Correspondence
Cystatin C and the Risk of Death
N Engl J Med 2005; 353:842-844August 25, 2005
- Article
To the Editor:
Shlipak et al. (May 19 issue)1 report on cystatin C and the risk of death and cardiovascular events among elderly persons. However, we have a comment on cystatin C as a measure of kidney function. In patients with hypothyroidism, levels of creatinine tend to be elevated, and in patients with hyperthyroidism, creatinine is lowered.2 In contrast, levels of cystatin C are low in cases of hypothyroidism and elevated in hyperthyroidism.3 However, the authors state in the Discussion section that “cystatin C levels appear to be elevated in patients with hypothyroidism and depressed in those with hyperthyroidism,” citing authors who made similar erroneous observations.4 Our hypothesis is that the production of cystatin C is under the influence of thyroid hormone. Thyroid disorders are prevalent in the elderly population. Of interest in this respect is the association between a low level of serum thyrotropin and mortality related to cardiovascular disease.5 Thus, the association of cystatin C with the risk of cardiovascular events could be true, though not solely explained by kidney function; it probably also is explained by thyroid function.
5 ReferencesArie Berghout, M.D.
Remi W. Wulkan, Ph.D.
Jan G. den Hollander, M.D.
Medical Centre Rijnmond Zuid, 3066 RC Rotterdam, the Netherlands
berghouta@mcrz.nl 1
Shlipak MG ,Sarnak MJ ,Katz R , et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049-2060
Full Text | Web of Science | Medline2
den Hollander JG ,Wulkan RW ,Mantel MJ ,Berghout A . Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol (Oxf) 2005;62:423-427
CrossRef | Web of Science | Medline3
den Hollander JG ,Wulkan RW ,Mantel MJ ,Berghout A . Is cystatin C a marker of glomerular filtration rate in thyroid dysfunction? Clin Chem 2003;49:1558-1559
CrossRef | Web of Science | Medline4
Fricker M ,Wiesli P ,Brandle M ,Schwegler B ,Schmid C . Impact of thyroid function on serum cystatin C. Kidney Int 2003;63:1944-1947
CrossRef | Web of Science | Medline5
Parle JV ,Maisonneuve P ,Sheppard MC ,Boyle P ,Franklyn JA . Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865
CrossRef | Web of Science | Medline
To the Editor:
Shlipak et al. found cystatin C to be a stronger predictor of the risk of death and cardiovascular events than creatinine. In this context, it is important to consider the nonrenal factors that influence serum cystatin C concentrations. In addition to thyroid disorders, glucocorticoid therapy has also been shown to be associated, in a dose-dependent manner, with increased concentrations of cystatin C.1-3 A promoter-mediated increase in cystatin C production has been described as a mechanism.4 In the study by Shlipak et al., glucocorticoids were not considered a confounding factor in multivariate adjustment. It would be interesting to find out whether patients receiving glucocorticoid therapy and having increased cystatin C concentrations and normal renal function also have a higher risk of cardiovascular events.
4 ReferencesLorenz Risch, M.D.
Heinz Drexel, M.D.
Academic Teaching Hospital, 680 Feldkirch, Austria
lorenzrisch@hotmail.com Andreas R. Huber, M.D.
Kantonsspital, 5001 Aarau, Switzerland1
Risch L ,Herklotz R ,Blumberg A ,Huber A . Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001;47:2055-2059
Web of Science | Medline2
Poge U ,Gerhardt T ,Bokenkamp A , et al. Time course of low molecular weight proteins in the early transplantation period -- influence of corticosteroids. Nephrol Dial Transplant 2004;19:2858-2863
CrossRef | Web of Science | Medline3
Cimerman N ,Brguljan PM ,Krasovec M ,Suskovic S ,Kos J . Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients. Clin Chim Acta 2000;300:83-95
CrossRef | Web of Science | Medline4
Bjarnadottir M ,Grubb A ,Olafsson I . Promoter-mediated, dexamethasone-induced increase in cystatin C production by HeLa cells. Scand J Clin Lab Invest 1995;55:617-623
CrossRef | Web of Science | Medline
To the Editor:
The results of the study by Shlipak et al. raise a fundamental question: is increased cardiovascular risk related to the level of renal function or to the rate of change of renal function over time? Specifically, can patients with early renal-function loss who are actively losing renal function while sustaining a level of glomerular filtration within normal limits be at risk, even though they do not have impaired renal function?
Ultimately, a method for the early identification of patients at risk for the development of impaired renal function is needed, before such impairment occurs. Estimates that are based on levels of creatinine, such as the Modification of Diet in Renal Disease equation, are accurate only when function is abnormally low.1 Cystatin C overcomes this limitation by approximating the reference standard (iothalamate clearance) even when glomerular filtration is normal or elevated, as seen in patients with early kidney disease associated with diabetes (Figure 1Figure 1
Serial Determinations of Glomerular Filtration Rate by Measurement of Iothalamate Clearance and 100/Cystatin C and the Modification of Diet in Renal Disease Equation.).2 The observation by Shlipak et al. that a subgroup of patients are at increased risk of cardiovascular events despite normal levels of renal function may be reconciled by identifying those with active early renal-function loss. This can be achieved by extending the cross-sectional analysis of cystatin C at baseline to a longitudinal analysis of cystatin C over time.2 ReferencesBruce A. Perkins, M.D., M.P.H.
University of Toronto, Toronto, ON M5G 2C4, Canada
bruce.perkins@uhn. on. ca Robert G. Nelson, M.D., Ph.D.
