Plasma concentrations of histidine-rich glycoprotein in primary graft dysfunction after lung transplantation

Abstract

OBJECTIVES

Histidine-rich glycoprotein has been reported as an anti-inflammatory glycoprotein that inhibits acute lung injury in mice with sepsis and as a prognostic biomarker in patients with sepsis. We investigated the relationship between plasma concentrations of histidine-rich glycoprotein and the risk of occurrence of primary graft dysfunction.

METHODS

According to the primary graft dysfunction grade at post-transplant 72 h, patients who underwent lung transplantation were divided into three groups: non-primary graft dysfunction group (grade 0–1), moderate primary graft dysfunction group (grade 2), and severe primary graft dysfunction group (grade 3). The plasma concentrations of histidine-rich glycoprotein measured daily during the first post-transplant 7 days were compared among the three groups. Appropriate cutoff values of the concentrations were set for survival analyses after lung transplantation.

RESULTS

A total of 68 patients were included. The plasma histidine-rich glycoprotein concentration at post-transplant 72 h was significantly lower in the severe primary graft dysfunction group (n = 7) than in the other two groups [non-primary graft dysfunction group (n = 43), P = 0.042; moderate primary graft dysfunction group (n = 18), P = 0.040]. Patients with plasma histidine-rich glycoprotein concentration ≥34.4 µg/ml at post-transplant 72 h had significantly better chronic lung allograft dysfunction-free survival (P = 0.012) and overall survival (P = 0.037) than those with the concentration <34.4 µg/ml.

CONCLUSIONS

Plasma histidine-rich glycoprotein concentrations at post-transplant 72 h might be associated with the risk of development of primary graft dysfunction.

Lung transplantation (LT) is now an established rescue therapy for patients with end-stage lung diseases [1].

INTRODUCTION

Lung transplantation (LT) is now an established rescue therapy for patients with end-stage lung diseases [1]. However, the long-term survival after LT still remains worse than that after heart, liver, and kidney transplantations [2]. Severe primary graft dysfunction (PGD) is a major cause of both early and late mortality after LT [3]. PGD is a syndrome of acute lung injury caused by lung ischaemia–reperfusion injury (IRI) [4] and is known as an independent risk factor for the development of chronic lung allograft dysfunction (CLAD) [4]. Therefore, preventing the development or progression of PGD is key to improving the long-term survival after LT.

Histidine-rich glycoprotein (HRG) is a 75-kDa plasma glycoprotein produced in and secreted from the liver and presents at a concentration of ∼100 µg/ml in humans [5]. HRG is also detected on the surface of leukocytes, such as macrophages and monocytes [6]. HRG has been shown to inhibit inflammation by maintaining circulating neutrophils in a quiescent state and prevent uncontrolled activation of vascular endothelial cells [7]. Recently, decreased plasma concentrations of HRG have been shown to be associated with the severity and mortality in patients with sepsis [8]. Moreover, in a mouse sepsis model, supplementary HRG therapy was shown to prevent the development of severe acute respiratory distress syndrome (ARDS) following sepsis, contributing to improved survival [7]. The pathogenesis of ARDS involves activation of neutrophils and alveolar macrophages induced by damage-associated molecular patterns [9].

Similar to the case in ARDS, damage-associated molecular patterns induced by the lung IRI are associated with the development of PGD [4]. Furthermore, the clinical manifestations of PGD are similar to those of ARDS, including severe hypoxaemia, pulmonary oedema, and diffuse lung infiltrates on chest X-ray [10]. However, the relationship between the plasma concentration of HRG in LT recipients and the risk of development of PGD after LT remains unclear. In the present study, we investigated the relationship of the plasma concentration of HRG with the severity of PGD after LT, as well as the CLAD-free survival and overall survival after LT.

PATIENTS AND METHODS

Ethics statement

The institutional review board of Okayama University Hospital approved the blood collection in previous studies (No. K1609-026 and K1605-013) in 24 July 2012, and the study protocol of the present study (No. 2012-026) using blood samples from previous studies on December 22, 2020. Written informed consent for this study was obtained from each patient. All methods were performed in accordance with the relevant guidelines and regulations. Detailed data of brain-dead donors were not available due to the regulation of the Japan Organ Transplantation Network (JOTN) in place at the time of conduct of the present study.

