器官移植

2021 Vol. 12, No. 3

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Editorial
Banff Allograft Pathology
Expert Forum
Transplantation Forefront
Original Article
Review Article

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Editorial

Improving efficacy of liver transplantation for hepatocellular carcinoma by comprehensive treatment

Wang Genshu

2021, 12(3): 249-256. doi: 10.3969/j.issn.1674-7445.2021.03.001

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Currently, several major challenges still exist in liver transplantation for hepatocellular carcinoma (HCC), including the opportunity of liver transplantation for HCC patients beyond selection criteria, drop-out from the waiting list for HCC patients within selection criteria due to tumor progression and the tumor recurrence after liver transplantation. In recent years, revolutionary efficacy has been achieved in treating advanced HCC by employing systemic drugs, such as lenvatinib and systemic drug-based comprehensive treatment, which also sheds light on the down-staging therapy and bridging therapy for HCC patients listed for liver transplantation, and prevention and treatment of tumor recurrence after liver transplantation for HCC individuals. Systemic drug-based comprehensive treatment probably has the potential to improve the clinical efficacy of liver transplantation for HCC, which deserves in-depth investigation. In this review, we summarize the progress on down-staging therapy, bridging therapy as well as prevention and treatment of tumor recurrence after liver transplantation for HCC individuals, aiming to provide reference for clinical managementof HCC.

Clinical value of conventional ultrasound and contrast-enhanced ultrasound in evaluating donor liver quality in liver transplantation

Jin Jieyang, Ren Jie

2021, 12(3): 257-261. doi: 10.3969/j.issn.1674-7445.2021.03.002

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At present, a large quantity of patients with end-stage liver diseases are still waiting for liver transplantation. Evaluation of donor liver quality with rapid, convenient, non-invasive and accurate methods plays a pivotal role in improving the prognosis and quality of life of liver transplant recipients. No standard evaluation criteria of donor liver quality have been established in clinical practice. Comprehensive evaluation methods have been primarily adopted, including clinical parameters of donors, laboratory examination, imaging examination and pathological examination, etc. Conventional ultrasound and contrast-enhanced ultrasound may evaluate the quality of donor liver before liver transplantation and predict the incidence of complications after liver transplantation, which are of significant application prospect in liver transplantation. In this article, the basic methods and research progress on conventional ultrasound and contrast-enhanced ultrasound in evaluating the vascular variation of donor liver, micro-circulatory perfusion of liver parenchyma, degree of steatosis of donor liver, degree of fibrosis of donor liver, volume and quality of donor liver were reviewed, aiming to provide more methods and ideas for clinical evaluation of donor liver quality.

Banff Allograft Pathology

Pathology of antibody-mediated rejection in renal allograft

Guo Hui

2021, 12(3): 262-271. doi: 10.3969/j.issn.1674-7445.2021.03.003

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Antibody-mediated rejection (AMR), also known as humoral rejection, is an immune injury caused by rejection involved with multiple humoral immune effectors, such as antibodies and complements, etc. AMR plays a pivotal role in hyperacute, acute and chronic rejection. In this article, the basic definition of AMR, the research progress and major achievements on AMR pathology according to Banff classification on allograft pathology (Banff classification), and main pathological characteristics of AMR in renal allograft were reviewed, aiming to provide reference for accurate diagnosis and timely treatment of AMR, and guarantee the long-term survival of renal graft and recipients.

Expert Forum

Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer

Liu Shaoru, Xu Leibo

2021, 12(3): 272-279. doi: 10.3969/j.issn.1674-7445.2021.03.004

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Primary liver cancer (liver cancer) is one of the main indications of liver transplantation in China. Nevertheless, the 5-year survival rate of liver transplant recipients is lower than 50%. Recurrence and metastasis after operation are the main causes affecting the long-term survival of the recipients. At present, immunotherapy, represented by programmed cell death protein 1(PD-1)/programmed cell death protein-ligand 1(PD-L1) immune checkpoint inhibitor, has achieved remarkable clinical efficacy in the treatment of middle-stage and advanced liver cancer. However, whether it can be applied in recipients with recurrence and metastasis after liver transplantation for liver cancer remains controversial. The main reason is that it may cause acute rejection at the same time. In this article, the research progresses on the application of immunotherapy in recipients with recurrence and metastasis after liver transplantation for liver cancer were reviewed, aiming to improve the survival rate of recipients undergoing liver transplantation forliver cancer.

