The relevance of donor-specific HLS antibodies in renal transplantation

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 %. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA% value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13% (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48% and 26%, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.
Original languageEnglish
Supervisors/Advisors
  • Merenmies, Jussi, Supervisor
  • Jaatinen, Taina, Supervisor, External person
  • Jalanko, Hannu J, Supervisor
Award date6 Apr 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-952-5457-45-2
Electronic ISBNs978-952-5457-46-9
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3126 Surgery, anesthesiology, intensive care, radiology
  • 3121 Internal medicine

Cite this

Peräsaari, Juha. / The relevance of donor-specific HLS antibodies in renal transplantation. Helsinki : Finnish Red Cross Blood Service, 2018. 80 p.
@phdthesis{9866f9a03d794f35976e03e79a6ae308,
title = "The relevance of donor-specific HLS antibodies in renal transplantation",
abstract = "Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 {\%}. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA{\%} value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13{\%} (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48{\%} and 26{\%}, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.",
keywords = "Alleles, Delayed Graft Function, +immunology, Gene Frequency, Glomerular Filtration Rate, Graft Rejection, +epidemiology, +physiopathology, Graft Survival, HLA Antigens, +genetics, Haplotypes, Histocompatibility, Histocompatibility Testing, Isoantibodies, +blood, Kidney Failure, Chronic, +surgery, Kidney Transplantation, +adverse effects, Predictive Value of Tests, Risk Factors, Time Factors, Tissue Donors, Treatment Outcome, 3126 Surgery, anesthesiology, intensive care, radiology, 3121 Internal medicine",
author = "Juha Per{\"a}saari",
note = "M1 - 80 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-952-5457-45-2",
series = "Academic dissertations from the Finnish Red Cross Blood Service",
publisher = "Finnish Red Cross Blood Service",
number = "63",
address = "Finland",

}

The relevance of donor-specific HLS antibodies in renal transplantation. / Peräsaari, Juha.

Helsinki : Finnish Red Cross Blood Service, 2018. 80 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - The relevance of donor-specific HLS antibodies in renal transplantation

AU - Peräsaari, Juha

N1 - M1 - 80 s. + liitteet

PY - 2018

Y1 - 2018

N2 - Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 %. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA% value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13% (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48% and 26%, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.

AB - Renal transplantation is a preferred choice of treatment for patients who have lost their kidney function due to end-stage renal disease (ESRD). Transplantations in Finland have been centralized to Helsinki University Hospital for both paediatric and adult patients. The results of the kidney transplantation program in Finland have improved over the years and are now excellent, with a one-year graft survival of over 90 %. The major improvements concern short-term problems, and the main challenge today is chronic rejection and long-term survival. The key to further improvements is prevention of chronic rejection and the adequate level of immunosuppression. This thesis was designed to study the prevalence of human leukocyte antigen (HLA) antibodies and to evaluate the relevance of identified donor-specific antibodies (DSA) in the graft outcome. The focus was on graft function, as assessed by the glomerular filtration rate (GFR) and occurrence of delayed graft function (DGF). Another goal for this study was to evaluate various techniques for measuring the immunisation status of a patient and the sensitivity and specificity of different crossmatch techniques with the aim of developing practices in histocompatibility testing. Several cohorts were used in this study. HLA allele frequency, haplotype and panel reactive antibody (PRA) calculations included the data provided by the Finnish Bone Marrow Donor Registry (19807 individuals) and the Finnish Cord Blood Bank (2699 individuals). In addition, 30 immunised patients were included. A total of 235 patients waiting for kidney transplant and 40 deceased donors were used in the prediction of crossmatch outcome. Retrospective clinical studies included 123 pediatric and 771 adult kidney transplant patients. In our study of the Finnish population, a limited amount of allelic diversity was found. For many HLA antigens, practically only one allele is identified. For example, it is extremely unlikely that A3, A11 and A24 are found to be alleles other than A*03:01, A*11:01 or A*24:02, respectively. Also, the most common Finnish HLA haplotypes have very high frequencies when compared to other populations and some haplotypes are unique to the Finnish population. In virtual PRA, HLA antibodies identified against all potential donors were assessed and reported as a PRA% value. This value describes the percentage of donors that present antigens that the patient is immunised against. Due to the uniqueness of the Finnish HLA composition, the use of a calculated population-specific PRA provides a more accurate and reliable estimate of the level of immunisation against available donors Three different crossmatch methods were compared against virtual crossmatch (VXM) results. The flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) proved to be the most accurate methods according to the receiver operating characteristic (ROC) analysis, with area under curve (AUC) values of 0.861 and 0.805, respectively. The performance of the complement-mediated lymphocytotoxicity crossmatch (CDCXM) was not as good (AUC: 0.724). There was no clear correlation between the serum samples providing false positive and negative results in each crossmatch technique, which indicates that the main reason for the differences is that each method identifies a different type of antibodies. In the pediatric cohort, HLA antibodies were detected in half of the samples. During the follow-up, one third of the patients presented antibodies against the transplanted kidney. We did not find any association between DSA and poor GFR at the time of sampling or later during the follow-up. In the adult cohort one third (265/771) of the patients were immunised. DSA was detected in 13% (103/771) of the patients at the time of transplantation, even with a negative CDCXM. DGF was more common in patients with DSA than in non-immunised patients (48% and 26%, respectively). DSA against all loci contributed a risk for DGF, but DRB1 seemed to provide the highest relative risk (RR) individually (RR 2.4). Also, the number of DSA and the strength of DSA as measured by cumulative mean fluorescence intensity were significant factors.

KW - Alleles

KW - Delayed Graft Function

KW - +immunology

KW - Gene Frequency

KW - Glomerular Filtration Rate

KW - Graft Rejection

KW - +epidemiology

KW - +physiopathology

KW - Graft Survival

KW - HLA Antigens

KW - +genetics

KW - Haplotypes

KW - Histocompatibility

KW - Histocompatibility Testing

KW - Isoantibodies

KW - +blood

KW - Kidney Failure, Chronic

KW - +surgery

KW - Kidney Transplantation

KW - +adverse effects

KW - Predictive Value of Tests

KW - Risk Factors

KW - Time Factors

KW - Tissue Donors

KW - Treatment Outcome

KW - 3126 Surgery, anesthesiology, intensive care, radiology

KW - 3121 Internal medicine

M3 - Doctoral Thesis

SN - 978-952-5457-45-2

T3 - Academic dissertations from the Finnish Red Cross Blood Service

PB - Finnish Red Cross Blood Service

CY - Helsinki

ER -

Peräsaari J. The relevance of donor-specific HLS antibodies in renal transplantation. Helsinki: Finnish Red Cross Blood Service, 2018. 80 p. (Academic dissertations from the Finnish Red Cross Blood Service ; 63).