Pharmacotherapy in renal impairment
Jitka Rychlíčková
Summary
● Renal functions assessment
● Pharmacokinetics
● When to reduce dose and how?
1. In renal impairment must be drug doses reduced true false
2. Highly protein bound drugs are freely filtered true false
3. There are five stages of chronic kidney disease true false
4. In AKI the glomerular filtration rate can be calculated true false
Renal functions assessment
basic processes in kidneys:
● GF
● TS
● TR
Which of them can we measure?
Which of them can we replace?
Renal functions assessment
basic processes in kidneys:
● GF
○ intraglomerular pressure
○ pressure gradient vas afferens - vas efferens
○ not filtered:
● size
● charge
○ normal rate:
● CKD 1 > 1,5 ml/s/1,73 m2
● CKD 2 1,0 - 1,49 ml/s/1,73 m2
● CKD 3 0,5 - 0,99 ml/s/1,73 m2
● CKD 4 0,25 - 0,49 ml/s/1,73 m2
● CKD 5 < 0,25 ml/s/1,73 m2
What is needed for the effective glomerular filtration?
What is not filtered under physiological conditions?
Is albumin filtered under physiological conditions?
When to think about dose reduction in general?
ml/min
ml/min
ml/min
ml/min
ml/min
× 60 > 90
60 - 89
30 - 59
15 - 29
< 15
Renal functions assessment
basic processes in kidneys:
● GF
● TS
● TR
Which of them can we measure?
Which of them can we replace?
How to estimate/meassure glomerular filtration rate?
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
urea
● endogenous substance - protein catabolism
● physiological range 2,5-7,5 mmol/L
● osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular resorption
creatinine
● endogenous substance - muscle metabolism
● physiological range 44-100 μmol/L
● no osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular secretion
Na 145 mmol/L
K 8,0 mmol/L
Cl 100 mmol/L
urea 40 mmol/L
crea 800 μmol/L
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
urea
● endogenous substance - protein catabolism
● physiological range 2,5-7,5 mmol/L
● osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular resorption
creatinine
● endogenous substance - muscle metabolism
● physiological range 44-100 μmol/L
● no osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular secretion
Pt. A: male, 30 yo, bricklayer, BH 185 cm, BW 100 kg
Pt. B: woman, 70 yo, retired, BH 165 cm, BW 45 kg
both of them serum creatinine 110 μmol/L
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
urea
● endogenous substance - protein catabolism
● physiological range 2,5-7,5 mmol/L
● osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular resorption
creatinine
● endogenous substance - muscle metabolism
● physiological range 44-100 μmol/L
● no osmotic activity !
● kinetics:
○ freely filtered
○ partial/minor tubular secretion
cystatin C
● endogenous substance - cell nucleus (any)
● kinetics:
○ freely filtered
○ intracellular metabolism in tubular cells
● higher sensitivity in mild impairment
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
estimation:
● CKD vs. AKI
○ Cocroft-Gault
○ MDRD
○ CKD-EPI
measurement:
24 hours collection, total volume, SCr, UCr
scintigraphy
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
estimation:
● CKD vs. AKI
○ Cocroft-Gault
○ MDRD
○ CKD-EPI
measurement:
24 hours collection, total volume, SCr, UCr
scintigraphy
Renal functions assessment
basic processes in kidneys: GF, TS, TR
biochemical parameters:
● urea
● creatinine
● cystatin C
estimation:
● CKD vs. AKI
○ Cocroft-Gault
○ MDRD
○ CKD-EPI
measurement:
24 hours collection: total volume, SCr, UCr
scintigraphy
renal function assessment:
● basic processes, biochemical parameters
● not only urea, creatinine → BW, PS, personal
history, nutrition
● CG, MDMD, CKD-EPI are not for AKI
● CG, MDRD, CKD-EPI in CKD
● diagnostic criteria for AKI
Practical aspects of pharmacokinetics
(L)ADME process
● low/no oral bioavailability
● protein bound
● metabolized/excreted unchanged
● hepatal/renal excretion
zoledronic acid metformin amlodipinevancomycin
Practical aspects of pharmacokinetics
Male, 65 yo, BH 180 cm, BW 65 kg,
urea 20 mmol/L, creatitine 210 μmol/L, albumine 35 g/L
fluconazole IV 400 mg/200 ml NS (during 30 min) every 12 hours the day 4
personal history: CKD 4 (25 ml/min) (vascular nefropathy)
What is the indication of fluconazole?
Normal dosing of fluconazole?
Would you recommend dose reduction?
Would you recommend to reduce the dosing as early as on the day 1?
Possible adverse effects/toxicity?
When to reduce a dose?
before automatic dose reduction think about:
● absorption/bioavailability
● % excreted renally unchanged
● potential toxicity (consequence of cummulation)
● risk of underdosing
● non-effective tubular concentrations
Which drugs are excreted renally unchanged (>60%)?
Reduction of loading dose?
Reduction of dose vs. extension of dosing interval vs. both?
Renal excretion vs. nephrotoxicity
● mechanisms:
○ direct toxicity, toxic metabolites
● cis-Pt (vs. oxaliplatin, carboplatin)
● ...
○ hemodynamic changes
○ tubular obstruction
tubuloglomerular feedback
prevention: hydration, pH changes, mineral substitution
rychlickova@med.muni.cz
1. In renal impairment must be drug doses reduced true false
2. Highly protein bound drugs are freely filtered true false
3. There are five stages of chronic kidney disease true false
4. In AKI the glomerular filtration rate can be calculated true false