PK 09: Renal Clearance and GFR Flashcards
What are the 3 processes that contribute to renal clearance?
- glomerular filtration (passive)
- tubular secretion (active)
- tubular reabsorption (active/passive)
What is glomerular filtration?
passive filtration of plasma water (and unbound compounds) as blood flows through glomerulus
- low E (around 0.1) process
What is glomerular filtration rate (GFR)?
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)
What factors influence glomerular filtration of drugs? (3)
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)
What is tubular secretion?
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
What is tubular reabsorption?
- ~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
What factors influence tubular reabsorption? (2)
- drug ionization / urine pH
- urine flow rate
Can ionized or unionized drugs permeate biological membranes to facilitate reabsorption?
unionized – pH partition hypothesis
What is normal urine pH, acidification, and alkalinization?
- normally ~6.3 but can range between 5-7.5
- acidification (administration of ammonium chloride) ~5
- alkalinization (administration of sodium bicarbonate) ~7.5
What can exhibit pH-dependent renal reabsorption?
weak acid and bases (pKa ~3-11)
How does urine acidification affect renal drug reabsorption?
- ↑ tubular ionization of weak bases (↓ reabsorption)
- ↓ tubular ionization of weak acids (↑ reabsorption)
How does urine alkalinization affect renal drug reabsorption?
- ↓ tubular ionization of weak bases (↑ reabsorption)
- ↑ tubular ionization of weak acids (↓ reabsorption)
How does urine flow affect renal drug reabsorption?
↑ 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
What processes are drugs always subject to?
What processes may occur?
- ALWAYS subject to glomerular filtration
- tubular secretion and tubular reabsorption MAY occur
What processes are influencing renal clearance when CLR ~ GFR x fu,p?
glomerular filtration
What processes are influencing renal clearance when CLR > GFR x fu,p?
- glomerular filtration
- tubular secretion
What processes are influencing renal clearance when CLR < GFR x fu,p?
- glomerular filtration
- tubular reabsorption
Alterations in CLr due to renal impairment is generally based on what?
intact nephron hypothesis (INH)
What is the intact nephron hypothesis (INH)?
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
What are the different measures of renal function?
- true GFR
- eCrCl
- eGFR
What is true GFR used for?
research purposes
What is eCrCl used for?
drug PK and dosing
- adjustment of drug dosing in renal impairment
What is eGFR used for?
staging CKD
How is true GFR (measured GFR) measured?
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
What are the properties of an ideal marker of GFR?
- free filtered (MW < ~15,000 g/mol)
- not protein bound
- not reabsorbed
- not secreted
- not metabolized
- inert (non-toxic)
creatinine is an ideal marker
How is estimated creatinine clearance (eCrCl) measured?
estimated using Cockcroft-Gault equation
What is creatinine clearance?
volume of plasma cleared of creatinine per unit time (approximation of GFR)
What is creatinine?
- 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
Describe how creatinine is an ideal marker of GFR.
- 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
What are the limitations of eCrCl?
- 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)
How is estimated glomerular filtration rate (eGFR) measured?
using chronic kidney disease epidemiology collaboration equation (CKD-EPI)
- equations developed to approximate GFR from a single serum creatinine value and subject demographics
eGFR
What are the 4 variables of the chronic kidney disease epidemiology collaboration equation (CKD-EPI)?
- age (years)
- sex
- serum creatinine (Scr, umol/L)
- race (variable is not implemented by Canadian labs)
What are the limitations of eGFR?
- not applicable for children (< 18 years)
- questionable accuracy in elderly (> 70 years)
- unclear accuracy non-White/non-Black subjects
- stable renal function only
eGFR vs. eCrCl
- 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)
What are the 4 variables when calculating eCrCl?
- age (years)
- weight (kg) – for this course, use ‘actual body weight’
- serum creatinine (umol/L)
- sex
for this course, use eCrCl to approximate GFR
