Renal Allograft Rejection - Diagnostic and Pathophysiologic Aspects

Episodes of acute allograft rejection (AR) are a negative prognostic factor for the development of interstitial fibrosis and tubular atrophy (IF/TA), the morphological surrogate of chronic renal allograft deterioration, and for long-term graft survival. Hence, early detection and treatment of AR is crucial to limit the inflammatory process and preserve the function of the transplant. Core needle biopsies are still the "gold-standard" in rejection diagnostics. Nevertheless, they are cumbersome to the patient and carry the risk of significant hematuria, arteriovenous fistulas, and graft loss. Therefore, a non-invasive tool for specific detection of AR, which can be applied in the early phase of rejection, is desirable. As in small animals such as rats and mice (widely used in biomedical research as models for human diseases) blood and urine sampling is difficult and may yield inaccurate data due to low volumes, we first established 18F-fluoride positron emission tomography (18F PET) for the noninvasive assessment of renal function in rats. We observed an impaired energy status in grafts undergoing rejection. In the acute scenario this was associated with recruitment of activated leukocytes and decreased expression and function of important renal transporters like the Na+/H+ exchanger type 3 (NHE-3). Interestingly, a therapy with a NHE-3 blocker was able to reduce energy consumption of the graft and preserve NHE-3 function. In the chronic situation disturbance of energy homeostasis might be critically involved in the development of IF/TA. 18F-Fluor-Desoxy-Glucose (FDG) PET is a tool widely used to assess regional metabolic activities of tissues. Thus we aimed to validate FDG PET for the detection of rejection. This thesis will focus on the processes occurring in allograft rejection. Moreover, based on our findings in renal transplant and failure models, entirely image-based methods like 18F PET and FDG PET have been established and validated to non-invasively assess renal (graft) failure in small-animals.