Creatinine Clearance When Does It Matter?

Bruce Lang, BSPPAS ConferenceApril 25, 2015

ObjectivesDescribe the difference between creatinine

clearance (CrCl ) and estimated glomerular filtration rate (eGFR)

Explain when and how to use which formulaIdentify when to recommend a change in

dose or medication

CaseCG 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 PMRosuvastatin 20mg AMCoversyl Plus HD 8/2.5mg dailyWarfarin 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 (10-15%) 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): 820-834Curr Opin Nephol Hypertens 2014; 23: 258-266

Creatinine Clearance - 1976Is 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 calculationPharmacotherapy 2011; 31(11): 1130-1144Nephron 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 CKDeGFR 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 functionModified 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 Obes Surg 2013; 23: 1427-1430Pharmacotherapy 2011; 31(7): 658-664 Am J Health-Syst Pharmacy 2009; 66: 642-648

MDRDGFR = 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 calculationProvides a more accurate estimate of eGFR, but

MDRD underestimates eGFR at levels > 60 ml/min/1.732

Pharmacotherapy 2011; 31(11): 1130-1144

CKD-EPIChronic 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): 1941-51Am 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 Clin Pharm Therapeutics 2009; 86(5):468-470Am J Health-Syst Pharm 1996; 53: 1028-32

Which equation for drug dosing?CrCl (CG) or eGFR (MDRD/CKD-EPI)

eGFREasy availability as reported on all or most lab

reportsStevens 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): 33-42Am J Kidney Dis 2014; 63(5) 820-834Clin Pharm Therapeutics 2009; 86(5): 465-467

The Answer

Both can be used to recommend drug dosingNational 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 2010Am J Kidney Dis. 2015; 65(2): 177-205NKDEP. Chronic Kidney Disease nd Drug Dosing: Information for Providers. Jan. 2010Kidney International 2011; 80: 1122-1137

Concerns with MDRDTends 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 Pharmacotherpay 2011; 31(11): 1130-1144PLOS ONE 2015; March: 1-31 J Am Pharmacists Association 2013; 53(1): 54-57Int J Clin Pract 2015; 69(3): 313-320

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,

19,20Hudson, JQ et al. Int J Clin Pract(2015): 69(3) 313-320Pharmacotherapy 2013; 33(9): 912-921Ann Pharmacotherapy 2012; 46: 1174-87

Bottom LineCG 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 makingPharmacotherapy 2011; 31(11): 1130-1144 J Am Pharmacists Association 2013; 53: 54-57

Pharmacotherapy 2013; 33(9): 912-921Curr Opin Nephrol Hypertens 2011; 20: 482-491

Drug therapy in CKDGeneral 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: 1174-87Ann Acad Med Singapore 2009; 38: 1095-1103

When should a change in drug or dosing recommendation be made in CKD?

With a narrow therapeutic windowNew oral anticoagulants, digoxin

With significant or increased adverse event profileDiabetic medications, statins

Substitution with an alternate agent Certain antibiotics, thiazide diuretics

Direct toxic effects on the kidneyACE inhibitors

Toxic or active metabolitesMeperidine, morphine

Drug Classes Requiring Dosage Adjustment in CKDDrug Class Adjust Dose Avoid in Stages 4 and 5 CKD

BBeta Blockers

Acebutolol, atenolol, bisoprolol, nadolol, sotalol Sotalol

A ACE inhibitors/ARBs Most ACE inhibitors(adjust according to response)

Watch for hyperkalmia and possible decrease in renal function

N NSAIDS, Opioids Codeine, Morphine, oxycodone, tramadol, long term NSAIDS

All NSAIDS, meperidine

DDiuretics

Potassium sparing diuretics, loop diuretics Thiazide diuretics, caution with potassium sparing diuretics-monitor closely for hyperkalemia

DDiabetic medications

Gliclazide, acarbose, insulin, gliptinsMetformin: 50% of present or max dose at eGFR 30-60ml/min/1.732

Glyburide exanitideMetformin: may be used with caution in select individuals

C Cholesterol medications Statins.Fibrates –may increase serum creatinine

Avoid fibrate/statin combinations due to risk of muscle side effects

A Antimicrobials(Dose reductions are often delayed for 24-48 hours to

allow for aggressive dosing/drug to reach steady

state)

Antibiotics: Most antibiotics EXCEPTCloxacillin, clindamycin, metronidazole, erythromycin, azithromycinAntifungals: fluconazole, itraconazoleAntivirals, acyclovir, famciclovir, valacyclovir, valgancyclovir

NitrofurantoinWatch for hyperkalemia and increase in serum creatinine with trimethoprim

M Miscellaneous Allopurinol, colchicines, digoxin, H2RAs, New anticoagulants: rivaroxiban, dabigatranApixaban: decrease dose; avoid <15ml/min)Magnesium/Phosphate containing bowel preps or laxatives

P Psychotropics 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 AnticoagulantsApixiban: Usual dose: 5mg bid

2.5mg bid if ≥2 of: age ≥ 80, wt ≤60kg, CrCl <25ml/min

Avoid: CrCl<15mL/minRivaroxiban: Usual dose: 20mg daily with food

CrCl 30‐50mL/min: 15mg daily with foodCrCl <30mL/min: not recommended

Dabigatran: usual dose: 150mg bid110mg if >75yr & CrCl 30‐50mL/minAvoid if CrCl <30ml/min

Diabetic MedicationsRequiring 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

MetforminKDIGO 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” rulesKidney International 2011; 80: 1122-37Am J Kidney Dis 2015; 65(2): 177-205JAMA 2014; 312(23): 2668-2675

Date of download: 4/2/2014

Copyright © American College of Physicians.

All rights reserved.

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

Antihypertensive agentsMany require dose adjustment but do so in conjunction with

pharmacodynamic effectsDiuretics

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 blockersLipid soluble β-blockers such as atenolol or sotalol

can accumulate in CKD stages 3-5D Bradycardia can be severe

ACE inhibitorsWatch for declining kidney function/hyperkalemia

in those with declining function (stage 3b-5)

AntimicrobialsDose reductions often delayed 24-48 hours to allow for

aggressive managementMaintenance doses of most penicillins, cephalosporins,

antifungals and antivirals require dose reductionNitrofurantoin

Ineffective with eGFR <45ml/minToxic metabolite can accumulate peripheral neuropathy

CotrimoxazoleDecrease 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 outcomeSulfonylureas 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 contractionDecrease 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

CaseCG 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 PMRosuvastatin 20mg AMCoversyl Plus HD 8/2.5mg dailyWarfarin 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)

SummaryMay use both CG or MDRD/CKD-EPI for

estimating renal function for the purposes of drug dosingCG may be preferable in elderly particularly

for drugs with narrow therapeutic windowMany 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