Transplantation Forefront

Belatacept: a new weapon in anti-rejection battlefield

Sun He, Sun Yini, Cheng Ying

2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005

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As a co-stimulatory blocker against CD28 receptor, belatacept has been approved and applied to the treatment of rejection in organ transplantation in Europe and America. Belatacept has been proven to outperform calcineurin inhibitor (CNI) in improving the long-term survival rate of recipients and grafts, and enhancing graft function. Nevertheless, it might cause a high incidence of rejection. To resolve this issue, transplant workers have attempted to optimize belatacept immunosuppressive regimen and achieved good clinical efficacy. Although belatacept has been proven to exert poor effect on memory T cells, it has potential value in exploring new co-stimulatory molecular targets to optimize immunosuppressive regimes due to its specificity for immune cells and mild adverse effects. In this article, the advent of co-stimulatory blocker, clinical efficacy and application of belatacept, and the causes of belatacept-resistant rejection were reviewed.

Original Article

Role of tenascin-C in acute rejection early after liver transplantation

Cao Weiwei, Yang Peijun, Li Xiao

2021, 12(3): 288-293. doi: 10.3969/j.issn.1674-7445.2021.03.006

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Objective To investigate the relationship between tenascin-C (TNC) and acute rejection (AR) early after liver transplantation. Methods Six Brown Norway (BN) rats and 16 Lewis rats were divided into the AR group (Lewis→BN, 6 donors and 6 recipients) and control group (Lewis→Lewis, 5 donors and 5 recipients). The transplant liver tissues from rats in two groups were subjected to pathological examination. The rejection activity index (RAI) was evaluated by Banff schema. The expression of TNC proteins in the transplant liver tissues were determined by immunohistochemical staining and Western blot. The expression level of serum TNC was detected by enzyme-linked immune absorbent assay (ELISA), and the correlation between TNC and RAI score was analyzed. Results Pathological examination of the transplant liver at 7 d after liver transplantation showed that the RAI score in the AR group was higher than that in the control group. Immunohistochemical staining results found that the distribution of TNC positive cells of the transplant liver in the AR group was more than that in control group at postoperative 7 d. Western blot showed that the relative expression level of TNC protein in the AR group was significantly higher than that in the control group at 7 d after liver transplantation (t=5.112, P=0.007). ELISA results revealed that the serum TNC expression level in the AR group was significantly higher than that in the control group at 7 d after liver transplantation (t=3.152, P=0.012). The serum TNC expression level was positively correlated with the RAI score (r=0.790 9, P=0.004). Conclusions The expression level of TNC is associated with AR after liver transplantation. TNC may become a novel target for diagnosis and treatment of AR early after liver transplantation.

Mechanism of human umbilical cord mesenchymal stem cells alleviating ischemia-reperfusion injury of hepatocytes through mitochondrial transfer

Shan Jiarou, Ni Beibei, Li Cuiping, Xu Ruixuan, Chen Wenjie

2021, 12(3): 294-301. doi: 10.3969/j.issn.1674-7445.2021.03.007

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Objective To explore the mechanism of human umbilical cord mesenchymal stem cell (HUC-MSC) alleviating ischemia-reperfusion injury (IRI) of liver cells through mitochondrial transfer. Methods Normal human liver cell line L02 was divided into the blank control group, oxygen-glucose deprivation (OGD) group, experimental control group, and L02 and HUC-MSC co-culture group (L02+HUC-MSC group). L02+HUC-MSC group was further divided into 10:1 co-culture subgroup (group A), 4:1 co-culture subgroup (group B), 2:1 co-culture subgroup (group C), 1:1co-culture subgroup (group D) and 1:2 co-culture subgroup (group E) according to different co-culture ratio of L02 and HUC-MSC. The apoptosis rate and relative reactive oxygen species (ROS) level of L02 cells were detected by flow cytometry. The MitoTracker positive rate of L02 cells was detected by flow cytometry. The mitochondrial transfer from HUC-MSC to L02 cells was observed by laser confocal microscope. Results The apoptosis rate and relative ROS level of L02 cells in the OGD group were significantly higher than those in the blank control group (both P < 0.05). Compared with the OGD group, the apoptosis rates of L02 cells in group B, C, D and E were significantly decreased (all P < 0.05), and the relative ROS level of L02 cells in group E was significantly declined (P < 0.05). The MitoTracker positive rate of L02 cells did not significantly differ between group A and experimental control group (P>0.05), whereas the MitoTracker positive rates of L02 cells in group B, C, D and E were significantly higher than that in the experimental control group in a concentration-dependent manner (all P < 0.05). Under the laser confocal microscope, mitochondrial transfer fromHUC-MSC to L02 cells could be observed through tunneling nanotube (TNT). Conclusions HUC-MSC may alleviate cell apoptosis and reduce ROS level of liver cells after IRI via direct mitochondrial transfer between cells.

