http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(9): 1390–1394 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.945183
CLINICAL STUDY
Relationship between late arteriovenous fistula (AVF) stenosis and neutrophil–lymphocyte ratio (NLR) in chronic hemodialysis patients Hakki Yilmaz1, Alper Bozkurt2, Muzaffer Cakmak3, Huseyin Tugrul Celik4, Mukadder Ayse Bilgic1, Nuket Bavbek1, and Ali Akcay1
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1
Department of Internal Medicine, Section of Nephrology, School of Medicine, Turgut Ozal University, Ankara, Turkey, 2Department of Interventional Radiology, School of Medicine, Turgut Ozal University, Ankara, Turkey, 3Department of Internal Medicine, School of Medicine, Turgut Ozal University, Ankara, Turkey, and 4Department of Biochemistry, School of Medicine, Turgut Ozal University, Ankara, Turkey
Abstract
Keywords
Objectives: Primary cause of late arteriovenous fistula (AVF) dysfunction is venous stenosis as result of neointimal hyperplasia. The mechanism of AVF stenosis is not exactly understood. But inflammation is a contributing factor for development of AVF stenosis. Neutrophil– lymphocyte ratio (NLR) reflects systemic inflammation, and it was investigated in many diseases. The aim of this study was to investigate the relationship between NLR and AVF stenosis in chronic hemodialysis patients. Materials and methods: Of 593 patients applied to the department of interventional radiology between January 2011 and November 2012, a total of 108 patients meeting the appropriate criteria were included in this study. All patients were assessed with Color Doppler ultrasonography and then digital subtraction angiography was used for the patients with abnormal results. Sixty-four patients were classified as patients with AVF stenosis (group 1) and 44 patients without AVF stenosis (group 2). Routine biochemical and complete blood count values measured six months ago were recorded for all patients. Results: Mean NLR (3.47 ± 0.46 vs. 2.27 ± 0.22; p50.001) was higher in group 1 compared to group 2, whereas high-density lipoprotein (HDL; 31.8 ± 12.6 mg/dL vs. 51.5 ± 11.9 mg/dL; p50.001) was lower in group 1. NLR level was correlated with degree of AVF stenosis (r ¼ 0.625; p50.01). Receiver operating characteristic curve analysis showed that NLR (optimalcut-off ¼ 2.70) was a useful parameter in prediction of AVF stenosis (AUC ¼ 0.893, sensitivity ¼ 98.4% and specificity ¼ 75%; p50.001). NLR level and HDL530 mg/dL in logistic regression analysis are independent predictors of AVF stenosis. Conclusions: For hemodialysis patients with increased level of NLR and decreased level of HDL, regular monitoring with regard to the development of AVF stenosis may be beneficial. Our study suggests that the mechanism of AVF stenosis might have similarities to that of atherosclerosis.
AVF stenosis, Color Doppler ultrasonography, digital subtraction angiography, inflammation, NLR
Introduction The primary vascular access of choice in hemodialysis patients is arteriovenous fistula (AVF).1 AVF has a lower risk of complication and also has a very low risk of infection compared to catheter.2,3 Two most common complication experienced during the chronic use of AVF are thrombosis and stenosis.2,3 As known, thrombosis generally occurs next to the stenotic site, and the treatment is more difficult in stenosis cases accompanied by thrombosis and also there is a decreased chance for success from the treatment.3 The main factor that can lead to the development of thrombosis is the presence of stenosis.3 In general, access stenosis is considered to be developed as a result of neointimal hyperplasia.2–4 Although the exact mechanisms of neointimal hyperplasia have not been
Address correspondence to Dr. Hakki Yilmaz, Alparslan Tu¨rkes Cad. No: 57, 06510 Emek/ANKARA, Turkey. Tel: + 90-0312-2035555; Fax: + 90-0312-2035029; E-mail: [email protected]
History Received 11 March 2014 Revised 24 June 2014 Accepted 10 July 2014 Published online 23 September 2014
understood yet, hemodynamic factors and coagulation system were shown to have contribution to the mechanism.4 Furthermore, inflammation was shown to play a role in the development of AVF stenosis in both experimental and clinical studies.5–9 Therefore, it is an obvious fact that inflammation makes a significant contribution to the development of AVF stenosis. Neutrophil–lymphocyte ratio (NLR) is an easy-to-calculate and cost-efficient indicator, which is widely used recently and shows the systemic inflammatory activity. Many studies showed that NLR has prognostic value in patients with a variety of solid organ malignancies including colorectal,10 gastric,11 esophageal,12 pancreatic,13 liver,14 bladder15 and gynecological cancers.16 NLR was a predictor of survival in patients with acute coronary syndrome.17,18 In addition, NLR was associated with coronary artery disease severity and prognosis in patients undergoing coronary angiography for various indications.19 Recently, Turak et al. revealed that NLR is a strong predictor of bare-metal stent restenosis.20 Two studies showed that
DOI: 10.3109/0886022X.2014.945183
preoperative NLR is associated with saphenous vein graft disease (SVGD) in patients undergoing coronary artery bypass grafting surgery.21,22 NLR is a strong inflammatory indicator and associated with both coronary atherosclerosis and restenosis. Given the undeniable role of inflammation in AVF stenosis as well as the histopathological similarity of AVF stenosis with atherosclerosis, the correlation of NLR with the AVF stenosis is an object of interest. The aim of this study is to investigate the association of NLR with AVF stenosis and the severity of stenosis in hemodialysis patients with AVF.
