Antibody-mediated rejection (AMR) is responsible for the majority of kidney graft losses in the recent years. Late AMR is caused by the development of donor specific antibodies (DSA) directed against the HLA class I and II antigens. However, the steps of the pathogenic process along AMR leading to graft loss are only partially known and the role of complement, although suggested to be important, has not been explored in details. Furthermore, the diagnosis of AMR is challenging even if kidney biopsy is performed and the potential utility of serum, plasma or urinary complement biomarkers has not been investigated yet. Therefore, the aim of the current study is to measure multiple complement markers in a large cohort of post kidney transplant patients with de novo DSA to explore if these markers may help the diagnosis and classification of AMR. Furthermore, explorative analysis will also be performed to identify associations between variants of selected complement genes and various histological phenotypes of AMR. The patients will be followed and re-biopsy will be performed if indicated, thus the initial diagnosis of AMR will be validated allowing drawing firm conclusions at the end of the study. The results of this study may help to improve the diagnostic algorithm of late AMR and facilitate to better understand the different clinical and pathological phenotype of this complex entity. Furthermore, we expect that this improved diagnosis and classification may contribute to earlier initiation of successful treatment and thereby lead to better graft survival after kidney transplantation in the long term.
Since until now, no in-depth parallel analysis of donor specific antibodies, histopathological data and complement investigations have been performed in kidney transplant patients, we hypothesize that we will be able to identify markers in the complement profile to improve the diagnosis and classification of AMR. Functional variants of selected complement genes (complotype) may affect the biological effects of DSA, we further hypothesize that variants of the complotype may partially explain the various histology phenotypes of DSA-positive AMR patients. To investigate these hypotheses approximately 1000 kidney transplanted patients will be screened for DSA in the Medical University of Vienna. At the time of blood draw for DSA detection, blood and urine samples will be taken and stored and examination of serum, plasma and urinary complement profile and complotype will be performed for DSA positive (and matched DSA negative control) patients in the Semmelweis University. We expect the following results in this study:
a.) Descriptive part to identify the diagnostic/ classification biomarkers in case-control design: DSA positive patients stratified according to C4d staining (yes/no) and presence of AMR on biopsy (yes/no).
b.) Explorative part to identify correlates of biomarkers: Levels of complement biomarkers will be correlated to variants of complotype, characteristics of DSA and to histopathology data.
c.) Validation part: 12-months follow-up of DSA-positive patients (with re-biopsy of AMR positives) will be done and baseline results will be analyzed for associations and predictions of 12-months diagnosis of AMR and renal function.
What is the significance of the research?
In the framework of an already funded project (BORTEJECT, Medical University Vienna) 1000 post-kidney transplant patients will be screened for the presence of DSA and for positives kidney biopsy will be done. The study proposed in this project could utilize this unique and well characterized cohort to study the pathomechanism of AMR in a collaborative manner. With the advent of effective immunosuppressive treatments incidence of acute cellular rejection of kidney grafts declines but the long-term graft survival could not improve because of the increasing emergence of late AMR. The team in the Semmelweis University has long lasting experience in clinical studies on complement, an aspect not studied in details in AMR previously. Therefore, the most important results expected from this project would be the identification of complement biomarkers for the early diagnosis and precise characterization of AMR. Early markers in patients suspected to have (or screened for) AMR could help stratify for more effective treatment and hence, improve long-term graft survival. We specifically aim to identify urinary biomarkers with a future potential of home-screening for AMR.
The current proposal is based on already established and documented ongoing collaborative activities between the applicants in Vienna and Budapest. The joining of clinical and laboratory expertise and resources, sharing of data between the institutes would certainly result in a fruitful international collaboration. The novel results of the proposed project on complement biomarkers in AMR could easily be translated to daily medical care in the future and would therefore improve the effectivity and quality of management of patients with kidney grafts and suspected AMR.
The incidence and prevalence of end-stage renal disease is worldwide increasing. For these patients, kidney transplantation is the treatment of choice, leading to better survival and quality of life and lowering costs compared to dialysis. There is, therefore a globally and constantly growing need for improving outcome of kidney transplantation in order to preserve long-term graft function.
The development of potent immunosuppressive agents has constantly decreased acute cellular rejection rates, however long-term survival not improved in a similar way. The challenge to be overcome nowadays is the chronic deterioration of graft function which can be caused by various non-immunological and immunological factors.
The current study aims to investigate basic immuno-pathogenic processes in chronic kidney graft rejection, namely in antibody mediated rejection. The diagnosis and classification of this condition is complex and mostly relies on the results of an invasive, potentially dangerous procedure, kidney biopsy. According to our aims we are going to identify easily measurable blood (serum or plasma) or urinary biomarkers related to the action of antibodies harming the transplanted kidney graft.
In case of successful execution our project may improve the understanding the mechanism of antibody mediated rejection, and could identify such markers that (for example measured in urine at home of the patients) help identify at risk patients early and indicate early biopsy and/or alternate therapy. Therefore, our clinical research data could easily find their way to patient care and improve the quality of clinical management of affected subjects.