Patients

Between September 2012 and January 2020, patients who underwent LT for end-stage lung diseases at Okayama University Hospital were enrolled. Since the plasma concentration of HRG in children are lower than those in adults [11], paediatric patients were excluded from this study. Patients who underwent retransplantation and patients who refused consent were also excluded. Blood samples were prospectively collected from the remaining patients, including patients who underwent living-donor lobar lung transplantation (LDLLT) and cadaveric LT. The patients were divided into three groups according to the PGD grade determined at 72 h after LT (T72): non-PGD group: patients with PGD grade 0 or 1; moderate PGD group: patients with PGD grade 2; severe PGD group: patients with PGD grade 3. The preoperative and intraoperative patient characteristics, and the postoperative course were evaluated. The lung allocation score calculator on the OPTN website (https://optn.transplant.hrsa.gov/resources/allocation-calculators/las-calculator/) was used to evaluate the priority of the patient before the LT in January 2020. The maximum total number of HLA mismatches could be 12, because LDLLT involves two different donors for each recipient. The primary outcome was to assess the relationship between the plasma concentration of HRG and the development of PGD at T72. The secondary outcomes were to assess the relationship between the plasma concentration of HRG at T72 and CLAD-free survival and overall survival after LT. CLAD-free survival was defined as the time from LT to the diagnosis of CLAD, and overall survival was defined as the time from LT to the date of death.

Procedure

Patients who require cadaveric LT are registered with the JOTN. The allocation system for organ donation from brain-dead donors is mainly based on the waiting time, because the lung allocation score system is not yet applied in Japan. LDLLT is considered for critically ill patients who cannot afford to wait for cadaveric LT. Patients who undergo LDLLT must meet all the criteria for cadaveric LT. At our institution, only third-degree blood relatives or a spouse are accepted as living donors. The size-matching protocol and transplant procedures are described in a previous report [12]. The graft ischaemic time was defined as the ischaemic time to the second transplanted lung.

Postoperative care

The postoperative management of the LT recipients, including the immunosuppressive therapy and prophylactic therapies, has been described previously [12]. The PGD grades were determined upon admission to the intensive care unit (ICU) after LT and at 24, 48 and 72 h after admission, according to the definition of PGD proposed by the International Society for Heart and Lung Transplantation (ISHLT) [10]. CLAD was diagnosed from decline of the forced expiratory volume in 1 s (FEV1) to <80% of the baseline, according to the classification system proposed by the ISHLT [13]. The baseline FEV1 value was calculated as the average of the two best FEV1 values obtained at least 3 weeks apart [13]. At the same time as the pulmonary function test, blood examinations, chest X-ray, chest computed tomography, electrocardiogram, lung ventilation scintigraphy and lung perfusion scintigraphy were performed for the differential diagnosis of CLAD.

Blood collection and plasma HRG assay

For the first 7 days after LT, 7 ml of whole-blood samples were collected from the patients daily into EDTA tubes. The first blood sample on postoperative day 0 was collected immediately after admission to the ICU. The blood samples were centrifuged at 3500 × g for 10 min. The separated plasma samples were transferred into microcentrifuge tubes and centrifuged at 16 000 × g for 10 min to remove residual cells and then stored at −20°C, as previously described [14]. After the frozen plasma samples were thawed, the HRG concentrations were measured using an enzyme-linked immunosorbent assay Pair set (SEK10836; Sino Biological, Inc., Beijing, China).

Statistical analysis

All statistical analyses were performed using the EZR statistical software [15]. It is a modified version of R commander that is designed to perform statistical functions frequently used in biostatistics. Differences among the groups were analysed by one-way analysis of variance, followed by Holm’s test. Associations with categorical variables were analysed using the Fisher’s exact test. The time course of the plasma HRG concentrations is described as means ± standard error of the means. Missing data are not replaced. A receiver operating characteristic (ROC) analysis using the Youden index was performed to determine the cutoff value of plasma HRG concentrations for overall survival after LT. Based on the ROC analysis, the CLAD-free survival and overall survival of the patients with high and low HRG concentrations were analysed by the Kaplan–Meier method, and the differences among the groups were evaluated by the log-rank test. Differences were considered significant at P < 0.05.

