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Association of plasma neutrophil gelatinase-associated lipocalin and thoracic aorta calcification in maintenance hemodialysis patients with and without diabetes

Abstract

Background

Neutrophil gelatinase-associated lipocalin (NGAL) is not only a bone-derived factor involved in metabolism, but also a biomarker of kidney disease and cardiovascular pathophysiology. We conducted this cross-sectional observational study to explore relationships between plasma NGAL and thoracic aorta calcification (TAC) in maintenance hemodialysis (MHD) patients with and without diabetes.

Methods

Plasma NGAL was measured by ELISA, TAC was evaluated via computed tomography scan using a 3D quantification method or chest radiography aortic arch calcification score. Spearman correlation, Logistic regression and Partial correlation analysis were used to describe the correlations between NGAL and TAC.

Results

Plasma NGAL levels were lower in MHD patients with diabetes compared to those without diabetes (49.33(42.37, 55.48) vs 56.78(44.37, 674.13) ng/mL, P = 0.026). In MHD patients without diabetes, lg (NGAL) was positively correlated with ARC value(R = 0.612, P = 0.003) analyzed by Spearman correlation; for partial correlation analysis, lg (NGAL) was positively correlated with ARC value, after adjusting for age and sex (R = 0.550, P = 0.015), adjusting for age, sex and CHD (R = 0.565, P = 0.015), adjusting for age, sex, CHD and Alb (R = 0.536, P = 0.027), or adjusting for age, sex, CHD, Alb, and dialyzer membrane (polysulfone) (R = 0.590, P = 0.016); however, when adjusting for age, sex, CHD, Alb and Ca, the correlation between lg (NGAL) and ARC value disappeared. Positive correlation were found between NGAL and Ca (R = 0.644, P < 0.001), Ca and ACR (R = 0.534, P = 0.013) in Spearman coefficient analysis.

Conclusion

There were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification, in non-diabetic MHD.

Peer Review reports

Background

NGAL, also known as 24p3 or lipocalin2, is a 25-kDa secretory protein, which has been found to be involved in numerous functions such as bacteriostasis, iron trafficking, metabolic regulation, chemotaxis, differentiation, proliferation and so on [1,2,3,4]. Under basal conditions, NGAL is mainly expressed by osteoblasts and has been identified as a bone-derived hormone involved in appetite control and metabolism [5]. In pathological states, the expression of NGAL can be induced in many other cells and tissues [6, 7], including neutrophil granules [8], macrophages [9], dendritic cells [10], adipocytes [6, 11], cardiomyocytes [12], smooth muscle cells [7], neurons [13], liver [14] and so on. Evidence from both mouse and human studies demonstrates that NGAL is highly expressed in damaged kidney tubule cells, and it is widely accepted as one of the optimal biomarkers for kidney injury [15,16,17]. Moreover, NGAL is also a biomarker for cardiovascular disease [18], such as heart failure, coronary artery disease (CAD), abdominal aortic aneurysm (AAA). Our previous study [19] has demonstrated that “plasma NGAL is positively associated with parameters of CKD-MBD such as calcium (Ca), alkaline phosphatase (ALP) in maintenance hemodialysis patients (MHD)”. However, few data are available on the possible relationship between NGAL and vascular calcification, which is a common and intractable character of CKD-MBD; so we conducted this study to explore the association between plasma NGAL and thoracic aorta calcification in MHD patients. Considering that lots of studies have suggested that NGAL is closely related to diabetes and insulin resistance [18], patients were divided to 2 groups according to with or without diabetes for subgroup analysis.

Methods

Study population and data source

Stable adult MHD patients with available plasma samples and chest radiography or computed tomography (CT) in our center from July 2019 to December 2020 were included in the cross-sectional observational study. Inclusion criteria were age ≥ 18 years and underwent MHD for at least 3 months; exclusion criteria were Kt/V < 1.2, hospitalization within 3 months before enrollment, cancer, active inflammation, or high serum C-reactive protein. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University, and all subjects gave their informed consent.

