Angiotensin II type 1 receptor antibodies as a contributor to microvascular inflammation in kidney transplant recipients: insights from statistical and artificial intelligence based approaches

Introduction: In recent years, advancements in the classification of renal allograft pathology have led to a notable increase in the diagnosis of antibody-mediated rejection (ABMR). Particular attention has been given to microvascular inflammation (MVI), a subcategory of ABMR that was reappraised in the Banff 2022 classification. Recognizing a significant discrepancy between the number of patients testing positive for donor-specific anti-HLA antibodies (DSAs) and those clinically diagnosed with ABMR, this study aims to explore the potential role of non-HLA antibodies, specifically, antibodies against the angiotensin II type 1 receptor (AT1R), in the development of MVI. Material and methods: A retrospective analysis was performed on clinical and pathological data from 167 kidney transplant recipients. MVI was diagnosed histologically based on biopsy findings, specifically a glomerulitis score (g) > 0 and/or peritubular capillaritis (ptc) > 0. Based on these criteria, two patient cohorts were identified: 88 patients without MVI and 79 patients with MVI. Statistical analyses were conducted using appropriate methods, including chi-square tests, Student's t-tests, and Mann-Whitney U tests. Additionally, complementary analyses utilizing artificial intelligence techniques such as correlation analysis, logistic regression and association rule mining were applied to maximize insights from the dataset. Results: Patients with MVI demonstrated a statistically significantly higher prevalence of AT1R antibodies compared to those without MVI. The finding was confirmed by both traditional statistical methods and artificial intelligence analysis. Furthermore, the MVI-positive cohort exhibited a higher frequency of C4d positivity compared to patients without MVI. Conclusions: The presence of AT1R antibodies may be associated with the development of microvascular inflammation, potentially contributing to allograft injury in a subset of cases of kidney transplant recipients. High AT1R abs titers (>12 U/ml) were particularly important, while lower levels did not show the meaningful association. These findings underscore the importance of broadening immunologic surveillance beyond conventional anti-HLA antibody screening.