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ABSTRACT Background Evidence supporting glucagon-like peptide-1 receptor agonists (GLP-1RAs) in kidney transplant recipients (KTRs) remains scarce. This systematic review and meta-analysis aims to evaluate the safety and efficacy of GLP-1RAs in this population. Methods A comprehensive literature search was conducted in the MEDLINE, Embase and Cochrane databases from inception through May 2023. Clinical trials and observational studies that reported on the safety or efficacy outcomes of GLP-1RAs in adult KTRs were included. Kidney graft function, glycaemic and metabolic parameters, weight, cardiovascular outcomes and adverse events were evaluated. Outcome measures used for analysis included pooled odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes and standardized mean difference (SMD) or mean difference (MD) with 95% CI for continuous outcomes. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023426190). Results Nine cohort studies with a total of 338 KTRs were included. The median follow-up was 12 months (interquartile range 6–23). While treatment with GLP-1RAs did not yield a significant change in estimated glomerular filtration rate [SMD −0.07 ml/min/1.73 m2 (95% CI −0.64–0.50)] or creatinine [SMD −0.08 mg/dl (95% CI −0.44–0.28)], they were associated with a significant decrease in urine protein:creatinine ratio [SMD −0.47 (95% CI −0.77 to −0.18)] and haemoglobin A1c levels [MD −0.85% (95% CI −1.41 to −0.28)]. Total daily insulin dose, weight and body mass index also decreased significantly. Tacrolimus levels remained stable [MD −0.43 ng/ml (95% CI −0.99 to 0.13)]. Side effects were primarily nausea and vomiting (17.6%), diarrhoea (7.6%) and injection site pain (5.4%). Conclusions GLP-1RAs are effective in reducing proteinuria, improving glycaemic control and supporting weight loss in KTRs, without altering tacrolimus levels. Gastrointestinal symptoms are the main side effects.

Background and Objectives: Limited evidence exists regarding the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) patients with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). Thus, we conducted a systematic review and meta-analysis to assess the safety and efficacy of GLP-1RAs in T2DM patients with advanced CKD and ESKD. Materials and Methods: We performed a systematic literature search in MEDLINE, EMBASE, and Cochrane database until 25 October 2023. Included were clinical trials and cohort studies reporting outcomes of GLP-1RAs in adult patients with T2DM and advanced CKD. Outcome measures encompassed mortality, cardiovascular parameters, blood glucose, and weight. Safety was assessed for adverse events. The differences in effects were expressed as odds ratios with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean difference or standardized mean difference (SMD) with 95% confidence intervals for continuous outcomes. The Risk of Bias In Non-randomized Studies—of Interventions (ROBIN-I) tool was used in cohort and non-randomized controlled studies, and the Cochrane Risk of Bias (RoB 2) tool was used in randomized controlled trials (RCTs). The review protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023398452) and received no external funding. Results: Eight studies (five trials and three cohort studies) consisting of 27,639 patients were included in this meta-analysis. No difference was observed in one-year mortality. However, GLP-1RAs significantly reduced cardiothoracic ratio (SMD of −1.2%; 95% CI −2.0, −0.4) and pro-BNP (SMD −335.9 pmol/L; 95% CI −438.9, −232.8). There was no significant decrease in systolic blood pressure. Moreover, GLP-1RAs significantly reduced mean blood glucose (SMD −1.1 mg/dL; 95% CI −1.8, −0.3) and increased weight loss (SMD −2.2 kg; 95% CI −2.9, −1.5). In terms of safety, GLP-1RAs were associated with a 3.8- and 35.7-time higher risk of nausea and vomiting, respectively, but were not significantly associated with a higher risk of hypoglycemia. Conclusions: Despite the limited number of studies in each analysis, our study provides evidence supporting the safety and efficacy of GLP-1RAs among T2DM patients with advanced CKD and ESKD. While gastrointestinal side effects may occur, GLP-1RAs demonstrate significant improvements in blood glucose control, weight reduction, and potential benefit in cardiovascular outcomes.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8 + T cells. We have termed the rebound of cytotoxic CD8 + T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1 + CD8 + T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8 + T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Abstract Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score >= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p< 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.