Supplementary Material for: Positive Long-term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results Estimated 10-year overall graft survival between the PRA-0 and AM cohorts were similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody mediated rejection rates (ABMR) was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of dnDSA was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion/Conclusion The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help to reduce dnDSA formation, particularly in high-risk AM patients

Supplementary Material for: Urine Metabolomics by ¹H-NMR Spectroscopy Indicates Associations between Serum 3,5-T₂ Concentrations and Intermediary Metabolism in Euthyroid Humans

<b><i>Context:</i></b> 3,5-Diiodo-L-thyronine (3,5-T₂) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T₂ and glucose but not lipid metabolism. <b><i>Objective:</i></b> The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T₂ concentrations in healthy individuals. <b><i>Study Design and Methods:</i></b> Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by ¹H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T₂ concentrations. <b><i>Results:</i></b> Serum 3,5-T₂ concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T₂ concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. <b><i>Conclusion:</i></b> Our findings in humans confirmed the metabolic effects of circulating 3,5-T₂ on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T₂ exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones