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The Patient 20300 > Renal 3 > Flashcards

Renal 3 Flashcards

1
Q

What is renal clearance. Give an example of a product which is removed from the body by renal clearance

A

Removal of compounds from blood and their elimination in urine is known as renal clearance.

e.g. urea, a product of protein metabolism, is removed from the body by renal clearance

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2
Q

Give examples of drugs which are excreted from the body via renal clearance

A

Amiodarone, digoxin, gentamycin, lithium, methotrexate, pitvastatin, salmeterol, tacrolimus

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3
Q

Give a factor which affect renal clearance rates

A

With age, the number of functional nephrons tends to decrease.
Consequently, the ability of kidneys to filter and clear compounds, including drugs, is decreased.

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4
Q

Pathology can also affect renal clearance. Give examples of conditions which may affect clearance

A

Tumours
Glomerularnephritis (inflammation)
Glomerularsclerosis (blood vessel scarring or hardening)

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5
Q

What happens to the drug dosage when renal clearance is affected

A

When renal clearance is affected

drug dose may be reduced

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6
Q

What parameter do we use to measure kidney function

A

Glomerular filtration rate (GFR) can be used to measure kidney function (i.e. filtration).
INULIN can be used to measure GFR directly

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7
Q

What is inulin

A

Inulin is a fructose polymer with a MW 5 kDa (relatively low)
Its administered IV and freely filtered at the glomerulus due to its low mw
Its not reabsorbed nor secreted by the nephron and its also not metabolised by the kidney

This means the amount of inulin filtered = amount excreted in urine

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8
Q

How do we derive the eGFR

A

GFR can also be estimated (eGFR) using serum creatinine in combination with other factors e.g. age, race and gender, and by using equations

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9
Q

Why would we use the eGFR over the GFR in practice

A

Estimating the GFR is more convenient than using inulin as creatinine is produced by the muscles (no IV)

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10
Q

Define renal clearance (mathematically)

A

Renal Clearance is the volume of plasma from which a substance is completely removed per unit time

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11
Q

How is renal clearance important in drug formulation

A

Important in drug development and in understanding how the body handles drugs
E.g. if a drug is cleared by the kidneys, dose adjustment may be needed (age, pathology)

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12
Q

What are the three measurements needed to calculate renal clearance

A

Three measurements are needed
V = rate of urine production (vol/time)
[UA] = urine conc. of A
[PA] = plasma conc. of A

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13
Q

What is the formula to work out renal clearance

A

Clearance(A) = ([UA] x V)/[PA]

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14
Q

Where are the two places drugs are filtered out of the plasma

A

Drugs can be cleared from the plasma by being filtered at the glomerulus

Drugs may also be cleared from the plasma by secretion from the vasa recta into the tubule

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15
Q

Describe the pathway drugs take through the kidney when being filtered out of the plasma

A

During renal clearance drugs may be initially transported out of the vasa recta capillary into kidney tubule epithelial cells

Drugs are then transported out of tubule cells into the tubular fluid and may be excreted in the urine

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16
Q

Which are the transporters expressed on the basolateral membrane which pump drugs out of the vasa recta capilliary and into the kidney tubule epithelial cells

A

OAT1 & 3: organic anion transporter
OATP1: organic anion transporting polypeptide
OCT1: organic cation transporter

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17
Q

Which are the transporters expressed on the apical membrane which pump drugs out of the the kidney tubule epithelial cells and into the tubular fluid

A

MRP2 & 4: multidrug resistance-associated protein
ABCG2 (BCRP): breast cancer resistance protein
ABCB1 (P-gp): P-glycoprotein

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18
Q

Which transporters move methotrexate into and out of the kidney tubule cells

A

Methotrexate in - OCT1 & OAT1

Methotrexate out - MRP2, MRP4 & ABCG2

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19
Q

Which transporters move pitvastatin into and out of the kidney tubule cells

A

Pitvastatin in - OAT3

Pitvastatin out - ABCG2

20
Q

Which transporters move Rosuvastatin into and out of the kidney tubule cells

A

Rosuvastatin in - OAT3

Rosuvastatin out - ABCG2

21
Q

Which transporters move Fexofenidine into and out of the kidney tubule cells

A

Fexofenidine in - OAT3

Fexofenidine out - ABCB1

22
Q

Which transporters move digoxin into and out of the kidney tubule cells

A

Digoxin in - OATP1

Digoxin out - ABCB1

23
Q

In healthy individuals hat happens to the glucose filtered at the glomerelus

A

In healthy individuals, all the glucose filtered at the glomerelus into the tubular fluid is reabsorbed into the blood

24
Q

Which transporters moveglucose from the tubular fluid and into the kidney cells

A

SGLT2 transporter

sodium glucose transporter 2

25
Q

How does sodium play a part in the transport of glucose into kidney cells

A

sodium ions move down their electrochemical gradient and energise the transport of glucose into the cell

26
Q

How do we exploit the SGLT2 receptors in diabetes treatment

A

In diabetes treatment the aim is to reduce blood glucose

By blocking the SGLT2 glucose transporter we reduce reabsorption into the blood

27
Q

Give an example of a SGLT2 inhibitor

A

Dapagliflozin (Forxiga) – licensed for Type 2 diabetes

It inhibits SGLT2 and aids glucose elimination and reduces blood glucose reabsorption

Part of the molecule mimics a glucose molecule and so binds well to the transporter but blocks its action.

28
Q

How does sodium aid homeostasis

A

Na+ is involved many processes in the body, e.g. generation of electrical impulses, muscle contraction and nutrient transport.

It also influences blood volume and pressure.

This is why it is important to regulate Na+ levels within the body

29
Q

WHat can high sodium levels lead to

A

High Na+ levels can cause:

Hypertension
Heart disease
Stroke
(Worldwide strokes are the second leading cause of death and the third leading cause of disability)

30
Q

How does the kidney regulate sodium levels (and what are the key transporters which facilitate this)

A

Na+ levels are regulated by the kidney.
Na+ is freely filtered at the glomerulus.
70% of filtered Na+ is reabsorbed in the proximal tubule.
Key transporters are:
SGLT2 transporter
Na+, H+ (proton) antiporter
Na+, K+ ATPase

31
Q

Each of the following transporters carry sodium into or out of the kidney cells. Explain where each is found:
SGLT2 transporter

Na+, H+ (proton) antiporter

Na+, K+ ATPase (x2)

A

SGLT2 transporter - found on the apical membrane and pumps sodium and glucose into the kidney cells

Na+, H+ (proton) antiporter - found on the apical membrane and pumps sodium into the kidney cells and pumps protons out of the cells and into the tubular fluid

Na+, K+ ATPase - both are found on the basolateral membrane and pump sodium out on the kidney cells and into the vasa recta capilliary. They also pum potassium from the blood into the kidney cells

32
Q

Where else is sodium reabsorbed and what processes control it

A

Na+ is also reabsorbed in the collecting duct – and this is under hormonal control

33
Q

How do high sodium levels result in increased blood pressure

A

When Na+ is reabsorbed, water follows by passive diffusion.

High Na+ reabsorption can lead to increased blood pressure

34
Q

How do we regulate sodium levels in the body

A

So, if Na+ levels drop, we need to increase the amount in the body.

To do this, we increase Na+ reabsorption in the kidney and this is controlled by the steroid hormone aldosterone.

35
Q

Where is aldosterone produced

A

Aldosterone is produced in the cortex of the adrenal gland in the top of the kidney

36
Q

WHat happens when aldoseterone is released

A

Release of aldosterone causes:

An increase in the number of Na+ channels in the apical membrane of the cell.

An increase in the number of Na+, K+-ATPase pumps in the basolateral membrane – which hydrolyse ATP to energise Na+ transport.

This allows more Na+ to be reabsorbed

37
Q

How is aldosterone secretion stimulated (7 steps)

A

Via the renin angiotensin system:

Drop in plasma Na+ and blood pressure are sensed by the kidney juxtaglomerular cells.

These cells then release the enzyme renin

The liver produces angiotensinogen

Renin converts angiotensinogen to angiotensin I

Kidney and lung capillary cells produce angiotensin converting enzyme (ACE)

ACE converts angiotensin I to angiotensin II

Angiotensin II triggers synthesis of aldosterone within the adrenal cortex

38
Q

What does aldosterone do

A

Aldosterone triggers synthesis of Na+ channels and Na+, K+-ATPase pumps which allows increased Na+ reabsorption.

39
Q

Give examples of drugs which act on the renin angiotensin system

A

ACE inhibitors (e.g. captopril, fosinopril) block ACE activity, prevent formation of active angiotensin II and prevent production of aldosterone.

These are used to treat heart disease (+ diuretic) and high blood pressure

40
Q

When are diuretics used

A

In the treatment of oedema, hypertension and congestive heart disease

41
Q

Briefly describe the action of spironalactone

A

Spironolactone
(an aldosterone analogue)

Indication: Oedema

It blocks aldosterone receptor which prevents aldosterone from binding to it

Blocks aldosterone function – so additional Na+ channels and Na+, K+-ATPase pumps are not synthesised by the cell.

42
Q

Briefly describe the action of amiloride

A

Amiloride: Na+ channel blocker
Indication: Oedema

Reduces Na+ reabsorption

If less Na+ is reabsorbed, less water is reabsorbed

43
Q

What can cause a build up of acid in the body and how can the kidneys counter this

A

Poor gaseous exchange and release of carbon dioxide due to diseased lungs (e.g. emphysema) may lead to Respiratory Acidosis (a build up of CO2 in blood which causes it to become acidic)

Kidneys correct this disorder by increasing H+ secretion

44
Q

Give the chemical equation for the acid base balance in the body and note where the acid and base are usually delt with

A

(excreted by the lungs) CO2 + H2O <=> H2CO3 <=> HCO3- + H+ (kidneys)

45
Q

What happens in ineffecient lungs to the chemical acid-base equilibrium

A

With inefficient lungs there is a build up of CO2 in plasma, the equilibrium shifts to the right and H+ are secreted renally.

46
Q

How is proton secretion connected to sodium reuptake in the kidney

A

H+ secretion is coupled to Na+ uptake by the H+ and Na+ antiporter

47
Q

What is a byproduct of proton secrection by the kidney and why is it important

A

HCO3- (bicarbonate) is produced during H+ secretion

HCO3- is an important biological buffer

The Patient 20300 (24 decks)

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