PK 09: Renal Clearance and GFR

Question 1

What are the 3 processes that contribute to renal clearance?

Answer 1

• glomerular filtration (passive)
• tubular secretion (active)
• tubular reabsorption (active/passive)

Question 2

What is glomerular filtration?

Answer 2

passive filtration of plasma water (and unbound compounds) as blood flows through glomerulus

• low E (around 0.1) process

Question 3

What is glomerular filtration rate (GFR)?

Answer 3

volume of plasma water entering glomerulus that is filtered into renal tubule per unit time

• maximum clearance due to passive filtration by kidney
• 120 mL/min
• can be thought of as a type of intrinsic clearance (CLint)

Question 4

What factors influence glomerular filtration of drugs? (3)

Answer 4

size

• < 15,000 g/mol – freely filtered
• > 15,000 g/mol – restricted filtration

protein binding
- drugs bound to plasma proteins are not filtered (ie. albumin)

pathology

• ↓ glomerular integrity (diabetic nephropathy, nephrotic syndrome)
• ↓ number of functional nephrons (chronic kidney disease, aging)

Question 5

What is tubular secretion?

Answer 5

carrier-mediated transport (active process)

• can result in saturable renal (urinary) drug elimination
• transporter-based drug-drug interaction can alter PK of drugs whose elimination is dependent on renal transporters

Question 6

What is tubular reabsorption?

Answer 6

• ~170 L (120 mL/min x 60 min/hr x 24 hr/day) of plasma water is filtered by the kidneys each day – 99% of filtered water is returned to systemic circulation
• water reabsorption along nephron concentrates drug present in filtrate and sets up concentration gradient favouring drug reabsorption (tubule → blood) – drug reabsorption occurs mainly through passive diffusion, while active transport is generally less important

Question 7

What factors influence tubular reabsorption? (2)

Answer 7

• drug ionization / urine pH
• urine flow rate

Question 8

Can ionized or unionized drugs permeate biological membranes to facilitate reabsorption?

Answer 8

unionized – pH partition hypothesis

Question 9

What is normal urine pH, acidification, and alkalinization?

Answer 9

• normally ~6.3 but can range between 5-7.5
• acidification (administration of ammonium chloride) ~5
• alkalinization (administration of sodium bicarbonate) ~7.5

Question 10

What can exhibit pH-dependent renal reabsorption?

Answer 10

weak acid and bases (pKa ~3-11)

Question 11

How does urine acidification affect renal drug reabsorption?

Answer 11

• ↑ tubular ionization of weak bases (↓ reabsorption)
• ↓ tubular ionization of weak acids (↑ reabsorption)

Question 12

How does urine alkalinization affect renal drug reabsorption?

Answer 12

• ↓ tubular ionization of weak bases (↑ reabsorption)
• ↑ tubular ionization of weak acids (↓ reabsorption)

Question 13

How does urine flow affect renal drug reabsorption?

Answer 13

↑ urine flow ~ ↑ volume of filtrate in tubule (↓ reabsorption)

• lowers concentration of dissolved drug in tubule, reducing diffusion gradient between tubule and blood

↑ urine flow ~ ↑ speed of filtrate through tubule (↓ reabsorption)

• reduces time window for reabsorption

Question 14

What processes are drugs always subject to?
What processes may occur?

Answer 14

• ALWAYS subject to glomerular filtration
• tubular secretion and tubular reabsorption MAY occur

Question 15

What processes are influencing renal clearance when CLR ~ GFR x fu,p?

Answer 15

glomerular filtration

Question 16

What processes are influencing renal clearance when CLR > GFR x fu,p?

Answer 16

• glomerular filtration
• tubular secretion

Question 17

What processes are influencing renal clearance when CLR < GFR x fu,p?

Answer 17

• glomerular filtration
• tubular reabsorption

Question 18

Alterations in CLr due to renal impairment is generally based on what?

Answer 18

intact nephron hypothesis (INH)

Question 19

What is the intact nephron hypothesis (INH)?

Answer 19

impaired renal function is caused by a reduction in number of complete (functionally intact) nephrons

• all renal excretory processes (ie. filtration, tubular secretion, and tubular reabsorption) decline in parallel to number of complete nephrons
• GFR ∝ number of intact nephrons

Question 20

What are the different measures of renal function?

Answer 20

• true GFR
• eCrCl
• eGFR

Question 21

What is true GFR used for?

Answer 21

research purposes

Question 22

What is eCrCl used for?

Answer 22

drug PK and dosing

• adjustment of drug dosing in renal impairment

Question 23

What is eGFR used for?

Answer 23

staging CKD

Question 24

How is true GFR (measured GFR) measured?

Answer 24

measured via exogenous administration of glomerular filtration markers that are excreted exclusively via glomerular filtration (CLmarker = GFR)

• inulin is considered the ‘gold standard’ marker for measuring GFR

Question 25

What are the properties of an ideal marker of GFR?

Answer 25

- free filtered (MW < ~15,000 g/mol) - not protein bound - not reabsorbed - not secreted - not metabolized - inert (non-toxic) creatinine is an ideal marker

Question 26

How is estimated creatinine clearance (eCrCl) measured?

Answer 26

estimated using Cockcroft-Gault equation

Question 27

What is creatinine clearance?

Answer 27

volume of plasma cleared of creatinine per unit time (approximation of GFR)

Question 28

What is creatinine?

Answer 28

- metabolic waste product of muscle metabolism - formed by non-enzymatic breakdown of phophocreatinine and creatine in skeletal muscle - constant/continuous rate of production proportional to muscle mass - predominantly cleared via glomerular filtration

Question 29

Describe how creatinine is an ideal marker of GFR.

Answer 29

- 10-20% cleared via tubular secretion – ↑ proportion secreted with decreasing renal function - creatinine clearance systematically overestimates GFR - despite its drawbacks, creatinine clearance has been extensively used as a clinical measure of renal function over the last half-century

Question 30

What are the limitations of eCrCl?

Answer 30

- overestimates true GFR (creatinine is also secreted) - not applicable for children (< 18 years) - stable renal function only - uncertainty for patients at the extremes of muscle mass or body size – amputees, bodybuilders (ie. athletes), obesity, pregnancy, muscle atrophy (muscular dystrophies, paraplegics)

Question 31

How is estimated glomerular filtration rate (eGFR) measured?

Answer 31

using chronic kidney disease epidemiology collaboration equation (CKD-EPI) - equations developed to approximate GFR from a single serum creatinine value and subject demographics

Question 32

eGFR What are the 4 variables of the chronic kidney disease epidemiology collaboration equation (CKD-EPI)?

Answer 32

- age (years) - sex - serum creatinine (Scr, umol/L) - race (variable is not implemented by Canadian labs)

Question 33

What are the limitations of eGFR?

Answer 33

- not applicable for children (< 18 years) - questionable accuracy in elderly (> 70 years) - unclear accuracy non-White/non-Black subjects - stable renal function only

Question 34

eGFR vs. eCrCl

Answer 34

- both provide approximations of GFR - eGFR equations provide relatively more accurate estimates of GFR - eGFR developed based on studies where renal function was measured using exogenous glomerular filtration markers (ie. provide estimates of GFR) - eCrCl developed based on studies where renal function was measured using urinary excretion (ie. provides an estimate of the clearance of creatinine)

Question 35

What are the 4 variables when calculating eCrCl?

Answer 35

- age (years) - weight (kg) – for this course, use ‘actual body weight’ - serum creatinine (umol/L) - sex for this course, use eCrCl to approximate GFR