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PHRM 100 – PK > PK 09: Renal Clearance and GFR > Flashcards

PK 09: Renal Clearance and GFR Flashcards

1
Q

What are the 3 processes that contribute to renal clearance?

A
  • glomerular filtration (passive)
  • tubular secretion (active)
  • tubular reabsorption (active/passive)
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2
Q

What is glomerular filtration?

A

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

  • low E (around 0.1) process
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3
Q

What is glomerular filtration rate (GFR)?

A

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)
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4
Q

What factors influence glomerular filtration of drugs? (3)

A

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)
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5
Q

What is tubular secretion?

A

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
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6
Q

What is tubular reabsorption?

A
  • ~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
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7
Q

What factors influence tubular reabsorption? (2)

A
  • drug ionization / urine pH
  • urine flow rate
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8
Q

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

A

unionized – pH partition hypothesis

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9
Q

What is normal urine pH, acidification, and alkalinization?

A
  • normally ~6.3 but can range between 5-7.5
  • acidification (administration of ammonium chloride) ~5
  • alkalinization (administration of sodium bicarbonate) ~7.5
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10
Q

What can exhibit pH-dependent renal reabsorption?

A

weak acid and bases (pKa ~3-11)

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11
Q

How does urine acidification affect renal drug reabsorption?

A
  • ↑ tubular ionization of weak bases (↓ reabsorption)
  • ↓ tubular ionization of weak acids (↑ reabsorption)
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12
Q

How does urine alkalinization affect renal drug reabsorption?

A
  • ↓ tubular ionization of weak bases (↑ reabsorption)
  • ↑ tubular ionization of weak acids (↓ reabsorption)
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13
Q

How does urine flow affect renal drug reabsorption?

A

↑ 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
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14
Q

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

A
  • ALWAYS subject to glomerular filtration
  • tubular secretion and tubular reabsorption MAY occur
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15
Q

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

A

glomerular filtration

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16
Q

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

A
  • glomerular filtration
  • tubular secretion
17
Q

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

A
  • glomerular filtration
  • tubular reabsorption
18
Q

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

A

intact nephron hypothesis (INH)

19
Q

What is the intact nephron hypothesis (INH)?

A

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
20
Q

What are the different measures of renal function?

A
  • true GFR
  • eCrCl
  • eGFR
21
Q

What is true GFR used for?

A

research purposes

22
Q

What is eCrCl used for?

A

drug PK and dosing

  • adjustment of drug dosing in renal impairment
23
Q

What is eGFR used for?

A

staging CKD

24
Q

How is true GFR (measured GFR) measured?

A

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
25
Q

What are the properties of an ideal marker of GFR?

A
  • free filtered (MW < ~15,000 g/mol)
  • not protein bound
  • not reabsorbed
  • not secreted
  • not metabolized
  • inert (non-toxic)

creatinine is an ideal marker

26
Q

How is estimated creatinine clearance (eCrCl) measured?

A

estimated using Cockcroft-Gault equation

27
Q

What is creatinine clearance?

A

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

28
Q

What is creatinine?

A
  • 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
29
Q

Describe how creatinine is an ideal marker of GFR.

A
  • 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
30
Q

What are the limitations of eCrCl?

A
  • 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)
31
Q

How is estimated glomerular filtration rate (eGFR) measured?

A

using chronic kidney disease epidemiology collaboration equation (CKD-EPI)

  • equations developed to approximate GFR from a single serum creatinine value and subject demographics
32
Q

eGFR

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

A
  • age (years)
  • sex
  • serum creatinine (Scr, umol/L)
  • race (variable is not implemented by Canadian labs)
33
Q

What are the limitations of eGFR?

A
  • not applicable for children (< 18 years)
  • questionable accuracy in elderly (> 70 years)
  • unclear accuracy non-White/non-Black subjects
  • stable renal function only
34
Q

eGFR vs. eCrCl

A
  • 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)
35
Q

What are the 4 variables when calculating eCrCl?

A
  • age (years)
  • weight (kg) – for this course, use ‘actual body weight’
  • serum creatinine (umol/L)
  • sex

for this course, use eCrCl to approximate GFR

PHRM 100 – PK (15 decks)

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