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Materials and methods A total of 593 patients with AVF access dysfunction and AVF access routine control between January 2011 and November 2012 who were referred to Interventional Radiology were included in this study. The patients (n ¼ 485) were excluded if they had multiple repetitive endovascular intervention or surgery, AVF stenosis was accompanied by one or more complications of AVF dysfunction (thrombosis, steal syndrome, aneurysm, pseudo-aneurysm and infection), a history of hematological malignancy, a known bleeding diathesis or coagulopathy or concomitant warfarin therapy and patent AVF at least six months. To identify the possible risk factors for AVF stenosis, variables including age; gender; body mass index; co-morbidities such as diabetes, hypertension, coronary arterial occlusive disease, stroke and peripheral arterial occlusive disease; age of AVF; side of the AVF; type of AVF; number of lesions; degree of stenosis; and residual stenosis were collected. Color Doppler ultrasonography (CDUS) studies were performed on a Doppler ultrasound device (Philips, HD15 Pure Wave Ultrasound System, Bothell, WA) with a 5 MHz linear probe (C5-1 Pure Wave transducer) by two blinded radiologists experienced in the use of Doppler US. At CDUS analysis, AVF flow volume, peak-systolic (PSV) and fistula diameter were measured. Fistula anastomosis area and calibration, flow velocities and lumens of vascular structures in the arterial and venous tree were analyzed. Visual narrowing (diameter narrowing greater than 50%) as assessed on grayscale imaging and an increased ratio of the PSV at the stenosis as compared to the PSV measured 2-cm upstream from the stenosis are to major features to characterize AVF stenosis.23 The diagnostic criteria vary in accordance with the location of the stenosis.23 Cases with a PSV ratio in the anastomosis region of three and above were regarded as significant (50% and above) anastomosis stenosis23. A draining vein and inflow artery stenosis are defined by visible narrowing and by a PSV ratio of greater than or equal to 2:1.23 In addition, peak systolic velocities rising above 400 cm/s were regarded as other assistant findings.23 The site of stenotic lesions were classified into six categories based upon location24: (1) native artery; (2) arteriovenous anastomosis; (3) juxtaanastomotic vein (initial 2 cm of fistula); (4) venous outflow 42 cm from anastomosis (cannulation zone); (5) distal outflow (defined as above elbow joint for radial cephalic fistulae and above mid-humerus for brachial fistulae); and (6) central venous system. All patients were assessed with CDUS.
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Cardiovascular disease (CVD) was defined as coronary artery disease, myocardial infarction, coronary angioplasty, coronary artery bypass surgery, congestive heart failure or stroke. If the patients had an abnormal CDUS finding, their AVF stenosis was confirmed with the gold standard method, digital subtraction angiography (DSA). DSA examinations were performed by two experienced interventional radiologists using a digital subtraction system (Philips Allura Xper FD 20 Release 2, Best, The Netherlands). The degree of stenosis was classified into four groups: 50–74%, 75–89%, 90–99% and 100%.25 Complete blood count and biochemical tests, such as serum creatinine, urea, aspartate aminotransferase, alanine aminotransferase, calcium (Ca), albumin, uric acid, C-reactive protein (CRP), total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride, Ca and phosphorus, measured six months ago were meticulously recorded. This study was approved by local ethics committee (IRB number: 99950669/166), and informed consent was obtained from all participants prior to enrolment. Continuous data were presented as median (interquartile range) or mean ± standard deviation. To test the distribution pattern, the Kolmogorov–Smirnov test was used. Categorical variables were summarized as percentages and compared with chi-square test. We classified patients into two groups. Group 1 has AVF stenosis and group 2 has patent (¼ no stenosis) AVF. Comparisons between groups were performed using the Mann–Whitney U test or unpaired Student’s t test. Spearman correlation coefficient was computed to examine the association between two continuous variables. We performed univariate logistic regression analyses to assess the association of clinical and laboratory markers with the binary presence of AVF stenosis (yes/no). We reduced the model using stepwise multivariate logistic regression analyses. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated. A p value50.05 was considered statistically significant. All analyses were performed using SPSS software, version 17.0 (SPSS Inc., Chicago, IL).
Results This study included 108 patients meeting the appropriate criteria. Forty-six patients applied for routine fistula check; 62 patients have clinical features of AVF stenosis (difficulties in cannulation, painful arm edema and prolonged bleeding time after cannulation or after removal of the dialysis needles). The ultrasonography of 108 patients revealed that 68 patients had abnormal ultrasound results (Table 1). Fistulography was performed in 68 patients. Stenosis 50% was found in four patients. Furthermore, there was stenosis 50% in 64 patients at DSA. A total of 44 patients—40 with normal ultrasonography results and four with stenosis 50% from fistulography—were considered as the control group. The patients were divided into two groups with AVF stenosis (group 1; n ¼ 64) and without AVF stenosis (group 2; n ¼ 44). The demographics of all patients included in the study are listed in Table 1. The mean age of the patients was 55.2 ± 18.8 (range 18–80) years and 51.5% of the patients were male, and the mean duration of hemodialysis was
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Ren Fail, 2014; 36(9): 1390–1394
Table 1. Baseline characteristics and laboratory parameters of study population.
