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Cystatin C and the Risk of Death
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     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.

    Arie 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

    References

    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.

    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.

    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.

    Fricker M, Wiesli P, Brandle M, Schwegler B, Schmid C. Impact of thyroid function on serum cystatin C. Kidney Int 2003;63:1944-1947.

    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.

    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.1,2,3 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.

    Lorenz Risch, M.D.

    Heinz Drexel, M.D.

    Academic Teaching Hospital

    680 Feldkirch, Austria

    lorenzrisch@hotmail.com

    Andreas R. Huber, M.D.

    Kantonsspital

    5001 Aarau, Switzerland

    References

    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.

    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.

    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.

    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.

    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 1).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.

    Figure 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.

    100/Cystatin C is the reciprocal of cystatin C (in milligrams per liter) multiplied by 100; it is a commonly used transformation that approximates the glomerular filtration rate (in milliliters per minute).2 MDRD denotes Modification of Diet in Renal Disease. (The figure is derived from data reported by Perkins et al. for a representative participant in the Diabetic Renal Disease Study.2)

    Bruce 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 85014

    Andrzej S. Krolewski, M.D., Ph.D.

    Harvard University

    Boston, MA 02215

    References

    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:Suppl 1:S1-S266.

    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.

    The authors reply: 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.

    Michael 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 02111

    Linda F. Fried, M.D., M.P.H.

    Veterans Affairs Pittsburgh Healthcare System

    Pittsburgh, PA 15240

    References

    Fricker M, Wiesli P, Brandle M, Schwegler B, Schmid C. Impact of thyroid dysfunction on serum cystatin C. Kidney Int 2003;63:1944-1947.

    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.

    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.

    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.