Cystatin C, many answers but some unmet questions

Cystatin C, many answers but some unmet questions

Med Clin (Barc). 2015;145(5):201–202 Editorial Cystatin C, many answers but some unmet questions夽 Cistatina C, much...

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Med Clin (Barc). 2015;145(5):201–202


Cystatin C, many answers but some unmet questions夽 Cistatina C, muchas respuestas y algunas cuestiones pendientes Juan Ignacio Pérez Calvo a,∗ , Juan José Puente Lanzarote b a Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Instituto de Investigación Sanitaria de Aragón, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain b Servicio de Bioquímica Clínica, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

Blood concentrations of cystatin C (CysC) have been proven to be useful in predicting the development of hypertension in middle-age men1 and cardiovascular complications in general population.2,3 Its predictive capacity for future development of heart failure (HF) is particularly strong,4–6 and once this has been established, its prognostic value is unquestionable in both HF with decreased7–9 and preserved ejection fraction,10 adding further information to the one provided by natriuretic peptides.11–14 In the current issue of Clinical Medicine, Garcia Gallego et al.15 provide a new observation about the association between higher concentrations of CysC, the all-cause mortality and the incidence of cardiovascular events in hypertensive patients. In hypertensive subjects CysC concentrations have also been correlated with the decline of renal function16,17 subclinical cerebral microvascular disease18 and recurrent stroke risk.19 The usefulness of the CysC as a prognostic biomarker in cardiovascular disease is thus undeniable. It has been unanimously supported that its prognostic capacity depends on more accurate estimation of glomerular filtration rate (GFR) as an overall expression of renal function. However, it is uncertain whether or not this is the only reason to explain their performance as a prognostic biomarker in cardiovascular disease. The estimated GFR is one of the most important parameters commonly used in clinical practice. In recent years, various assessment formulas have been validated based on various endogenous GFR markers. Among them, the so-called CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), based on CysC and in its 2012 version, appears to be the most accurate formula, especially for use in the general population without significant kidney disease.20 The advantage of using CysC in estimating GFR is that, in blood, CysC is not influenced by age, sex, weight or race,21 just the opposite to what happens with creatinine.22 Therefore, the estimates obtained are more accurate and easy to understand. The best correlation

DOI of original article: 夽 Please cite this article as: Pérez Calvo JI, Puente Lanzarote JJ. Cistatina C, muchas respuestas y algunas cuestiones pendientes. Med Clin (Barc). 2015;145:201–202. ∗ Corresponding author. E-mail address: [email protected] (J.I. Pérez Calvo). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,

between the concentrations of CysC and the GFR are due to multiple factors related to the protein itself and its intrarenal process. The gene encoding CysC synthesis was cloned in1987,23 it is located on chromosome 20, its size is 4.3 kb and is organized in 3 exons and 2 intronic regions.24 It belongs to the family of the housekeeping genes, so all nucleated cells produce it at a constant rate.25 In addition, the physicochemical properties of CysC, a small protein with a molecular mass of 13 kDa, made up of 120 amino acids in a single polypeptide chain26 and neutral electric charge,27 allow a free GFR, which is followed by a full catabolism in the proximal convoluted tubule, so there is no resorption that might influence its serum levels.28,29 It has also been suggested that CysC might be involved in the left ventricle remodeling in hypertensive patients since their early stages.5,30 In a multiethnic cohort of 2548 subjects from the Dallas Heart Study, aged 30–65 years,31 CysC concentration was associated independently with a specific cardiac phenotype with concentric left ventricular hypertrophy, with a more spherical ventricular chamber morphology, relationship persisting even after being adjusted to kidney function.31 Although this hypothesis is very attractive due to the involvement of the balance between proteases and antiproteases in left ventricular remodeling,32,33 the involvement of CysC in ventricular remodeling remains a matter of discussion. As shown in the paper by Gallego Garcia et al., the levels of serum CysC continues to provide valuable information for the clinician and is completing the prospect of a complex puzzle where a few pieces remain unplaced.

References 1. Otsuka T, Kato K, Kachi Y, Ibuki C, Seino Y, Kodani E, et al. Serum cystatin C, creatinine-based estimated glomerular filtration rate, and the risk of incident hypertension in middle-aged men. Am J Hypertens. 2014;27:596–602. 2. Méndez Bailón M, Audibert Mena L. Cistatina C: ¿un nuevo marcador de riesgo cardiovascular? Med Clin (Barc). 2008;130:13–4. 3. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352:2049–60. 4. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Jenny NS, Psaty BM, et al. Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med. 2005;142:497–505.


J.I. Pérez Calvo, J.J. Puente Lanzarote / Med Clin (Barc). 2015;145(5):201–202

5. Djoussé L, Kurth T, Gaziano JM. Cystatin C and risk of heart failure in the Physicians’ Health Study (PHS). Am Heart J. 2008;155:82–6. 6. Moran A, Katz R, Smith NL, Fried LF, Sarnak MJ, Seliger SL, et al. Cystatin C concentration as a predictor of systolic and diastolic heart failure. J Card Fail. 2008;14:19–26. 7. Deo R, Fyr CL, Fried LF, Newman AB, Harris TB, Angleman S, et al. Kidney dysfunction and fatal cardiovascular disease – an association independent of atherosclerotic events: Results from the Health, Aging, and Body Composition (Health ABC) study. Am Heart J. 2008;155:62–8. 8. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen CO, Newman AB, et al. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol. 2005;45:268–71. 9. Naruse H, Ishii J, Kawai T, Hattori K, Ishikawa M, Okumura M, et al. Cystatin C in acute heart failure without advanced renal impairment. Am J Med. 2009;122:566–73. 10. Carrasco-Sánchez FJ, Galisteo-Almeda L, Páez-Rubio I, Martínez-Marcos FJ, Camacho-Vázquez C, Ruiz-Frutos C, et al. Prognostic value of cystatin C on admission in heart failure with preserved ejection fraction. J Card Fail. 2011;17: 31–8. 11. Tang WH, van Lente F, Shrestha K, Troughton RW, Francis GS, Tong W, et al. Impact of myocardial function on cystatin C measurements in chronic systolic heart failure. J Card Fail. 2008;14:394–9. 12. Alehagen U, Dahlström U, Lindahl TL. Cystatin C and NT-proBNP, a powerful combination of biomarkers for predicting cardiovascular mortality in elderly patients with heart failure: Results from a 10-year study in primary care. Eur J Heart Fail. 2009;11:354–60. 13. Manzano-Fernández S, Boronat-Garcia M, Albaladejo-Otón MD, Pastor P, Garrido IP, Pastor-Pérez FJ, et al. Complementary prognostic value of cystatin C, N-terminal pro-B-type natriuretic Peptide and cardiac troponin T in patients with acute heart failure. Am J Cardiol. 2009;103:1753–9. 14. Pérez-Calvo J, Ruiz-Ruiz F, Carrasco-Sánchez FJ, Morales-Rull JL, ManzanoFernández S, Galisteo-Almeda L, et al. Prognostic value of serum cystatin c and N-terminal pro B-type natriuretic peptide in patients with acute heart failure. Eur J Intern Med. 2012;23:599–603. 15. Garcia Gallego F, Robles NR, Matias Orozco N, Mena C, Cidoncha A. Cistatina C como predictor de mortalidad en población hipertensa. Med Clin (Barc). 2015;145:198–200. 16. Salgado JV, Franc¸a AK, Cabral NA, Lages J, Ribeiro VS, Santos AM, et al. Cystatin C, kidney function, and cardiovascular risk factors in primary hypertension. Rev Assoc Med Bras. 2013;59:21–7. 17. Bloomfield GS, Yi SS, Astor BC, Kramer H, Shea S, Shlipak MG, et al. Blood pressure and chronic kidney disease progression in a multi-racial cohort: the Multi-Ethnic Study of Atherosclerosis. J Hum Hypertens. 2013;27: 421–6.

18. Zhang JB, Liu LF, Li ZG, Sun HR, Jü XH. Associations between biomarkers of renal function with cerebral microbleeds in hypertensive patients. Am J Hypertens. 2015;28:739–45. 19. Zeng Q, Lin K, Yao M, Wei L. Significant correlation between cystatin C, cerebral infarction, and potential biomarker for increased risk of stroke. Curr Neurovasc Res. 2015;12:40–6. 20. Levey AS, Inker LA, Coresh J. GFR estimation: from physiology to public health. Am J Kidney Dis. 2014;63:820–34. 21. Herget-Rosenthal S, Trabold S, Pietruck F, Holtmann M, Philipp T, Kribben A. Cystatin C: efficacy as screening test for reduced glomerular filtration rate. Am J Nephrol. 2000;20:97–102. 22. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38:1933–53. 23. Abrahamson M, Grubb A, Olafsson I, Lundwall A. Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C. FEBS Lett. 1987;216:229–33. 24. Abrahamson M, Olafsson I, Palsdottir A, Ulvsbäck M, Lundwall A, Jensson O, et al. Structure and expression of the human cystatin C gene. Biochem J. 1990;268:287–94. 25. Abrahamson M, Barrett AJ, Salvesen G, Grubb A. Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids. J Biol Chem. 1986;261:11282–9. 26. Grubb A, Löfberg H. Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis. Proc Natl Acad Sci U S A. 1982;79:3024–7. 27. McMurray MD, Trivax JE, McCullough PA, Serum cystatin C. Renal filtration function, and left ventricular remodeling. Circ Heart Fail. 2009;2:86–9. 28. Coll E, Botey A, Alvarez L, Poch E, Quintó L, Saurina A, et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. 2000;36:29–34. 29. Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal dysfunction in the elderly. Am J Kidney Dis. 2001;37:79–83. 30. Drazner MH, Dries DL, Peshock RM, Cooper RS, Klassen C, Kazi F, et al. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: The Dallas Heart Study. Hypertension. 2005;46:124–9. 31. Patel PC, Ayers CR, Murphy SA, Peshock R, Khera A, de Lemos JA, et al. Association of cystatin C with left ventricular structure and function: The Dallas Heart Study. Circ Heart Fail. 2009;2:98–104. 32. López B, González A, Querejeta R, Larman M, Díez J. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol. 2006;48:89–96. 33. Shirwany A, Weber K. Extracellular matrix remodeling in hypertensive heart disease. J Am Coll Cardiol. 2006;48:97–8.