Table 2. CDUS and fistulographic findings of AVF stenosis. Category
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Parameters Patient numbers Age, years Sex, male/female BMI SBP, mmHg DBP, mmHg Smoking, n (%) History of CVD, n (%) HD duration, months Albumin, g/dL Ca (corrected), mg/dL P, mg/dL Ca P product mg2/dL2 iPTH, pg/mL HDL-C, mg/dL Triglycerides, mg/dL LDL-C, mg/dL Hb, g/dL TSAT, % Ferritin, ng/mL CRP, mg/L Uric acid, mg/dL WBC NLR Weekly Epo dose, IU ACE or ARB, n (%) ß-Blockers, n (%) CCB, n (%) Alpha-blockers, n (%)
AVF stenosis 64 55.2 ± 18.8 33/31 28.47 ± 6.17 144.25 ± 14.28 94.38 ± 10.75 19 (29.6) 21 (32.8) 33.5 ± 12.8 3.76 ± 0.68 8.02 ± 0.64 6.29 ± 1.51 48.29 (16.22) 371.70 ± 301.04 31.8 ± 12.6 195.58 ± 89.41 102.69 ± 36.13 10.83 ± 1.97 28.99 (9.77) 542.43 ± 230.45 9.75 ± 11.97 7.29 ± 1.28 7650 ± 2100 3.47 ± 0.46 8468.8 ± 5234.9 40 (62.5) 19 (29.6) 22 (33.4) 7 (10.6)
AVF without stenosis
p Value
44 54.5 ± 11.9 0.932 23/21 0.881 28.29 ± 4.76 0.904 145.93 ± 13.85 0.641 95.19 ± 11.72 0.332 12 (27.3) 0.726 14 (31.8) 0.623 32.7 ± 11.9 0.765 3.73 ± 0.56 0.005 8.10 ± 0.55 0.422 6.13 ± 1.49 0.375 48.92 (15.61) 0.795 361.57 ± 327.48 0.815 51.5 ± 11.9 50.001 198.78 ± 96.436 0.865 99.86 ± 39.49 0.378 10.75 ± 1.82 0.848 27.82 (11.43) 0.382 539.15 ± 286.37 0.657 8.94 ± 12.3 0.502 7.38 ± 1.53 0.589 7820 ± 2215 0.713 2.27 ± 0.22 50.001 8470.6 ± 5360.5 0.999 28 (63.6) 0.897 14 (31.8) 0.578 15 (34.1) 0.659 5 (11.4) 0.731
Color Doppler ultrasonography (n ¼ 104) Luminal diameter reduction (n ¼ 104) A peak systolic velocity ratio (n ¼ 104) Peak systolic flow velocity (n ¼ 104) Fistulography with DSA (n ¼ 64) Degree of stenosis (n ¼ 64) Total occlusion Stenosis Number of lesions (n ¼ 64) Location of lesions (total lesions ¼ 70)
n (%)
50 %
67 (62)
550% 2:1
41 (38) 68 (62.9)
52:1 4400 cm/s
40 (37.1) 65 (60.1)
5400 cm/s
43 (69.9)
100% 90–99% 75–89% 50–74% One site Two sites 3 sites Native artery Arteriovenous anastomosis Juxtaanastomotic vein Venous outflow Distal outflow Central venous system
4 14 25 21 59 4 1 3
(6.25) (21.9) (39) (32.85) (92.2) (6.25) (1.55) (4.2)
19 (27.1) 33 (47.1) 10 ( 14.3) 5 (7.2) 0
Note: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; AVF, arteriovenous fistula; BMI, body mass index; Ca, calcium; CCB, calcium channel blockers; CRP, C-reactive protein; DBP, diastolic blood pressure; Epo, erythropoietin; Hb, hemoglobin; HDL-C, high-density lipoprotein cholesterol; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; NLR, neutrophil–lymphocyte ratio’ P, phosphate, SBP, systolic blood pressure; SD, standard deviation; TSAT, transferrin saturation; and WBC, white blood cell.
33.5 ± 12.8 months in group 1 (Table 2). There was no difference in age, gender, duration of hemodialysis, time of exposure to fistula and body mass index between groups 1 and 2. Furthermore, no difference was found between the groups in use of medication and CVDs (Table 2). In the biochemical assessment, HDL cholesterol (31.8 ± 12.6 mg/dL vs. 51.5 ± 11.9 mg/dL; p50.001) was lower in group 1, whereas mean NLR levels [3.47 ± 0.46 vs. 2.27 ± 0.22; p50.001] were higher compared to group 2 patients (Table 2). No difference was found between the groups in terms of other biochemical parameters. The correlation analysis showed that NLR level was increased as the severity of AVF stenosis increased (r ¼ 0.625, p5 0.01) (Figure 1). However, no relation was found between CRP and WBC—from the inflammatory indicators—and the severity of AVF stenosis (r ¼ 0.045, p ¼ 0.889; r ¼ 0.031, p ¼ 0.912). After the parameters, which might lead to AVF stenosis, were identified in univariate analysis, multivariate logistic regression analysis was performed. In multivariate model (Table 3), NLR was independent predictor of AVF stenosis in chronic hemodialysis patients (OR ¼ 4.734; 95% CI: 2.987– 7.321; p ¼ 0.001; p ¼ 0.001) together with presence of
Figure 1. NLR is associated with degree of AVF stenosis.
HDL530 mg/dL (OR ¼ 2.976; 95% CI: 1.654–4.125; p ¼ 0.034) (Table 3). We evaluated the usefulness of plasma NLR level as an AVF stenosis. The best cut-off value calculated from the receiver operating characteristic analysis was 2.70 for determination of AVF stenosis, AUC amount to 0.893 (0.829–0.956), sensitivity was 98.4% and specificity was 75% (Figure 2).
Discussion The primary result of this study is that the NLR level is increased in patients with AVF stenosis. NLR level is a strong and independent predictor for determining the presence of AVF stenosis. In addition, the HDL level was found low in
Relationship between late AVF stenosis and NLR
DOI: 10.3109/0886022X.2014.945183
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Table 3. Significant predictors of late AVF stenosis in univariable and multivariable logistic regression analyses. Univariate OR (95% CI)
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Age, year BMI, kg/m2 Smoker HD duration (months) Ca P product (mg2/dL2) Albumin (g/dL) HDL 530 (mg/L) LDL (mg/L) WBC (/mL) Hb (g/dL) CRP (mg/L) iPTH, pg/mL TSAT (%) NLR
0.965 0.832 0.997 2.045 0.940 0.988 3.789 1.116 1.294 0.915 1.296 1.170 1.072 6.611
(0.945–1.023) (0.761–1.109) (0.965–1.056) (1.456–2.698) (0.894–0.997) (0.968–1.035) (2.078–4.135) (0.956–1.245) (1.023–1.397) (0.903–0.975) (1.190–1.305) (1.056–1.234) (1.008–1.121) (3.567–8.912)
Figure 2. ROC analysis showed that best cut-off of NLR is 2.70 for prediction of late AVF stenosis.
