the blood. In alkaleamia, H ions unbind from plasma binding proteins and this increases number of available binding proteins eg albumin for calcium to bind to. Thus calcium leaves extra cellular fluid, binding to bone and proteins. Hypocalaemia causes tetany – muscle spasms and paresthesis. At pH 7.55, mortality is 45% & 80% if pH exceeds 7.65.

Front 3

Describe the carbon dioxide/hydrogen carbonate buffer system and the factors influencing Pco2 and [HCO3].

Back 3

CO2 + H2O <-> HCO3- + H+
This reaction takes place in the plasma as well as in red blood cells.
In the plasma, there is 20 times as much HCO3 as CO2 as it is produced in the red blood cells and the forward reaction is slow as there is little carbonic anhydrase. In the red blood cell CO2 reacts with water rapidly due to lots of carbonic anhydrase. The H ions react with haemoglobin which has a large buffering capacity especially when in tense form. The amount of HCO3 therefore depends on the buffering capacity of haemoglobin.

The equilibrium is driven towards dissociated by rises in dissolved CO2. The plasma PCO2 is directly proportional to alveolar PCO2. Content = alveolar PCO2 X 0.23.
The equilibrium is driven backwards if there is a rise in [HCO3] which is normally 25mmol-1.

Front 4

Describe and be able to identify from values, respiratory acidaemia and alkalaemia and metabolic acidosis and alkalosis.

Back 4

Looking at values:
1. Look at Ph – below 7.38 it is acidosis, above 7.42 it is alkalosis
2. If acidosis then look at metabolic gap – if increased then it is metabolic acidosis.
3. If don’t know metabolic gap, look at pCO2, if high then this is respiratory acidosis, if low then this is metabolic acidosis.
4. If alkalosis then look at [HCO3]


.

Front 5

ph- 7.3, PCO2 – 7.6, [HCO3] – 25mmol/l, PO2 – 10
Comment on these results.

Back 5

ph is lower than 7.38 therefore this is acidosis. There is no anion gap so PCO2 is high, abover 6.1kpa. Therfore this is respiratory acidosis. Hypoventilation causes increased CO2 concentration, causing decreased pH. Compensation would show increase in HCO3 to react with excess H ions.

Front 6

ph – 7.5, PCO2 – 4.6 [HCO3] – 22mmol/l, PO2 – 14. Comment on results.

Back 6

Ph is high, above 7.42, therefore this is alkalosis. PCO2 is low, below 4.8kpa and PO2 is high, abover 13.3kpa. so this is respiratory alkalosis caused by hyperventilation. Compensation would show decreased HCO3 to increase free H ion

Front 7

A normal ph, low PCO2, low [HCO3] and high PO2. What 2 things could this be?

Back 7

Fully compensated respiratory alkalosis could also be fully compensated metabolic acidosis if anion gap is unknown. In fullycompensated respiratory alkalosis, Po2 will be high and PCO2 will be low due to hyperventilation and [HCO3] would decrease to compensate.
In Metabolic acidosis Po2 would be high and PCO2 low due to respiratory compensation (hyperventilation). There would be a low [HCO3] due to decreased production or bound to excess H ions.

Front 8

ph 7.3, PCO2- 5.3 , [HCO3] – 16, PO2 – 13.3

Back 8

Low ph, below 7.38 therefore it is acidosis. No anion gap so not sure. Pco2 is very low so it is not respiratory acidosis, [HCO3] is low, less than 22mmol/l therefore it is metabolic acidosis. Tissues produce acid which reacts with HCO3 reducing concentration. Compensation is by hyperventilation to remove CO2 and mainly be reabsorbing all filtered HCO3 and secreting more HCO3 in intercalted cells of the collecting duct

Front 9

ph 7.6, PCO2 – 5.3, [HCO3] -30, PO2 – 13.3

Back 9

Ph is high, above 7.42 therefore it is alkalosis. PCO2 and PO2 are normal so it is not respiratory alkalosis. [HCO3] is very high, above 26mmol/l, therefore it is metabolic alkalosis. There is increased production or retension of [HCO3] eg due to vomiting, acid is expelled in vomit and as there is no acid in duodenum, alkaline tide is not triggered and HCO3 remains in blood. Compensation is by hypoventilation but this can't be done so mainly be excretiong of HCO3.