Comparison of clinical efficacy of different anti-tumor therapies for recurrence and metastasis after liver transplantation for liver cancer

Wang Meixi, Zhao Yuanyuan, Yang Bo, Wei Lai, Chen Dong, Jiang Jiping, Chen Zhishui

2021, 12(3): 302-308. doi: 10.3969/j.issn.1674-7445.2021.03.008

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Objective To analyze the clinical efficacy of different anti-tumor therapies for recurrence and metastasis after liver transplantation for primary liver cancer (liver cancer). Methods Clinical data of 145 recipients undergoing liver transplantation for liver cancer were retrospectively analyzed. The overall survival and recurrence and metastasis after liver transplantation for liver cancer were analyzed. The clinical efficacy of different anti-tumor therapies for recipients with recurrence and metastasis were compared. Results Sixty-five recipients (44.8%) developed recurrence and metastasis. The median recurrence time was 6 months. Among them, 1 case underwent secondary liver transplantation after recurrence and died of intestinal perforation. Twenty-four recipients (37%) received targeted drug therapy with a median tumor-bearing survival of 22 months. Eleven recipients (17%) received radiotherapy or chemotherapy with a median tumor-bearing survival of 11 months. Nine recipients (14%) received local treatment (surgical resection or radiofrequency ablation), and the median tumor-bearing survival was 8 months. Twenty recipients (31%) abandoned anti-tumor therapy, and the median tumor-bearing survival was 3 months. The tumor-bearing survival of recipients receiving anti-tumor therapy was significantly longer than that of recipients without anti-tumor therapy (P < 0.001). The tumor-bearing survival of recipients receiving targeted drug therapy was significantly longer than that of those receiving other anti-tumor therapies (P=0.03). The tumor-bearing survival of recipients receiving local treatment, radiotherapy and chemotherapy was considerably longer than that of those who abandoned anti-tumor therapy (P=0.004). Conclusions Surgical resection and radiofrequency ablation are the optimal therapies for recipients with recurrence and metastasis after liver transplantation for liver cancer. For recipients with multi-focal tumors who fail to receive local treatment, those receiving targeted drug therapy obtain the longest survival. In addition, radiotherapy and chemotherapy can also prolong the survival of recipients with recurrence and metastasis.

Clinical study of microvascular invasion on prognosis of recipients after liver transplantation for liver cancer

Wang Jianfeng, Zeng Kaining, Li Haibo, Deng Yinan, Zhang Yingcai, Zhang Tong, Yi Shuhong, Wang Genshu, Yang Yang, Chen Guihua

