HOMER - Healthcare Orientated Machine-LEarning Research
Lcn2 in Kidney Transplantation | Sub-project of CRC Renoprotection (SFB 1365)
Despite advances in immunosuppression and modern surgical techniques that have significantly improved short-term graft survival, overall long-term graft survival has not changed considerably in the last decades. Besides, patients have to take immunosuppressive drugs for lifetime to avoid graft rejection after transplantation. Such a therapy is, nonetheless, associated with a variety of undesirable side effects including, increased incidence of infections, tumor diseases, cardiovascular diseases, etc. Moreover, in addition to immunological reactions due to donor and recipient incompatibility, IRI poses significant threats to allograft function early after transplantation, and limits long-term graft survival. Increased tendency of including extended criteria donors (ECD) in the transplantation programs due the shortage of donor organs has further substantiated the need to minimize or prevent early injury, which increases the risk of developing DGF, acute rejection and graft loss. To obtain longterm allograft and patient survival, novel strategies are therefore needed, including (i) prevention of renal allograft IRI and (ii) targeted immunosuppression and thus reduction and/or avoidance of steroid and CNI usage in the end.
Therapeutic Potential of Lcn2 in Kidney Transplantation
Lipocalin-2 (Lcn2), a member of the lipocalin family, is distinctly upregulated in kidney transplants, and its level in the body fluids serves as a promising early marker of AKI, DGF and acute rejection of the renal allografts. Apart from its role as a biomarker, Lcn2 actively protects against AKI, such as IRI. However, which route the protein takes, and the functional role and mechanisms underlying Lcn2 up-regulation within the transplanted organs, remain largely unknown. We recently employed a murine model of kidney transplantation to address a potential therapeutic effect of Lcn2 to kidney allografts (Ashraf et al. Am J Transplant, 2016). Using Lcn2 deficient (Lcn2-/-) mice in both donor and recipient combinations, we demonstrated that endogenously expressed Lcn2 had little or no effect early after kidney transplantation Figure-1. However, peri-operative administration of rLcn2:Siderophore:Fe complex (rLcn2) to the recipient resulted in functional and morphological amelioration of the allograft injury.
Figure 1: Kidneys were transplanted syngeneically from C57Bl/6 (Bl/6) to Bl/6 mice and allogeneically from Bl/6 wt or Lcn2-/- to Balb/c and Balb/c to Bl/6 wt or Lcn2 -/- mice. At post-transplant day 7, cumulative Banff score of histological lesions (A, B) and serum creatinine levels (C) were assessed. While no effect of endogenous Lcn2 was observed, peri-operative application of rLcn2 significantly reduced histological lesions and ameliorated allograft function. Black and white arrows highlight the examples of tubulitis and peri-arterial lymphocytic aggregates (PALA), respectively. *p<0.05 (adapted from Ashraf et al. Am J Transplant, 2016).
Nevertheless, the molecular and cellular events underlying the renoprotective effects of rLcn2 in kidney allografts remain unclear, which is mandatory for comprehensive translation of the therapy into clinical practice. Elucidating these events forms the main aim and primary focus of this DFG funded project. Moreover, it is essential to determine whether the Lcn2 produced in the allograft or detected in the body fluids following kidney transplantation is complexed with mammalian siderophore/Fe and may provide renoprotection to the allograft in the long run. Therefore, the major aims of the project are:
understanding the route and mechanisms of immunoregulation and/or cytoprotection, mediated by exogenously administered rLcn2 during the allograft damage and
characterizing the source and nature of endogenous Lcn2 i.e. whether it is complexed with mammalian iron binding catechols and may contribute to allograft survival in the long run
Our ultimate goal is to pave the way for transplant renoprotection via rLcn2.
This is a sub project (C2) of CRC-Renoprotection (1365). The CRC is an interdisciplinary research consortium aiming at identify and targeting common pathways to kidney failure and thereby devise new treatment approaches (Spokesperson: Prof. Dr. Pontus B. Persson, Charité - Universitätsmedizin Berlin).