Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease

  1. Michael G. Shlipak, MD, MPH;
  2. Ronit Katz, PhD;
  3. Mark J. Sarnak, MD;
  4. Linda F. Fried, MD, MPH;
  5. Anne B. Newman, MD, MPH;
  6. Catherine Stehman-Breen, MD, MS;
  7. Stephen L. Seliger, MD;
  8. Brian Kestenbaum, MD;
  9. Bruce Psaty, MD, PhD;
  10. Russell P. Tracy, PhD; and
  11. David S. Siscovick, MD, MPH
  1. From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.

    Abstract

    Background: Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] ≥60 mL/min per 1.73 m2).

    Objective: To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.

    Design: Cohort study.

    Setting: The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.

    Participants: 4663 elderly persons.

    Measurements: Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).

    Results: At baseline, 78% of participants did not have chronic kidney disease (estimated GFR ≥60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 µmol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (≥1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.

    Limitations: Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.

    Conclusions: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a “preclinical” state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

    Article and Author Information

    • Grant Support: Drs. Shlipak, Fried, and Katz are funded by R01 HL073208-01. Dr. Shlipak is also supported by the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program), by the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program), and by R01 DK066488. Drs. Sarnak, Fried, Shlipak, Siscovick, and Newman are also supported by R01 AG027002. Dr. Fried is supported by an Advanced Research Career Development award from the Office of Research and Development, Clinical Science Research and Development, U.S. Department of Veterans Affairs. The Cardiovascular Health Study (CHS) is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01-HC-15103 from the National Heart, Lung, and Blood Institute (NHLBI). A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

    • Potential Financial Conflicts of Interest:Employment: C. Stehman-Breen (Amgen); Stock ownership or options (other than mutual funds): C. Stehman-Breen (Amgen).

    • Requests for Single Reprints: Michael G. Shlipak, MD, MPH, General Internal Medicine Section, Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121; e-mail, michael.shlipak{at}ucsf.edu.

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

    • Dr. Katz: Collaborative Health Studies Coordinating Center, University of Washington, Box 354922, Building 29, Suite 310, 6200 NE 74th Street, Seattle, WA 98115.

    • Dr. Sarnak: Tufts-New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111.

    • Dr. Fried: Veterans Affairs Pittsburgh Healthcare System, University Drive, 111F-U, Pittsburgh, PA 15240.

    • Dr. Newman: Healthy Aging Research Program, Bellefield Professional Building, 130 North Bellefield Avenue, Room 532, Pittsburgh, PA 15213.

    • Dr. Stehman-Breen: Amgen, One Amgen Center Drive, Mailstop 38-3-C, Thousand Oaks, CA 91320.

    • Dr. Seliger: University of Maryland, N3W143, 22 South Greene Street, Baltimore, MD 21201.

    • Dr. Kestenbaum: Department of Medicine, Division of Nephrology, University of Washington, Veterans Affairs Puget Sound Health Care System, Mail Stop 111A, 1660 South Columbian Way, Seattle, WA 98108.

    • Drs. Psaty and Siscovick: Cardiovascular Health Research Unit, University of Washington, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101-1448.

    • Dr. Tracy: University of Vermont College of Medicine, Colchester Research Facility, 208 South Park Drive, Suite 2, Colchester, VT 05446.

    • Author Contributions: Conception and design: M.G. Shlipak, M.J. Sarnak, A.B. Newman, C. Stehman-Breen, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.

    • Analysis and interpretation of the data: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, C. Stehman-Breen, S.L. Seliger, B. Psaty, D.S. Siscovick.

    • Drafting of the article: M.G. Shlipak, R. Katz, D.S. Siscovick.

    • Critical revision of the article for important intellectual content: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, A.B. Newman, C. Stehman-Breen, S.L. Seliger, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.

    • Final approval of the article: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, A.B. Newman, C. Stehman-Breen, S.L. Seliger, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.

    • Provision of study materials or patients: B. Psaty, R.P. Tracy, D.S. Siscovick.

    • Statistical expertise: R. Katz.

    • Obtaining of funding: M.G. Shlipak, R.P. Tracy.

    • Administrative, technical, or logistic support: M.G. Shlipak, R.P. Tracy.

    • Collection and assembly of data: R. Katz, B. Psaty, R.P. Tracy.

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    1. Ann Intern Med August 15, 2006 vol. 145 no. 4 237-246
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