2021, 12(3): 309-316. doi: 10.3969/j.issn.1674-7445.2021.03.009

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Objective To evaluate the effect of microvascular invasion (MVI) on prognosis of recipients after liver transplantation for primary liver cancer (liver cancer). Methods Clinical data of 177 recipients after liver transplantation for liver cancer were retrospectively analyzed. All patients were divided into the MVI-positive group (n=64) and MVI-negative group (n=113) according to postoperative pathological examination results. Clinical data were statistically compared of all recipients between the negative and positive MVI groups. The prognosis and risk factors of liver transplantation recipients for liver cancer were analyzed. Results Among 177 recipients, 64 cases (36.2%) were positive for MVI and 113 (63.8%) negative for MVI. Compared with the MVI-negative recipients, MVI-positive recipients had significantly lower degree of tumor differentiation, higher preoperative alpha-fetaprotein (AFP) level, larger maximal tumor diameter, a larger quantity of tumors, more satellite lesions and more recipients who did not meet the Milan criteria (all P < 0.05). The 1-, 3- and 5-year overall survival (OS) and recurrence-free survival (RFS) of recipients after liver transplantation for liver cancer were 80.2%, 62.1%, 58.5% and 66.3%, 57.5%, 51.2%, respectively. The 1-, 3- and 5-year OS and RFS of MVI-positive recipients were 70%, 39%, 35% and 53%, 39%, 33%, significantly lower than 86%, 75%, 72% and 73%, 68%, 63% of their counterparts negative for MVI (all P < 0.05). Cox regression analysis showed that the maximal tumor diameter >8 cm, preoperative AFP level ≥20 ng/mL, low degree of tumor differentiation and positive MVI were the independent risk factors for OS of recipients after liver transplantation for liver cancer (all P < 0.05). Positive MVI, low degree of tumor differentiation and preoperative down-staging failure were the independent risk factors for RFS of recipients after liver transplantation for liver cancer (all P < 0.05). Conclusions MVI is of significant clinical value in predicting clinical prognosis of recipients after liver transplantation for liver cancer.

Analysis of risk factors of high-level BK viruria after renal transplantation

Xiong Rui, Ding Limin, Yang Hua, Li Xinchang

2021, 12(3): 317-323. doi: 10.3969/j.issn.1674-7445.2021.03.010

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Objective To analyze the risk factors of high-level BK viruria after renal transplantation and the significance in preventing BK virus-associated nephropathy (BKVAN). Methods Clinical data of 262 renal transplant recipients with regular follow-up data were retrospectively analyzed. According to the DNA load of BK virus, all recipients were divided into the high-level BK viruria group (n=35) and non-high-level BK viruria group (n=227). The incidence of high-level BK viruria after renal transplantation was summarized. The risk factors of high-level BK viruria after renal transplantation were analyzed by univariate analysis and multivariate analysis. Survival curve was delineated by Kaplan-Meier method, and survival analysis of recipients was performed. Results Among 262 renal transplant recipients, 35 cases developed high-level BK viruria with an incidence of 13.4%. The median time of occurrence of high-level BK viruria was 181 (126, 315) d. The incidence was the highest within 6 months after renal transplantation, gradually decreased from 6 months to 2 years, and then increased after 2 years. Univariate analysis showed that the history of antithymocyte globulin (ATG) treatment, acute rejection (AR), donation type and delayed graft function (DGF) were the risk factors of high-level BK viruria after renal transplantation (all P < 0.05). Multivariate Cox regression analysis demonstrated that donation after brain death followed by cardiac death (DBCD), AR and DGF were the independent risk factors of high-level BK viruria after renal transplantation. The 1-, 3- and 5-year survival rates of recipients with ATG treatment history, AR, DGF and donation type of DBCD were significantly lower than those with non-ATG treatment history, non-AR, non-DGF and other donation types [donation after brain death (DBD), donation after cardiac death (DCD) and living organ donation] respectively (all P < 0.05). Conclusions DBCD, AR and DGF are the independent risk factors of high-level BK viruria after renal transplantation. Strengthening the postoperative monitoring of these recipients and delivering early intervention may effectively prevent BKVAN.

Preliminary study of early diagnosis by contrast-enhanced ultrasound combined with mesenchymal stem cell therapy in improving prognosis of biliary ischemia after liver transplantation

Lin Yuejun, Zheng Bowen, Wu Tao, Zhou Huichao, Liao Mei, Lyu Yan, He Yuting, Ren Jie

