Cystatin C as a Risk Factor for Outcomes in Chronic Kidney Disease

  1. Vandana Menon, MD, PhD;
  2. Michael G. Shlipak, MD, MPH;
  3. Xuelei Wang, MS;
  4. Josef Coresh, MD, PhD;
  5. Tom Greene, PhD;
  6. Lesley Stevens, MD, MS;
  7. John W. Kusek, PhD;
  8. Gerald J. Beck, PhD;
  9. Allan J. Collins, MD;
  10. Andrew S. Levey, MD; and
  11. Mark J. Sarnak, MD, MS
  1. From Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Medical Center, San Francisco, California; The Cleveland Clinic Foundation, Cleveland, Ohio; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; University of Utah, Salt Lake City, Utah; National Institutes of Health, Bethesda, Maryland; and Hennepin County Medical Center, Minneapolis, Minnesota.

    Abstract

    Background: No study has compared cystatin C level, serum creatinine concentration, and estimated glomerular filtration rate (GFR) as risk factors for outcomes in chronic kidney disease (CKD), and none has compared measured GFR with CKD in any population.

    Objective: To compare cystatin C level with serum creatinine concentration and iothalamate GFR as risk factors for death and kidney failure.

    Design: Observational study using serum cystatin C assayed from baseline samples of the Modification of Diet in Renal Disease Study (1989–1993).

    Setting: 15 clinical centers in the United States that participated in the Modification of Diet in Renal Disease Study.

    Participants: 825 trial participants with stage 3 or 4 nondiabetic CKD who had measurements of serum cystatin C.

    Measurements: All-cause mortality, cardiovascular (CVD) mortality, and kidney failure until December 2000.

    Results: Mean cystatin C level, creatinine concentration, and GFR were 2.2 mg/L (SD, 0.7), 212.16 µmol/L (SD, 88.4) (2.4 mg/dL [SD, 1.0]), and 33 mL/min per 1.73 m2 (SD, 12), respectively. Median follow-up was 10 years. Twenty-five percent of patients (n = 203) died of any cause, 15% (n = 123) died of CVD, and 66% (n = 548) reached kidney failure. In multivariate-adjusted models, 1-SD decreases in 1/creatinine, GFR, and 1/cystatin C were associated with increased risks for all-cause mortality of 1.27 (95% CI, 1.06 to 1.49), 1.27 (CI, 1.08 to 1.49), and 1.41 (CI, 1.18 to 1.67), respectively. For CVD mortality, the increased risks were 1.32 (CI, 1.05 to 1.64), 1.28 (CI, 1.04 to 1.59), and 1.64 (CI, 1.28 to 2.08), respectively. For kidney failure, the increased risks were 2.81 (CI, 2.48 to 3.18), 2.41 (CI, 2.15 to 2.70), and 2.36 (CI, 2.10 to 2.66), respectively.

    Limitation: The Modification of Diet in Renal Disease Study cohort may not be representative of all patients with nondiabetic CKD because participants were more likely to reach kidney failure than death in follow-up.

    Conclusion: The association of cystatin C level with all-cause and CVD mortality was as strong as or perhaps stronger than that of iothalamate GFR with these outcomes in stage 3 or 4 CKD.

    Article and Author Information

    • Disclaimer: Any opinions, findings, conclusions, or recommendations expressed in the paper are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.

    • Acknowledgment: The authors thank Frederick Van Lente, PhD, The Cleveland Clinic, for help in splitting the frozen samples and measuring cystatin C.

    • Grant Support: By the National Institute of Diabetes and Digestive and Kidney Diseases (grants K23 DK067303 and K23 DK02904, UO1 DK 35073, and DK53869-05). Dr. Shlipak is supported by the National Heart, Lung, and Blood Institute (grant RO1 HL073208-01) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant RO1 DK066488-01), the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program), the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program), and the American Heart Association (Established Investigator Award). Dr. Stevens is supported by the American Society of Nephrology–Association of Specialty Professors Award in Geriatric Nephrology.

    • Potential Financial Conflicts of Interest: Honoraria: L. Stevens (Quest Diagnostics); Other: A.J. Collins (President of the National Kidney Foundation).

    • Requests for Single Reprints: Mark J. Sarnak, MD, MS, Division of Nephrology, Tufts-New England Medical Center, 750 Washington Street, #391, Boston, MA 02111; e-mail, msarnak{at}tufts-nemc.org.

    • Current Author Addresses: Drs. Menon, Stevens, Levey, and Sarnak: Division of Nephrology, Tufts-New England Medical Center, 750 Washington Street, #391, Boston, MA 02111.

    • Dr. Shlipak: General Internal Medicine Section, Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121.

    • Ms. Wang and Dr. Beck: Department of Quantitative Health Sciences, The Cleveland Clinic Foundation, Desk Wb-4, 9500 Euclid Avenue, Cleveland, OH 44195.

    • Dr. Coresh: Epidemiology, Biostatistics and Medicine, The Johns Hopkins University, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21287.

    • Dr. Greene: Division of Clinical Epidemiology, 30 North 1900 East, Room AC221, Salt Lake City, UT 84132.

    • Dr. Kusek: Clinical Trials, Division of Kidney, Urologic, and Hematologic Diseases, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Building 45, Room 6AS-13J, 45 Center Drive, Bethesda, MD 20892-6600.

    • Dr. Collins: Hennepin Faculty Associates, 914 South 8th Street, Suite S206, Minneapolis, MN 55404.

    • Author Contributions: Conception and design: V. Menon, M.G. Shlipak, A.J. Collins, M.J. Sarnak.

    • Analysis and interpretation of the data: V. Menon, M.G. Shlipak, X. Wang, T. Greene, L. Stevens, J.W. Kusek, G.J. Beck, A.S. Levey, M.J. Sarnak.

    • Drafting of the article: V. Menon, A.J. Collins, A.S. Levey, M.J. Sarnak.

    • Critical revision of the article for important intellectual content: V. Menon, M.G. Shlipak, J. Coresh, T. Greene, L. Stevens, J.W. Kusek, G.J. Beck, A.S. Levey, M.J. Sarnak.

    • Final approval of the article: V. Menon, M.G. Shlipak, J. Coresh, T. Greene, L. Stevens, J.W. Kusek, G.J. Beck, A.J. Collins, A.S. Levey, M.J. Sarnak.

    • Statistical expertise: X. Wang, J. Coresh, T. Greene, G.J. Beck.

    • Obtaining of funding: J. Coresh, J.W. Kusek, G.J. Beck, M.J. Sarnak.

    • Administrative, technical, or logistic support: X. Wang, J.W. Kusek.

    • Collection and assembly of data: G.J. Beck, M.J. Sarnak.

    Responses to this article

    • In Response
      • Mark J Sarnak and
      • Michael Shlipak and Vandana Menon
      Ann Intern Med published online October 26, 2009
    • Cystatin C, renal function and cardiovascular risk
      • Pierre Delanaye and
      • Etienne Cavalier, Jean-Marie Krzesinski
      Ann Intern Med published online October 26, 2009
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