Clinical trial NCT03466775: Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes
Official title: Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Kidney Transplant Failure and Rejection
Keywords: Kidney transplantation
Allograft rejection
Allograft survival
Anti-angiotensin II type 1 receptor antibody
Lead sponsor: Paris Translational Research Center for Organ Transplantation
Sponsor class: OTHER
Collaborators: name: Center for Cardiovascular Research Berlin
First posted: 2018-03-15
Enrollment: 1845
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population includes kidney recipients undergoing transplantation between January 1, 2008 and December 31, 2012 at Necker and Saint-Louis Hospitals (Paris, France).

Brief summary: Incompatibility between non-genetically identical donors and recipients has been increasingly recognized as the main contributing factor to solid allograft rejection and failure, through the triggering of donor-specific responses mediated by T- and B-lymphocytes. The Human Leucocyte Antigen (HLA) system has been identified as the main target of donor-specific responses, especially through the production by the recipient of antibodies directed toward non-self donor HLA molecules expressed on the allograft endothelium. As a consequence, in organ transplantation, the current approach to immunological risk stratification, patient monitoring and rejection diagnosis is based on biomarkers derived from the HLA system. However, this approach does not provide a sufficient accuracy for the risk stratification and the diagnosis of immunological complications in solid organ transplantation, which still remain the dominant cause of allograft failure.

A recent body of evidence supports that specific non-HLA antigens expressed on the allograft endothelium may be relevant to allograft rejection, suggesting that a new strategy to transplant diagnostic testing at a non-HLA level would help to overcome the limitations of the current HLA-based approach to immunological assessment of transplant recipients. Among antibodies to non-HLA endothelial antigens, angiotensin II type 1 receptor activating antibodies have been the most widely reported antibodies to associate with the occurrence of allograft rejection, dysfunction and loss, even if their independent role, with respect to the presence of concomitant anti-HLA antibodies, has not been demonstrated.

Detailed description: The aims of this study are:

1. To assess the incidence of post-transplant anti-angiotensin II type 1 receptor antibodies within the first year after transplantation in an unselected population of kidney transplant recipients.
2. To investigate the incidence of biopsy-proven kidney allograft rejection according to the presence of post-transplant anti-angiotensin II type 1 receptor antibodies and of post-transplant concomitant donor-specific anti-HLA antibodies within the first year after transplantation, and to evaluate the incidence of rejection cases associated with anti-angiotensin II type 1-receptor antibodies that are not recognized by the current diagnostic approach based on HLA testing.
3. To investigate the allograft injury phenotype associated with post-transplant anti-angiotensin II type 1 receptor, using histopathology, immunochemistry and measurement of endothelial-associated transcript (ENDAT) expression level in allograft.
4. To evaluate the impact of post-transplant anti-angiotensin II type 1 receptor antibodies on kidney allograft survival up to 7 years after inclusion, in univariate and multivariable survival models including clinical, histological and immunological risk factors for allograft loss.

This study includes kidney recipients transplanted between January 1, 2008 and December 31, 2012 at Necker and Saint-Louis Hospitals (Paris, France), who undergo screening for post-transplant anti-angiotensin II type 1 receptor antibodies and simultaneous kidney allograft biopsy within the first year after transplantation, either at the time of an episode of rejection in the first year after transplantation or at 1 year after transplantation in the absence of previous rejection episode.

Eligibility criteria: Inclusion Criteria:

* Kidney recipient transplanted between January 1, 2008 and December 31, 2012
* Kidney recipient over 18 years of age
* Simultaneous histological and serological assessment within the first year after transplantation, including i) kidney allograft biopsy, ii) assessment of donor-specific anti-HLA antibodies, and available stored serum for anti-angiotensin II type 1 receptor antibody assessment

Exclusion Criteria:

* No simultaneous histological and serological assessment within the first year after transplantation, including i) absence of serum available for anti-angiotensin II type 1 receptor antibody assessment, and/or ii) absence of donor-specific anti-HLA antibody testing, and/or iii) absence of kidney allograft biopsy
* Inadequate kidney allograft biopsy according to the Banff classification for allograft rejection
* Combined transplantation

Primary outcomes:
measure: Incidence of biopsy-proven kidney allograft rejection according to the presence of post-transplant circulating anti-angiotensin II type 1 receptor antibodies within the first year after transplantation
timeFrame: One year after transplantation
measure: Comparison of allograft injury phenotype according to post-transplant anti-angiotensin II type 1 receptor antibody status and concomitant donor-specific anti-HLA antibody status
timeFrame: One year after transplantation
measure: Association between the presence of post-transplant circulating anti-angiotensin II type 1 receptor antibodies and time to kidney allograft
timeFrame: Up to seven years after inclusion
Secondary outcomes:
measure: Incidence of anti-angiotensin II Type 1 receptor antibodies in kidney transplant recipients within the first year after transplantation
timeFrame: One year after transplantation
measure: Comparison of endothelial-associated transcript expression (ENDAT) levels according to anti-angiotensin II type 1 receptor antibody status and donor-specific anti-HLA antibody status
timeFrame: One year after transplantation
Other outcomes:
Locations:
city: Paris
country: France
facility: Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
city: Paris
country: France
facility: Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
Study officials:
affiliation: Paris Translational Research Center for Organ Transplantation
name: Carmen Lefaucheur
role: PRINCIPAL_INVESTIGATOR
affiliation: Paris Translational Research Center for Organ Transplantation
name: Alexandre Loupy
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin
name: Duska Dragun
role: PRINCIPAL_INVESTIGATOR
References: