Predictive value of lymphocyte-to-monocyte ratio in patients with contrast-induced nephropathy after percutaneous coronary intervention for acute coronary syndrome

INTRODUCTION

Contrast-induced nephropathy (CIN) is characterized by the development of acute renal impairment following contrast medium exposure during cardiovascular procedures such as coronary angiography, percutaneous coronary intervention (PCI), or transcatheter valve interventions.^{[1, 2]} The incidence changes between 5% and 25% after cardiovascular interventions in several studies.^{[3, 4]} It has been demonstrated that CIN is associated with worse clinical outcomes and prognosis in these patients.^{[5, 6]} The patients with acute coronary syndrome (ACS) tend to develop higher rates of CIN than elective patients.^{[3, 4]} CIN can be observed nearly in half of patients with diabetes mellitus or chronic kidney disease (CKD). Because of the increased incidence of CIN after urgent percutaneous coronary intervention (PCI), easily accessible markers might be useful for detection of the patients who might develop CIN.^[6] Early identification of CIN affects its progression and clinical outcomes.^[4]

Various studies have showed that systemic inflammatory response severity associated with poor prognosis in cardiovascular diseases could be measured from peripheral blood-based parameters.^{[7, 8]} Lymphocytes and monocytes are the two important cells included in inflammatory response and immune reaction. The lymphocyte-to-monocyte ratio (LMR) is recently developed inflammatory marker and was associated with various cardiovascular diseases.^{[7,9,10,11,12]} Although underlying pathophysiology of CIN has not been fully understood, it has been found that inflammation plays a central role in acute renal injury and CIN.^{[13, 14]} In this study, we aim to investigate the role of admission LMR to predict CIN development in patients with acute coronary syndrome who underwent primary PCI.

PATIENTS AND METHODS

RESULTS

A total of 873 patients were enrolled after applying inclusion-exclusion criteria in this study, and there were 95 (10.9%) patients in the with-CIN group, and 778 (89.1%) patients in the without-CIN group. Baseline clinical characteristics of study patients with and without CIN are summarized in Table 1. The mean age of with-CIN group (66.2 ± 9.3; 66.3% male) was higher than that of the without-CIN group (58.7 ± 11.6; 72.8% male), and the difference was statistically significant (p < 0.001). There was no statistical difference between with-CIN group and without-CIN group in terms of gender, blood pressure, BMI, and heart rate on admission. The patients in the with-CIN group had significantly a higher prevalence of diabetes mellitus, hypertension, previous MI, previous CABG, and lower LVEF than those in the without-CIN group. No significant differences in the frequency of smoking, hyperlipidemia, previous PCI, and type of rhythm on admission were observed between the groups. Additionally, there was no difference in terms of use of statin and ACEi or ARB therapy on hospital admission between the groups.

Laboratory findings on admission of study patients in with- and without-CIN group are shown in Table 2. In the with-CIN group, basal creatinine (1.47 ± 0.94 vs. 1.06 ± 0.71, P < 0.001) and serum glucose level (162.9 ± 98.3 vs. 127.3 ± 66.3, P = 0.004) were higher, whereas eGFR (56.1 ± 27.6 vs. 81.7 ± 27.4, P < 0.001), hemoglobin (12.48 ± 2.12 vs. 13.58 ± 1.88, P < 0.001), total cholesterol (170.9 ± 44.5 vs. 184.4 ± 41.2, P < 0.001), and HDL cholesterol (36.4 ± 10.1 vs. 38.2 ± 8.9, p = 0.012) were lower. Postprocedural creatinine level at 48–72 hours was significantly higher in the patients with CIN than those without CIN (2.64 ± 1.23 vs. 1.08 ± 0.73, P < 0.001). No significant differences in the monocyte, lymphocyte, and platelet count were observed between the groups. The neutrophil count [0.64 (0.44–0.95) vs. 0.61 (0.44–0.80), P = 0.030] and mean platelet volume [9.4 (8.4–10.5) vs. 8.7 (7.7–9.9), P < 0.001)] were significantly higher in the with-CIN group than in the without-CIN group. NLR was nearly significantly higher in the with-CIN group than in the without-CIN group [3.99 (2.88–7.52) vs. 3.79 (2.24–6.06), P = 0.055]. However, LMR was significantly lower in the with-CIN group than in the without-CIN group [2.42 (1.67–3.49) vs. 3.25 (2.40–4.99), P < 0.001, respectively].

