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Original Research |

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

Vandana Menon, MD, PhD; Michael G. Shlipak, MD, MPH; Xuelei Wang, MS; Josef Coresh, MD, PhD; Tom Greene, PhD; Lesley Stevens, MD, MS; John W. Kusek, PhD; Gerald J. Beck, PhD; Allan J. Collins, MD; Andrew S. Levey, MD; and Mark J. Sarnak, MD, MS
[+] Article, Author, and Disclosure Information

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.

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@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.

Ann Intern Med. 2007;147(1):19-27. doi:10.7326/0003-4819-147-1-200707030-00004
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In the MDRD Study cohort of patients with stage 3 or 4 CKD, cystatin C level and the gold standard of measured GFR were strongly correlated. The association of cystatin C with all-cause and CVD mortality was as strong as and perhaps stronger than the relationship of iothalamate GFR, serum creatinine concentration, and estimated GFR with these outcomes.

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Grahic Jump Location
Correlations between 1/cystatin C and measured glomerular filtration rate (GFR) (top) and 1/serum creatinine (bottom).
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Submit a Comment/Letter
Cystatin C, renal function and cardiovascular risk
Posted on July 27, 2007
Pierre Delanaye
University of Liège, Service de Néphrologie,CHU Sart Tilman, Belgium
Conflict of Interest: None Declared

We read with interest the article by Menon et al concerning cystatin C as a cardiovascular risk factor (1). From our point of view, this article considerably increases the quality of articles published on this topic, especially because glomerular filtration rate (GFR) was measured with a reference method. We have some comments. First of all, it is important to keep in mind that this study analyses cystatin C as a cardiovascular risk factor. As all the patients have chronic kidney diseases (GFR < 55ml/min/1.73m²), this study can not permit to assert that cystatin C is definitively better than creatinine for the detection of stage 3 kidney disease (GFR<60 ml/min/1.73 m²). Regarding the methodology of the study, the authors do not mention when cystatin C has been measured in the frozen samples. Have the samples been measured retrospectively? If so, are the authors sure of the stability of the cystatin C in samples frozen, for example, for more then ten years? The authors found that cystatin C is associated with body mass index. This interesting result should be discussed in the light of the recent literature (2). The authors compared cystatin C with estimated GFR to predict cardiovascular risk. Why have the authors not studied a cystatin C -based equation, such as the equation published by Rule et al? (3). In their interesting discussion, the authors make speculations as to why cystatin C may be a better predictor of cardiovascular risk than actual GFR by iothalamate clearance. We would like to suggest another hypothesis. Of course, Cystatin C is strongly related to GFR. Nevertheless, cystatin C concentration seems also influenced by other factors as muscular mass (2), dysthyroidism (hyperthyroidism increases cystatin C concentration although increasing GFR) and corticotherapy (which increases cystatin C concentration) (3). From comparative physiology, we know that GFR is strongly related to basal metabolic rate (BMR)(4). Moreover, corticotherapy and hyperthyroidism also increase BMR. BMR is also influenced by muscular mass which is, in the body, the greatest reserve of nucleated cells which produce cystatin C (2). All the factors influencing cystatin C concentration could thus be related to one common "superior" factor: BMR. This working hypothesis is further reinforced by data from the comparative physiology that suggests BMR (like cystatin C) could be one important predictor of lifespan (5).

Acknowledgments: We want to thank Dr Jamie Macdonald for his help in the redaction of the manuscript.

Reference List

(1) Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L et al. Cystatin C as a risk factor for outcomes in chronic kidney disease. Ann Intern Med. 2007;147:19-27.

(2) Macdonald J, Marcora S, Jibani M, Roberts G, Kumwenda M, Glover R et al. GFR estimation using cystatin C is not independent of body composition. Am J Kidney Dis. 2006;48:712-19.

(3) Rule AD, Bergstralh EJ, Slezak JM, Bergert J, Larson TS. Glomerular filtration rate estimated by cystatin C among different clinical presentations. Kidney Int. 2006;69:399-405.

(4) Singer MA. Of mice and men and elephants: metabolic rate sets glomerular filtration rate. Am J Kidney Dis. 2001;37:164-78.

(5) Speakman JR. Body size, energy metabolism and lifespan. J Exp Biol. 2005;208:1717-30.

Conflict of Interest:

None declared

In Response
Posted on August 13, 2007
Mark J Sarnak
Tufts-New England Medical Center
Conflict of Interest: None Declared

Vandana Menon MD PhD1, Michael G. Shlipak MD2 and Mark J. Sarnak MD MS1

Affiliations: 1 Department of Medicine, Division of Nephrology, Tufts-New England Medical Center, Boston, MA 2General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, CA

Address correspondence to: Mark J. Sarnak, MD MS 750 Washington Street, #391 Boston, MA 02111 Telephone: 617-636-1182 Fax: 617-636-1355 Email: msarnak@tufts-nemc.org

Conflict of Disclosures: None

In response to the letter regarding our analyses examining cystatin C as a risk factor for outcomes in chronic kidney disease (CKD): 1) We do not make the assertion that cystatin C is better than creatinine in diagnosing stage 3 kidney disease. 2) As stated in the methods section, cystatin C was measured in frozen samples collected at baseline from participants of the randomized cohort of the Modification of Diet in Renal Disease Study. There is a precedent for using frozen stored samples to analyze cystatin C (1-3). Serum and plasma samples stored at temperatures ranging from room temperature to "“200C and from 2 days to more than a month were found to be stable (4, 5). Our samples were stored at "“70oC. Moreover, the associations of cystatin C with variables such as creatinine, estimated glomerular filtration rate (GFR), and BMI are similar to those seen in other studies. 3) While it is possible that there are other factors such as BMI that may be associated with cystatin C, the strong correlation of cystatin with iothalamate GFR (r=0.85) suggests that kidney function is the primary determinant of cystatin C. 4) Studying a cystatin based equation was outside the scope of this paper. Our primary focus was to compare cystatin C, creatinine, and iothalamate GFR as risk factors for outcomes in CKD given that prior manuscripts only had estimated GFR available for comparison. Equations which use cystatin C alone are useful in showing the level of estimated GFR, which correspond to a given level of cystatin C but will fundamentally have the same strength as risk factors. The question is more complex and needs to be addressed separately for equations which include multiple factors. 5) As noted above, the correlation between iothalamate GFR and cystatin C in our study was 0.85; therefore, the letter-writer's hypothesis that basal metabolic rate (BMR) is the underlying mechanism for cystatin C's prognostic utility assumes an overwhelming correlation of BMR with GFR by proxy. While BMR may influence GFR to some extent we believe that it is not the sole or primary determinant of GFR. Further, this postulated mechanism would not be limited to the literature of cystatin C, but rather to all studies of CKD as a risk factor for cardiovascular disease. Without reliable measures of BMR in large cohort studies its importance cannot be evaluated directly. In our opinion, the BMR is unlikely to be the major mechanism to explain the cardiovascular disease risk of CKD.

Vandana Menon MD PhD Mark J Sarnak MD MS Division of Nephrology Tufts-New England Medical Center Boston, MA

Michael G. Shlipak MD MPH General Internal Medicine Section Veterans Affairs Medical Center San Francisco, CA

Conflict of Interest:

None declared

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