patients with AVF stenosis, and a HDL level530 mg/dL is an independent predictor of AVF stenosis. However, no difference was found between the HDL level and the severity of AVF stenosis. The potential contribution of hemodynamic factors and coagulation system to the development of AVF stenosis is well-known.4 In experimental rat—monocyte chemotactic protein 1 (MCP1)—knock-out rats—models, AVF patency was shown to be increased.5 It was shown that it caused AVF dysfunction when MCP-1 expression was increased after producing AVF, whereas the development of neointimal hyperplasia was reduced when MCP-1 was inhibited.5,6 The clinical trials showed that IL-6, pentraxin and complement system had roles in AVF dysfunction.7,8 However, RoyChaudhury et al. showed that there was a focal macrophage infiltration in the pig model of AVF stenosis.9 However, they could not reveal the relation between NLR, an inflammatory indicator, and AVF stenosis. In this study, we showed that the patients with increased levels of NLR had AVF stenosis, and the severity of stenosis was positively correlated with the NLR level. We also showed that NLR was the strong and
p Value 0.846 0.741 0.875 0.038 0.918 0.906 50.001 0.753 0.795 0.539 0.646 0.416 0.357 50.001
Multivariate OR (95% CI)
p Value
1.345 (0.978–2.145)
0.276
2.976 (1.654–4.125)
0.034
4.734 (2.987–7.321)
0.001
independent predictor of AVF stenosis. We revealed the significance of inflammation in the development of AVF stenosis one more time. An increased level of NLR reflects inflammation and its correlation with AVF stenosis is consistent with the results of other studies.5–9 Neointimal hyperplasia, the primary pathology of AVF stenosis, is histopathologically similar to atherosclerosis.26 The correlation of NLR with the coronary artery disease,19 stent restenosis20 and SVGD,21,22 in which cases the primary pathology is atherosclerosis, has already been presented. In addition to these, the most important two components in the physiopathology of SVGD are neointimal hyperplasia and atherosclerosis.25 AVF stenosis shows similarity with both atherosclerosis and SVGD. Therefore, the atherosclerosis mechanism may be another explanation for finding NLR correlated with AVF stenosis. In our study, the level of HDL was found decreased in the patients with AVF stenosis. However, HDL level530 mg/dL is an independent risk factor for AVF stenosis. A low level of HDL-C is one of main risk factors for CVD.27 Increase HDL levels are profoundly anti-atherogenic, anti-apoptotic, antiinflammatory, anti-oxidative, anti-aggregatory, anti-coagulant and pro-fibrinolytic.28 HDL also stimulates the synthesis of prostacyclin and activation of endothelial nitric oxide synthase.28 The decreased level of HDL may also be an important risk factor in the development of AVF stenosis. As HDL level decreases; atherosclerosis, inflammation, oxidative stress activity increases and nitric oxide level decreases.28 As a consequence, it contributes to the development of AVF stenosis due to neointimal hyperplasia. In conclusion, an increased level of NLR and a decreased level of HDL may be the new risk factors in the development of AVF stenosis. The correlation of AVF stenosis with the increased NLR and decreased HDL may be explained through the inflammation and atherosclerosis being the cause of the development of neointimal hyperplasia. For hemodialysis patients with increased level of NLR and decreased level of HDL, regular monitoring with regard to the development of stenosis if there is AVF.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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References 1. Vachharajani TJ. Diagnosis of arteriovenous fistula dysfunction. Semin Dial. 2012;25(4):445–450. 2. Hayashi R, Huang E, Nissenson AR. Vascular access for hemodialysis. Nat Clin Pract Nephrol. 2006;2(9):504–513. 3. Stolic R. Most important chronic complications of arteriovenous fistulas for hemodialysis. Med Princ Pract. 2013;22(3):220–228. 4. Roy-Chaudhury P, Sukhatme VP, Cheung AK. Hemodialysis vascular access dysfunction: A cellular and molecular viewpoint. J Am Soc Nephrol. 2006;17(4):1112–1127. 5. Juncos JP, Grande JP, Kang L, et al. MCP-1 contributes to arteriovenous fistula failure. J Am Soc Nephrol. 2011;22(1):43–48. 6. Schepers A, Eefting D, Bonta PI, et al. Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2006;26:2063–2069. 7. Marrone D, Pertosa G, Simone S, et al. Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients. Am J Kidney Dis. 2007; 49(5):664–673. 8. Castellano G, Di Vittorio A, Dalfino G, et al. Pentraxin 3 and complement cascade activation in the failure of arteriovenous fistula. Atherosclerosis. 2010;209(1):241–247. 9. Roy-Chaudhury P, Khan R, Campos B, et al. Pathogenetic role for early focal macrophage infiltration in a pig model of arteriovenous fistula (AVF) stenosis. J Vasc Access. 2014;15(1):25–28. 10. Shibutani M, Maeda K, Nagahara H, et al. A high preoperative neutrophil-to-lymphocyte ratio is associated with poor survival in patients with colorectal cancer. Anticancer Res. 2013; 33(8):3291–3294. 11. Ubukata H, Motohashi G, Tabuchi T, Nagata H, Konishi S. Evaluations of interferon-gamma/interleukin-4 ratio and neutrophil/ Lymphocyte ratio as prognostic indicators in gastric cancer patients. J Surg Oncol. 2010;102(7):742–747. 12. Noble F, Hopkins J, Curtis N, et al. The role of systemic inflammatory and nutritional blood-borne markers in predicting response to neoadjuvant chemotherapy and survival in oesophagogastric cancer. Med Oncol. 2013;30(3):596. 13. Garcea G, Ladwa N, Neal CP, Metcalfe MS, Dennison AR, Berry DP. Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with reduced disease-free survival following curative resection of pancreatic adenocarcinoma. World J Surg. 2011; 35(4):868–872. 14. Motomura T, Shirabe K, Mano Y, et al. Neutrophil–lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58(1):58–64.