Demographic and clinical characteristics were collected from medical records as we have described before [19]. In detail, demographic factors (age, sex, vintage); smoking, residual urine volume, blood pressure, comorbid coronary heart disease (CHD) or not,comorbid diabetes or not; serum Ca, phosphate (P), iPTH, ALP, potassium(K), carbonate ion (HCO3-), urea nitrogen (BUN), creatinine (Cr), albumin (Alb), low density lipoprotein (LDL), triglyceride (TG) and ferritin (SF); blood hemoglobin (Hb), white blood cells (WBC) and platelet (PLT). Prescription drugs for CKD-MBD and arteriosclerosis were also collected, including calcium free phosphorus binders (sevelamer or lanthanum carbonate), calciums, active vitamin D, paricalcitol and statins.

Detection of plasma NGAL and klotho

Blood samples were collected and detected as previously described [19]. Blood samples were drawn from the dialysis pipeline immediately after initiation of single hemodialysis treatment. The plasma were multiple aliquoted after centrifugation and stored at − 80 °C until use. The concentrations of NGAL and Klotho were measured by ELISA Kit (Sandwich-ELISA Systems, Elabscience, China) with intra-assay and inter-assay CVs of less than 5 and 8%, respectively.

Assessment of thoracic aorta calcification

Thoracic aorta calcification (TAC) was evaluated via chest computed tomography (CT) or routine chest radiography [20,21,22]. Thoracic aorta calcium was estimated by CT in mediastinal window with slice is 1.25 mm: calcification volume was quantified by extracting the aorta calcium with density ≥ 130 HU from the volume-rendered image under the assistance of semi-automatic software; thoracic aorta was divided into 4 sites, aortic root calcium (ARC), ascending aorta calcium (ATAC), aortic arch calcium (AAC), descending thoracic aorta calcium (DTAC) and total calcium (TC) were all calculated. AAC by routine chest radiography: the circumferences of aortic arch was divided into 16 sites, the number of sectors with calcification was counted and divided by 100 to express the results as a percentage.

Statistical analyses

Categorical data are presented as frequencies and percentages. Continuous variables are expressed as mean ± standard deviation (SD) for normally distributed variables and as median (interquartile range [IQR]) for variables with skewed distribution. Patients were subsequently divided into 2 groups according to comorbid diabetes or not for subgroup analysis. Differences between patients with and without diabetes were assessed using the t test, Mann–Whitney U test or Chi-square analysis, as appropriate. Spearman correlation coefficients, Logistic regression analyses and Partial correlation analysis were used to describe the correlations between NGAL and TAC. All statistical tests were two-sided, a P-value of less than 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS 20.0 (SPSS, Chicago, IL).

Results

Demographic, clinical characteristics, NGAL and TAC in all MHD patients

A total of 62 stable adult MHD patients were finally included in the cross-sectional observational study (in Table 1). All patients received the same dialysis modality, that is three sessions per week, for 4 h per session. The dialysate calcium concentration = 1.25 mmol/L for patients with adjusted serum calcium> 2.5 mmol/L or confirmed ectopic calcification, and dialysate calcium concentration = 1.5 mmol/L for other patients. The average age was 58.10 ± 15.98 years; male to female ratio was 1:0.94; median vintage was 29.27(8.65, 78.02) months; 43.55% of patients comorbid diabetes, 30.6% comorbid CHD. The median concentration of NGAL was 52.02(43.11, 422.30) ng/mL. As shown in the Table 2, there were 43 patients with chest CT, the TAC incidences were: TC 81.4%, ARC 30.2%, ATAC 34.9%, AAC 81.4%, DTAC 74.4%; 24 patients with routine chest radiography, the AAC incidence was 75%; 49 cases with AAC estimated by CT or routine chest radiography, the AAC incidence was 79%. Table 3 shows the values of TAC of 43 patients with chest CT: TC 9.55(0.70, 23.65) mL, ARC 0(0, 0.46) mL, ATAC 0(0, 0.58) mL, AAC 3.65(0.49, 8.08) mL, DTAC5.38(0, 11.71) mL; AAC values of 24 patients with routine chest radiography was 21.88(1.56, 35.94)%.

