Original Investigation
Pathogenesis and Treatment of Kidney Disease
Warfarin Dosing in Patients With Impaired Kidney Function

https://doi.org/10.1053/j.ajkd.2010.05.023Get rights and content

Background

In patients with kidney impairment, warfarin, a drug metabolized primarily by the cytochrome P-450 system, is initiated at similar doses and managed similarly as in the general medical population. Unfortunately, few data exist to guide dose adjustment in patients with decreased kidney function. Here, we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing.

Study Design

Cross-sectional analysis.

Setting & Participants

Long-term warfarin users followed up at anticoagulation clinics (n = 980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC).

Predictor

No/mild (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2), moderate (eGFR, 30-59 mL/min/1.73 m2), and severe (eGFR <30 mL/min/1.73 m2) kidney impairment; CYP2C9 and VKORC1 genotype; age; race; sex; body mass; sociodemographic factors; smoking status; alcohol; vitamin K intake; comorbid conditions (eg, congestive heart failure); and drug interactions (eg, amiodarone and statins).

Outcome & Measurement

Warfarin dose (milligrams per day) was evaluated using linear regression after adjustment for clinical, demographic, and genetic factors.

Results

Prevalences of moderate (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) were similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared with those with no/mild kidney impairment in the UAB (P < 0.001) and UIC (P < 0.001) cohorts. Compared with patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses (P < 0.001) and patients with severe kidney impairment required 19% lower doses (P < 0.001).

Limitations

No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin).

Conclusion

Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements.

Section snippets

University of Alabama at Birmingham Cohort

The Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) and the Genetic and Environmental Determinants of Warfarin (GEDWR) are ongoing prospective cohort studies aimed at defining the influence of polymorphisms in CYP2C9 and other genes on warfarin response. Patients 20 years and older were considered eligible if the intended duration of anticoagulation therapy was 2 years or longer, therapy was managed at the anticoagulation clinic, and international normalized ratio (INR) was 2-3.

Results

Of 797 eligible participants at the UAB (UAB cohort), 76 (9.5%) declined participation in the study and 13 were excluded because of missing serum creatinine values. The remaining 708 participants (mean age, 61 ± 15 years; 50.0% men) formed the UAB cohort (327 African Americans, 377 European Americans, 3 Hispanics, and 1 Asian). Of 303 eligible participants at UIC, 31 (10.2%) declined participation. The UIC cohort (n = 272) was composed of 207 African American, 23 European American, and 42

Discussion

The influence of kidney function on disposition of drugs excreted by the kidney is widely recognized and used to derive dosing reductions in patients with kidney impairment. However, there now is increasing appreciation that kidney impairment can also decrease nonrenal clearance and alter the bioavailability of and response to drugs predominantly metabolized by the liver.8, 24 The present study shows that dose requirement for warfarin, a drug primarily metabolized by the hepatic CYP450 system,

Acknowledgements

The authors thank Dr Joyce Goldstein and Joyce Blaisdell for work with CYP2C9 genotyping; the patients who participated in the study; Janice Ware, Joseph Huffstutler, Roberta Hill, Alison Del Carmen, Edith Nutescu, and Nancy Shapiro for untiring efforts with patient recruitment; the staff of the Anticoagulation Clinic at The Kirklin Clinic, Cooper Green Hospital, and Jefferson Clinic PC for help with identification of potential participants; the physicians, especially Drs Mark Wilson and

References (57)

  • W.G. Miller

    Reporting estimated GFR: a laboratory perspective

    Am J Kidney Dis

    (2008)
  • B.K. Meijers et al.

    A review of albumin binding in CKD

    Am J Kidney Dis

    (2008)
  • L.A. Stevens et al.

    Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD

    Am J Kidney Dis

    (2008)
  • Q.L. Zhang et al.

    Prevalence of chronic kidney disease in population-based studies: systematic review

    BMC Public Health

    (2008)
  • H. Watanabe et al.

    Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study

    Am Heart J

    (2009)
  • J. Coresh et al.

    Prevalence of chronic kidney disease in the United States

    JAMA

    (2007)
  • L.D. Bash et al.

    Defining incident chronic kidney disease in the research setting: the ARIC Study

    Am J Epidemiol

    (2009)
  • D.E. Weiner

    Public health consequences of chronic kidney disease

    Clin Pharmacol Ther

    (2009)
  • H. Reinecke et al.

    Dilemmas in the management of atrial fibrillation in chronic kidney disease

    J Am Soc Nephrol

    (2009)
  • F. Knauf et al.

    ESRD as a window into America's cost crisis in health care

    J Am Soc Nephrol

    (2009)
  • S. Anderson et al.

    Prediction, progression, and outcomes of chronic kidney disease in older adults

    J Am Soc Nephrol

    (2009)
  • Y. Zhang et al.

    Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications

    Clin Pharmacol Ther

    (2009)
  • T.D. Nolin

    Altered nonrenal drug clearance in ESRD

    Curr Opin Nephrol Hypertens

    (2008)
  • J. Michaud et al.

    Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure

    J Am Soc Nephrol

    (2006)
  • A.W. Dreisbach et al.

    The effect of chronic renal failure on drug metabolism and transport

    Expert Opin Drug Metab Toxicol

    (2008)
  • D.S. Budnitz et al.

    Medication use leading to emergency department visits for adverse drug events in older adults

    Ann Intern Med

    (2007)
  • A.W. Dreisbach et al.

    Cytochrome P4502C9 activity in end-stage renal disease

    Clin Pharmacol Ther

    (2003)
  • N.A. Limdi et al.

    Kidney function influences warfarin responsiveness and hemorrhagic complications

    J Am Soc Nephrol

    (2009)
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    Originally published online as doi:10.1053/j.ajkd.2010.05.023 on August 16, 2010.

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