2021, 12(3): 324-328. doi: 10.3969/j.issn.1674-7445.2021.03.011

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Objective To evaluate the clinical efficacy of early diagnosis by contrast-enhanced ultrasound (CEUS) combined with mesenchymal stem cell (MSC) therapy in the treatment of biliary ischemia after liver transplantation. Methods Clinical data of 9 recipients presenting with biliary ischemia detected by CEUS within 4 weeks after liver transplantation and diagnosed with non-anastomotic biliary stricture (NAS) within postoperative 1 year were retrospectively analyzed. In the conventional treatment group, 4 recipients were treated with conventional treatment including liver protection, cholagogic therapy and interventional therapy. In MSC treatment group, 5 recipients received intravenous infusion of MSC at 1, 2, 4, 8, 12 and 16 weeks after biliary ischemia detected by CEUS on the basis of conventional therapy. The interventional treatment and clinical prognosis within 1 year after liver transplantation were analyzed between two groups. Results Two recipients in the MSC treatment group required interventional therapy, which was initially given at 7-9 months after liver transplantation for 1-2 times. All recipients in the conventional treatment group required interventional therapy, which was initially delivered at postoperative 1-3 months for 2-6 times, earlier than that in the MSC treatment group. Within 1 year following liver transplantation, diffuse bile duct injury occurred in 2 recipients in MSC treatment group, and no graft dysfunction was observed. In the conventional treatment group, all recipients developed diffuse bile duct injury, and 2 recipients presented with graft dysfunction. Conclusions Early diagnosis of biliary ischemia after liver transplantation by CEUS combined with MSC therapy may delay and reduce the requirement of interventional therapy for NAS, and also improve clinical prognosis of the recipients.

Analysis of risk factors and establishment of prediction model for post transplantation diabetes mellitus in renal transplant recipients

Chen Rongxin, Lai Xingqiang, Zhang Lei, Fang Jiali, Xu Hailin, Liu Luhao, Zhang Peng, Wu Jialin, Cao Mibu, Ma Junjie, Chen Zheng

2021, 12(3): 329-335. doi: 10.3969/j.issn.1674-7445.2021.03.012

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Objective To analyze the risk factors for the occurrence of post transplantation diabetes mellitus (PTDM) in renal transplant recipients, establish a prediction model for PTDM and evaluate its prediction value. Methods Clinical data of 915 renal transplant recipients were retrospectively analyzed. According to the occurrence of PTDM, all recipients were divided into the PTDM group (n=78) and non-PTDM group (n=837). The main indexes of recipients were collected. The risk factors for the occurrence of PTDM in renal transplant recipients were analyzed by univariate and multivariate analysis. The prediction model for PTDM was established and its prediction value was evaluated. Results Family history of diabetes mellitus, body mass index (BMI), preoperative 2 h postprandial blood glucose and preoperative glycosylated hemoglobin were the independent risk factors for the occurrence of PTDM in renal transplant recipients. The prediction model for PTDM was logit (P)=2.199×family history of diabetes (yes=1, no=0)+0.109×BMI+0.151×2 h postprandial blood glucose (mmol/L)+0.508×glycosylated hemoglobin (%)-9.123. The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of these 4 predictors combined for predicting PTDM in renal transplant recipients was 0.830 [95% confidence interval (CI) 0.786-0.873], the cut-off value was 0.0608, the sensitivity was 0.821, the specificity was 0.700, and the Youden index was 0.521 (P < 0.05). Conclusions Family history of diabetes mellitus, BMI, preoperative 2 h postprandial blood glucose and preoperative glycosylated hemoglobin are the independent risk factors for the occurrence of PTDM in renal transplant recipients. The prediction model for PTDM combined with4 predictors yield relatively high prediction value for PTDM.

Review Article

Research progress on islet cell encapsulation technology

Yang Jijian, Huang Qingxian, Chen Li

2021, 12(3): 336-343. doi: 10.3969/j.issn.1674-7445.2021.03.013

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The incidence of diabetes mellitus tends to increase, and clinical treatment is extremely challenging. Although drugs exert certain therapeutic effect on reducing blood glucose level, it remains impossible to achieve clinical cure of type 1 diabetes mellitus with a risk of blood glucose fluctuations. Islet cell transplantation is one of the efficacious methods to solve the problem of blood glucose fluctuation caused by insulin injection. However, there are several problems in the clinical practice of islet cell transplantation, including long time use of immunosuppressants in recipients and massive loss of pancreatic islet cells after transplantation, which limit its wide application in clinical practice. Islet cell encapsulation technology can reduce the loss of islet cells and decrease or eliminate the rejection, which is a key link to improve the survival of islet cells. In this article, the development course of islet cell encapsulation technology was briefly reviewed, the challenges in different islet cell encapsulation technologies were analyzed and subsequent research on this technology was projected, aiming to provide reference for promoting the development of islet cell.

