Download Creatinine Clearance When Does It Matter?

Bruce Lang, BSP
PAS Conference
April 25, 2015
Objectives
 Describe the difference between creatinine clearance
(CrCl ) and estimated glomerular filtration rate (eGFR)
 Explain when and how to use which formula
 Identify when to recommend a change in dose or
medication
Case
 CG is a 75yr old male Caucasian with T2DM and stable
CKD. He is 175cm and 85kg. His serum creatinine =
198umol/L, eGFR (MDRD) on the lab is 31.2ml/min/1.732
and CrCl (CG)is 29.5ml/min. His BP is 135/86 and
ACR=60mg/mmol. He has some pitting edema and has a
history of A. Fib. He is also complaining of some muscle
soreness in his legs. He is taking the following:
 Metformin 1g AM and 500mg PM
 Rosuvastatin 20mg AM
 Coversyl Plus HD 8/2.5mg daily
 Warfarin to INR 2-3
 Have has had trouble stabilizing on warfarin and the Dr.
would like to switch to rivaroxiban and would like your
help to dose. Anything else?
Endogenous Filtration Markers
Creatinine & Cystatin C6,7
Creatinine
Cystatin C
Small Amino Acid derived from muscle mass
Relatively small molecule derived from all
nucleated cells
Both filtered by the glomerulus and secreted (1015%) by the proximal tubule
Filtered but not secreted by the kidney
Dependant on age, sex, race and muscle mass
Only determinants are age and sex, therefore more
uniform across populations
Can be affected by alterations in muscle mass and
drugs that inhibit tubular secretion (cimetidine,
trimethoprim)
Not affected by muscle mass. May be influenced by
thyroid function and corticosteroid use
Inexpensive and easy to use
Expensive, therefore will be reserved for
confirmatory testing of renal function
Used in estimation of CrCl and eGFR
Incorporated into equations (CKD-EPI) estimating
eGFR
Am J Kidney Dis. 2014; 63(5): 820-834
Curr Opin Nephol Hypertens 2014; 23: 258-266
Creatinine Clearance - 1976
 Is a measure of how much creatinine is filtered and
secreted by the kidney over time expressed as ml/min
 Surrogate used to estimated GFR, but tends to
overestimate true GFR
 Traditionally used for decades in conjunction with the
Cockcroft-Gault (CG) equation to estimate kidney
function for drug dosing purposes
 Uses serum creatinine in the calculation
Pharmacotherapy 2011; 31(11): 1130-1144
Nephron 1976; 16: 31-41
eGFR -1999
 Glomerular filtration rate is a measure of the ultrafiltrate of
blood as it passes through the glomerulus.
 Used to stage and monitor those with chronic kidney
disease (CKD) – and has been utilized for drug dosing???
 Uses the Modification of Diet in Renal Disease (MDRD) and
Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equations to provide a more accurate assessment of
GFR compared to CG. Expressed as ml/min/1.73m2. Also uses
serum creatinine in the calculation
 eGFR results reported by the laboratory are derived by MDRD
 MDRD is less accurate at levels above 60 ml/min/1.73m2 ,
therefore will eventually be replaced with the CKD-EPI
KDIGO classification of CKD
eGFR less the 60 ml/min/1.73m2 for 3 months or more is diagnostic for CKD
Albuminuria is an independent risk factor for the progression of CKD
Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk;
Orange: high risk; Red, very high risk.
Kidney International 2013; suppl 3(1)
Cockroft-Gault equation -1976
 [((140-age)x weight*) x 1.23] ÷ Scr(umol/L) x 0.85 if female reported in
ml/min. Reflective of actual renal function
 Modified CG equation normalized to 70kg10 (used by RQHR and found
in eCPS) does not use weight in its formula and correlates well with
weight based versions of CG11 . Reflects relative renal function.
