Jennifer P. Lee, PharmD, BCPS - Paralyzed Veterans of America

Evaluation of Methods to Estimate
Renal Function vs. Actual Drug
Clearance in Individuals with SCI
Jennifer Lee, Pharm.D., BCPS
Anthony Dang, Pharm.D., BCPS
VA Long Beach Healthcare System
jennifer.lee4332a@va.gov
Aug 28 th , 2012
IRB approved

Disclosures
This continuing education activity is
managed and accredited by Professional
Education Service Group. The information
presented in this activity represents the
opinion of the author(s) or faculty. Neither
PESG, nor any accrediting organization
endorses any commercial products
displayed or mentioned in conjunction
with this activity.
Commercial Support was not received for
this activity

Disclosures
• Jennifer Lee, Pharm.D., BCPS
• Anthony Dang, Pharm.D., BCPS
Has no financial interest or relationships
to disclose
• CME Staff Disclosures
Professional Education Services Group
staff have no financial interest or
relationships to disclose.

Objectives
At the conclusion of this activity, the participant will
be able to:
1. Evaluate different methods of estimating GFR
compared to patient-specific vancomycin and
AG drug clearance (CL DRUG ) in SCI patients.
2. Determine if a new equation can be developed
to more accurately estimate GFR in SCI
patients in order to optimize dosing for
vancomycin and AG.
3. Assess if there is a difference in the estimation
of renal function between anatomical degrees
of SCI when compared to CL DRUG.

VA Long Beach Healthcare System
• Tertiary Care Facility
• Total SCI beds: 90

Pre-Test Assessment Questions
• T / F: Higher peak and trough concentrations
increase risk of aminoglycoside-induced
ototoxicity and nephrotoxicity.
• T / F: Creatinine production declines with age,
immobility, and reduced muscle mass.
• T / F: Individuals with spinal cord injury (SCI)
have better drug clearance than the general
population

Creatinine
• A muscle breakdown product
• Produced at a constant rate
• Exclusively filtered by the kidneys
1. Macdiarmid S. BJU International 2000;85. 1014-1018.
2. Mirahmadi MK. Paraplegia. 1983 Feb;21(1):23-9.
3. Cherry RJ.Trauma 2002; 53: 267-271.

Chronic SCI
Limited
Mobility
↓
Muscle
Mass 1
↓ SCr
↑ CrCl
Overdosing
↑ ADR
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18.

Vancomycin & Aminoglycosides
• Dose related toxicity:
• Ototoxicity
• Nephrotoxicity
• Primarily renal elimination
4. Rybak M. Am J Health-Syst Pharm 2009; 66: 82-98.
5. Hidayat L. Arch Intern Med 2006; 166: 2138-2144.
6. Kahlmeter G. J Antimicrobial Chemotherapy 1984; 13: 9-22.

Methods to estimate GFR
• Cockcroft-Gault (CG) equation 7
• Modified CG equation
• MDRD equation 8
• CKD-EPI equation 9
• 24-Hour endogenous creatinine clearance 1,10
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18.
7. Cockcroft DW. Nephron 1976; 16: 31–41.
8. Stevens LA. J Am Soc Nephrol, 2007; 18: 2749-57.
9. Levey AS. Ann Intern Med, 2009; 150(9): 604-12.
10. Stabuc B. Clinical Chemistry, 2000; 46(2): 193-7.

Cockcroft-Gault (CG) 7
CL CG (mL/min) = [(140 – age) x IBW in kg] /
(72 x SCr); (multiply 0.85 for females)
Modified CG formula (CL M ):
• SCr rounded to 1 mg/dL for patients with SCr
< 1 mg/dL while using the actual SCr for patients
with SCr ≥ 1 mg/dL
7. Cockcroft DW. Nephron 1976; 16: 31–41.