RESULTS

A schematic of the present study and summary of the patient characteristics of the LT recipients are shown in Fig. 1 and Table 1. Of the total 104 patients, 27 paediatric patients, 5 patients who underwent retransplantation and 4 patients who refused consent were excluded. The remaining 68 patients, including 10 patients who underwent LDLLT and 58 patients who underwent cadaveric LT, were divided into three groups: non-PGD group (n = 43); moderate PGD group (n = 18); and severe PGD group (n = 7). All the patients who underwent LDLLT were categorized into the non-PGD group. The number of HLA mismatches in the severe PGD group was significantly lower as compared with that in the other groups (P = 0.041). There were no significant differences in the postoperative variables which could affect the plasma HRG concentrations, including the liver enzyme concentrations, albumin concentrations and volume of fresh frozen plasma (FFP) transfusion among the three groups. Frequency of use of postoperative extracorporeal membrane oxygenation (ECMO) was significantly higher in the severe PGD group than in the other two groups (P = 0.021). In addition, all patients in the non-PGD group were weaned from postoperative ECMO before T72, and only the patients in the severe PGD group were continuing to receive ECMO support at T72. Unsurprisingly, the patients in the severe PGD group had significantly worse overall survival and CLAD-free survival than those in the non-PGD or moderate PGD groups (severe PGD versus non-PGD, P < 0.001; severe PGD versus moderate PGD, P < 0.001) (Supplementary Material, Fig. S1). The concentrations of HRG at T72 did not differ between the patients with obstructive and restrictive CLAD (P = 0.19).

Figure 1:

Of the 104 patients who underwent lung transplantation (LT), 27 paediatric patients, 5 patients who underwent retransplantation and 4 patients who refused consent for participation were excluded from this study. The remaining 68 patients were divided into three groups according to the grade of primary graft dysfunction (PGD) at 72 h after LT.

Table 1:

Patient characteristics.

	Non-PGD (n = 43)	Moderate PGD (n = 18)	Severe PGD (n = 7)	P-value
Preoperative variables
Age (years)	42.8 ± 13.7	43.7 ± 11.6	41.4 ± 18.5	0.96
Sex, male	22 (51%)	6 (33%)	4 (57%)	0.38
BMI (kg/m2)	19.1 ± 5.6	18.5 ± 4.1	21.6 ± 6.3	0.42
Diagnosis				0.53
Interstitial lung disease	18 (42%)	3 (17%)	3 (43%)
Pulmonary hypertension	3 (7%)	3 (17%)	2 (29%)
Pulmonary GVHD	7 (16%)	4 (22%)	0
Lymphangioleiomyomatosis	4 (9%)	4 (22%)	1 (14%)
Bronchiolitis obliterans	4 (9%)	1 (6%)	0
COPD	2 (5%)	1 (6%)	1 (14%)
Other diseases	5 (12%)	2 (10%)	0
Lung allocation score	41.9 ± 14.0	44.4 ± 11.1	36.2 ± 4.4	0.36
Lung donor				0.033
Cadaveric	33 (77%)	18	7
Living	10 (23%)	0	0
Procedure				0.94
Single	10 (23%)	4 (22%)	2 (29%)
Bilateral	33 (77%)	14 (78%)	5 (71%)
CMV mismatch (recipient negative/donor positive)	5 (12%)	3 (17%)	3 (43%)	0.11
Total number of HLA-A, B and DR mismatches	4.3 ± 1.7	4.5 ± 0.92	2.9 ± 1.5	0.041
Intraoperative variables
Operative time (min)	485.3 ± 137.7	523.6 ± 130.1	470.0 ± 153.7	0.55
Total ischaemic time (min)	471.4 ± 188.9	522.4 ± 133.5	594.0 ± 89.8	0.16
Cardiopulmonary bypass use, yes	31 (72%)	13 (72%)	4 (57%)	0.71
Postoperative variables
Liver function at 72 h
AST (g/dl)	29.1 ± 1.5	25.9 ± 1.3	32.4 ± 4.7	0.25
ALT (g/dl)	19.4 ± 1.1	15.4 ± 1.2	23.6 ± 7.5	0.091
Serum levels of albumin at 72 h (g/dl)	3.3 ± 0.40	3.4 ± 0.39	3.5 ± 0.84	0.52
Total volume of FFP transfusion (0–72 h) (ml)	1490.2 ± 152.3	1613.3 ± 164.4	1405.7 ± 356.9	0.85
Postoperative ECMO use during 72 h, yes	2 (5%)	0	2 (29%)	0.021
Acute rejection, yes	12 (28%)	4 (22%)	2 (29%)	0.89
Antibody-mediated rejection, yes	5 (12%)	3 (17%)	2 (29%)	0.48
ICU stay (days)	20.0 ± 14.0	22.2 ± 8.9	23.3 ± 6.6	0.70
Hospital stay (days)	88.3 ± 61.3	87.6 ± 39.3	109.3 ± 54.3	0.64