Table 1 Characteristics of total MHD patients, MHD patients with and without diabetes
Table 2 Thoracic aorta calcification incidences of total MHD patients, MHD patients with and without diabetes
Table 3 Thoracic aorta calcification parameter values of total MHD patients, MHD patients with and without diabetes

Differences of demographic, clinical characteristics, NGAL and TAC between patients with and without diabetes

Characteristics of study participants are shown in Table 1. Compared with patients without diabetes, patients with diabetes were significantly older (65.33±13.17 vs 52.51±15.87 years, P = 0.001); and with shorter vintage (19.28(3.78, 52.50) vs 40.27(16.16, 98.00) months, P = 0.007), higher systolic blood pressure (SBP) (163.37 ± 17.68 vs 148.63 ± 22.24 mmHg, P = 0.005), lower diastolic blood pressure (DBP) (68.48 ± 11.92 vs 87.17 ± 14.32 mmHg, P < 0.001), lower plasma NGAL(49.33(42.37,55.48) vs 56.78(44.37,674.13) ng/mL, P = 0.026), lower Ca(2.21(2.12, 2.32) vs 2.35 (2.27, 2.51) mmol/L, P = 0.001), lower P (1.67(1.49, 1.91) vs 1.97(1.53, 2.53) mmol/L, P = 0.039), lower iPTH (165.00(79.53, 274.80) vs 745.60(162.30, 1775.00)pg/mL, P < 0.001), lower ALP(73.00(59.00, 91.00) vs 110.00(60.00, 353.00)U/L, P = 0.019), lower Cr(707.00(535.00, 752.00) vs 884.00(754.00, 1038.00) 38.00) P < 0.001), lower Alb(39.30(35.30, 42.10) vs 42.1(39.8, 44.60) g/L, P = 0.005), higher WBC(6.62(5.47, 7.98) vs5.11(4.23, 7.29) × 10^9/L, P = 0.025). In terms of the application of medicine, lesser proportion of patients with diabetes taking calcium (66.7% vs 88.6%, P = 0.037), sevelamer(3.7% vs 42.9%), active vitamin D(7.4% vs 45.7%, P = 0.001), while larger proportion of them taking statins(33.3% vs 2.9%, P = 0.002). All estimated TAC parameters incidences (Table 2) or values (Table 3) were higher in MHD patients with diabetes than those without diabetes; however, the differences were not statistically significant.

Correlation analysis between plasma NGAL and TAC

Univariable logistic regression analyses showed positive correlations between lg (NGAL) and ARC (Table 4, OR = 5.581, P = 0.028), no correlations were found between lg (NGAL) and other TAC parameters. Age, sex and positive factors calculated by univariable logistic regression analyses (supplemental Table 1) between ARC and all characters were used for multivariable models (Table 5); lg (NGAL) was positively correlated with ARC after adjusting for age and sex (OR = 13.335, P = 0.012), adjusting for CHD (OR = 18.675, P = 0.014), or adjusting for active vitamin D (OR = 4.988, P = 0.043); however, when adjusting for Ca or vintage, the correlation between lg (NGAL) and ARC disappeared.

Table 4 Univariable logistic regression analyses of lg (NGAL (ng/mL)) and thoracic aorta calcification in MHD patients (n = 62)
Table 5 Logistic regression analyses of lg (NGAL (ng/mL)) and aortic root calcium (ARC) in MHD patients (n = 43)

Spearman correlation analysis between lg (NGAL) and TAC parameter values are depicted in Table 6. In MHD patients without diabetes (n = 21), lg (NGAL) were positively correlated with ARC value (R = 0.612, P = 0.003); no other correlations were found in total group or subgroups. Spearman correlation analysis between ARC value and all demographic, clinical characters were further performed in without diabetes group (supplemental Table 2); and 4 potential confounders were found as follows, comorbid CHD (R = 0.481, P = 0.027), Ca (mmol/L)(R = 0.534, P = 0.013), Alb(g/L)(R = -0.539, P = 0.012), dalyzer membrane (polysulfone)(R = -0.458, P = 0.037). Age, sex and all confounders were employed in partial correlation analysis in patients without diabetes (Table 7). Lg (NGAL) was positively correlated with ARC value, after adjusting for age and sex(R = 0.550, P = 0.015), adjusting for age, sex and CHD(R = 0.565, P = 0.015), adjusting for age, sex, CHD and Alb(R = 0.536, P = 0.027), or adjusting for age, sex, CHD, Alb, and dialyzer membrane (polysulfone)(R = 0.590, P = 0.016); however, when adjusting for age, sex, CHD, Alb, and Ca, the correlation between lg (NGAL) and ARC value disappeared. Scatter diagrams and Spearman coefficient are shown in Fig. 1, positive correlation were found between NGAL and Ca(R = 0.644, P < 0.001), Ca and ARC(R = 0.534, P = 0.013), NGAL and ACR(R = 0.612, P = 0.003).