Overestimation by CG
Study Patient Population Methodology Findings
Macdiarmid et al. 1
25 Paraplegic
11 Tetraplegic
CL CG vs. CL 24H vs.
99mTc-DTPA
CL 24H more
accurate
Mirahmadi et al. 2
22 Paraplegic
36 Tetraplegic
22 ambulatory
CL CG vs. CL 24H vs.
Autoanalyser
Correction factor:
0.8 for paraplegic
0.6 for tetraplegic
Lavezo et al. 11
14 SCI
14 control
Actual vs.
Predicted CL VANCO
↑half-life in SCI
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18
2. Mirahmadi MK,. Paraplegia. 1983 Feb;21(1):23-9
11. Lavezo LA. J Spinal Cord Med 1995; 16: 233-235)

MDRD equation 8
4-Variable MDRD:
eGFR = 175 x standardized SCr -1.154 x
age -0.203 x 1.212 (if black) x 0.742 (if female)
8. Stevens LA. J Am Soc Nephrol, 2007; 18: 2749-57.

CG vs. MDRD
Study Patient Population Methodology Findings
Chikkalingaiah
KBM et al. 12
116 SCI
CL 24H vs. CL CG vs.
MDRD
Correction factor:
0.7 for MDRD
0.8 for CL CG
Bookstaver PB
et al. 13
71 non-SCI
Actual CL AG vs. CL CG
vs. MDRD
MDRD better
Ryzner KL. 14
55 non-SCI
Actual CL AG vs. CL CG
vs. MDRD
CL CG better
12. Bookstaver PB. Ann Pharmacother 2008, 42(12): 1758-1765.
13 Ryzner KL. Ann Pharmacother 2010; 44: 1030-1037.
14. Roberts GW. Age Ageing 2009; 38: 698-703.

CKD-EPI equation 9
eGFR = 141 x min (SCr/ĸ, 1) α x max
(SCr/ĸ, 1) -1.209 x 0.993 Age x 1.018 [if
female] x 1.159 [if black]
where ĸ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of SCr/ĸ or 1,
& max indicates the maximum of SCr/ĸ or 1.
9. Levey AS. Ann Intern Med, 2009; 150(9): 604-12.

CG vs. CKD-EPI
Study Patient Population Methodology Findings
Pai et al. 15
2073 non-SCI
CL AG vs. CL CG vs.
MDRD vs. CKD-EPI
CKD-EPI > MDRD >
CL CG
15. Pai MP. Antimicrob Agents Chemother. 2011 September; 55(9): 4006–4011.

24-Hour Endogenous Creatinine
Clearance 10
CL 24H (mL/min) = [urine creatinine x urine
volume (mL)] / [SCr x time (hours) x 60]
10. Stabuc B. Clinical Chemistry, 2000; 46(2): 193-7.

Methodology
• IRB Approved
• Study Design: Retrospective chart review
• Study Period: 1/1/2008 – 12/31/08

Inclusion Criteria
• Patients at VALB with an ICD-9 diagnosis
of spinal cord injury for >1 year
o Received amikacin, gentamicin, tobramycin,
or vancomycin with at least one steady state
level

Exclusion Criteria
• Hemodialysis or acute kidney injury
• Limb amputation
• Multiple sclerosis
• Inappropriate data for monitoring

Methodology
• VA electronic medical record (Computerized
Patient Record System)
• Pharmacokinetic calculations via non-steady
state short infusion model 16
o C peak = (Dose/t inf ) * (1-e -kt inf)/V d * K e
o C trough = C peak * e -kt
o CrCl (L/hr) = Vd x Ke
16. Winters M. Basic Clinical Pharmacokinetics. Fourth Ed, 2004, Lippincott Williams and Wilkins.

Methodology
• Volume of distribution calculations 17 :
o Vancomycin
• V d = 0.17(age) + 0.22 (TBW) + 15
o Aminoglycosides
• Peak levels were used to calculate V d
17 Rushing TA. J Pharm Technol, 2001; 17: 33-8.

