Abstract
Background
Familial Mediterranean fever (FMF) is characterized by sporadic, recurrent attacks of fever and serosal inflammation. AA amyloidosis (AAA) is a disorder characterized by the extracellular tissue deposition of serum amyloid A protein (SAA). Azurocidin is a neutrophil-derived granule protein. We aimed to investigate the significance of azurocidin in FMF and AAA and the correlation between azurocidin levels and carotid artery intima media thickness (CA–IMT) and cardiovascular plaque existence.
Methods
A sum of 52 FMF patients were enrolled in the study. FMF patients were composed of two groups. Group-1 included 30 patients with non-complicated FMF. Group-2 included 22 patients whom received renal transplantation due to FMF complicated with AAA and being followed up at stable state for at least one year. 24 healthy individuals who matched with FMF patients in terms of age and gender consisted the control group.
Results
We found statistically significant difference between patient and control groups in terms of urea (38.52 ± 19.96 mg/dl vs 29.08 ± 5.83 mg/dl; p = 0.003), creatinine (1.11 ± 0.39 mg/dl vs 0.91 ± 0.16 mg/dl; p = 0.002), serum uric acid (6.2 ± 2 mg/dl vs 4.5 ± 0.9 mg/dl; p < 0.001), serum CRP (8.62 ± 9.5 mg/dl vs 3.91 ± 3.9 mg/dl; p = 0.004), ferritin (151.4 ± 317 ng/ml vs 33.3 ± 34 ng/ml; p = 0.014), white blood cell (WBC) levels (7.97 ± 2.3 × 103/µL vs 6.6 ± 1.7 × 103/µL; p = 0.018), serum azurocidin levels (137.16 ± 65.62 ng/ml vs 102.35 ± 51.61 ng/ml; p = 0.015) and mean CA–IMT (0.57 ± 0.15 mm vs 0.47 ± 0.07 mm; p = 0.001). Comparison of group 1 and group 2 revealed statistically significant differences in terms of urea (26 ± 8 mg/dl vs 54 ± 19 mg/dl; p < 0.001), creatinine (0.87 ± 0.1 mg/dl vs 1.44 ± 0.3 mg/dl; p < 0.001), estimated glomerular filtration rate (eGFR) (99 ± 21 ml/min/1.73m2 vs 53 ± 16 ml/min/1.73m2; p < .001), uric acid (4.9 ± 1.3 mg/dl vs 7.6 ± 1.7 mg/dl; p < 0.001), ferritin (31.7 ± 27 ng/ml vs 292.8 ± 431 ng/ml; p = 0.010) and albumin (4.5 ± 0.3 g/dl vs 4.1 ± 0.3 g/dl; p = 0.001). There was no statistically significant difference between group 1 and group 2 in terms of mean CA–IMT (CA–IMT (M) (mm): 0.54 ± 0.14 vs 0.62 ± 0.17, p = 0.057). Serum azurocidin levels were not significantly different between group 1 and group 2 (121.73 ± 53.24 ng/ml vs 158.19 ± 75.77 ng/ml; p = 0.061). In multivariate linear regression analysis (variables: MBP, urea, creatinine, eGFR, ferritin, uric acid, CA–IMT) azurocidin was independently associated with urea (t:2.658; p = 0.010) and CA–IMT (t:2.464; p = 0.017).
Discussion
Based on our findings, azurocidin seems to be a good inflammation marker in patients with FMF. Increase in azurocidin levels might be associated with development of amyloidosis. Also, serum azurocidin levels may be used as a predictor of both inflammatory state and cardiovascular risk, especially when used with other markers such as CA–IMT.
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References
Erer B, Demirkaya E, Ozen S, Kallinich T (2016) What is the best acute phase reactant for familial Mediterranean fever follow-up and its role in the prediction of complications ? A systematic review. Rheumatol Int 36(4):483–487
Varan O, Kucuk H, Babaoglu H, Tecer D, Atas N, Bilici Salman R et al (2019) Chronic inflammation in adult familial Mediterranean fever patients: underlying causes and association with amyloidosis. Scand J Rheumatol 48(4):315–319
Lane T, Pinney JH, Gilbertson JA et al (2017) Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre. Amyloid 24:162
Papa R, Lachmann HJ (2018) Secondary, AA, amyloidosis. Rheum Dis Clin North Am 44(4):585–603
Westermark GT, Fandrich M, Westermark P (2015) AA amyloidosis: pathogenesis and targeted therapy. Annu Rev Pathol 10:321–344
StojanovicKSiGeorgin-Lavialle S, Grateau G. (2017) AA amyloidosis. NephrolTher 13(4):258–264
Sethi S, Theis JD (2018) Pathology and diagnosis of renal non-AL amyloidosis. J Nephrol 31(3):343–350
Ayar Y, Ersoy A, Oksuz MF, Ocakoglu G, Vuruskan BA, Yildiz A et al (2017) Clinical outcomes and survival in AA amyloidosis patients. Rev Bras ReumatolEngl Ed 57(6):535–544
Shafer WM, Martin LE, Spitznagel JK (1984) Cationic anti-microbial proteins isolated from human neutrophil granulocytes in the presence of diisopropylfluorophosphate. Infect Immun 45:29–35
Tapper H, Karlsson A, Morgelin M, Flodgaard H, Herwald H (2002) Secretion of heparin binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles. Blood 99:1785–1793
Gautam N, Olofsson AM, Herwald H et al (2001) Heparin binding protein (HBP/CAP37): a missing link in neutrophil evoked alteration of vascular permeability. NatMed 7:1123–1127