 ((140-age) x 90) ÷ Scr (umol/L) x 0.85 if female reported in
ml/min/70kg

eCPS reports as ml/second – multiply by 60 to get ml/min
 Because CG is creatinine based, adjustments may be required for obese
patients (BMI greater than 30 or 30% above ideal body weight)
 [((140-age) x ABW*) x1.23 ] ÷ Scr (umol/L) x 0.85 if female
 ABW = adjusted body weight
 Calculators: http://www.globalrph.com/multiple_crcl.htm
* weight in kg
Am J Health-Syst Pharm 1996: 53: 1028-32
Pharmacotherapy 2011; 31(7): 658-664
Obes Surg 2013; 23: 1427-1430
Am J Health-Syst Pharmacy 2009; 66: 642-648
MDRD
 GFR = 186.3 x (SCR)-1.154 x (age in years)-0.203 x 1.212 (if
patient is African American) x 0.742 (if female)
 Normalized to ml/min/1.732
 Calculator: many: http://www.globalrph.com/multiple_crcl.htm
 Does not require weight in calculation
 Provides a more accurate estimate of eGFR, but MDRD
underestimates eGFR at levels > 60 ml/min/1.732
Pharmacotherapy 2011; 31(11): 1130-1144
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
 Provides a more accurate estimate of eGFR at levels
greater than 60 ml/min/1.732 compared to MDRD
 Can be used with Cystatin C to estimated eGFR
 Likely to replace MDRD on laboratory reports
JAMA 2012; 307(18): 1941-51
Am J Kidney Dis. 2013; 62(3)” 595-603
Which equation for drug dosing?
CrCl (CG) or eGFR (MDRD/CKD-EPI)
 CrCl
 Considerable experience with CG (50 years)
 Pharmacokinetic studies (the relationship between CrCl
and total drug clearance) and recommendations for
dose adjustment in renal impairment based on CG
equation
 Reported in units (ml/min) not adjusted for body
surface area which is appropriate for drug dosage
adjustment
 May underestimate GFR in elderly as kidney function
does not decrease linearly with age as described in the
CG equation19
Current Opinion in Hephrology and Hypertension 2011; 20: 482-91
Am J Health-Syst Pharm 1996; 53: 1028-32
Clin Pharm Therapeutics 2009; 86(5):468-470
Which equation for drug dosing?
CrCl (CG) or eGFR (MDRD/CKD-EPI)
 eGFR
 Easy availability as reported on all or most lab reports
 Stevens et al15 studied 5504 participants comparing
MDRD and CG

Their conclusion was MDRD had greater concordance with
measured GFR for drug dosage recommendations relative to
the CG equation
 Stevens et al6 in a recent review found a 78% vs 73%
concordance of drug dosing recommendations with
MDRD and CG respectively.
Am J Kidney Dis 2009; 54(1): 33-42
Am J Kidney Dis 2014; 63(5) 820-834
Clin Pharm Therapeutics 2009; 86(5): 465-467
The Answer
 Both can be used to recommend drug dosing
 National Kidney Disease Education Program (2010)16
 U. S. FDA – Guidance for Industry (2010)4
 Kidney Disease: Improving Global Outcomes (KDIGO)
(2011)17
 Canadian Society of Nephrology (2015)8
 Remember, no equation can accurately estimate
kidney function for all patients. Therefore estimates
MUST be made in conjunction with the patients
clinical status (ie: creatinine must be at steady
state, etc.)
U.S. FDA. Center for Drug Evaluation and Research. Guidance for Industry: March 2010
Am J Kidney Dis. 2015; 65(2): 177-205
NKDEP. Chronic Kidney Disease nd Drug Dosing: Information for Providers. Jan. 2010
Kidney International 2011; 80: 1122-1137
Concerns with MDRD
 Tends to overestimate dosing compared to CG particularly in the
elderly greater than 75 years of age19,5.