Liver transplantation and comprehensive treatment of intrahepatic cholangiocarcinoma

Wu Fengdong, Shi Bin

2021, 12(3): 344-350. doi: 10.3969/j.issn.1674-7445.2021.03.014

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Liver transplantation is an effective approach to treat intrahepatic cholangiocarcinoma (ICC). It is necessary to strictly control surgical indications of ICC because of its high invasiveness, lymph node metastasis and recurrence rate after liver transplantation. Liver transplantation yields high efficacy for single ICC with a diameterof ≤2 cm. For advanced ICC, neoadjuvant therapies including locoregional treatment and systemic chemotherapy should be initially delivered. According to the response of these neoadjuvant therapies, whether liver transplantation should be performed can be determined, and individualized adjuvant therapy should be delivered after operation. At present, multiple gene mutation targets and targeted therapeutic drugs for cholangiocarcinoma have been identified. Comprehensive treatment before and after liver transplantation may expand surgical indications of liver transplantation for ICC and improve clinical prognosis of the recipients. In this article, liver transplantation for ICC, neoadjuvant therapy before liver transplantation, postoperative adjuvant therapy and targeted therapy for ICC were reviewed.

Mechanism of intravenous immunoglobulin and its application in renal transplantation

Ou Zhiyu, He Yu, Miao Yun

2021, 12(3): 351-356. doi: 10.3969/j.issn.1674-7445.2021.03.015

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Intravenous immunoglobulin (IVIG) is an immunoglobulin (Ig) isolated from the plasma of healthy human, and its main component is IgG. The mechanism of IVIG is complex, which may play a role via multiple pathways. For example, the combination of Fc fragment of IgG with various Fc gamma receptor (FcγR) regulates inflammatory response and autoantibody metabolism, and Fab fragment of IgG neutralizes multiple antigens and other molecules. IVIG may also inhibit complement activation and affect the balance of anti-inflammation and proinflammation among immune cells. In the treatment of diseases, IVIG constantly plays a role through multiple mechanisms simultaneously, primarily via one certain mechanism in different diseases. IVIG is commonly applied in the desensitization treatment of sensitized patients, ABO incompatible renal transplantation, antibody-mediated rejection and several infectious diseases. In this article, the mechanism of IVIG and its application in renal transplantation were reviewed.

Research progress on risk factors of primary graft dysfunction after lung transplantation

Hu Chunlan, Yu Huizhi, Wang Jing, Li Xiaoshan, Hu Chunxiao

2021, 12(3): 357-362. doi: 10.3969/j.issn.1674-7445.2021.03.016

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Lung transplantation is the only effective approach to treat end-stage lung diseases. Nevertheless, early prognosis of lung transplant recipients is significantly worse than that of other solid organ transplant recipients. Primary graft dysfunction (PGD) is one of the main causes affecting clinical prognosis of the recipients. PGD is an early acute lung injury after lung transplantation, which is the main cause of early death of lung transplant recipients. Risk factors of PGD after lung transplantation consist of donor, recipient and operation, etc. In this article, the risk factors of PGD after lung transplantation were reviewed, aiming to provide reference for clinical practice.

Application prospects of trigonelline in regulating metabolic disorders after renal transplantation

Li Zhongda, Liu Dong, Wang Xiao, Zhuang Jinyang

2021, 12(3): 363-368. doi: 10.3969/j.issn.1674-7445.2021.03.017

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Metabolic disorders, such as glucose and lipid, are likely to occur after renal transplantation, leading to graft dysfunction and reduced long-term survival. Trigonelline is a type of natural alkaloid with various biological activities, which can alleviate the metabolic disorders of glucose, lipid and other types, and relieve inflammatory reaction, oxidative stress and cell apoptosis of the kidney, thereby protecting the renal function. Therefore, trigonelline may be a potential drug to regulate metabolic disorders after renal transplantation. In this article, the role of trigonelline in metabolic disorders of glucose, lipid and other types, and its application prospect in renal transplantation were reviewed, aiming to provide reference for alleviating metabolic disorders after renal transplantation and improving the long-term survival of renal transplant recipients and transplanted kidneys.