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Archetypal Analysis of Deceased Donor Kidneys: A Molecular Approach for Posttransplant Outcomes

ABSTRACT: This prospective, single-center study (NCT06171438) included 276 kidneys from 174 deceased donors. Donor procurement biopsies were performed on the backtable and part of the biopsy was stored for future RNA extraction and molecular profiles analysis using Affymetrix microarrays. Three molecular classifiers (the logistic regression model, the Poisson regression and the extreme gradient boosting) with 10-fold cross validation were employed to identify donor categories based on clinical variables (age, BMI, hypertension, marginal kidney) and histological biopsy scores (the vascular fibrous intimal thickening (cv), interstitial fibrosis (ci) and tubular atrophy (ct) and arteriolar hyaline thickening (ah). Archetypal analysis was applied to determine molecular phenotypes and their association with short- and long-term transplant outcomes. Three donor molecular archetypes were identified. Marginal archetype was characterized by older age (median 68 years), extensive chronic morphological changes (IFTA>0 in 66%, ah>1 in 59%, cv>1 in 36%), and the highest Kidney Donor Risk Index (KDRI). Ideal archetype was associated with young age (median 42 years), low KDRI, minimal chronic histological changes (IFTA>0 in 39%, ah>1 in 33%, cv>1 in 13%) and the highest posttransplant eGFR at 12 months (p<0.001). Intermediate archetype 3 was associated with older age (median 63 years) however better eGFR at 12 months follow-up despite similar chronic histological changes (IFTA>0 in 73%, ah>1 in 63%, cv>1 in 56%). Molecular profiling outperforms histology in procurement biopsies and enables the identification of ECD kidneys with better posttransplant kidney allograft function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290167 | GEO | 2025/12/22

REPOSITORIES: GEO

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Project description:Rationale: Interstitial fibrosis and tubular atrophy (IFTA) is found in ~25% of 1-year biopsies post-transplant(1, 2). It correlates with decreased graft survival when histological evidence of inflammation is present¬.(3-5) Identifying the etiology of IFTA is important because longterm graft survival has not changed as expected given improved therapies and a dramatically reduced incidence of acute rejection.(6-8) Methods: Gene expression profiles of 234 samples were obtained with matching clinical and outcome data (7 transplant centers). 81 IFTA samples were divided into subphenotypes by the degree of inflammation on histology: IFTA with acute rejection (AR), IFTA with inflammation and IFTA without inflammation. Samples with AR (n=54) and normally functioning transplants (TX; n=99) were used in comparisons. Conclusions: Gene expression profiling of all IFTA phenotypes were strongly enriched for cAR gene dysregulation pathways, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. We also found that the relative expression of AR-affiliated genes correlated with future graft loss in IFTA samples without inflammation. We conclude that undetected and/or undertreated immune rejection is leading to IFTA and graft failure. RNA was extracted from biopsy samples using the RNEasy kit (Qiagen), biotinylated cRNA prepared using Ambion MessageAmp Biotin II and hybridized to Affymetrix HG U133 Plus PM peg arrays (http://affymetrix.com/index.affx). Probe intensity data were log2–transformed and normalized using a custom-designed frozen Robust Multichip Average (fRMA). Low-variance and low signal probes were filtered according to industry standards, resulting in a filtered gene list with 17,564 transcripts. This dataset is part of the TransQST collection.

Project description:BACKGROUND: Alcohol-related liver disease ranges from silent alcoholic steatohepatitis (sASH), an asymptomatic and compensated phenotype, to life- threatening alcoholic hepatitis (AH). A systematic comparative study of the clinical, histological and molecular features of these subtypes is lacking. METHODS : Two large cohorts of patients were recruited in an international, observational multi-center study: a retrospective cohort of patients with sASH (n=110) and a prospective cohort of patients with AH (two subgroups with n=121 and 104). sASH and AH were compared by doing clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis. FINDINGS: Age and mean alcohol intake were similar in patients with sASH vs AH. AH showed lower mean arterial pressure than sASH. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma- glutamyl transferase levels than AH. Individuals with AH demonstrated profound liver failure, lower blood pressure and increased mortality. Histologically, the grade of steatosis, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and progenitor cell expansion were more frequent among AH patients. One-year mortality was 10% in sASH and 50% in AH. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. Globally, AH patients exhibited changes in 4,921 genes, while the number of dysregulated genes in sASH patients was less pronounced -1,327-. While sASH was characterized by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. INTERPRETATION: Despite comparable daily alcohol intake, AH patients presented with worse liver function and hemodynamic status compared to sASH. Bilirubinostasis, severe fibrosis and progenitor cell expansion were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared to sASH.

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Archetypal Analysis of Deceased Donor Kidneys: A Molecular Approach for Posttransplant Outcomes

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