 This may have implications when making recommendations for
drugs:




with a narrow therapeutic window
With significant adverse event profile
Substitution with an alternate agent
Direct toxic effects on the kidney
 MDRD has not been validated for drug dosing in a number of
circumstances including the elderly and obesity18
 May require recalculation from ml/min/1.732 to ml/min
(MDRDIND) for drug dosing recommendations in those who
are below ideal body weight or above by >30% or BSA
>304,8,16,17
 http://mdrd.com/
Pharmacotherapy 2013; 33(9): 912-921
PLOS ONE 2015; March: 1-31
Int J Clin Pract 2015; 69(3): 313-320
Pharmacotherpay 2011; 31(11): 1130-1144
J Am Pharmacists Association 2013; 53(1): 54-57
Estimates of Kidney function by
age group
 The magnitude of difference
between CrCl and eGFR as
calculated by MDRD and
CKD-EPI increases with each
decade of life.
 In the elderly the MDRD
overestimates renal function
which could lead to higher
doses of drugs compared to
CG.5, 19,20
Hudson, JQ et al. Int J Clin Pract(2015): 69(3) 313-320
Pharmacotherapy 2013; 33(9): 912-921
Ann Pharmacotherapy 2012; 46: 1174-87
Bottom Line
CG vs MDRD/CKD-EPI
 Both equations can be used to estimate renal function for
drug dosing in particular for drugs with broad therapeutic
range where a 2-3 fold increase in drug exposure will not have
significant impact on safety and efficacy.
 At this time, it MAY be best to use CG in the elderly (>70
years) and with drugs with narrow therapeutic index such
as new oral anticoagulants
 MDRD should be “normalized” at extremes of body mass.
 Not for everyone:
 Amputees, low muscle mass (paraplegic), AKI, malnourished,
vegetarian diet.
 Must be combined with sound clinical judgment in drug dose
decision making
Pharmacotherapy 2011; 31(11): 1130-1144
Pharmacotherapy 2013; 33(9): 912-921
Curr Opin Nephrol Hypertens 2011; 20: 482-491
J Am Pharmacists Association 2013; 53: 54-57
Drug therapy in CKD
General Goals of Therapy 20,21
 Most renally excreted drugs (>30% renally excreted) will require
some dosage adjustment at <60ml/min / ml/min/1.732
 Loading doses may be required for drugs with long half life and
the need for rapid achievement of steady state (AMG,
levofloxacin, digoxin)
 Maintenance dose:
 Maintain usual peak/trough level  same dose with longer interval
(certain antibiotics : AMG; quinolones)
 Maintain average steady state  lower dose with same dosing
interval (antihypertensives, penicillins)
 Many references :
 “Drug Prescribing in Renal Failure: Dosing Guidelines for Adults”
(Bennett's), eCPS/e-Therapeutics, Lexi-Comp, Micromedex,
calculators : http://www.globalrph.com/renaldosing2.htm
Ann Pharmacotherapy 2012; 46: 1174-87
Ann Acad Med Singapore 2009; 38: 1095-1103
When should a change in drug or dosing
recommendation be made in CKD?
 With a narrow therapeutic window
 New oral anticoagulants, digoxin
 With significant or increased adverse event profile
 Diabetic medications, statins
 Substitution with an alternate agent
 Certain antibiotics, thiazide diuretics
 Direct toxic effects on the kidney
 ACE inhibitors
 Toxic or active metabolites
 Meperidine, morphine
Drug Classes Requiring Dosage Adjustment in CKD
Drug Class
B
Beta Blockers
A
ACE inhibitors/ARBs
N
NSAIDS, Opioids
D
Diuretics
D
Diabetic medications
C
Cholesterol medications
A
M
Antimicrobials
(Dose reductions are often
delayed for 24-48 hours to
allow for aggressive
dosing/drug to reach steady
state)
Miscellaneous
P
Psychotropics
Adjust Dose
Avoid in Stages 4 and 5 CKD
Acebutolol, atenolol, bisoprolol, nadolol, sotalol Sotalol
Most ACE inhibitors
(adjust according to response)
Codeine, Morphine, oxycodone, tramadol, long
term NSAIDS
Potassium sparing diuretics, loop diuretics
Watch for hyperkalmia and possible decrease
in renal function
All NSAIDS, meperidine
Thiazide diuretics, caution with potassium
sparing diuretics-monitor closely for
hyperkalemia
Gliclazide, acarbose, insulin, gliptins
Glyburide exanitide
Metformin: 50% of present or max dose at Metformin: may be used with caution in select
eGFR 30-60ml/min/1.732
individuals
Statins.