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15. Gondo T, Nakashima J, Ohno Y, et al. Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy. Urology. 2012;79(5):1085–1091. 16. Cho H, Hur HW, Kim SW, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother. 2009;58(1):15–23. 17. Muhmmed Suliman MA, Bahnacy Juma AA, Ali Almadhani AA, Pathare AV, Alkindi SS, Uwe Werner F. Predictive value of neutrophil to lymphocyte ratio in outcomes of patients with acute coronary syndrome. Arch Med Res. 2010;41(8):618–622. 18. Park JJ, Jang HJ, Oh IY, et al. Prognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol. 2013;111(5):636–642. 19. Arbel Y, Finkelstein A, Halkin A, et al. Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography. Atherosclerosis. 2012;225(2):456–460. 20. Turak O, Ozcan F, Isleyen A, et al. Usefulness of the neutrophil-tolymphocyte ratio to predict bare-metal stent restenosis. Am J Cardiol. 2012;110(10):1405–1410. 21. Tasoglu I, Turak O, Nazli Y, et al. Preoperative neutrophillymphocyte ratio and saphenous vein graft patency after coronary artery bypass grafting. Clin Appl Thromb Hemost. 2013. [Epub ahead of print]. DOI: 10.1177/1076029613484086. 22. Dogan M, Akyel A, Cimen T, et al. Relationship between neutrophil-to-lymphocyte ratio and saphenous vein graft disease in patients with coronary bypass. Clin Appl Thromb Hemost. 2013. [Epub ahead of print]. DOI: 10.1177/1076029613488935. 23. Hutchison SJ, Holmes KC, eds. Arteriovenous fistulas. In: Principles of Vascular and Intravascular Ultrasound. Philadelphia: Saunders; 2012:82–96. 24. Clark TW, Hirsch DA, Jindal KJ, Veugelers PJ, LeBlanc J. Outcome and prognostic factors of restenosis after percutaneous treatment of native hemodialysis fistulas. J Vasc Interv Radiol. 2002;13:51–59. 25. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: Pathogenesis, predisposition, and prevention. Circulation. 1998;97(9):916–931. 26. Gagliardi GM, Rossi S, Condino F, et al. Malnutrition, infection and arteriovenous fistula failure: Is there a link? J Vasc Access. 2011;12(1):57–62. 27. Assmann G, Gotto Jr. AM HDL cholesterol and protective factors in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III8–III14. 28. Hafiane A, Genest J. HDL, atherosclerosis, and emerging therapies. Cholesterol. 2013;2013:891403. doi: 10.1155/2013/891403.
CLINICAL STUDY
Relationship between late arteriovenous fistula (AVF) stenosis and neutrophil–lymphocyte ratio (NLR) in chronic hemodialysis patients Hakki Yilmaz1, Alper Bozkurt2, Muzaffer Cakmak3, Huseyin Tugrul Celik4, Mukadder Ayse Bilgic1, Nuket Bavbek1, and Ali Akcay1
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1
Department of Internal Medicine, Section of Nephrology, School of Medicine, Turgut Ozal University, Ankara, Turkey, 2Department of Interventional Radiology, School of Medicine, Turgut Ozal University, Ankara, Turkey, 3Department of Internal Medicine, School of Medicine, Turgut Ozal University, Ankara, Turkey, and 4Department of Biochemistry, School of Medicine, Turgut Ozal University, Ankara, Turkey
Abstract
Keywords
Objectives: Primary cause of late arteriovenous fistula (AVF) dysfunction is venous stenosis as result of neointimal hyperplasia. The mechanism of AVF stenosis is not exactly understood. But inflammation is a contributing factor for development of AVF stenosis. Neutrophil– lymphocyte ratio (NLR) reflects systemic inflammation, and it was investigated in many diseases. The aim of this study was to investigate the relationship between NLR and AVF stenosis in chronic hemodialysis patients. Materials and methods: Of 593 patients applied to the department of interventional radiology between January 2011 and November 2012, a total of 108 patients meeting the appropriate criteria were included in this study. All patients were assessed with Color Doppler ultrasonography and then digital subtraction angiography was used for the patients with abnormal results. Sixty-four patients were classified as patients with AVF stenosis (group 1) and 44 patients without AVF stenosis (group 2). Routine biochemical and complete blood count values measured six months ago were recorded for all patients. Results: Mean NLR (3.47 ± 0.46 vs. 2.27 ± 0.22; p50.001) was higher in group 1 compared to group 2, whereas high-density lipoprotein (HDL; 31.8 ± 12.6 mg/dL vs. 51.5 ± 11.9 mg/dL; p50.001) was lower in group 1. NLR level was correlated with degree of AVF stenosis (r ¼ 0.625; p50.01). Receiver operating characteristic curve analysis showed that NLR (optimalcut-off ¼ 2.70) was a useful parameter in prediction of AVF stenosis (AUC ¼ 0.893, sensitivity ¼ 98.4% and specificity ¼ 75%; p50.001). NLR level and HDL530 mg/dL in logistic regression analysis are independent predictors of AVF stenosis. Conclusions: For hemodialysis patients with increased level of NLR and decreased level of HDL, regular monitoring with regard to the development of AVF stenosis may be beneficial. Our study suggests that the mechanism of AVF stenosis might have similarities to that of atherosclerosis.