Front 10

What is the Henderson hassalbach equation?

Back 10

Ph = 6.1 + log( [HCO3]/PCO2x 0.23)
0.23 is the solubility constant for CO2.

Front 11

Explain the cellular mechanisms of re-absorption of HCO3 in the proximal tubule.

Back 11

Recovery of HCO3- occurs in PCT (80-90%) & the rest in distal tubule.
H ions are pumped out through the apical membrane and into the filtrate in exchange for sodium which flows down its concentration gradient ( Na-H exchanger). H ions react with HCO3 in filtrate to form CO2 and water. CO2 diffuses back into the cell and reacts with water to produce HCO3 and H ions. HCO3 then enters the plasma whereas H ions return back to the filtrate.
In the proximal convoluted tubule, glutamine is broken down to form NH4+ and alpha ketoglutarate. Alpha ketoglutarate forms 2 HCO3 molecule which are reabsorbed into the blood and NH4+ is excreted to act as a buffer for H ions.

Front 12

Explain the cellular mechanisms of HCO3 reabsorption and H+ excretion in the distal tubule.

Back 12

Around 15% of HCO3 is reabsorbed in the distal tubule of the nephron through intercalated cells. H ions are pumped out across the apical membrane by a H+ATPase pump as the sodium gradient is insufficient. At this stage there is little HCO3 in filtrate so little CO2 enters the cell to react with water. Co2 produced from kidney metabolism however is available and reacts with H20 to produce new HCO3 to enter the plasma. The H ions in the urine must be buffered to prevent a damaging urinary acidity. The monobasic phosphate (HPO2-4) is one of the buffers and becomes more effective as the ph drops. However the effect of phosphate buffers is limited by the amount filtered. The other buffers are excreted ammonia produced from breakdown of glutamine in PCT.

Front 13

How is new HCO3 formed by the kidneys?

Back 13

In the PCT, glutamine is broken down to ammonia and alpha ketoglutarate. Alpha ketoglutarate can form 2 molecules of HCO3 which is reabsorbed by the peritubular capillaries. The ammonia is released into the urine where it buffers H+ ions.
Also CO2 from renal metabolism reacts with water in tubular cells to form HCO3. The H ion are pumped out into the urine either in H/NA exchanger if sodium gradient is sufficient. If it is not, then H-atpase is used to actively pump H ions out.

Front 14

What is the miminim urine ph? define titratable acid. Describe H buffers in the urine.

Back 14

The minimum urine pH is 4.5 where there is no HCO3- released. The H ions in the urine must be buffered to prevent a damaging urinary acidity. The monobasic phosphate (HPO2-4) is one of the buffers and becomes more effective as the ph drops. However the effect of phosphate buffers is limited by the amount filtered. The other buffers are excreted ammonia produced from breakdown of glutamine in PCT. The titratable acid is the volume of H ions which are buffered by monophosphates. The rest is attached to ammonia as ammonium. The total acid secretion is 50-100 mmol H+ per day and this keeps plasma HCO3- normal.

Front 15

Describe the anion gap

Back 15

In Metabolic acidosis, acids are produced metabolically and form H+ & an anion (lactate, etc). The H+ reacts with HCO3- producing CO2 which is breathed out. Some HCO3- is replaced by anion from acid.
The anion gap indicates whether any HCO3- has been replaced with something other than Cl-. Anion gap = ([Na+] + [K+])-([Cl-]+ [HCO3-] i.e. Unaccounted anions. This should be 10-15 mmol.l-1. It is increased if anion from metabolic acid has replaced plasma HCO3-. Sometimes renal problems can reduce [HCO3-] without increasing the anion gap as it is replaced with Cl-.

Front 16

Explain the association with potassium plasma concentration and hydrogen plasma concentration.

