CURRENT AND EMERGING BEST PRACTICE IN ESTIMATION OF RENAL FUNCTION AND DRUG DOSE RECOMMENDATIONS

Joanna KuruvillaClinical Pharmacist – Infectious Diseases and Antimicrobial Stewardship, Alfred Health - MelbourneB.Pharm(Hons), GradCertPharmPrac, MClinPharm, MSHP

Learning ObjectivesAt the completion of the presentation, participants will be able to:

• Identify which formula is currently used in eGFR reporting

• Identify the medications which can lead to a falsely elevated serum creatinine

• Apply the knowledge gained during this presentation, to calculate a drug dosing eGFR using the appropriate equation

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Chronic kidney disease (CKD)• CKD is present if:

• GFR is <60mL/min/1.73 m2 for three months or more

or

• Evidence of kidney damage for more than three months • Albuminuria

• Haematuria

• Pathological abnormalities (e.g. abnormal biopsy result)

• Structural abnormalities (e.g. abnormal ultrasound result)

Glomerular Filtration Rate (GFR)• Total of the filtration rates of the functioning nephrons in

the kidney• Cannot be measured directly• Exogenous filtration markers - inulin, iothalamate, iohexol

• Gold standard for the measurement of GFR• Cumbersome, expensive, not used in clinical practice

• Serum creatinine (SCr) most commonly used to estimate GFR• Not an adequate marker on its own• Secreted in tubules

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eGFR• Recommend estimating GFR from SCr, using estimating

equations

• 50+ different equations for estimating GFR using SCr

• Three most commonly used equations:• Cockcroft-Gault

• Modification of Diet in Renal Disease (MDRD)

• The Chronic Kidney Disease Epidemiology Collaboration

(CKD-EPI)

Cockroft-Gault equation• Developed in 1973 • Used data from 249 Caucasian men aged 18-92 • eCrCl =[(140 - age yrs) x weight kg] / [0.8145 x SeCr mcmol/L]• eCrCl x 0.85 if female • Expressed in mL/min – created to estimate absolute renal

function• Later validated across several GFR markers and populations

satisfactorily• Most PK studies used this equation to develop dose

adjustment guides for PI leaflets

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Cockroft-Gault equation limitations• Correlation between mCrCl and eCrCl R2=0.69• Uses 24-h urine creatinine collection as standard • Non-standardised SCr laboratory values when developed• Underestimates at severely reduced kidney function• Less accurate in patients with extremes of age or body

size• Adjusted BW more accurate in obesity

• Adjustment for sex is empirical • 15% less muscle mass estimated in women

MDRD equation• Developed in 1999 • Using data from 1628 men and women mostly with CKD • Aged 18-70, mostly Caucasian, non-diabetic, non-kidney

transplant patients• GFR = 186 x (SCr)-1.154 x (age yrs)-0.203

• GFR x 0.742 if female• Expressed as mL/min/1.73m2

• Validated against BSA normalised population

• Reported in laboratories from 2005-2007

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Revised MDRD equation• Serum creatinine assays in Australia and NZ are now IDMS-

calibrated• Sample will give the same result in any laboratory

• The equation was re-expressed in 2005 post IDMS-calibration

• Constant changed from 186 to 175

• Reported by laboratories from 2007-2012

• P30 = 73%–93%

• Uses iothalamate clearance as standard

• Underestimates at GFR estimates >60 mL/min/1.73 m2

CKD-EPI equationeGFR (mL/min/1.73 m2)

• For females with SCr ≤ 62 mol/L= 144 × (SCr in mol/L × 0.0113/0.7)(2 0.329) × (0.993)age yrs

• For females with SCr > 62 mol/L = 144 × (SCr in mol/L × 0.0113/0.7)(2 1.209) × (0.993) age yrs

• For males with SCr ≤ 80 mol/L= 141 × (SCr in mol/L × 0.0113/0.9)(2 0.411) × (0.993) age yrs

• For males with SCr > 80 mol/L= 141 × (SCr in mol/L × 0.0113/0.9)(2 1.209) × (0.993) age yrs

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CKD-EPI equation• Developed in 2009• Using data from 12,150 men and women• Caucasian, African-American, Hispanic and Asian• With and without CKD, diabetes, kidney transplant recipients

and donors• Expressed as mL/min/1.73m2

• Developed for use with IDMS traceable creatinine assays• P30 = 87.5%• More accurate for values >60ml/min/1.73m2

• Currently reported by laboratories

Comparison of performance of eGFRequations - external validation dataset

Levey AS et al. Ann Intern Med. 2009 May 5; 150(9): 604–612.