Linder A, Arnold R, Boyd JH et al (2015) Heparin binding protein measurement improves the prediction of severe infection with organ dysfunction in the emergency department. Crit Care Med 43:2378–2386
Akdogan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Sahiner L et al (2006) Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? Impaired endothelial function and increased intima media thickness are found in FMF. J Am Coll Cardiol 48(11):2351–2353
Polak JF, O’Leary DH (2016) Carotid intima–media thickness as surrogate for and predictor of CVD. Glob Heart 11(3):295–312
Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T et al (2010) Carotid intima–media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (atherosclerosis risk in communities) study. J Am Coll Cardiol 55(15):1600–1607
Tyden J, Herwald H, Hultin M, Wallden J, Johansson J (2017) Heparin-binding protein as a biomarker of acute kidney injury in critical illness. Acta AnaesthesiolScand 4:1–7
Xing L, Zhongqian L, Chunmei S, Pingfa C, Lei H, Qin J et al (2018) Activation of M1 macrophages in sepsis-induced acute kidney injury in response to heparin-binding protein. PLoS ONE 13(5):e0196423
Linder A, Akesson P, Inghammar M, Treutiger CJ, Linner A, Sunden-Cullberg J (2012) Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care 16:90
Chew MS, Linder A, Santen S, Ersson A, Herwald H, Thorlacius H (2012) Increased plasma levels of heparin-binding protein in patients with shock: a prospective cohort study. Inflamm Res 61:375–379
Kaukonen KM, Herwald H, Lindbom L, Pettila V (2013) Heparin-binding protein in patients with acute respiratory failure treated with granulocyte colony-stimulating factor (filgastrim)—a prospective, placebo-controlled, double blind study. BMC Infect Dis 13:51
Yasui K, Furuta RA, Matsuyama N et al (2008) Possible involvement of heparin-binding protein in transfusion-related acute lung injury. Transfusion 48:978–987
Hirayama F (2010) Recent advances in laboratory assays for non-hemolytic transfusion reactions. Transfusion 50:252–263
Erken E, Erken E (2018) Cardiac disease in familial Mediterranean fever. Rheumatol Int 38:51–58
Yang X, Chang Y, Wei W (2016) Endothelial dysfunction and inflammation: immunity in rheumatoid arthritis. Mediators Inflamm 2016:1–9
Ben-Zvi I, Livneh A (2011) Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 7:105–112
Bilginer Y, Ozaltin F, Basaran C, Duzova A, Besbas N, Topaloglu R, Ozen S, Bakkaloglu A (2008) Evaluation of intima media thickness of the common and internal carotid arteries with inflammatory markers in familial Mediterranean fever as possible predictors for atherosclerosis. Rheumatol Int 28:1211–1216
Peru H, Altun B, Doğan M, Kara F, Elmaci AM, Oran B (2008) The evaluation of carotid intima-media thickness in children with familial Mediterranean fever. ClinRheumatol 27:689–694
Chen MA, Kawakubo M, Colletti PM, Xu D, Labree DL, Detrano R et al (2013) Effect of age on aortic atherosclerosis. J GeriatrCardiol 10(2):135–140
Tada H, Nakagawa T, Okada H, Nakahashi T, Mori M, Sakata K et al (2020) Clinical impact of carotid plaque score rather than carotid intima-media thickness on recurrence of atherosclerotic cardiovascular disease events. J AtherosclerThromb 27(1):38–46
Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Lourent S (2013) Reference values for arterial measurement collaboration. Reference intervals for common carotid intima–media thickness measured with echotracking: relation with risk factors. Eur Heart J 34(30):2368–2380
Polak JF, Szklo M, O’Leary DH (2015) Associations of coronary heart disease with common carotid artery near and far wall intima–media thickness: the multi-ethnic study of atherosclerosis. J Am SocEchocardiogr 28:1114–1121
Pawelec G, Goldeck D, Derhovanessian E (2014) Inflammation, ageing and chronic disease. CurrOpinImmunol 29:23–28
Zhao G, Huang L, Song M, Song Y (2013) Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis 231:61–68
Weiss A, Beloosesky Y, Koren-Morag N, Grossman A (2017) Association between mortality and blood pressure variability in hypertensive and normotensive elders: a cohort study. J ClinHypertens (Greenwich) 19(8):753–756
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IB: data collection and interpretation, manuscript preparation, literature search. ET: literature search, statistical analysis, manuscript preparation.
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Bozaci, I., Tatar, E. The role of azurocidin in patients with familial Mediterranean fever and AA amyloidosis and its association with cardiovascular risk factors. Int Urol Nephrol 53, 531–538 (2021). https://doi.org/10.1007/s11255-020-02652-2
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DOI: https://doi.org/10.1007/s11255-020-02652-2