Data are presented as n (%) or mean ± standard error of the mean.

ALT: serum alanine aminotransferase; AST: serum aspartate aminotransferase; BMI: body mass index; CMV: cytomegalovirus; COPD: chronic obstructive pulmonary disease; ECMO: extracorporeal membrane oxygenation; FFP: fresh frozen plasma; GVHD: graft versus host disease; HLA: human leucocyte antigen; ICU: intensive care unit; PGD: primary graft dysfunction.

Figure 2 shows the postoperative changes of the plasma HRG concentration from the time of admission to the ICU to day 7 after LT. The plasma HRG concentration peaked on day 3 in all the groups and subsequently decreased in a time-dependent manner to similar concentrations in all the three groups within day 7 after LT. The plasma HRG concentrations on 3 days after LT, i.e. at T72, were significantly lower in the severe PGD group than in the other groups (non-PGD group, P = 0.042: moderate PGD group, P = 0.040) (Fig. 3). In addition, the level of C-reactive protein peaked on day 2 and subsequently decreased in a time-dependent manner during the first 7 days after LT in all the groups (Supplementary Material, Fig. S2). There were no significant differences in the level of C-reactive protein at T72 as well as any time points of the first 7 days between the groups (Supplementary Material, Fig. S3).

Figure 2:

The plasma histidine-rich glycoprotein (HRG) concentrations peaked on day 3 after lung transplantation (LT) in all the groups, decreasing subsequently in a time-dependent manner to similar concentrations in all the three groups. In all the three groups, the mean plasma HRG concentrations were >16 µg/ml until day 7 after LT. The mean plasma HRG concentrations in the non- and moderate primary graft dysfunction (PGD) groups were significantly higher than the mean concentration in the severe PGD group on day 3 (P < 0.05). The plots represent the mean, and the vertical bars indicate the standard error of the mean.

Figure 3:

The mean plasma histidine-rich glycoprotein (HRG) concentrations in the non- and moderate primary graft dysfunction (PGD) groups were significantly higher than the mean concentration in the severe PGD group at 72 hours after lung transplantation (non-PGD group vs severe PGD group, 48.85 ± 2.40 vs 31.43 ± 5.49 µg/ml, P = 0.042: moderate PGD group vs severe PGD group, 51.97 ± 5.59 vs 31.43 ± 5.49 µg/ml, P = 0.040).

An ROC analysis conducted to determine the cutoff value of the plasma HRG concentration at T72 for predicting the overall survival after LT yielded an area under the curve of 0.62, with a sensitivity of 44% and a specificity of 80% associated with the cutoff value of 34.4 µg/ml (Supplementary Material, Fig. S4). Using this cutoff value, the patients were divided into two groups: those with the plasma HRG ≥34.4 µg/ml (high HRG) (n = 51) and those with plasma HRG <34.4 µg/ml (low HRG) (n = 17), and the characteristics of the two groups were summarized in Table 2. The patients with high HRG had significantly lower rate of single LT (P = 0.0022), longer operative time (P = 0.030) and lower PGD grade at T72 (P = 0.012) than those with low HRG. The CLAD-free survival was significantly better in the patients with high HRG than in those with low HRG (P = 0.012) (Fig. 4). The overall survival after LT was significantly better in the patients with high HRG than in those with low HRG (P = 0.037) (Fig. 5).