Avoid fibrate/statin combinations due to risk
Fibrates –may increase serum creatinine
of muscle side effects
Antibiotics: Most antibiotics EXCEPT
Nitrofurantoin
Cloxacillin, clindamycin, metronidazole,
Watch for hyperkalemia and increase in serum
erythromycin, azithromycin
creatinine with trimethoprim
Antifungals: fluconazole, itraconazole
Antivirals, acyclovir, famciclovir, valacyclovir,
valgancyclovir
Allopurinol, colchicines, digoxin, H2RAs,
New anticoagulants: rivaroxiban, dabigatran
Apixaban: decrease dose; avoid <15ml/min)
Magnesium/Phosphate containing bowel
preps or laxatives
Lithium; gabapentin, pregabalin, topiramate,
vigabatrin, bupropion, fluoxetine, paroxetine,
venlafaxine
Adapted from: Saskatchewan Drug Information Services, College of Pharmacy and Nutrition, U of S. www.druginfo.usask.ca
New Oral Anticoagulants
 Apixiban: Usual dose: 5mg bid
 2.5mg bid if ≥2 of: age ≥ 80, wt ≤60kg, CrCl <25ml/min
 Avoid: CrCl<15mL/min
 Rivaroxiban: Usual dose: 20mg daily with food
 CrCl 30‐50mL/min: 15mg daily with food
 CrCl <30mL/min: not recommended
 Dabigatran: usual dose: 150mg bid
 110mg if >75yr & CrCl 30‐50mL/min
 Avoid if CrCl <30ml/min
Diabetic Medications
 Requiring dose adjustment: – monitor for signs of
hypoglycemia22
 Sufonylureas
 Avoid glyburide <60ml/min
 Gliclazide: consider lower dose <30ml/min. Switch to
alternative <15ml/min such as meglitinide.
 Insulin
 30-50% renal elimination. Dose adjustments usually required
as renal function declines
 DPP-4 inhibitors (gliptins)
 Linagliptin only agent that does not require dose adjustment
in renal dysfunction.
Can J Diabetes 2014; 38: 334-343
Metformin
 KDIGO and CSN
 Renally cleared and clearance decreases by ~75% with CrCl
<60ml/min
 Concern of lactic acidosis (LA)


Limited evidence for increased incidence of LA in those with renal
function 30-60ml/min (3-10 per 100,000 person-years)23
Greater reduction in 2-year mortality compared to other glucose
lowering therapies.
 May be used with dose reduction in those with
CrCl 30-60ml/min (50% reduction from present or max dose)
 Reasonable to consider in <30ml/min for those with

Obesity, stable renal function, close observation and able to follow
“sick day” rules
Kidney International 2011; 80: 1122-37
Am J Kidney Dis 2015; 65(2): 177-205
JAMA 2014; 312(23): 2668-2675
From: Lipid Management in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global
Outcomes 2013 Clinical Practice Guideline. Dosing is generally decreased due to decreased renal clearcence,
increased ADR profile and complexity of disease.
Ann Intern Med. 2014;160(3):182-189. doi:10.7326/M13-2453
Date of download:
4/2/2014
Copyright © American College of Physicians.
All rights reserved.