Back 16

Metabolic acidosis is associated with Hyperkalaemia. Potassium hydrogen exchanger functions so K+ moves out of cells and H+ ions move into cells to increase plasma pH. Plasma potassium concentration also influences HCO3 reabsorption and ammonium excretion so that as [k] increases, the capacity of the kidney to reabsorb and create HCO3 is reduced.
Metabolic alkalosis is associated with hypokalaemia. Due to hydrogen potassium exchange, K+ moves into cells and H ions move out. There is less K+ reabsorption and so less interaction with HCO3 reabsorbtion, therefore the capacity of the kidney to reabsorb and create HCO3 is increased.

Front 17

Describe the action of a loop diuretic and how the patient may become alkalotic.

Back 17

Loop diuretics treat hypertension and oedema particularly in patients with impaired renal function. They target the Na-K-2Cl symporter on the thick ascending limb of loop of henle and prevent the uptake of these electrolytes. The extra sodium in filtrate at DCT favours H+ excretion into filtrate causing metabolic alkalosis and favours K secretion causing hypokalaemia. Hypokalaemia worsens metabolic alkalosis as K ions will leave the cells in exchange for H ions.

Front 18

What is the major intracellular cation and what are its intracellular and extracellular values?

Back 18

The major intracellular cation is K+, therefore maintenance of K+ is essential for life.
Plasma 4-5 mmol/l & intracellular 150- 160 mmol/l
Normal diet contains 80-120mmol K+ which is more than enough to satisfy the needs of the body.
80% of ingested K is excreted in urine by the kidneys and the remaining excess is excreted in faeces and sweat. Intracellular stores buffer any changes in plasma [K+]. I.e. if decrease in plasma [K+], there is movement of K+ out of cells & hence change in plasma [K+] is minimised. The plasma [K] is very low at only 2% of body potassium and therefore any small change to plasma concentration will have great effects.

Front 19

What is the acute and long term regulation of ECF potassium?

Back 19

Acute regulation is the Na/K/ATPase pump in skeletal muscle during exercise
- Muscles cells have the largest store of K ions and so they buffer extracellular changes in [K]. If plasma [k] decreases, K moves out from myocytes into the plasma.
- During exercise, contraction of skeletal muscle cells causes release of potassium into plasma which is taken up by non-contracting cells. The plasma [k] is directly proportional to intensity of exercise. After exercise, the plasma potassium levels can drop dramatically to 3mmol/l and this can cause sudden onset of cardiac death!! Eat a banana.
Long term regulation is Na/K/ATPase pump in kidneys

Front 20

Describe excretion, reabsorbtion and secretion of potassium from PCT to loop of henle.

Back 20

Na & K intake are roughly the same and so to maintain K+ balance there must be a higher fractional excretion of K+ than Na+ ( fraction excretion = the proportion of filtered solute that remains unabsorbed by the nephron). Normally 800mmol/day of K is filtered and dietary intake is 80-120mmol/day. K balance can be achieved by excreting 10% of filtered potassium, at low dietary intakes of potassium, the excretion drops to 1-3% and under this there is no k excretion.
Secretion of K is necessary when there is chronically high K intake.
- In the PCT – around 80% of filtered K is reabsorbed, this is predominantly passively through tight junctions ( paracellular transport) via a concentration gradient.
- Some K+ secretion in the descending thin limb if high plasma[k]
- K+ reabsorbed from the ascending limb together with Na+ & Cl- ( Na K 2Cl symporter – inhibited by local diuretic). Most k+ however diffuses back into lumen.

Front 21

Describe reabsorption and secretion of potassium from DCT and collecting duct.

Back 21

In the early distal tubule, k+ reabsorption and leakage back are approximately equal.
In the late tubule & subsequent segments of collecting-duct system, K+ is secreted into the tubular fluid via apical K channels driven by electrochemical gradient established by Na/K atpase on basolateral membrane. Secretion is according to body’s needs ( increased cellular K concentration results in increased secretion and vice versa).
Increased flow rate in lumen, achieved by some diuretics, will increase rate of potassium secretion. ADH stimulates K secretion by the collecting ducts by enhancing Na reabsorption. Aldosterone increases K secretion. Increased plasma K concentration stimulates aldosterone production by the adrenal cortex, so plasma aldosterone levels rise.
In the intercalated cells of the cortical collecting tubule, k is reabsorbed in k depletion. Apical H/K antiporters actively pump K ions into cells and k ions then diffuse passively into the blood via k channels on basolateral membrane. This also mediates the simultaneous secretion of H ions for acid-base maintenance.

