Renal Physiology: Potassium & Magnesium (Zoysa)

Question 1

What are the key roles of the kidney?

Answer 1

• Elimination of waste products
• Control of fluid balance
• Control of minerals
• Regulate acid-base balance
• Produce hormones

Question 2

Where is Magnesium found in our body?

Answer 2

99% Mg²⁺ found in bone (hydroxyapatite), muscle and soft tissue

• Intracellular [Mg²⁺] range from 5 to 20mmol/L
• Extracellular [Mg²⁺] accounts for 1%

Question 3

What is Magneisum responsible for?

Answer 3

Magnesium is responsible for:

• Bone formation
• _Co-facto_r in >300 enzymatic reactions (ATP metabolism, muscle contraction and relaxtion, neurological function, release of neurotransmitters)
• Regulation of vascular tone
• Cardiac rhythm
• Platelet activated thrombosis

Question 4

In humans, hydrated Mg²⁺ bind tightly to _______________, therefore_________________________________

Answer 4

In humans, hydrated Mg²⁺ bind tightly to many water molecules, therefore it has a big diameter and difficult to travel through intracellular channels.

It often needs to be stripped of water molecules to travel through channels (active processes).

Question 5

Where do we get our Magneisum from and where do we absorb it in our system

Answer 5

Daily dietary intake requirement is ~300mg Mg²⁺.

• Some content in water, depending on how water is processed (low content in NZ).
• High content in plants, e.g. green leafy vegetables, cereals and nuts.
• Intermediate content in meat and fish
• Low content in dairy products

Mg²⁺ absorption occurs mostly in small intestine via paracellular receptor channels.

Question 6

Describe the Reabsorption and Excretion of Magnesium

Answer 6

Kidney plays a key role in terms of serum Mg²⁺ regulation (reabsorption and excretion).

• ~2400mg is filtered by the glomeruli
• 95% immediately reabsorbed (10-20% proximal convoluted tubule, 60-70% thick ascending limb of Henle, 10% distal convoluted tubule)
• 5% (100mg) excreted in the urine
• Proximal Convoluted Tubule
  
  • In proximal convoluted tubule, 10-20% Mg²⁺ is reabsorbed via paracellular mechanism (unknown Mg²⁺ paracellular channels).
    
    • There is possible involvement of Na/K ATPase (Mg²⁺ follows Na+)?
• Thick Ascending Limb
  
  • In thick ascending limb of Henle, _60-70% Mg²⁺ i_s reabsorbed via paracellular mechanism (Claudin 16-19 channels).
    
    • Water is reabsorbed in descending limb, which drives electrolytes reabsorption in ascending limb (due to increased electrolyte concentration after water is reabsorbed)
    • There is involvement of claudin 16-19, NKA, NKCC2, ROMK and CLC-Kb with Bartin to drive Mg²⁺ reabsorption.
      
      • NKCC2 mutations lead to hypomagnesaemia, hypokalemia, such as Bartter’s syndrome and Gitelman’s syndrome.
      • Claudin 16-19 mutations lead to hypomagnesaemia (unable to reabsorb Mg²⁺ so low serum Mg²⁺)
• Distal Convoluted Tubule
  
  • In distal convoluted tubule, 10% Mg²⁺ is reabsorbed via transcellular mechanism (active transport) (TRPM6, EGFR, HNF1B, CNNM2).
  • TRPM6 (transient receptor potential ion channels) are very important for Mg²⁺ reabsorption.
    
    • TRPM6 mutations lead to hyomagnesaemia and hypercalcemia (formation of calcium stones in neonates).

Question 7

How do you assess serum Mg concentrations?

Answer 7

• Serum [Mg²⁺] (0.7-1mmolL) (tightly regulated)
• Red cell [Mg²⁺] (sometimes serum [Mg²⁺] are not good overall markers)
• _24 hour excretio_n
  
  • (more Mg²⁺ excretion nocturnally, therefore important for 24 hour test)
• _Mg²⁺ retention tes_t (if [Mg²⁺] do not rise via oral route, then absorption problem)
• Isotope analysis (not often used clinically)

Question 8

What are some symptoms of Hypomagnesaemia?

Answer 8

• Initially
  
  • Weakness and fatigue
• Later
  
  • Fasciculation and cramps
  • Tetany and carpopedal spasm
• Numbness (paresthesiae)
• Seizures
• Arrhythmias

Question 9

What are some casues of Hypomagnesaemia

Answer 9

1. Decreased dietary intake
2. GI malabsorption and loss
3. Endocrine, e.g. hyperaldosteronism, DM, SIADH, ‘hungry bone’ syndrome
4. Renal loss

• Congenital
• Acquired
• Drug-induced
  
  • (increase magnesium loss), e.g. aminoglycosides, amphotericin B, CNI, cisplatin, cetuximab, proton pump inhibitors (omeprazole), pentamidine, foscarnet

Question 10

How do you treat hypomaynesaemia?

