Cystatin C as a Risk Factor for Outcomes in Chronic Kidney Disease
Publication: Annals of Internal Medicine
Volume 147, Number 1
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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.
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Published In
Annals of Internal Medicine
Volume 147 • Number 1 • 3 July 2007
Pages: 19 - 27
History
Published online: 3 July 2007
Published in issue: 3 July 2007
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© 2007 American College of Physicians.
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Cystatin C as a Risk Factor for Outcomes in Chronic Kidney Disease. Ann Intern Med.2007;147:19-27. [Epub 3 July 2007]. doi:10.7326/0003-4819-147-1-200707030-00004
Cystatin C as a Risk Factor for Outcomes in Chronic Kidney Disease. Ann Intern Med.2007;147:19-27. [Epub 3 July 2007]. doi:10.7326/0003-4819-147-1-200707030-00004
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Cystatin C, renal function and cardiovascular risk
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
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: [email protected]
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