Identifying the hla allele frequency of renal donors and recipients and evaluating the influence of hla mismatching rates to graft survival in renal transplanted patients - NCS. Phạm Lê Nhật Minh

Tên luận án: Identifying the hla allele frequency of renal donors and recipients and evaluating the influence of hla mismatching rates to graft survival in renal transplanted patients
Chuyên ngành: Công nghệ sinh học              
Mã ngành: 9420201
Họ và tên NCS: Phạm Lê Nhật Minh
Mã số NCS: PBTIU17001            
Giảng viên hướng dẫn: PGS.TS Nguyễn Thị Thu Hoài
Cơ sở đào tạo: Trường Đại học Quốc tế, Đại học Quốc gia TP.HCM
Tóm tắt luận án
1.   General introduction
Organ  transplantation  is  a  great  achievement  of  mankind.  It  is  considered  a fantastic progress in medicine. Nowadays, transplantation becomes the main part of the globalization procedure of the world. Organ transplantation can save lives in each country in the world with different economies, culture and social conditions.  However, we have to face some problems in the new century on the transplantation.
Human leukocyte antigen (HLA) genes encode major histocompatibility complex proteins in humans and are responsible for immune system regulation. The association between HLA alleles and renal disorders has been described from many years ago. In recent years, the association between HLA alleles and end stage chronic renal disease (ESRD) has been proposed, as several of both HLA class I and class II alleles were found as protective or risk factors of ESRD in a variety of studies worldwide. The identification of such associated alleles is not only important for screening high risk ESRD patients, but also extends our understanding of the disease mechanism which could help to accelerate the development of more effective, safe and targeted therapies. Moreover, the susceptible alleles can be avoided when selecting optimal donors to increase the post-transplant long- term survival for ESRD patients.
In previous publications, HLA mismatching has been recorded as the critical issue for graft survival on renal transplantation. Furthermore, these studies also suggested risk factors  related  to  graft  survival  and  HLA  alleles  mismatching  between  donors  and recipients on renal transplantation. However, there is not much information in Vietnam on the  HLA  profile  of  patients  with  ESRD  as  well  as  healthy  donors,  especially  the relationship between the HLA mismatching on prior-renal transplantation and its influence to graft survival on post transplantation has not fully reported. The lack of this information in Vietnam causes lots of difficulties in finding matched donors in due time as well as performing early warning for clinicians to choose the matching pairs for renal transplantation and ensure the long graft survival as well as prevent the graft rejection for patients. Therefore, we would like to perform this study.
This study aims to analyse HLA profiles of healthy donors and ESRD patients and investigate the impact of HLA mismatching rates on graft survival in recipients after renal transplantation.
A prospective study was conducted in Cho Ray Blood Transfusion Center, Cho Ray Hospital in Ho Chi Minh City, Vietnam from March 2018 to December 2020. The study included 458 participants, consisting of healthy donors and ESRD patients. Participants were divided into two groups: unrelated group included unrelated donors- patients (URD) and related group included related donors-patients (RD). The URD group had
98 ESRD patients and 108 unrelated donors, while the RD group had 126 ESRD patients with their corresponding related donors. HLA typing was conducted using the PCR-SSO method with Luminex technology. Mismatching rates for HLA alleles were recorded for recipients and donor pairs in each group for five loci: HLA-DRB1, HLA-B, HLA-A, HLA-DQA1, and HLA- DQB1.The graft survival rates among 458 previous participants were monitored, including 82 transplanted unrelated donor-pairs and 126 transplanted related donor-pairs (416/458). The transplanted patients were followed up in post-transplantation in Cho Ray hospital and People’s Hospital 115, Ho Chi Minh City, Vietnam. There were 124 transplanted recipients in RD group and 45 transplanted recipients in URD group at Cho Ray Hospital were monitored for changing some crucial laboratory indicators in pre- and post-transplant to investigate the graft function, such as: hemoglobin, BUN, serum creatinine, eGFR, proteinuria levels and the detection of BK virus.
2.   Scientific contributions and the novelty of PhD dissertation
The most common alleles found in each HLA locus were consistent with those observed in the general Vietnamese population and other countries in East and Southeast Asia. The study results specially detected some certain alleles such as HLA-B*07 (OR =1.951; 95% CI = 1.032–3.688; p = 0.040), DQA1*06 (OR = 1.630; 95% CI = 1.044–2.545; p = 0.031) and DQB1*03 (OR = 1.515; 95% CI = 1.027–2.235; p = 0.036) were associated with susceptibility to ESRD while others like HLA-B*27 (OR = 0.175; 95% CI = 0.039–
0.793; p = 0.024) and DQB1*02 (OR = 0.337; 95% CI = 0.154–0.736; p = 0.006) showed a decreased  risk  of  developing  ESRD.  This  finding  may  consistent  or  contradict  some studies conducted by authors in Pakistani, Turkey. This disparity in allele frequencies may contribute to varying associations between specific HLA alleles and ESRD across different ethnic groups.
In addition, we detected that URD group had higher rates of HLA mismatch (MM). Meanwhile, RD group showed higher rates of both partial and complete matches for all HLA loci. An HLA mismatch of 9-10 MM was associated with a significantly higher risk of suspected graft rejection, being 7.99 times greater than the risk associated with an HLA mismatch of 5-8 MM with 1-2 DRB1 MM (p = 0.013). While positive anti-HLA antibodies raised this risk with a hazard ratio of 4.5. Our study underscores the significance of HLA matching in determining compatibility but also highlights the potential impact of anti-HLA antibodies on graft survival outcomes. The findings further emphasize the importance of assessing these factors when evaluating transplantation suitability to help optimize patient care and long-term success-transplantation.
Moreover, over the 30-month follow-up, RD group showed significantly higher overall survival rate (p=0.0086) and better-free survival rate (p=0.0025) compared to URD group. There was a distinct advantage in terms of overall and event-free survival for recipients who received kidneys from related donors. These findings contributed to our understanding of transplantation outcomes based on different types of living donations.
In URD group, the donors older than five years increased the risk of suspected graft rejection by a hazard ratio of 4.2. Our analysis underscores the importance of considering age compatibility between donors and recipients during unrelated kidney transplantations. The significant impact observed in terms of higher risks for suspected graft rejection when there is a substantial age disparity emphasizes the need for caution when selecting potential unrelated living organ donors to optimize transplant success rates Male-male donor-recipient pairs decreased the risk of suspected graft rejection by 88% when compared to female-female pairs. These findings underscore the importance of considering gender matching when evaluating potential organ donors and recipients for transplantation procedures. The significant difference observed regarding risk rates for suspected graft rejection based on gender pairing highlights how this factor can influence transplant outcomes and should be carefully considered during patient assessment and organ allocation processes.
We monitored the changes some crucial laboratory data for transplanted patients to investigate graft function as for hemoglobin, BUN, creatinine in serum, eGFR, Protein level in urine, detection of BK virus and observed that these data showed dramatic improvement  post-transplantation  in  both  groups.  However,  the  transplanted  patients within RD group had a higher proportion of BK virus infections compared to patients in the URD  group. Therefore, regular monitoring and early detection through laboratory screening are essential for proper management and reducing immunosuppression to optimize long-term success-transplantation as needed.
Additional research with higher resolution and a larger sample size, preferably multi-center, should be carried out to confirm our findings. It is important to conduct further research to investigate the mechanisms behind these observations and develop strategies for improved donor selection and matching in renal transplantation. Continuous monitoring and recording of information during follow-up examinations after renal transplantation are essential. Patient monitoring should adhere to the hospital's treatment plan and the guidelines of the Ministry of Health.