Front 22

Give an outline of reabsorbtion and secretion of potassium in the kidney.

Back 22

Summary
• PCT – predominantly passively reabsorbs K
• Descending thin limb –some K+ secretion into filtrate ( if HIGH PLAMSA [K])
• Ascending thick limb – K+ reabsorbed from the ascending limb –Na-K-2Cl symporter
• DCT – Secrete in normal or high plasma levels and reabsorb in low levels.
• Principle cells of cortical collecting tubule – K+ is secreted into filtrate. There is an increase in K secretion with increase in plasma [K]. The rate of potassium secretion is also affected by Na+ reabsorption, changes in cellular [K+] & changes in DCT lumen [K+]. 20-180% of K filtered can be secreted.
• Intercalated cells of cortical collecting duct – H-K channels reabsorb 10%
• Na-K-ATPase containing Medullary collecting duct - reabsorbs 5%

Front 23

Describe medullary trapping of potassium.

Back 23

Medullary Trapping of K+ is where the kidney traps K+ in medullary intersticium
1. interstitial [K+] ↑ towards papillary
2. JMN secrete K+ passively into descending limb – K+ reabsorbed into plasma but at a slower rate than secretion result is trapping of K+ in medulla
3. reabsorption by medullary collecting duct cells - this always happens
This process may help to maximize K+ excretion when dietary intake is high

Front 24

Describe the hormonal regulation of potassium.

Back 24

The following hormones promote the movement of K from ECF to ICF using Na-K-ATPase.
Insulin: increase in plasma [insulin] following a meal activates Na-K-ATP’ase to pump ingested and absorbed K+ into cells rather thanraise ECF [K+]. Insulin stimulates glucose uptake and metabolism necessary to drive Na-KATP’ase. A large rise in ECF [K+] stimulates insulin secretion at any time. Treatment of hyperkalaemia with insulin and glucose i.v

Adrenaline: is released from adrenal gland medulla and effects cellular K+ uptake. It is important during exercise and trauma. In exercise K + leaks out of cells and with trauma damaged cells leak K+ causing raised ECF [K+]. Exercise and trauma both cause release of Adrenaline which causes non exercising or non damaged cells to uptake K+.

Aldosterone: Increases in plasma [K+] act directly on the adrenal cortex to increase aldosterone output & decreases in plasma [K+] reduce aldosterone output. Aldosterone increases the number of K+ channels in the apical membrane in the distal nephron & hence enhances K+ secretion. Aldosterone enhances H+ secretion by Increasing Na H exchange in principal cells & by Increasing H ATPase activity in intercalated cells.

ADH stimulates K+ secretion by the collecting ducts by enhancing na reabsorption & prevents changes in urine volume from disturbing K+ homeostasis.

Front 25

Describe causes of Hypokalaemia and symptoms.

Back 25

Describe causes of Hypokalaemia and symptoms.
- Diarrhoea – Faecal loss of K+ from GI secretions
• Vomiting – direct K+ loss in vomit & urinary K+ excretion (hyperkalaemia -> increased filtered)
• Insulin – increases K+ entry into cells (of skeletal muscle & liver) via the Na K ATPase. Total body K+ unaltered but extracellular K+ decreases.
Hypokalaemia à most subjects symptom free until down to 2-2.5 mmol/l
• Initial symptom is muscle weakness, usually affecting the lower extremities & gradually extending upwards, death occurs when respiratory function is affected.
• Also, synthesis of liver & muscle glycogen required K so hypoK produces an abnormal glucose tolerance.
• Vasoconstriction occurs and cardiac arthymias
• Polyuria & thirst – renal response to impaired ADH so patients are unable to produce concentrated urine.
• Metabolic alkalosis – since the K+ deficit causes an increase in intracellular H concentration
• Hypokalemia causes hyperpolarised resting membrane potential. After excitation, the repolarisation of cardiac muscle is brought about by an increase in K+ permeability, causing K+ to move out of the cells, in hypoK the time for cardiac to repolarise is prolonged and this causes cardiac arrhymias.
Management – ECG monitoring & muscle strength,.
Treatment is IV K+ salt.