Antihypertensive agents
Many require dose adjustment but do so in conjunction with
pharmacodynamic effects
 Diuretics
 Thiazide ineffective as a diuretic at <30ml/min. Switch to loop
diuretic
 K+ sparing diuretics: dose adjustment and avoidance in stage
4 & 5 CKD.
 β blockers
 Lipid soluble β-blockers such as atenolol or sotalol can
accumulate in CKD stages 3-5D

Bradycardia can be severe
 ACE inhibitors
 Watch for declining kidney function/hyperkalemia in those
with declining function (stage 3b-5)
Antimicrobials
 Dose reductions often delayed 24-48 hours to allow for
aggressive management
 Maintenance doses of most penicillins, cephalosporins,
antifungals and antivirals require dose reduction
 Nitrofurantoin
 Ineffective with eGFR <45ml/min
 Toxic metabolite can accumulate peripheral neuropathy
 Cotrimoxazole
 Decrease dose by 50% for those with CrCl 15-30ml/min. Avoid in
<15ml/min
 trimethoprim component can worsen hyperkalemia (usually not
until stage 4-5). Increase in creatinine – competition for tubular
secretion
 Sulfa component requires adequate hydration to avoid crystaluria.
“Sick Day Rules”
Hold the following medications if nausea or vomiting
Drug Class
Mechanism of action
Adverse outcome
Sulfonylureas
Reduced renal elimination
Increased risk of hypoglycemia
ACE inhibitors
Interfere with kidney’s response to
intravascular volume contraction.
Decrease intraglomerular pressure
Increased risk of decline in renal function
Diuretics
Exacerbate intravascular volume
contraction
Increased risk of decline in renal function
Metformin
Reduced renal elimination; dehydration
Increased risk of lactic acidosis
Angiotensin receptor
blocker
Interfere with kidney’s response to
intravascular volume contraction
Decrease intraglomerular pressure
Increased risk of decline in renal function
NSAID
Afferent arteriolar constriction
decreased renal blood flow (renal
prostaglandins)
Increased risk of decline in renal function
Can J Diabetes 38(2014) 334-43
Case
 CG is a 75yr old male Caucasian with T2DM and stable
CKD. He is 175cm and 85kg. His serum creatinine =
198umol/L, eGFR (MDRD) on the lab is 31.2ml/min/1.732
and CrCl (CG)is 29.5ml/min. His BP is 135/86 and
ACR=60mg/mmol. He has some pitting edema and has a
history of A. Fib. He is also complaining of some muscle
soreness in his legs. He is taking the following:
 Metformin 1g AM and 500mg PM
 Rosuvastatin 20mg AM
 Coversyl Plus HD 8/2.5mg daily
 Warfarin to INR 2-3
 Have had trouble stabilizing on warfarin and the Dr. would
like to switch to rivaroxiban and would like your help to
dose. Anything else?
Case
 Rivaroxiban? dose?
 Use CG estimation of CrCl
 CrCl <30ml/min
 Consider switching to apixiban 5mg bid as CrCl <30ml/min
 Metformin
 Use CG estimation of CrCl
 ?decrease dose or discontinue?


Consider switching to meglitinide or even insulin
Could also consider continuing with metformin 500mg AM and 250mg PM if there is
enough follow-up and he is able to follow sick day rules.
 Rosuvastatin
 Could use eGFR or CrCl
 Decrease dose to no more than 10mg daily or switch to less potent agent such as
pravastatin
 Cosversyl Plus HD
 Could use eGFR or CrCl.
 Change to perindopril 8mg + furosemide 40mg daily (renal panel 7 days)
Summary
 May use both CG or MDRD/CKD-EPI for estimating
renal function for the purposes of drug dosing
 CG may be preferable in elderly particularly for drugs
with narrow therapeutic window
 Many drugs require dose adjustment in CKD
 Dose adjustment, if required, must always be done in
consideration of the clinical condition of the patient and
the desired pharmacodynamic effects, adverse
effect/toxicity profile, and desired outcome of the
particular drug