Methodology
• Actual drug clearance (CL DRUG )
• CG CrCl (CL CG )
• Modified CG CrCl (CL M )
• Adjusted 24-hour endogenous CrCl (CL 24H )
• MDRD equation
• CKD-EPI equation

Statistical Analyses
• 2-sided students t-test with alpha=0.01 for
significance
• 95% Power
• Determined Post Hoc given results
• Linear Regression
• All analyses performed using Microsoft ® Excel

Results

Baseline Characteristics
Mean ± S.D.
Total # of patients 141
Male/Female, N 140/1
Tetraplegic/ Paraplegic, N 89/52
Vancomycin/ Amikacin, N 109/32
SCr >1 mg/dL, N 30
Age (years) 65.72 ± 10.54
Height (cm) 179.96 ± 7.01
Weight (kg) 80.35 ± 20.69
BMI (kg/m 2 ) 24.6 ± 5.78
SCr (mg/dL) 0.74 ± 0.29

Evaluation of different methods to
estimate GFR
(N=141)
Mean ± S.D.
(mL/min)
Difference from
CL DRUG (mL/min)
P-Value
CL DRUG
49.77 ± 19.97 0 --
MDRD 119.76 ± 61.49 69.99

Number of Patients
Difference between MDRD and CL DRUG
50
48
40
38
30
20
25
22
10
0
7
1
90
MDRD - CL DRUG (mL/min)
Abbreviations: MDRD, the Modification of Diet in Renal Disease equation; CL DRUG, actual drug clearance.

Number of Patients
Difference between CL M and CL DRUG
80
75
60
45
40
20
0
18
2
1 0
90
CL M - CL DRUG (mL/min)
Abbreviations: CL M , modified Cockcroft-Gault formula; CL DRUG, actual drug clearance.

Evaluation of CL M to estimate
CL DRUG for vancomycin and AG
Mean ± S.D.
(mL/min)
Difference
from CL DRUG
(mL/min)
P-Value
Combined
Amikacin and
Vancomycin
(N=141)
Amikacin
(n=32)
Vancomycin
(n=109)
CL DRUG 49.77 ± 19.97 0 --
CL M 69.38 ± 13.49 19.61

Actual Drug Clearance (mL/min)
120
Determining SCI Study Equation
100
80
60
40
y = 2.3286x 0.7
R = 0.4
20
0
0 20 40 60 80 100 120
Modified Cockcroft-Gault Predicted
Drug Clearance (mL/min)

Actual Drug Clearance (mL/min)
80
Linear Regression Plots
60
40
y = 0.8425x + 6.7281
R = 0.4
20
0
0 20 40 60 80
Predicted Drug Clearance using CL SCI (mL/min)
Abbreviation: CL SCI , spinal cord injury equation

CL DRUG vs. CL SCI
• T-Test showed no difference between
SCI equation and actual drug clearance.
Mean S.D.
(mL/min)
Difference
from CL DRUG
(mL/min)
P-Value
CL DRUG 47.57 +/- 16.34 -- --
CL SCI 45.22 +/- 6.16 -2.35 0.16

Different anatomical degrees of SCI
(N=141)
Mean Difference from
CL DRUG S.D. (mL/min)
P-Value
Paraplegics
(n = 52)
Tetraplegics
(n = 89)
CL SCI
-3.11 13.14 -5.39 21.16 0.48
CL M
21.04 13.81 18.76 22.26 0.5
CL 24H
32.60 30.78 37.02 35.29 0.45
CL CG
27.26 20.56 49.76 38.55

DISCUSSION

Discussion
• Current methods for estimating GFR grossly
overestimate drug clearance in chronic SCI
patients compared to the SCI Study
Equation

Discussion
• CL SCI = 2.3286 * x 0.7006 , where x = CL M with
SCr rounded to 1 if SCr

Limitations
• Small number of patients in amikacin group
• Veterans population
• Variability inherent in using clinical data
• Assumption: CL CR =CL V =CL AG
• Accuracy of vancomycin Vd
• Actual GFR values for > 60 ml/min
• Abbreviated MDRD
• No adjustment for BSA
• Retrospective study: limited control over certain
confounding variables

Conclusion
• Current methods used to calculate CL CR
overestimate CL DRUG in SCI patients
• The proposed SCI equation:
CL SCI = 2.3*x 0.7
(x = CL M with SCr rounded to1 if SCr

Future Plans
• Validate CL SCI in a prospective analysis
• Further analysis with aminoglycosides