Answer 10

• Treatment of primary cause!
• Oral magnesium (used in most cases)
• IV magnesium (magnesium sulphate)

Question 11

What can cause Hypermagnesamia?

Answer 11

• Very uncommon
• In advanced CKD, compensatory mechanisms start to become inadequate and hypermagesaemia may develop (although this may be balanced by decreased Mg²⁺ intake)
• Excessive oral administration of Mg²⁺ salts or Mg²⁺-containing drugs (e.g. milk of Mg²⁺)
• Iatrogenic

Question 12

Potassium is the most abundant cation in ___________\_

Answer 12

Potassium is the most abundant cation in intracellular fluid.

Question 13

Describe the Homeostasis of Potassium

• Where we get it from
• What influences its homeostasis
• How we excrete it

Answer 13

Potassium daily oral intake is 1560-5850mg/day.

At healthy steady state, 90-95% excreted in urine, 5-10% in faeces.

• Kidney is primarily responsible for maintaining total body K+
  
  • K+ freely filtered in glomerulus
  • K+ reabsorption occurs in proximal convoluted tubule (60%), thick ascending limb of Henle (30%), distal convoluted tubule (variable) and collecting ducts (variable).
• Initial changes in extracellular K+ are buffered by K+ movement into or out of skeletal muscle regulated by insulin and catecholamines

It is affected by:

• Tonicity (hyperglycemia drives K+ efflux, e.g. diabetic ketoacidosis (DKA), hyperosmolar non-ketotic hyperglycaemia (HONK))
• pH (acidosis drives K+ efflux, alkalosis drives K+ influx)

Question 14

What might lead to hyperkaelmia?

Answer 14

It is affected by:

• Tonicity
  
  • ​(hyperglycemia drives K+ efflux, e.g. diabetic ketoacidosis (DKA), hyperosmolar non-ketotic hyperglycaemia (HONK))
• pH
  
  • ​(acidosis drives K+ efflux, alkalosis drives K+ influx)

Question 15

Describe the regulation of potassium via kidney

Answer 15

In proximal convoluted tubule, 60% K+ is reabsorbed via paracellular mechanism (driven by Na/K ATPase).

In thick ascending limb of Henle, 30% K⁺ is reabsorbed via transcellular and paracellular mechanism

• Passive K⁺ reabsorption via paracellular pathway via electrochemical gradient.
• Secondary active K⁺ reabsorption via NKCC2, driven by Na/K ATPase.

At distal convoluted tubules, it is regulated by aldosterone and angiotensin

• Serum potassium load (excess) stimulates aldosterone production.
• Serum sodium depletion or extracellular volume depletion stimulates renin production, which leads to increased aldosterone

Question 16

What Affects Serum [K+]?

Answer 16

Serum [K+] is affected by

(1) K+ intake;
(2) K+ losses;
(3) K+ redistribution from ECF in/out of cells

Question 17

When are people deemed to be ‘hypokaelmic’?

Answer 17

Symptoms of Hypokalemia

Hypokalemia is serum [K+] <3.5mmol/L.

Symptoms include:

• Muscle weakness
• Paralysis
• Cardiac conduction abnormalities
• Cramp
• Constipation

Question 18

What are the symptoms of Hypokalaemia?

Answer 18

Symptoms of Hypokalemia

Hypokalemia is serum [K+] <3.5mmol/L. Symptoms include:

• Muscle weakness
• Paralysis
• Cardiac conduction abnormalities (e.g. palpatations)
• Cramp
• Constipation

Question 19

Describe the Hypokalemimc Periodic Paralysis

Answer 19

Hypokalemic Periodic Paralysis

Hypokalemic period paralysis is autosomal dominant (rare) or thyrotoxic conditions

• There is _abnormal K+ channel_s on cell membrane
• This is often triggered by high carbohydrate meal (insulin) or SNS activation (b-agonist), e.g. anxiety or exercise
• This leads to _excessive movement of K+ into cell_s, results in extreme weakness

Question 20

What are some causes of Potassium Loss? (Hypokaelemia)

Answer 20

Causes of Hypokalemia (Potassium Loss)

Renal Loss

• Renal tubular acidosis
• Hyperaldosteronism
  
  • Conn’s syndrome is due to adrenal adenoma (tumor), which secretes aldosterone
  • Presents with hypertension and hypokalaemia
• Licorice
  