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MDRD vs. CKD-EPI

Effect of Obesity

Bouquegneau A et al. Br J Clin Pharmacol 2015 Nov; 81:2 349–361

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Corrected eGFR for extremes in body size

Dubois and Dubois formula

• BSA (m2) = (W0.425 x H0.725) x 0.007184

• Where height is measured in centimeters, and weight in kilograms

• GFR estimate (mL/min)

= GFR estimate (mL/min/1.73 m2) x BSA/1.73

Effect of eGFR on drug dosing recommendations

N= 5504, 6 simulation studies~88% concordance Stevens LA et al Am J Kidney Dis. 2009 Jul; 54(1): 33–42.

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Dose adjustment at different levels of renal function according to estimates with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease Study (MDRD) and the Cockcroft-Gault (CG) formula. Szummer K et al. Open Heart. 2017 Jun 8;4(2):e000568

Comparison of equations for DOACs in heart failure patients with AF

Receiver operating curve analysis for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease Study (MDRD) and Cockcroft-Gault (CG) renal function formula for 1-year mortality in the Swedish Heart Failure Registry. Szummer K et al. Open Heart. 2017 Jun 8;4(2):e000568

Renal function formula and prediction of 1-year mortality

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Limitations of eGFR and eCrCl• Factors affecting serum creatinine

• Gender• Ethnicity• Extremes of age • Extreme muscle mass, malnutrition or obesity• Skeletal muscle disease, neuromuscular disease or amputees• Variations in dietary intake of protein• Certain medications interacting with creatinine excretion e.g. trimethoprim• Acute changes in renal function (SCr not at steady state)• Dialysis patients• Severe liver impairment• Children under 18 years of age• eGFR values above 90mL/min/1.73m2

Limitations of eGFR and eCrCl

Frequently Asked Questions about GFR Estimates. National Kidney Foundation 2014, United States of America, Accessed 21 May 2019.

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Pharmacokinetic considerations in CKD

Dosing considerations in CKD•Largely excreted by kidneys

• Many anti-infectives – amoxycillin (60%), ciprofloxacin (40-70%), fluconazole (80%), aciclovir (40-70%)

• Active metabolites excreted into the kidneys• Morphine morphine-6-glucuronide• Allopurinol oxipurinol

•Toxicity profile• Digoxin (highly tissue bound)• Phenytoin (highly protein bound)

•Drugs metabolised by the kidneys• Insulin

•Patient clinical status (toxicity vs. treatment failure)

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Dosing considerations for dialysis patientsPharmacokinetic properties influencing clearance:•Volume of Distribution•Water/Lipid solubility•Protein Binding•Molecular Weight•% excreted unchanged

*If removed by dialysis, give after dialysis*•Refer to dialysis dosing guidelines

•Pharmacodynamic properties e.g. withhold antihypertensives on dialysis days

Medications to use with caution in CKD• Nephrotoxic drugs

• NSAIDs

• Aminoglycoside antibiotics e.g. gentamicin

• Renally cleared drugs/metabolites that may cause toxicity due to accumulation• Pethidine norpethidine (seizures, death)

• Metformin lactic acidosis

• Methotrexate bone marrow suppression

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Medications that can reduce secretion of creatinine• Trimethoprim• Dolutegravir• Cobicistat• Imatinib• Sorafenib• Sunitinib• Pazopanib• Cimetidine (ranitidine and famotidine to a much less

extent)

Considerations in estimation of renal function for drug dosing during a HMR

Pathology eGFR (CKD-EPI) indicates eGFR<60

Questions:• Is the medication significantly cleared by the kidney?• Are they elderly?• Are they extreme in weight?• Is there a risk of toxicity from the medication?• Clinical status of patient? Treatment failure risk?

