Relación entre inmunosupresión e inflamación subclínica en biopsias de seguimiento de trasplante renal

Abstract

Chronic kidney disease (CKD) is a major global health issue, affecting about 10% of the population and projected to be the fifth leading cause of death by 2040. Kidney transplantation (KT) is the preferred treatment for advanced CKD due to its benefits in survival, quality of life, and cost-effectiveness compared to dialysis. Despite these advantages, KT is associated with long-term complications, particularly related to immunosuppression, where both excessive and insufficient exposure pose significant risks. Excessive immunosuppression can lead to infections and cancers, while insufficient immunosuppression increases the risk of immune-mediated rejections, including antibody-mediated rejection (AMR) and T-cell-mediated rejection (TCMR). Furthermore, subclinical inflammation in the graft can result in the development of de novo donor-specific HLA antibodies (dnDSA), complicating graft outcomes further. The standard post-transplant immunosuppressive regimen typically consists of tacrolimus (TAC), mycophenolate mofetil (MMF), and sometimes low-dose steroids. TAC, though effective, is challenging to manage due to its narrow therapeutic range, low bioavailability, and significant variability in drug levels among patients. Low levels of TAC during the first year post-transplant are associated with an increased risk of both acute and subclinical rejection and dnDSA development. Conversely, high levels of TAC are linked to nephrotoxicity, viral infections, and cancer. To address these challenges, rigorous post-transplant monitoring is essential. Recent advancements in biopsy techniques have enabled better detection of subclinical inflammation and fibrosis progression. Research has shown that such subclinical inflammation correlates with immunosuppressive drug exposure, HLA incompatibility, and dnDSA formation. Graft monitoring involves non-invasive biomarkers like serum creatinine, proteinuria, and HLA antibodies. Additionally, new technologies, including gene expression profiling in blood and urine and donor-derived cell-free DNA (dd-cfDNA), are enhancing diagnostic accuracy and understanding of the underlying immunopathological mechanisms. These advances facilitate more precise and effective interventions. The thesis in question explores the interplay between subclinical inflammation in kidney grafts, immunosuppressive drug exposure, and gene expression related to graft rejection. It comprises three studies addressing different facets of this issue. The first study examines gene expression in kidney transplant biopsies, categorizing them as normal, rejected, or with incomplete rejection phenotypes. A new scoring system, the RAG-score, was developed to distinguish between normal and rejection biopsies and was found to be associated with graft survival independent of histological diagnosis. The RAG-score also identified subclinical rejection in biopsies with incomplete rejection phenotypes. The second study assessed the relationship between histological lesions and TAC exposure in biopsies taken at 3 and 12 months post-transplant. A lower concentration/dose ratio of TAC was associated with increased progression of interstitial fibrosis and tubular atrophy (IF/TA), while higher TAC levels correlated with reduced inflammation in non-fibrotic areas. The third study investigated how TAC levels relate to the expression of genes associated with rejection, using RT-PCR on microfluidic cards. Nineteen genes were identified as correlating with TAC-C0 levels at the time of biopsy. The analysis revealed two patient groups based on gene expression profiles: those with lower TAC-C0 levels exhibited subclinical rejection and a progressive decline in renal function. These studies provide valuable insights into how immunosuppression and subclinical inflammation affect kidney graft outcomes, offering new perspectives for improving post-transplant management strategies

Date of Award	6 Nov 2024
Original language	Spanish
Supervisor	Irina Betsabé Torres Rodriguez (Director)