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The Cystatin C Paradox
Cystatin C not a marker for kidney function
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Regina Bökenkamp, MD Dpt. of Pediatric Cardiology, LUMC, Albinusdreef 2, 2300 RC Leiden, The Netherlands, Arend Bökenkamp, MD, PhD, Dpt. of Pediatric Nephrology, VUMC, Postbox 7057, 1007 MB Amsterdam, The Netherlands
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R.Bokenkamp.kjc{at}lumc.nl Regina Bökenkamp, et al.
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Sir, in a recent issue of this journal, Samak et al have shown an elevated serum cystatin C concentration to be an independent predictor of heart failure in adults older than 65 years (1). It can be assumed that heart failure in this age group is mostly due to coronary heart disease. It should therefore not be left unmentioned that a different line of evidence in the literature suggests just a protective role of cystatin C in the pathogenesis of atherosclerosis. Cystatin C is the most powerful inhibitor of cystein-proteinases such as cathepsin B and as such may play a pivotal role in tissue remodeling by reducing the elastolytic activity of vascular smooth muscle cells (2). Shi et al demonstrated that cystatin C, which is normally expressed in vascular smooth muscle cells, is severely reduced in both atherosclerotic and aneurysmal aortic lesions (2). Interestingly, this group found an inverse relationship between serum cystatin C and aortic diameter in patients with aortic aneurysms but not in healthy controls. In keeping with these results, Eriksson et al (3) found significantly diminished cystatin C concentrations in survivors of a first myocardial infarction before the age of 60 years compared to age- and sex-matched controls. This study excluded only patients with moderate renal failure (serum creatinine concentrations above 200 µmol/l). Analyzing cystatin C gene polymorphisms in the promotor region, they were able to show an association with polymorphisms that impair cystatin C production and the number of stenoses on cardiac angiography. The differences between these studies probably relate to (i) timing of cystatin C measurement (i.e. years prior vs. just after the cardiac event), (ii) baseline demographics and (iii) the endpoints used (i.e. undefined heart failure vs. documented systemic atherosclerosis). Unfortunately, neither Samak (1) nor Eriksson (3) corrected their cystatin C data for kidney function measured by a gold-standard technique. Until the role of cystatin C in atherosclerosis is better understood, clinical studies on the relationship between cystatin C and cardiovascular disease must include a gold-standard measurement of GFR to assess whether cystatin C in this setting is an independ marker of atherosclerosis or reflects early changes of renal function. It would also be very important to specifically study atherosclerosis in the cystatin C knock-out mouse, which has a normal life-span and no clinical or histological signs of disease at the age of six months (4). References (1) Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Swords JN, Psaty BM et al 2005;142:497-505 (2) ShiG-P, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 1999;104:1191-7 (3) Eriksson P, Deguchi H, Samnegard A, Lundman P, Boquist S, Tornvall P et al. Human evidence that the cystatin C gene is implicated in focal progression of coronary atery disease. Arterioscler Thromb Vasc Biol 2004;24:551-7 (4) Huh C-G, Hakansson K, Nathanson C-M, Thorgeirsson UP, Jonsson N, Grubb A et al. Decrease metastatic spread in mice homozygous for a null allele of the cystatin C protease inhibitor gene. J Clin Pathol: Mol Pathol 1999;52:332-40 Conflict of Interest:None declared |
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Arie Berghout, md, frcp mcrz hospital, rotterdam, nl, Remi Wulkan, Jan den Hollander
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berghouta{at}mcrz.nl Arie Berghout, et al.
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Letter to the editor Arie Berghout (1), Raymond Wulkan (2), Jan den Hollander(1) Dear Sir, With interest we read the article by Sarnak et al (1) on the use of cystatin C as a risk factor for heart failure in older adults. Although we can agree with the conclusion that cystatin C levels are independently associated with the risk to develop heart failure, we have a comment on cystatin C as a measure of kidney function. Recently, we have shown that in patients with thyroid dysfunction cystatin C is unsuitable as such. In hypothyroidism creatinine levels tend to be elevated, and, conversely, in hyperthyroidism creatinine levels are lowered (2). In contrast to our expectations, cystatin C levels turned out to be low in hypothyroid patients and elevated in hyperthyroid patients (3). These findings have now been confirmed by other authors. Our hypothesis is that the production of cystatin C is under the influence of thyroid hormone. Thyroid disorders are prevalent in the elderly population. Furthermore, most patients with heart failure will have low plasma T3 values due to changes in thyroid hormone metabolism during illness. We are not aware of studies that measured cystatin C levels in patients with critical illness. 1. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Swords Jenny N, Psaty BM, Newman AB, Sisovick D, Shlipak MG. Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med. 2005;142:497-505. 2. Den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol. 2005;62:423-7. 3. Den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Is Cystatin C a marker of glomerular filtration rate in thyroid dysfunction? Clin Chem. 2003;49:1558-9 Author details: Dr.A.Berghout, Consultant Physician Email BerghoutA@mcrz.nl Dr.J.den Hollander, Consultant Physician Dr.R.W.Wulkan, Clinical Biochemist Department of Medicine, Hospital MCRZ, Groene Hilledijk 315, 3075 EA Rotterdam, The Netherlands. Conflict of Interest:None declared |
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