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Considerations in estimation of renal function for drug dosing during a HMRIf yes to any questions:• Consider calculating eCrCl using Cockcroft-Gault with adjusted

BW • Or adjust eGFR for BSA• If risk of toxicity – consider using lower result• If risk of treatment failure – consider using higher result

• Consider other PK and PD factors e.g. ESKD on dialysis, absorption/metabolism, nutrition, disease

• Consider product information and appropriate references

Conclusion• eGFR is currently a more reliable indicator of renal function for

drug dosing compared to in the past

• Most pharmacokinetic studies use the Cockcroft-Gault equation to determine level of renal function for dosage adjustment

• Various factors affect SCr levels, which can lead to SCr being an inadequate marker on its own for drug dosing

• Treat the patient, not the number, during medication reviews

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References• Stevens LA et al. Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate. N Engl J Med 2006; 354:2473-2483

• Faull R, Lee L. Prescribing in renal disease. Aust Prescr 2007;30:17-20

• Chin et al. The performances of the Cockcroft-Gault, Modification of Diet in Renal Disease Study and Chronic Kidney Disease Epidemiology Collaboration equations in predicting gentamicin clearance. Annals of Clinical Biochemistry50(6) 546–55

• Stevens LA et al. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis. 2010;55(4):660-670.

• Casal MA. Estimation of Kidney Function in Oncology. CJASN April 2019, 4 (4) 587-595

• Hallan SI, Gansevoort RT. Moderator’s view: Estimating glomerular filtration rate- the past, present and future. Nephrol Dial Transplant (2013) 28: 1404–1406

• Johnson, David. ‘eGFR and Drug Dosing’. SHPA Queensland Branch Symposium Presentation. SHPA Geriatric medicine stream forum. Vodcast

• Myrna Y. Drug Dosing Adjustments in Patients with Chronic Kidney Disease. Am Fam Physician. 2007 May 15;75(10):1487-1496.

• Szummer K et al. Comparison of the Chronic Kidney Disease Epidemiology Collaboration, the Modification of Diet in Renal Disease study and the Cockcroft-Gault equation in patients with heart failure. Open Heart. 2017 Jun 8;4(2):e000568

• Defining chronic kidney disease. Kidney Health Australia 2019. Accessed 22 May 2019. Available at: https://kidney.org.au/your-kidneys/detect/kidney-disease/defining-chronic-kidney-disease

• Earley A et al. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med. 2012 Jun 5;156(11):785-95

• Park EJ et al. The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults. Ann Pharmacother. 2012 Mar;46(3):317-28.

• Rhee J. Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations for estimating glomerular filtration rates in cancer patients receiving cisplatin-based chemotherapy. Kidney Res Clin Pract. 2017 Dec; 36(4): 342–348.

• Pieroni L et al. Did Creatinine Standardization Give Benefits to the Evaluation of Glomerular Filtration Rate? EJIFCC. 2017 Dec; 28(4): 251–257

• Bouquegneau A et al. Creatinine-based equations for the adjustment of drug dosage in an obese population. Br J Clin Pharmacol 2015 Nov; 81:2 349–361

• White SL. Comparison of the prevalence and mortality risk of CKD in Australia using the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study GFR estimating equations: the AusDiab (Australian Diabetes, Obesity and Lifestyle) Study. Am J Kidney Dis. 2010 Apr;55(4):660-70

• National Kidney Disease Education Program. Chronic kidney disease and drug dosing: information for providers. Available at: http:// www.nkdep.nih.gov/professionals/drug- dosing-information.htm. Posted September2009. Revised January 2010.

• Frequently Asked Questions about GFR Estimates. National Kidney Foundation 2014, United States of America, Accessed 21 May 2019. Available at: https://www.kidney.org/content/frequently-asked-questions-about-gfr-estimates

• Cockcroft, D.W. and M.H. Gault. Prediction of creatinine clearance from serum creatinine. Nephron. 1976. 16(1):31-41.

• Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-70.

• Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-54

• Levey AS, Stevens LA, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5; 150(9): 604–612.Levey AS, al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612.

• Nolin TD. A Synopsis of Clinical Pharmacokinetic Alterations in Advanced CKD. Semin Dial. 2015 Jul; 28(4): 325–329.

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