  • Licorice contains glycyrrhizin, which acts like aldosterone by activating mineralocorticoid receptors in kidney
  • Results in hypertension and hypokalaemia
  • This is termed pseudohyperaldosteronism
• Diuretics (either increase/decrease [K+] depends on drugs)
  
  • Hypokalaemia is caused by drugs that act more proximally (e.g. mannitol, frusemide, bumetanide)

Gut Loss

• Vomiting
• Diarrhoea (e.g. laxatives)
• Ileostomy
• Bowel fistulae
• NG tube losses

Question 21

Describe the treatment of hypokalemia

Answer 21

• Treat the underlying problem!
• In mild hypokalemia, use oral K+
• In severe hypokalemia (<3mmol/L), use IV K+ replacement

Question 22

When is someone deemed to have “hyperkalemia”?

Answer 22

Hyperkalemia is serum [K+] >5mmol/L.

Symptoms include:

• Fatigue or weakness
• Paraesthesia
• Nausea or vomiting
• Dyspnoea
• Palpitations

Severe hyperkalemia is an emergency, due to action potential widening (PR prolongation, wide QRS, peaked T waves), can develop into ventricular fibrillation and cardiac arrest.

Question 23

What are the symptoms of hyperkalemia?

Answer 23

Hyperkalemia is serum [K+] >5mmol/L.

Symptoms include:

• Fatigue or weakness
• Paraesthesia
• Nausea or vomiting
• Dyspnoea
• Palpitations

_Severe hyperkalemia is an emergen_cy, due to action potential widening (PR prolongation, wide QRS, peaked T waves), can develop into ventricular fibrillation and cardiac arrest.

Question 24

Describe Pseudohyperkalemima

Answer 24

Occasionally, pseudohyperkalemia is seen on lab tests due to haemolysed sample.

Exclusion by no symptoms, unlikely to be proper problem, repeat test if possible.

Question 25

What are some causes of hyperkalemia?

Answer 25

• Increased intake
  
  • (harder if normal excretion mechanism, but easier in CKD)
• Disruption of cell intake
  
  • (e.g. beta blockers, acidosis, rhabdomyolysis)
• _Decreased excretio_n
  
  • (e.g. renal failure, hypoaldosteronism, ACEi/ARB, other drugs)

Question 26

Describe Addison’s Disease

• Characterisitics
• Symptoms
• Lab results
• Diagnostic test
• Treatment

Answer 26

Addison’s disease is deficient secretion of adrenocortical hormone (aldosterone, cortisol). Symptoms include:

• Characteristic h_yperpigmented/tanned appearance_ (due to excessive ACTH excretion, stimulating melanocytes)
• Lethargy and weakness
• Weight loss,
• Hypotension

Laboratory tests show hyperkalemia, hyponatremia

Diagnosis via short synacthen test (check cortisol production) and scans

Treatment is dexamethasone, fludrocortisone

Question 27

Describe the treatment of hyperkalemia

Answer 27

1) Stabilise action potential

• ​(calcium gluconate normalize membrane excitability prevent cardiac arrest) (short term ~0.5hr)

2) Push K+ into cells

• Beta Agonists
  
  • Use ventolin nebulisers (5mg salbumatomol nebulized). Can do it hourly.
  • Reduces K+ by 0.9-1.5mmol/L by driving K+ intracellularly
  • Takes about 0.5-1hr to act
  • Duration of effect 4-6hr
• ​Insulin
  
  • Use 10 units short acting insulin and 50ml 50% dextrose over 10 mins
  • Takes about 10–20min to act
  • Peak effect 30-60min
  • Duration of effect 4-6hr
  • Remember dextrose bolus!
• Treat Acidosis
  
  • Oral bicarbonate tablets 840mg bd/tds
  • IV bicarbonate 8.4% 50mL over 1hr and repeat (in emergency)

3) Reduce Absorption

• Cation exchange products such as calcium resonium 15g tds (oral or rectal)
• Bind to K+ in gut and increase faecal elimination
  
  • Takes about 4-6hr to act
  • Side effect of constipation, give with laxative

4) Increase Elimination

• K losing diuretic drugs
• Dialysis (particularly if already a dialysis patient, or if rhabdomyolosis)

5) Fix underlying problem

Question 28

(Summary of Magnesium and Potassium)

Answer 28

Summary

Magnesium

• A common cation.
• Hypomagnesaemia is common.
• Can be due to GI, endocrine or renal (congenital, acquired, or drugs).

Potassium

• The most common cation.
• Tightly regulated.
• Affected by renal function, acid base, drugs, aldosterone.
• Hypo/hyperkalaemia is an emergency.