Studies on the role of complement in antibody-mediated rejection of kidney transplants

Late antibody-mediated rejection (AMR) has been recently suggested to be responsible for the majority of chronic graft losses after kidney transplantation. Late AMR is caused by the development of donor specific antibodies (DSA) directed mainly against the donor 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 involvement of the complement system, although suggested to be a critical pathogenic step, has not sufficiently been explored. Furthermore, the diagnosis of AMR is challenging even if kidney biopsy is performed and there is still an urgent need for novel diagnostic markers to improve early and proper treatment. In this context, there could be a potential utility of blood and urinary complement biomarkers; however, there diagnostic value has not yet been investigated. Therefore, the aim of the current study is to measure multiple complement markers in a large cohort of renal transplanted 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 clinical course of 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 project may help to improve the diagnostic algorithm of late AMR and facilitate the better understanding of different clinical and pathological phenotype of this complex entity. Furthermore, we expect that improved diagnostic system and classification may contribute to earlier initiation of successful treatment and thereby lead to better graft survival after kidney transplantation in the long term.

The incidence of end-stage kidney diseases increases worldwide leading to significant number of patients requiring dialysis. Kidney transplantation is the best therapy option for these patients which was established in the 1950s. Nowadays, short term survival of the patients and the transplanted organ is excellent, however, long-term transplant outcome has not significantly improved in the last decades. The median survival of the graft is approx. 10 years necessitating dialysis therapy again. Thus, the major need in transplantation medicine at the moment is to prolong long-term graft survival.The so-called late antibody-mediated rejection (ABMR) has been suggested to be responsible for the majority after kidney transplantation in the long term. Late ABMR is caused by the development of donor specific antibodies (DSA) which is the consequence of the immunological incompatibility between donor and recipient which is at a certain level always present unless donor and recipient are identical twins.Although much effort has been made in the last years, the early diagnosis and proper treatment of ABMR are still a challenge. Early identification / diagnosis of patients could lead to earlier initiation of therapy which could potentiate a better graft survival.The role of the so-called complement system which is part of the patients immune system enhancing cell damage has been intensively investigated and discussed in ABMR.The complement system consists of a number of proteins that can be measured in different body fluids such as blood and urine.Our hypothesis was that the level of some complement proteins might be abnormal in patients with late ABMR and measurement of these proteins could help the diagnosis of ABMR.In our study, therefore, several complement proteins were analyzed in the blood and urine of kidney transplanted patients with late ABMR and in patients without ABMR. The statistical analysis showed that there was no significant difference in the level of the studied complement proteins between the two groups.Our conclusion is therefore, that the level complement proteins during late ABMR does not change significantly during late ABMR in peripheral fluids such as blood and urine.However, since the role of the complement system is a highly discussed topic in ABMR, the results of this project have a high relevance and complete our current knowledge about the involvement of complement in kidney transplantation. No other group has previously investigated this specific question from this aspect.