The angiographic and interventional characteristics of the study patients with and without CIN are presented in Table 3. There was no difference in term of type of ACS between the with-CIN group and without-CIN group. There was no difference in terms of FMC to wire time (minutes) in STEMI patients with CIN and without CIN (60.8 ± 29.5 vs. 55.9 ± 24.6, P = 0.436). FMC to wire time (hours) was higher in NSTE-ACS patients with CIN than those without CIN, and it was statistically nearly significant (12.9 ± 5.9 vs. 14.6 ± 4.4, P = 0.056). Total amount of contrast media (171.6 ± 36.7 vs. 161.4 ± 31.9, P = 0.118), the frequency of multivessel disease [48 (50.5%) vs. 318 (40.9%), P = 0.072], and the use of tirofiban during PCI [20 (21.1%) vs. 149 (19.2%), P = 0.658] were higher in the with-CIN group, but these differences were not statistically significant. The ratio of culprit vessel of ACS was similar between the two groups. In the with-CIN group, the use of ACEi or ARB therapy during hospitalization [66 (69.5%) vs. 662 (85.1%), P < 0.001] was lower, whereas the use of diuretic therapy [17 (17.9%) vs. 61 (7.8%), P = 0.001] was higher compared with the without-CIN group.

Univariate and multivariate logistic regression analysis model of predictors for the postprocedural CIN in study population is presented in Table 4. In univariate analysis, age, previous MI, hypertension, diabetes mellitus, LVEF, admission serum glucose, hemoglobin, eGFR, and LMR were found to be associated with CIN. In the multivariate analysis, eGFR (P < 0.001, odds ratio [OR] 0.978, 95% CI 0.968–0.988), serum glucose on admission (P = 0.030, [OR] 1.004, 95% CI 1.000–1.007), and LMR (P = 0.012, [OR] 0.850, 95% CI 0.749–0.965) were found to be independent predictors of CIN in the study patients (Table 4). The optimal cutoff point of LMR for CIN prediction was found to be 2.52 in the ROC curve analysis (AUC = 0.638, 95% CI 0.605–0.670, P < 0.001). The LMR <2.52 predicted CIN development with sensitivity of 66.3% and specificity of 55.8% (Figure 1).

Figure 1

The receiver-operating characteristic (ROC) analysis for the lymphocyte-to-monocyte ratio in predicting contrast-induced nephropathy in patients with acute coronary syndrome.

DISCUSSION

This study showed that a lower LMR was an independent predictor of CIN in patients with ACS who underwent PCI. In addition, eGFR and admission glucose level were also related with the development of CIN. To the best of our knowledge, this study is the first to show the relationship between LMR and development of CIN in patients with ACS. The present study showed that preprocedural LMR <2.52 predicted CIN, although its sensitivity and specificity are relatively low (66.3% and 55.8%, respectively).

CIN is an important issue, despite a successful coronary intervention it might be the cause of morbidity and mortality. It affects short- and long-term prognosis of the patients with ACS regardless of whether revascularization was successful.^[18] Its incidence ranges from 2% to 50% according to the risk level of investigated population.^{[19, 20]} The uses of high contrast medium volume, heart failure, age, diabetes, previous renal disease, and hypovolemia are the established risk factors for the development of CIN.^{[21, 22]} The underlying mechanism of CIN was not fully understood, but decreased renal blood flow, medullary hypoxia, inflammation, endothelial dysfunction, and direct tubular injury by contrast media might be included in pathogenesis.^{[23, 24]} Many factors are involved in pathogenesis of CIN, and the contrast media is found to be in the center of the process.^[25] Inflammatory reaction and aggravated prothrombotic status occur in the development of CIN, and mediators reflecting these reactions could be a marker of CIN.^[2] Significant relationship has been found between inflammation and acute renal injury.^{[26, 27]}