AVF stenosis, Color Doppler ultrasonography, digital subtraction angiography, inflammation, NLR
Introduction The primary vascular access of choice in hemodialysis patients is arteriovenous fistula (AVF).1 AVF has a lower risk of complication and also has a very low risk of infection compared to catheter.2,3 Two most common complication experienced during the chronic use of AVF are thrombosis and stenosis.2,3 As known, thrombosis generally occurs next to the stenotic site, and the treatment is more difficult in stenosis cases accompanied by thrombosis and also there is a decreased chance for success from the treatment.3 The main factor that can lead to the development of thrombosis is the presence of stenosis.3 In general, access stenosis is considered to be developed as a result of neointimal hyperplasia.2–4 Although the exact mechanisms of neointimal hyperplasia have not been
Address correspondence to Dr. Hakki Yilmaz, Alparslan Tu¨rkes Cad. No: 57, 06510 Emek/ANKARA, Turkey. Tel: + 90-0312-2035555; Fax: + 90-0312-2035029; E-mail: [email protected]
History Received 11 March 2014 Revised 24 June 2014 Accepted 10 July 2014 Published online 23 September 2014
understood yet, hemodynamic factors and coagulation system were shown to have contribution to the mechanism.4 Furthermore, inflammation was shown to play a role in the development of AVF stenosis in both experimental and clinical studies.5–9 Therefore, it is an obvious fact that inflammation makes a significant contribution to the development of AVF stenosis. Neutrophil–lymphocyte ratio (NLR) is an easy-to-calculate and cost-efficient indicator, which is widely used recently and shows the systemic inflammatory activity. Many studies showed that NLR has prognostic value in patients with a variety of solid organ malignancies including colorectal,10 gastric,11 esophageal,12 pancreatic,13 liver,14 bladder15 and gynecological cancers.16 NLR was a predictor of survival in patients with acute coronary syndrome.17,18 In addition, NLR was associated with coronary artery disease severity and prognosis in patients undergoing coronary angiography for various indications.19 Recently, Turak et al. revealed that NLR is a strong predictor of bare-metal stent restenosis.20 Two studies showed that
DOI: 10.3109/0886022X.2014.945183
preoperative NLR is associated with saphenous vein graft disease (SVGD) in patients undergoing coronary artery bypass grafting surgery.21,22 NLR is a strong inflammatory indicator and associated with both coronary atherosclerosis and restenosis. Given the undeniable role of inflammation in AVF stenosis as well as the histopathological similarity of AVF stenosis with atherosclerosis, the correlation of NLR with the AVF stenosis is an object of interest. The aim of this study is to investigate the association of NLR with AVF stenosis and the severity of stenosis in hemodialysis patients with AVF.
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Materials and methods A total of 593 patients with AVF access dysfunction and AVF access routine control between January 2011 and November 2012 who were referred to Interventional Radiology were included in this study. The patients (n ¼ 485) were excluded if they had multiple repetitive endovascular intervention or surgery, AVF stenosis was accompanied by one or more complications of AVF dysfunction (thrombosis, steal syndrome, aneurysm, pseudo-aneurysm and infection), a history of hematological malignancy, a known bleeding diathesis or coagulopathy or concomitant warfarin therapy and patent AVF at least six months. To identify the possible risk factors for AVF stenosis, variables including age; gender; body mass index; co-morbidities such as diabetes, hypertension, coronary arterial occlusive disease, stroke and peripheral arterial occlusive disease; age of AVF; side of the AVF; type of AVF; number of lesions; degree of stenosis; and residual stenosis were collected. Color Doppler ultrasonography (CDUS) studies were performed on a Doppler ultrasound device (Philips, HD15 Pure Wave Ultrasound System, Bothell, WA) with a 5 MHz linear probe (C5-1 Pure Wave transducer) by two blinded radiologists experienced in the use of Doppler US. At CDUS analysis, AVF flow volume, peak-systolic (PSV) and fistula diameter were measured. Fistula anastomosis area and calibration, flow velocities and lumens of vascular structures in the arterial and venous tree were analyzed. Visual narrowing (diameter narrowing greater than 50%) as assessed on grayscale imaging and an increased ratio of the PSV at the stenosis as compared to the PSV measured 2-cm upstream from the stenosis are to major features to characterize AVF stenosis.23 The diagnostic criteria vary in accordance with the location of the stenosis.23 Cases with a PSV ratio in the anastomosis region of three and above were regarded as significant (50% and above) anastomosis stenosis23. A draining vein and inflow artery stenosis are defined by visible narrowing and by a PSV ratio of greater than or equal to 2:1.23 In addition, peak systolic velocities rising above 400 cm/s were regarded as other assistant findings.23 The site of stenotic lesions were classified into six categories based upon location24: (1) native artery; (2) arteriovenous anastomosis; (3) juxtaanastomotic vein (initial 2 cm of fistula); (4) venous outflow 42 cm from anastomosis (cannulation zone); (5) distal outflow (defined as above elbow joint for radial cephalic fistulae and above mid-humerus for brachial fistulae); and (6) central venous system. All patients were assessed with CDUS.
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Cardiovascular disease (CVD) was defined as coronary artery disease, myocardial infarction, coronary angioplasty, coronary artery bypass surgery, congestive heart failure or stroke. If the patients had an abnormal CDUS finding, their AVF stenosis was confirmed with the gold standard method, digital subtraction angiography (DSA). DSA examinations were performed by two experienced interventional radiologists using a digital subtraction system (Philips Allura Xper FD 20 Release 2, Best, The Netherlands). The degree of stenosis was classified into four groups: 50–74%, 75–89%, 90–99% and 100%.25 Complete blood count and biochemical tests, such as serum creatinine, urea, aspartate aminotransferase, alanine aminotransferase, calcium (Ca), albumin, uric acid, C-reactive protein (CRP), total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride, Ca and phosphorus, measured six months ago were meticulously recorded. This study was approved by local ethics committee (IRB number: 99950669/166), and informed consent was obtained from all participants prior to enrolment. Continuous data were presented as median (interquartile range) or mean ± standard deviation. To test the distribution pattern, the Kolmogorov–Smirnov test was used. Categorical variables were summarized as percentages and compared with chi-square test. We classified patients into two groups. Group 1 has AVF stenosis and group 2 has patent (¼ no stenosis) AVF. Comparisons between groups were performed using the Mann–Whitney U test or unpaired Student’s t test. Spearman correlation coefficient was computed to examine the association between two continuous variables. We performed univariate logistic regression analyses to assess the association of clinical and laboratory markers with the binary presence of AVF stenosis (yes/no). We reduced the model using stepwise multivariate logistic regression analyses. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated. A p value50.05 was considered statistically significant. All analyses were performed using SPSS software, version 17.0 (SPSS Inc., Chicago, IL).