Table 6 Spearman coefficients between lg (NGAL (ng/mL)) and thoracic aorta calcification parameter values of total MHD patients, MHD patients with and without diabetes
Table 7 Partial coefficients between lg (NGAL (ng/mL)) and aortic root calcium (ARC) parameter values of MHD patients without diabetes (n = 21)
Fig. 1
figure 1

Scatter diagrams and Spearman coefficient between NGAL, Ca and ARC of MHD patients without diabetes (n = 21)

Discussion

Cardiovascular calcification is a common and refractory complication of MHD patients, and is closely related to the high cardiovascular morbidity and mortality [18, 23]. In addition to conventional risk factors such as diabetes, hypertension and lipid metabolism disorder; disturbance of mineral metabolism is also associated with cardiovascular calcification [24,25,26]. To assess thoracic aorta calcification through chest CT, we employed a 3D visualization and quantification method to divided thoracic aorta into 4 sites, ARC, ATAC, AAC, DTAC [22]. The final results showed that NGAL, a bone-derived factor involved in metabolism and a biomarker of kidney injury and cardiovascular pathophysiology, were positively correlated with serum Ca and ARC in MHD patients without diabetes. Previous studies have confirmed that ARC is associated with total coronary artery calcification and the number of coronary stenotic vessels in patients with an intermediate pretest probability of ischemic heart disease [27]. NGAL is also an independent factor for predicting major adverse cardiac events in familial hypercholesterolemia [28]. To our knowledge, this is the first study to find an association between NGAL and ARC in MHD patients; the result suggests that NGAL is an important link in the cross-talk between bone and vascular. Former observational studies have demonstrated that increased circulating NGAL levels are associated with the severity of coronary artery disease [29] and increased risk of future cardiovascular disease events [23, 30, 31]. Results from basic researches reveal the detrimental roles of NGAL in the development of cardiovascular pathophysiological process, such as atherosclerosis [18], abdominal aortic aneurysm [32] and endothelial dysfunction [33, 34].

In physiological condition, NGAL was once thought to be secreted mainly by adipose tissue; however recent study showed that it is “expressed by osteoblasts, at levels that are at least tenfold higher in osteoblasts than in white adipose tissue or other organs” [5]. In pathological conditions, NGAL is expressed by various injured cells and tissues. It is an excellent biomarker in acute kidney injure secreted by tubular epithelial cell. In MHD population, there is no difference in plasma NGAL in patients with or without kidneys, which suggest that kidney is not the main source of increased circulating NGAL [35]. In our former study [19], positive correlations between circulating NGAL and CKD-MBD parameters (serum ALP and Ca) were found in MHD patients; while a downward trend in plasma NGAL was observed after PTX + AT in MHD patients with severe SHPT. These results suggested that “bone maybe one of the main sources of increased NGAL in MHD patients”. In the present study, MHD patients with diabetes showed lower plasma NGAL level, the absent correlation between NGAL and ARC may due to impaired osteoblast function in diabetes [36,37,38]. It is confirmed that CKD patients with diabetes are more prone to present with low bone turnover states [39], the potential mechanisms probably lie in the suppression of parathyroid hormone secretion, osteoblast activity and bone turnover by hyperglycemia and insulin deficiency [40, 41].

Above all, the major finding of our study is that there were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification under MHD condition. However, this is a cross-sectional observational study. Small sample size and no follow-up observations of cardiovascular event or mortality are limitations of this study and also the direction of future research.