Table 2:

Patient characteristics between the two groups, according to plasma histidine-rich glycoprotein concentration.

	High HRG (n = 51)	Low HRG (n = 17)	P-value
Preoperative variables
Age (years)	41.3 ± 1.8	47.2 ± 3.6	0.12
Sex, male	22 (43%)	10 (59%)	0.28
BMI (kg/m2)	18.4 ± 0.73	20.0 ± 1.3	0.36
Diagnosis			0.14
Interstitial lung disease	16 (31%)	8 (47%)
Pulmonary hypertension	7 (14%)	1 (6%)
Pulmonary GVHD	9 (18%)	1 (6%)
Lymphangioleiomyomatosis	6 (12%)	3 (17%)
Bronchiolitis obliterans	2 (4%)	2 (12%)
COPD	2 (4%)	2 (12%)
Other diseases	9 (17%)	0
Lung allocation score	43.1 ± 1.9	38.4 ± 2.2	0.19
Lung donor			0.43
Cadaveric	42 (82%)	16 (94%)
Living	9 (18%)	1 (6%)
Procedure			0.0022
Single	7 (14%)	9 (53%)
Bilateral	44 (86%)	8 (47%)
CMV mismatch (recipient negative/donor positive)	7 (14%)	1 (6%)	0.67
Total number of HLA-A, B and DR mismatches	4.3 ± 0.21	4.1 ± 0.36	0.64
Intraoperative variables
Operative time (min)	514.5 ± 19.6	431.9 ± 26.3	0.030
Total ischaemic time (min)	502.5 ± 25.2	483.3 ± 35.1	0.69
Cardiopulmonary bypass use, yes	38 (75%)	10 (59%)	0.24
Postoperative variables
Liver function at 72 h
AST (g/dl)	28.5 ± 1.2	29.1 ± 2.7	0.82
ALT (g/dl)	19.0 ± 1.3	18.1 ± 1.7	0.70
Serum levels of albumin at 72 h (g/dl)	3.3 ± 0.062	3.5 ± 0.12	0.11
Total volume of FFP transfusion (0–72 h) (ml)	1562.4 ± 125.0	1369.4 ± 238.0	0.45
Postoperative ECMO use during 72 h, yes	3 (6%)	1 (6%)	1.00
PGD grade at 72 h	0.76 ± 0.99	1.5 ± 1.2	0.012
Acute rejection, yes	14 (28%)	4 (24%)	1.00
Antibody-mediated rejection, yes	7 (14%)	3 (18%)	0.70
ICU stay (days)	21.4 ± 1.8	19.4 ± 2.1	0.57
Hospital stay (days)	88.6 ± 7.9	95.4 ± 13.0	0.67

Data are presented as n (%) or mean ± standard error of the mean.

ALT: serum alanine aminotransferase; AST: serum aspartate aminotransferase; BMI: body mass index; CMV: cytomegalovirus; COPD: chronic obstructive pulmonary disease; ECMO: extracorporeal membrane oxygenation; FFP: fresh frozen plasma; GVHD: graft versus host disease; HLA: human leucocyte antigen; HRG: histidine-rich glycoprotein; ICU: intensive care unit; PGD: primary graft dysfunction.

Figure 4:

The cutoff value of the plasma histidine-rich glycoprotein (HRG) concentrations at 72 h after lung transplantation (LT) was determined as 34.4 µg/ml by receiver operating characteristic curve analysis; using this cutoff value, our analysis revealed that patients with plasma concentrations of HRG ≥34.4 µg/ml (high HRG) (n = 51) showed significantly better chronic lung allograft dysfunction (CLAD)-free survival than those with plasma concentrations of HRG <34.4 µg/ml (low HRG) (n = 17) (P = 0.012).