Results This study included 108 patients meeting the appropriate criteria. Forty-six patients applied for routine fistula check; 62 patients have clinical features of AVF stenosis (difficulties in cannulation, painful arm edema and prolonged bleeding time after cannulation or after removal of the dialysis needles). The ultrasonography of 108 patients revealed that 68 patients had abnormal ultrasound results (Table 1). Fistulography was performed in 68 patients. Stenosis 50% was found in four patients. Furthermore, there was stenosis 50% in 64 patients at DSA. A total of 44 patients—40 with normal ultrasonography results and four with stenosis 50% from fistulography—were considered as the control group. The patients were divided into two groups with AVF stenosis (group 1; n ¼ 64) and without AVF stenosis (group 2; n ¼ 44). The demographics of all patients included in the study are listed in Table 1. The mean age of the patients was 55.2 ± 18.8 (range 18–80) years and 51.5% of the patients were male, and the mean duration of hemodialysis was
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Table 1. Baseline characteristics and laboratory parameters of study population.
Table 2. CDUS and fistulographic findings of AVF stenosis. Category
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Parameters Patient numbers Age, years Sex, male/female BMI SBP, mmHg DBP, mmHg Smoking, n (%) History of CVD, n (%) HD duration, months Albumin, g/dL Ca (corrected), mg/dL P, mg/dL Ca P product mg2/dL2 iPTH, pg/mL HDL-C, mg/dL Triglycerides, mg/dL LDL-C, mg/dL Hb, g/dL TSAT, % Ferritin, ng/mL CRP, mg/L Uric acid, mg/dL WBC NLR Weekly Epo dose, IU ACE or ARB, n (%) ß-Blockers, n (%) CCB, n (%) Alpha-blockers, n (%)
AVF stenosis 64 55.2 ± 18.8 33/31 28.47 ± 6.17 144.25 ± 14.28 94.38 ± 10.75 19 (29.6) 21 (32.8) 33.5 ± 12.8 3.76 ± 0.68 8.02 ± 0.64 6.29 ± 1.51 48.29 (16.22) 371.70 ± 301.04 31.8 ± 12.6 195.58 ± 89.41 102.69 ± 36.13 10.83 ± 1.97 28.99 (9.77) 542.43 ± 230.45 9.75 ± 11.97 7.29 ± 1.28 7650 ± 2100 3.47 ± 0.46 8468.8 ± 5234.9 40 (62.5) 19 (29.6) 22 (33.4) 7 (10.6)
AVF without stenosis
p Value
44 54.5 ± 11.9 0.932 23/21 0.881 28.29 ± 4.76 0.904 145.93 ± 13.85 0.641 95.19 ± 11.72 0.332 12 (27.3) 0.726 14 (31.8) 0.623 32.7 ± 11.9 0.765 3.73 ± 0.56 0.005 8.10 ± 0.55 0.422 6.13 ± 1.49 0.375 48.92 (15.61) 0.795 361.57 ± 327.48 0.815 51.5 ± 11.9 50.001 198.78 ± 96.436 0.865 99.86 ± 39.49 0.378 10.75 ± 1.82 0.848 27.82 (11.43) 0.382 539.15 ± 286.37 0.657 8.94 ± 12.3 0.502 7.38 ± 1.53 0.589 7820 ± 2215 0.713 2.27 ± 0.22 50.001 8470.6 ± 5360.5 0.999 28 (63.6) 0.897 14 (31.8) 0.578 15 (34.1) 0.659 5 (11.4) 0.731
Color Doppler ultrasonography (n ¼ 104) Luminal diameter reduction (n ¼ 104) A peak systolic velocity ratio (n ¼ 104) Peak systolic flow velocity (n ¼ 104) Fistulography with DSA (n ¼ 64) Degree of stenosis (n ¼ 64) Total occlusion Stenosis Number of lesions (n ¼ 64) Location of lesions (total lesions ¼ 70)
n (%)
50 %
67 (62)
550% 2:1
41 (38) 68 (62.9)
52:1 4400 cm/s
40 (37.1) 65 (60.1)
5400 cm/s
43 (69.9)
100% 90–99% 75–89% 50–74% One site Two sites 3 sites Native artery Arteriovenous anastomosis Juxtaanastomotic vein Venous outflow Distal outflow Central venous system
4 14 25 21 59 4 1 3
(6.25) (21.9) (39) (32.85) (92.2) (6.25) (1.55) (4.2)
19 (27.1) 33 (47.1) 10 ( 14.3) 5 (7.2) 0
Note: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; AVF, arteriovenous fistula; BMI, body mass index; Ca, calcium; CCB, calcium channel blockers; CRP, C-reactive protein; DBP, diastolic blood pressure; Epo, erythropoietin; Hb, hemoglobin; HDL-C, high-density lipoprotein cholesterol; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; NLR, neutrophil–lymphocyte ratio’ P, phosphate, SBP, systolic blood pressure; SD, standard deviation; TSAT, transferrin saturation; and WBC, white blood cell.