References
1. Macdiarmid S, Mcintyre W, Anthony A, et. Al. “Monitoring of Renal Function in Patients with
Spinal Cord Injury” BJU International 2000;85. 1014-1018
2. Mirahmadi MK, Byrne C, Barton C, et. Al. “Prediction of creatinine clearance from serum
creatinine in spinal cord injury patients.” Paraplegia. 1983 Feb;21(1):23-9
3. Cherry R, Eachempati S, Hydo L et al. “Accuracy of Short-Duration Creatinine Clearance
Determinations in Predicting 24-Hour Creatinine Clearance in Critically Ill and Injured Patients”
J Trauma 2002; 53:267-271.
4. Rybak M, Lomaestro B, Rotschafer J et al. Therapeutic monitoring of vancomycin in adult
patients: a consensus review of the American Society of Health-System Pharmacists, the
Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
Am J Health-Syst Pharm 2009; 66: 82-98.
5. Hidayat L, Hsu D, Quist R et al. High-Dose Vancomycin Therapy for Methicillin-Resist
Staphylococcus aureus Infections: Efficacy and Toxicity. Arch Intern Med 2006; 166: 2138-
2144.
6. Kahlmeter G, Dahlager JI. Aminoglycoside Toxicity - A review of clinical studies published
between 1975 and 1982. J Antimicrobial Chemotherapy 1984; 13: 9-22.
7. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron
1976; 16: 31–41.
8. Stevens LA, Coresh J, Feldman HI, et al. Evaluation of the Modification of Diet in Renal
Disease Study Equation in a Large Diverse Population. J Am Soc Nephrol, 2007; 18: 2749-57.
9. Levey AS, Stevens LA, Schmid CH, et al. A New Equation to Estimate Glomerular Filtration
Rate. Ann of Intern Med, 2009; 150(9): 604-12.

References
10. Stabuc B, Vrhovec L, Stabuc-Silih M, et al. Improved Prediction of Decreased Creatinine
Clearance by Serum Cystatin C: Use in Cancer Patients Before and During Chemotherapy.
Clinical Chemistry, 2000; 46(2): 193-7.
11. Lavezo LA, Davis RL. Vancomycin pharmacokinetics in spinal cod injured patients: a
comparison with age-matched, able-bodied controls. J Spinal Cord Med 1995; 16: 233-235)
12. Chikkalingaiah KBM, Grant ND, Mangold TM et al. Performance of Simplified Modification of
Diet in Renal Disease and Cockcroft-Gault Equations in Patients With Chronic Spinal Cord
Injury and Chronic Kidney Disease. Am J Med Sci 2010; 339(2): 108-16.
13. Bookstaver PB, Johnson JW, McCoy TP et al. Modification of Diet in Renal Disease and
modified Cockcroft-Gault formulas in predicting aminoglycoside elimination. Ann Pharmacother
2008, 42(12): 1758-1765.
14. Ryzner KL. Evaluation of Aminoglycoside Clearance Using the Modification of Diet in Renal
Disease Equation Versus the Cockcroft-Gault Equation as a Marker of Glomerular Filtration
Rate. Ann Pharmacother 2010; 44: 1030-1037.
15. Pai MP, Nafziger AN, Bertino JS. Simplified Estimation of Aminoglycoside Pharmacokinetics in
Underweight and Obese Adult Patients. Antimicrob Agents Chemother. 2011 September;
55(9): 4006–4011.
16. Winters M Basic Clinical Pharmacokinetics. Fourth Edition. 2004 Lippincott Williams and
Wilkins
17. Rushing TA, Ambrose PJ. Clinical application and evaluation of vancomycin dosing in adults. J
Pharm Technol 2001; 17: 33–38.

Post-Test Assessment Questions
• T / F: Higher peak and trough concentrations
increase risk of aminoglycoside-induced
ototoxicity and nephrotoxicity.
• T / F: Creatinine production declines with age,
immobility, and reduced muscle mass.
• T / F: Individuals with spinal cord injury (SCI)
have better drug clearance rates than the
general population.

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