White blood cell count and subtypes are known as inflammatory markers in cardiovascular diseases, and they are easily obtained with complete blood count.^[28] Neutrophils, monocytes, and lymphocytes are the main cells of systemic inflammatory reactions in the body. Decreased lymphocyte count and increased monocyte count are associated with cardiovascular prognosis.^{[10, 29, 30]} The PLR and NLR were extensively studied in various studies.^{[31, 32]} The NLR has been described widely as a predictor of long-term prognosis, mortality, and infarct size in acute coronary syndrome.^[33] It was also introduced as a potential predictor of CIN development in ACS patients who underwent primary PCI.^[34] Recently, the LMR has been investigated as a new hematological marker which binds two independent cells of inflammation. Firstly, it has been showed that LMR is associated with prognosis in various cancers.^{[35, 36]} LMR is an emerging inflammatory marker, and high monocyte levels and low lymphocyte levels were related with coronary atherosclerosis.^[7] Murat et al. also reported that the low level of LMR is associated with bare metal stenosis in patients with stable coronary artery disease.^[37]

Lymphocytes are important mediators of immune system, and lymphopenia is considered a surrogate marker of the immune dysregulation.^[38] Blood monocytes are penetrated into the vascular intima and subintima, differentiate into macrophages in response to several locally produced cytokines, and initiate the inflammatory process. In this context, LMR is considered an indicator of systemic inflammation. The decreased LMR is not directly a component of CIN and reflects an increased inflammatory status, which leads to the development of CIN.^[39] LMR could be easily obtained from peripheral blood and may be used to predict CIN in patients who underwent urgent coronary angiography. Usage of this marker allows monitoring patients more closely and paying more attention to give more effort for CIN prevention. On the other hand, NLR was not found to be an independent predictor of CIN in the present study. But, it should be remembered that the NLR was nearly significantly higher in the with-CIN group than in the without-CIN group. In fact, if the number of study patients was slightly higher, NLR could be a predictor of CIN.

In addition to LMR, we found that admission glucose levels and eGFR were also independent predictors of CIN. As expected, chronic kidney disease is the most important intrinsic predisposing factor for CIN. The risk is proportionally increasing every impairment of GFR, and in patients with GFR of 10–15 mL/min, possibility to develop CIN may exceed 50%.^[21] Diabetes is also a well-known important risk factor to develop CIN.^[40] In this study, diabetes mellitus was not an independent factor; however, admission glucose level was an independent predictor of CIN. Parallel to our study, Baydar et al. reported that the presence of acute hyperglycemia in NSTE-ACS patients undergoing primary PCI was associated with a significant increase in the incidence of CIN.^[41] They also showed that hyperglycemia was associated with increased CIN risk and associated with in-hospital mortality and morbidity.^[41] Higher admission glucose level may indicate both worse regulated diabetes and a higher inflammatory stress response via noninsulin mechanisms. These may make admission glucose level more valuable instead of diabetes in the context of CIN in patients with ACS.

In conclusion, we found that LMR is an independent predictor of CIN in patients with ACS who underwent PCI. Our results suggest that LMR may be used as a simple biomarker in the identification of patients with increased risk of CIN.

LIMITATIONS

This study is an observational, retrospective, and single-center study. We did not measure LMR variation during the clinical follow-up, and other inflammatory markers like C-reactive protein were not measured in the present study. Repeated measurement of serum creatinine levels was not made after 72 hours; hence, we may have missed some patients with CIN. Also, the sensitivity and the specificity of predicted LMR value (<2.52) were relatively low. Therefore, our results should be confirmed with large prospective randomized studies.

CONCLUSION

Inflammation is an important factor in the development of CIN. Decreased LMR values may represent a pro-oxidant and pro-inflammatory effect on CIN in patients with ACS undergoing PCI. Thus, the LMR value <2.52 predicted the development of CIN in our study with a relatively low sensitivity and specificity. In this context, LMR may be used as a simple biomarker for predicting the CIN in patients with ACS who underwent PCI.