Figure 5:

Using the cutoff value (34.4 µg/ml) of the plasma histidine-rich glycoprotein (HRG) concentrations at 72 hours after LT, the overall survival after lung transplantation (LT) was significantly better in patients with high plasma HRG concentrations than in those with low plasma HRG concentrations (P = 0.037).

DISCUSSION

Our study showed that the plasma HRG concentrations measured in the LT recipients during the first 7 days after LT peaked at T72, and that the plasma HRG concentration in patients with severe PGD (grade 3) was significantly lower than the concentrations in patients with non- and moderate PGD (grade 0–2) at T72. Moreover, patients with high plasma HRG concentrations at T72 showed better CLAD-free survival and overall survival after LT than those with low plasma HRG concentrations at T72. Our results suggest that the plasma HRG concentrations might be predictive of the risk of development of severe PGD after LT.

We found that the peak plasma HRG concentration occurred at T72, and that the patients with PGD grade 3 had a significantly lower mean plasma HRG concentration than those with PGD grade 0–2 at T72. As compared with the normal concentrations of human plasma HRG (60–100 µg/ml) [5], the lower concentrations of plasma HRG until day 7 after LT might be attributable to the enhanced immunosuppressive therapy in the early phase after LT [16]. The extreme low HRG concentration at T72 in some patients of all the groups might reflect individual variation or genetic variation of HRG. Considering that HRG maintains circulating neutrophils in a resting state and protects vascular endothelial cells from excessive activation [7], the production of HRG in the liver might be increased to control PGD during the first 3 days after LT and eventually reach a peak at T72. Furthermore, elevation of the plasma HRG concentration might also be suppressed by severe IRI in the patients with PGD grade 3, as in patients with sepsis [8]. In mice with septic ARDS, reduced plasma HRG concentrations were found to be associated with reduction in the expression of the gene encoding HRG in the liver, and supplementary treatment with HRG improved the survival, by causing strong inhibition of the tight attachment of neutrophils to the pulmonary vasculatures, lung inflammation, hypercytokinaemia, and activation of vascular endothelial cells [7]. These findings may suggest the importance of maintaining the plasma HRG concentrations in cases of acute lung injury, including PGD and septic ARDS. Since the mechanisms of PGD caused by IRI differs from those in cases of septic ARDS, further basic research is warranted to elucidate the role of HRG in the development of PGD. In addition, consistent with our results, patients with PGD grade 3 showed the most obvious differences in the concentrations of several plasma biomarkers as compared with patients with lesser grades of PGD [3, 17].

The production of HRG in the liver is dependent on the liver function [18]. In the present study, there were no significant differences in the distribution of the underlying lung diseases that could be complicated by liver dysfunction, such as pulmonary hypertension, or in the postoperative liver function parameters, including the serum concentrations of liver enzymes and albumin at T72 among the three groups. Although healthy human plasma contains HRG [5], the total volume of FFP transfused during the first 72 h after LT did not differ among the groups. Therefore, the postoperative liver function and volume of FFP transfusion may exert no influence on the differences in the plasma HRG concentrations observed among the groups in this study. Considering the differences in the plasma HRG concentrations depending on whether the patients were initiated on postoperative ECMO or not in the present study, the effect of ECMO on the plasma HRG concentrations needs to be evaluated in the future.

With regard to the patient characteristics of the lung donors, all of the patients with PGD grade 3 in this study had received cadaveric LT, and not LDLLT, and also exhibited a lower total number of HLA mismatches than the patients with PGD grade 0–2. In general, the PGD grade after LDLLT is lower than that after cadaveric LT, because LDLLT is performed with less ischaemic time using a small, but ideal graft from living donors [19]. Additionally, the maximum total number of HLA mismatches in LDLLT could be 12 due to the involvement of two different donors, likely leading to a lower total number of HLA mismatches in the patients with PGD grade 3. Except for the type of lung donor, we could not assess the characteristics of the brain-dead donors in detail due to the regulation of the JOTN that were in place at the time of the study. However, considering that HRG is produced in the liver, the effect of the donor lungs on the recipient’s plasma HRG concentrations might be limited.

