Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes

Kidney Transplant Failure and Rejection Clinical Trial

Official title:

Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03466775
• Other study ID #: AT1R001
• Status: Completed
• Phase: N/A
• First received: March 9, 2018
• Last updated: March 9, 2018
• Start date: January 1, 2008
• Est. completion date: December 31, 2017

Study information

• Verified date: March 2018
• Source: Paris Translational Research Center for Organ Transplantation
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1845
• Est. completion date: December 31, 2017
• Est. primary completion date: December 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Kidney Transplant Failure and Rejection

Intervention

Diagnostic Test:
• Anti-angiotensin II type 1 receptor antibody measurement
Anti-angiotensin II type 1 receptor antibodies are assessed using quantitative ELISA in stored serum samples obtained within the first year after transplantation
• Measurement of ENDAT expression level allograft
Endothelial-associated transcript expression level is assessed using microarray in stored kidney allograft biopsies obtained within the first year after transplantation

Other:
• Allograft survival

• Allograft rejection appearance

Locations

Country	Name	City	State
France	Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France	Paris
France	Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Paris Translational Research Center for Organ Transplantation	Center for Cardiovascular Research Berlin

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Anti-angiotensin II type 1 receptor antibody positivity is defined by serum concentration >10 U/mL using quantitative ELISA. Stratified analysis is performed according to the presence of post-transplant concomitant circulating donor-specific anti-HLA antibodies detected by single antigen bead assay in serum. Allograft rejection is defined on the basis of the 2015 update of the Banff classification for allograft rejection.	One year after transplantation
Primary	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	Injury phenotype is based on histological allograft elementary lesions defined by the Banff classification (glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, endarteritis, chronic allograft glomerulopathy, interstitial fibrosis, tubular atrophy, arteriosclerosis, arteriolar hyalinosis, C4d deposition in peritubular capillaries).	One year after transplantation
Primary	Association between the presence of post-transplant circulating anti-angiotensin II type 1 receptor antibodies and time to kidney allograft	Univariate and multivariable models are performed, including adjustment for recipient age and gender, biopsy indication, glomerular filtration rate, proteinuria, presence of post-transplant circulating donor-specific anti-HLA antibodies and histological elementary lesions defined by the Banff classification, assessed at the time of antibody detection.	Up to seven years after inclusion
Secondary	Incidence of anti-angiotensin II Type 1 receptor antibodies in kidney transplant recipients within the first year after transplantation	Anti-angiotensin II type 1 receptor antibody positivity is defined by serum concentration >10 U/mL using quantitative ELISA.	One year after transplantation
Secondary	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	ENDAT expression levels are measured in kidney allograft biopsies performed at the time of antibody detection, showing microcirculation inflammation (sum of glomerulitis and peritubular capillaritis Banff scores >1), using microarray technology.	One year after transplantation