Objective Cystatin C is growing to be an ideal indicator for renal function and cardiovascular events. The aim of this study was to investigate the relationship between serum cystatin C levels and peripheral arterial disease and to explore its diagnostic value for lower limb ischemia (LLI) in type 2 diabetic population. Methods A total of 1609 T2DM patients were included in this cross-sectional study. Their clinical and biochemical characteristics, ankle-brachial index (ABI), carotid and lower extremity arterial ultrasound were detected. LLI was defined by ABI <0.9 and lower extremity arterial stenosis >50% by ultrasound examination. Patients were divided to two groups: with LLI and without. The risk factors of LLI were explored by binary logistic regression analysis. Results The serum concentrations of cystatin C were 1.53±0.60 and 1.08±0.30 mg/L in patients with and without LLI, respectively. Binary logistic regression analysis showed that the significant risk factors were cystatin C (P = 0.007, OR = 5.081), the presence of hypertension (P = 0.011, OR = 3.527), age (P<0.001, OR = 1.181), GA (P = 0.002, OR = 1.089) and diabetes duration (P = 0.008, OR = 1.074). The prevalence of coronary artery disease, cerebral infarction and LLI increased with cystatin C (P<0.01), and the prevalence of LLI in patients with cystatin C >1.2 mg/L was much higher than other three quartile groups. Receiver operating characteristic curve analysis revealed the cut point of cystatin C for LLI was 1.2 mg/L. The risk of LLI dramatically increased in patients with cystatin C >1.2 mg/L (OR = 21.793, 95% confidence interval 10.046？47.280, P<0.001). After adjusting for sex, age, duration, HbA1c, GA and hypertension, its OR still remained 3.395 (95% confidence interval 1.335–8.634). Conclusions There was a strong and independent association between cystatin C and limb arterial disease in diabetic population, and cystatin C >1.2 mg/L indicated a great increased risk of LLI.
References
[1]
Peripheral arterial disease in people with diabetes. Diabetes Care 26: 3333–3341.
[2]
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1998) Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 97: 425–428.
[3]
Singh D, Whooley MA, Ix JH, Ali S, Shlipak MG (2007) Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study. Nephrol Dial Transplant 22: 1087–1092.
[4]
Laterza OF, Price CP, Scott MG (2002) Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 48: 699–707.
[5]
Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40: 221–226.
[6]
Filler G, Bokenkamp A, Hofmann W, Le Bricon T, Martinez-Bru C, et al. (2005) Cystatin C as a marker of GFR–history, indications, and future research. Clin Biochem 38: 1–8.
[7]
Bokenkamp A, Herget-Rosenthal S, Bokenkamp R (2006) Cystatin C, kidney function and cardiovascular disease. Pediatr Nephrol 21: 1223–1230.
[8]
Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, et al. (2006) Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med 145: 237–246.
[9]
Xie L, Terrand J, Xu B, Tsaprailis G, Boyer J, et al. (2010) Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation. Cardiovasc Res 87: 628–635.
[10]
Deo R, Shlipak MG, Ix JH, Ali S, Schiller NB, et al. (2009) Association of cystatin C with ischemia in patients with coronary heart disease. Clin Cardiol 32: E18–22.
[11]
O'Hare AM, Newman AB, Katz R, Fried LF, Stehman-Breen CO, et al. (2005) Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study. Arch Intern Med 165: 2666–2670.
[12]
Urbonaviciene G, Shi GP, Urbonavicius S, Henneberg EW, Lindholt JS (2011) Higher cystatin C level predicts long-term mortality in patients with peripheral arterial disease. Atherosclerosis 216: 440–445.
[13]
Standards of medical care in diabetes–2012. Diabetes Care 35 Suppl 1S11–63.
[14]
Cheung BM, Ong KL, Wong LY (2009) Elevated serum alkaline phosphatase and peripheral arterial disease in the United States National Health and Nutrition Examination Survey 1999–2004. Int J Cardiol 135: 156–161.
[15]
Baetta R, Corsini A (2010) Role of polymorphonuclear neutrophils in atherosclerosis: current state and future perspectives. Atherosclerosis 210: 1–13.
[16]
Dijk JM, Wangge G, Graaf Y, Bots ML, Grobbee DE, et al. (2006) Hemoglobin and atherosclerosis in patients with manifest arterial disease. The SMART-study. Atherosclerosis 188: 444–449.
[17]
Ishizaka N, Ishizaka Y, Nagai R, Toda E, Hashimoto H, et al. (2007) Association between serum albumin, carotid atherosclerosis, and metabolic syndrome in Japanese individuals. Atherosclerosis 193: 373–379.
[18]
Wattanakit K, Folsom AR, Selvin E, Coresh J, Hirsch AT, et al. (2007) Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study. J Am Soc Nephrol 18: 629–636.
[19]
O'Hare AM, Glidden DV, Fox CS, Hsu CY (2004) High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999–2000. Circulation 109: 320–323.
[20]
Selvin E, Erlinger TP (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 110: 738–743.
[21]
Sheen YJ, Lin JL, Lee IT, Hsu YN, Li TC, et al. (2012) Low estimated glomerular filtration rate is a major determinant of low ankle-brachial index and toe-brachial index in type 2 diabetes. Angiology 63: 55–61.
[22]
Selvin E, Kottgen A, Coresh J (2009) Kidney function estimated from serum creatinine and cystatin C and peripheral arterial disease in NHANES 1999–2002. Eur Heart J 30: 1918–1925.
[23]
Chen JH, Chen SC, Liu WC, Su HM, Chen CY, et al. (2009) Determinants of peripheral arterial stiffness in patients with chronic kidney disease in southern Taiwan. Kaohsiung J Med Sci 25: 366–373.
[24]
Chen J, Mohler ER, 3rd, Xie D, Shlipak MG, Townsend RR, et al (2012) Risk factors for peripheral arterial disease among patients with chronic kidney disease. Am J Cardiol 110: 136–141.
[25]
Shlipak MG, Praught ML, Sarnak MJ (2006) Update on cystatin C: new insights into the importance of mild kidney dysfunction. Curr Opin Nephrol Hypertens 15: 270–275.
[26]
Koenig W, Twardella D, Brenner H, Rothenbacher D (2005) Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem 51: 321–327.
[27]
Ix JH, Shlipak MG, Chertow GM, Whooley MA (2007) Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study. Circulation 115: 173–179.
[28]
Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, et al. (2004) Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 65: 1416–1421.
[29]
Lee SH, Park SA, Ko SH, Yim HW, Ahn YB, et al. (2010) Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients. Metabolism 59: 241–246.
[30]
Arpegard J, Ostergren J, de Faire U, Hansson LO, Svensson P (2008) Cystatin C–a marker of peripheral atherosclerotic disease? Atherosclerosis 199: 397–401.
[31]
Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, et al. (1999) Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 104: 1191–1197.
[32]
Eriksson P, Deguchi H, Samnegard A, Lundman P, Boquist S, et al. (2004) Human evidence that the cystatin C gene is implicated in focal progression of coronary artery disease. Arterioscler Thromb Vasc Biol 24: 551–557.