33.5 ± 12.8 months in group 1 (Table 2). There was no difference in age, gender, duration of hemodialysis, time of exposure to fistula and body mass index between groups 1 and 2. Furthermore, no difference was found between the groups in use of medication and CVDs (Table 2). In the biochemical assessment, HDL cholesterol (31.8 ± 12.6 mg/dL vs. 51.5 ± 11.9 mg/dL; p50.001) was lower in group 1, whereas mean NLR levels [3.47 ± 0.46 vs. 2.27 ± 0.22; p50.001] were higher compared to group 2 patients (Table 2). No difference was found between the groups in terms of other biochemical parameters. The correlation analysis showed that NLR level was increased as the severity of AVF stenosis increased (r ¼ 0.625, p5 0.01) (Figure 1). However, no relation was found between CRP and WBC—from the inflammatory indicators—and the severity of AVF stenosis (r ¼ 0.045, p ¼ 0.889; r ¼ 0.031, p ¼ 0.912). After the parameters, which might lead to AVF stenosis, were identified in univariate analysis, multivariate logistic regression analysis was performed. In multivariate model (Table 3), NLR was independent predictor of AVF stenosis in chronic hemodialysis patients (OR ¼ 4.734; 95% CI: 2.987– 7.321; p ¼ 0.001; p ¼ 0.001) together with presence of
Figure 1. NLR is associated with degree of AVF stenosis.
HDL530 mg/dL (OR ¼ 2.976; 95% CI: 1.654–4.125; p ¼ 0.034) (Table 3). We evaluated the usefulness of plasma NLR level as an AVF stenosis. The best cut-off value calculated from the receiver operating characteristic analysis was 2.70 for determination of AVF stenosis, AUC amount to 0.893 (0.829–0.956), sensitivity was 98.4% and specificity was 75% (Figure 2).
Discussion The primary result of this study is that the NLR level is increased in patients with AVF stenosis. NLR level is a strong and independent predictor for determining the presence of AVF stenosis. In addition, the HDL level was found low in
Relationship between late AVF stenosis and NLR
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Table 3. Significant predictors of late AVF stenosis in univariable and multivariable logistic regression analyses. Univariate OR (95% CI)
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Age, year BMI, kg/m2 Smoker HD duration (months) Ca P product (mg2/dL2) Albumin (g/dL) HDL 530 (mg/L) LDL (mg/L) WBC (/mL) Hb (g/dL) CRP (mg/L) iPTH, pg/mL TSAT (%) NLR
0.965 0.832 0.997 2.045 0.940 0.988 3.789 1.116 1.294 0.915 1.296 1.170 1.072 6.611
(0.945–1.023) (0.761–1.109) (0.965–1.056) (1.456–2.698) (0.894–0.997) (0.968–1.035) (2.078–4.135) (0.956–1.245) (1.023–1.397) (0.903–0.975) (1.190–1.305) (1.056–1.234) (1.008–1.121) (3.567–8.912)
Figure 2. ROC analysis showed that best cut-off of NLR is 2.70 for prediction of late AVF stenosis.
patients with AVF stenosis, and a HDL level530 mg/dL is an independent predictor of AVF stenosis. However, no difference was found between the HDL level and the severity of AVF stenosis. The potential contribution of hemodynamic factors and coagulation system to the development of AVF stenosis is well-known.4 In experimental rat—monocyte chemotactic protein 1 (MCP1)—knock-out rats—models, AVF patency was shown to be increased.5 It was shown that it caused AVF dysfunction when MCP-1 expression was increased after producing AVF, whereas the development of neointimal hyperplasia was reduced when MCP-1 was inhibited.5,6 The clinical trials showed that IL-6, pentraxin and complement system had roles in AVF dysfunction.7,8 However, RoyChaudhury et al. showed that there was a focal macrophage infiltration in the pig model of AVF stenosis.9 However, they could not reveal the relation between NLR, an inflammatory indicator, and AVF stenosis. In this study, we showed that the patients with increased levels of NLR had AVF stenosis, and the severity of stenosis was positively correlated with the NLR level. We also showed that NLR was the strong and
p Value 0.846 0.741 0.875 0.038 0.918 0.906 50.001 0.753 0.795 0.539 0.646 0.416 0.357 50.001
Multivariate OR (95% CI)
p Value
1.345 (0.978–2.145)
0.276
2.976 (1.654–4.125)
0.034
4.734 (2.987–7.321)
0.001
independent predictor of AVF stenosis. We revealed the significance of inflammation in the development of AVF stenosis one more time. An increased level of NLR reflects inflammation and its correlation with AVF stenosis is consistent with the results of other studies.5–9 Neointimal hyperplasia, the primary pathology of AVF stenosis, is histopathologically similar to atherosclerosis.26 The correlation of NLR with the coronary artery disease,19 stent restenosis20 and SVGD,21,22 in which cases the primary pathology is atherosclerosis, has already been presented. In addition to these, the most important two components in the physiopathology of SVGD are neointimal hyperplasia and atherosclerosis.25 AVF stenosis shows similarity with both atherosclerosis and SVGD. Therefore, the atherosclerosis mechanism may be another explanation for finding NLR correlated with AVF stenosis. In our study, the level of HDL was found decreased in the patients with AVF stenosis. However, HDL level530 mg/dL is an independent risk factor for AVF stenosis. A low level of HDL-C is one of main risk factors for CVD.27 Increase HDL levels are profoundly anti-atherogenic, anti-apoptotic, antiinflammatory, anti-oxidative, anti-aggregatory, anti-coagulant and pro-fibrinolytic.28 HDL also stimulates the synthesis of prostacyclin and activation of endothelial nitric oxide synthase.28 The decreased level of HDL may also be an important risk factor in the development of AVF stenosis. As HDL level decreases; atherosclerosis, inflammation, oxidative stress activity increases and nitric oxide level decreases.28 As a consequence, it contributes to the development of AVF stenosis due to neointimal hyperplasia. In conclusion, an increased level of NLR and a decreased level of HDL may be the new risk factors in the development of AVF stenosis. The correlation of AVF stenosis with the increased NLR and decreased HDL may be explained through the inflammation and atherosclerosis being the cause of the development of neointimal hyperplasia. For hemodialysis patients with increased level of NLR and decreased level of HDL, regular monitoring with regard to the development of stenosis if there is AVF.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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