Conclusion

There were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification, in non-diabetic MHD.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

NGAL:

Neutrophil gelatinase-associated lipocalin

TAC:

Thoracic aorta calcification

MHD:

Maintenance hemodialysis

CAD:

Coronary artery disease

AAA:

Abdominal aortic aneurysm

Ca:

Calcium

P:

Phosphate

ALP:

Alkaline phosphatase

CT:

Computed tomography

CHD:

Coronary heart disease

K:

Potassium

HCO3-:

Carbonate ion

BUN:

Urea nitrogen

Cr:

Creatinine

Alb:

Albumin

LDL:

Low density lipoprotein

TG:

Triglyceride

SF:

Territin

Hb:

Hemoglobin

WBC:

White blood cells

PLT:

Platelet

ARC:

Aortic root calcium

ATAC:

Ascending aorta calcium

AAC:

Aortic arch calcium

DTAC:

Descending thoracic aorta calcium

TC:

Total calcium

SD:

Standard deviation

IQR:

Interquartile range

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

iPTH:

Intact Parathyroid hormone

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Acknowledgments

We would like to thank Dr. Fang Tang, at center for data science in health and medicine, the First Affiliated Hospital of Shandong First Medical University, Jinan, China, for their valuable inputs in data analysis.

Funding

National Natural Science Foundation of China (81970615 to Dongmei Xu) was responsible for the collection, management, and interpretation of data; National Natural Science Foundation of China (82004088 to Kai Wei) was responsible for analysis of data and manuscript writing; National Natural Science Foundation of China (82000728 to Xianglei Kong) contributed to data interpretation, preparation and review.

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XJ, KW and DX designed research; XJ, KW, JC, GS, YW, CS, PC, YL and LW conducted research; XJ, XK and YL analyzed data; XJ, DX, KW, LX and YW wrote the paper; XJ had primary responsibility for final content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaoyan Jia.

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This study was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University and carried out in accordance with the declaration of Helsinki. Written informed consent was obtained from each participant prior to study procedures.

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Additional file 1 Supplemental Table 1.

Univariable logistic regression analyses between aortic root calcium (ARC) and characters of all MHD patients (n = 43) MHD maintenance hemodialysis, SBP systolic blood pressure, DBP diastolic blood pressure, CHD Coronary heart disease, NGAL neutrophil gelatinase-associated lipocalin, Ca calcium, P phosphate, iPTH intact parathyroid hormone, ALP alkaline phosphatase, K potassium, HCO3- carbonate ion, BUN blood urea nitrogen, Cr creatinine, Alb albumin, LDL low density lipoprotein, TG triglyceride, SF serum ferritin; Hb hemoglobin, WBC white blood cells, PLT platelet, HD hemodialysis, HFD high-flux hemodialysis, HDF hemodiafiltration, CTA cellulose triacetate, PS polysulfone, PMMA polymethylmethacrylate. Supplemental Table 2. Spearman coefficients between aortic root calcium (ARC) and characters of MHD patients without diabetes (n = 21) MHD maintenance hemodialysis, SBP systolic blood pressure, DBP diastolic blood pressure, CHD Coronary heart disease, NGAL neutrophil gelatinase-associated lipocalin, Ca calcium, P phosphate, iPTH intact parathyroid hormone, ALP alkaline phosphatase, K potassium, HCO3- carbonate ion, BUN blood urea nitrogen, Cr creatinine, Alb albumin, LDL low density lipoprotein, TG triglyceride, SF serum ferritin; Hb hemoglobin, WBC white blood cells, PLT platelet, HD hemodialysis, HFD high-flux hemodialysis, HDF hemodiafiltration, CTA cellulose triacetate, PS polysulfone, PMMA polymethylmethacrylate.

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Wei, K., Song, G., Xi, L. et al. Association of plasma neutrophil gelatinase-associated lipocalin and thoracic aorta calcification in maintenance hemodialysis patients with and without diabetes. BMC Nephrol 23, 156 (2022). https://doi.org/10.1186/s12882-022-02773-z

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Keywords

  • Neutrophil gelatinase-associated lipocalin
  • Thoracic aorta calcification
  • Maintenance hemodialysis
  • Diabetes