Front 26

Describe the causes of Hyperkalaemia

Back 26

Causes of hyperkalaemia:
- Ingestion of K
- Metabolic acidosis ( diabtetes mellitus)
- Insulin deficiency ( ie addisons disease) – insulin promote K into cells
- Excess cell breakdown ( eg after cytotoxic cancer therapy)
- Renal failure: Excess K+ is normally removed from the body by renal secretion. Ingestion causes increased plasma K which stimulates the release of aldosterone from the adrenal cortex, which increases K+ secretion. Normal people can tolerate tenfold increase in K+ intake. This may be caused by decreased fluid delivery to distal K secreting site.
Hyperkalaemia depolarises the membrane to make the resting membrane potential decreased ( less negative). Therefore cells cannot repolarise after an action potential and this lead to paralysis. Fatal arrhymias can occur.

Front 27

Describe Treatment of hyperkalaemia.

Back 27

• Loop diuretics to promote K excretion
• Insulin (with dextrose) to promote intracellular entry of K
• The effects of hyperK on muscle function can be corrected even in the continuing presence of hyperK, by administering Ca2+. This makes the threshold potential less negative & restores the normal gap with the resting membrane potential

Front 28

Describe the renal function changes due to hypokalemia.

Back 28

Renal function changes: Initially, the kidney does not immediately conserve K+ effectively & urinary K output remains high for 2-3 weeks. Thus hypoK & low urinary K output is indicative of long-standing K depletion, caused by extra-renal factors.

Front 29

How will the kidneys respond to respiratory alkalosis? How will this help?

Back 29

The kidneys will respond by excreting more HCO3-. This will restore ratio of hydrogen carbonate to dissolved carbon dioxide back towards
20:1 and therefore pH back towards 7.4

Front 30

How many litres are filtered each day from the glomerulus?

Back 30

180l

Front 31

What is the cellular stimulus for changes in renal secretion of acid?

Back 31

Changes in HCO3 movement out of tubular cells in proximal convoluted tubule and into blood. If rate decreases, due to high levels in ECF, then this will increase pH of renal tubular cells, decreasing secretion of H ions.
If rate increases, due to low levels of HCO3 in ECF, then this will decrease pH of renal cells, stimulating secretion of H ions. Secreting ions stimulates HCO3 recovery and so plasma ph will be returned to normal ( 7.38-7.42).
Low ph also stimulates the enzymes which deaminate glutamine, producing alpha ketoglutarate, ammonium ions and 2 HCO3.

Front 32

When is metabolic alkalosis difficult to correct?

Back 32

Normally metabolic alkalosis is easy to correct as all plasma HCO3 is filtered and then reabsorption is controlled by the degree of H secretion which is controlled by the ph of renal tubular cells. However, if volume depletion has also occured eg due to vomiting, then mechanisms to restore volume eg soidum reabsorption also favour HCO3 reabsorption which worsens the alkalosis.

Front 33

Why should late distal diuretics not be administered in parallel with ACE inhibitors?

Back 33

Late distal diuretics dispose towards hyperkalaemia as they prevent secretion of K ions. ACE inhibitors cause hyperkalemia by inhibiting formation of angiotensin 2 which will function to increase potassium excretion. This is why these drugs must never be administered in parallel

Front 34

What is conn's syndrome?

Back 34

Conn's syndrome is primary hyperaldosteronism and can result in excessive potassium excretion causing hypokalemia ( alkalosis). It is diagnosed by an aldosterone/ rennin ratio of greater than 2000

Front 35

Describe the changes in plasma K during heavy exercise.

Back 35

Heavy exercise causes transient hyperkalaemia for 2 reasons. Firstly, K will be released into the
plasma from mechanically ruptured red cells. Secondly, many cell types, including myocytes,
contain ATP sensitive K channels; these are normally blocked by ATP. As ATP is depleted these
channels become unblocked and K leaks out. This has a beneficial effect, because K ions are
vasodilators, and blood flow to exercising muscle is thus increased