Our survival analysis showed that patients with high plasma HRG concentrations at T72 exhibited better CLAD-free survival and overall survival after LT than those with low plasma HRG concentrations. These results might be reflective of the finding that PGD grade 3 at T72 was associated with the development of CLAD and a poorer overall survival after LT [3]. In fact, experimental studies on LT have shown that severe IRI can prevent lung allograft acceptance [20]. Interestingly, sepsis patients with high plasma HRG concentrations on day 1 of ICU admission have been demonstrated to show better survival than those with low plasma HRG concentrations, and the median plasma HRG concentration in the non-survivors was 15.1 µg/ml [8]. In contrast, in the present study, the mean plasma HRG concentrations were over 16 µg/ml until day 7 after LT in all the groups. Since HRG is a human-derived biological plasma derivative [7], supplementary HRG therapy early after LT may be safely introduced in clinical settings. In liver IRI of mice, supplemental HRG therapy inhibits neutrophil inflammation and the formation of neutrophil extracellular traps, thereby minimizing the liver damage [21]. The effect of supplementary HRG therapy on the risk of PGD and CLAD, as also on the survival, should be evaluated in experimental LT.

Limitations

There were several limitations of the present study. First, this study was conducted on patients from a single LT centre, and the number of LT recipients, especially that of patients with severe PGD, was small. Second, the differences in the pre- and postoperative concentrations of plasma HRG were not assessed due to non-availability of preoperative blood samples. Third, the plasma HRG concentrations were not measured in the patients with and without CLAD in the chronic phase after LT. Fourth, the characteristics of the brain-dead donors could not be evaluated in detail due to the regulation of the JOTN in place at the time of conduct of the present study. Fifthly, the cut-off values obtained in the ROC analysis have not been tested for external validity, requiring further validation in the future. However, we believe that the present study provided valuable information about the relationship of the plasma HRG concentration with the risk of PGD and survival after LT.

CONCLUSION

At T72, the mean plasma HRG concentration in the LT recipients with PGD grade 3 was significantly lower than the concentrations in patients with PGD grade 0–2. The patients with high plasma HRG concentrations at T72 showed better CLAD-free survival and overall survival after LT than those with low plasma HRG concentrations at T72. Our results indicate that the decreased plasma HRG concentrations in LT recipients might be predictive of the risk of development of severe PGD after LT.

Glossary

ABBREVIATIONS

ARDS

Acute respiratory distress syndrome

CLAD

chronic lung allograft dysfunction

FEV1

forced expiratory volume in 1 s

FFP

fresh frozen plasma

HRG

histidine-rich glycoprotein

ICU

intensive care unit

IRI

ischaemia–reperfusion injury

ISHLT

International Society for Heart and Lung Transplantation

JOTN

Japan Organ Transplantation Network

LDLLT

living-donor lobar lung transplantation

LT

lung transplantation

PGD

primary graft dysfunction

ROC

receiver operating characteristic

T72

72 h after lung transplantation

 

Presented at the 41st Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Toronto, Canada, April 2021.

SUPPLEMENTARY MATERIAL

Supplementary material is available at ICVTS online.

FUNDING

This work was supported by a Grant-in-Aid for Scientific Research (Grant no. 20K17747 and 22K08974) from the Japan Society for the Promotion of Science.

Conflict of interest: none declared.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.

Author contributions

Toshio Shiotani: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Validation; Visualization; Writing – original draft. Seiichiro Sugimoto: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Supervision; Writing – original draft; Writing – review & editing. Yasuaki Tomioka: Data curation; Investigation. Shin Tanaka: Data curation; Investigation. Toshiharu Mitsuhashi: Formal analysis; Investigation; Methodology; Validation. Ken Suzawa: Resources. Kazuhiko Shien: Resources. Kentaroh Miyoshi: Data curation; Investigation. Hiromasa Yamamoto: Resources. Mikio Okazaki: Data curation; Resources. Shinichi Toyooka: Supervision; Writing – review & editing.

Reviewer information

Interdisciplinary CardioVascular and Thoracic Surgery thanks Bartosz Kubisa, Stephan Korom and the other anonymous reviewers for their contribution to the peer review process of this article.