National Institutes of Health, Phoenix, AZ 85014Andrzej S. Krolewski, M.D., Ph.D.
Harvard University, Boston, MA 022151
National Kidney Foundation
Web of Science | Medline2
Perkins BA ,Nelson RG ,Ostrander BE , et al. Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol 2005;16:1404-1412
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Berghout and colleagues have corrected our error in the discussion of the differential change in serum concentrations of cystatin C and creatinine in response to thyroid dysfunction.1 Thyroid dysfunction appears to alter the serum concentration of cystatin C independently from the glomerular filtration rate (GFR), although this finding should be confirmed by comparison with directly measured GFR data. In addition, Dr. Berghout and colleagues suggest that the presence of underlying subclinical hyperthyroidism could explain the association of cystatin C with cardiovascular risk in the Cardiovascular Health Study (CHS). In fact, both subclinical hyperthyroidism2 and hypothyroidism3 have been associated with cardiovascular risk in elderly patients. Thyroid function was not measured concurrently with cystatin C in CHS, and it is not measured in all participants. However, we believe that neither the prevalence of thyroid dysfunction in the elderly nor its strength of association with cardiovascular risk is adequate to explain the strong and linear relationship of cystatin C with these outcomes.
Dr. Risch and colleagues report that glucocorticoid use increases serum concentrations of cystatin C, and they hypothesize that use of glucocorticoids could confound the association of cystatin C with cardiovascular outcomes. The prevalence of glucocorticoid use in CHS did increase directly with levels of cystatin C (1.4, 1.8, 2.2, 3.2, and 3.6 percent, according to increasing quintiles of cystatin C; P for trend <0.001); however, glucocorticoid use was too infrequent to be a major confounder of our findings.
Dr. Perkins and colleagues note their recently published findings in persons with diabetes and normal kidney function that serial measurements of cystatin C tightly approximated GFR, as measured by iothalamate clearance, in contrast to creatinine-based estimates of GFR.4 These important results support our hypothesis that cystatin C is primarily a measure of GFR, rather than a marker of another pathologic process. We agree with these authors that evaluating changes in cystatin C over time is a logical next step for further exploration of the importance of cystatin C as a cardiovascular risk factor.
4 ReferencesMichael G. Shlipak, M.D., M.P.H.
San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121
shlip@itsa.ucsf. edu Mark J. Sarnak, M.D.
Tufts–New England Medical Center, Boston, MA 02111Linda F. Fried, M.D., M.P.H.
Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 152401
Fricker M ,Wiesli P ,Brandle M ,Schwegler B ,Schmid C . Impact of thyroid dysfunction on serum cystatin C. Kidney Int 2003;63:1944-1947
CrossRef | Web of Science | Medline2
Parle JV ,Maisonneuve P ,Sheppard MC ,Boyle P ,Franklyn JA . Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865
CrossRef | Web of Science | Medline3
Hak AE ,Pols HA ,Visser TJ ,Drexhage HA ,Hofman A ,Witteman JC . Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132:270-278
Web of Science | Medline4
Perkins BA ,Nelson RG ,Ostrander BE , et al. Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol 2005;16:1404-1412
CrossRef | Web of Science | Medline
- Citing Articles (8)
Citing Articles
1
Carlos Rabito, Elkan F. Halpern, James Scott, Nina Tolkoff-Rubin. (2010) Accurate, Fast, and Convenient Measurement of Glomerular Filtration Rate in Potential Renal Transplant Donors. Transplantation 90:5, 510-517
CrossRef2
Bruce A Perkins, Linda H Ficociello, Bijan Roshan, James H Warram, Andrzej S Krolewski. (2010) In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney International 77:1, 57-64
CrossRef3
Andrew S. Levey, Daniel Cattran, Aaron Friedman, W. Greg Miller, John Sedor, Katherine Tuttle, Bertram Kasiske, Thomas Hostetter. (2009) Proteinuria as a Surrogate Outcome in CKD: Report of a Scientific Workshop Sponsored by the National Kidney Foundation and the US Food and Drug Administration. American Journal of Kidney Diseases 54:2, 205-226
CrossRef4
Bruce A Perkins, Andrzej S Krolewski. (2009) Early nephropathy in type 1 diabetes: the importance of early renal function decline. Current Opinion in Nephrology and Hypertension 18:3, 233-240
CrossRef5
Aude Servais, Philippe Giral, Maguy Bernard, Eric Bruckert, Gilbert Deray, Corinne Isnard Bagnis. (2008) Is Serum Cystatin-C a Reliable Marker for Metabolic Syndrome?. The American Journal of Medicine 121:5, 426-432
CrossRef6
Jun Wang, Ah Siew Sim, Xing Li Wang, Chris Salonikas, Mary Moriatis, Daya Naidoo, David E.L. Wilcken. (2008) Relations between markers of renal function, coronary risk factors and the occurrence and severity of coronary artery disease. Atherosclerosis 197:2, 853-859
CrossRef7
A D Rule, T S Larson. (2006) Response to ‘Calculation of glomerular filtration rate using serum cystatin C in kidney transplant recipients’. Kidney International 70:10, 1878-1879
CrossRef8
David E. L. Wilcken, Jun Wang, Ah Siew Sim, Kathryn Green, Bridget Wilcken. (2006) Asymmetric dimethylarginine in homocystinuria due to cystathionine β-synthase deficiency: Relevance of renal function. Journal of Inherited Metabolic Disease 29:1, 30-37
CrossRef
