Selective Elimination and Rationalization of Cell-based Assays in Deceased Donor Kidney Transplant Crossmatching.

Background: While there is increasing reliance on a negative virtual crossmatch to proceed with deceased donor kidney transplantation, a flow cytometry crossmatch (FCXM) is still usually performed after the transplant has already occurred. Our center has eliminated pretransplant physical crossmatches for most patients, and since 2018, we have eliminated the systematic performance of posttransplant FCXMs. Methods: We studied all deceased donor kidney transplants in our program between June 1, 2018, and March 31, 2021, to evaluate the impact of eliminating retrospective FCXMs on resource utilization and graft outcomes (ie, the occurrence of antibody-mediated rejection [AMR] in the first 3-mo posttransplant). Results: A total of 358 kidney transplants occurred during the study period, and approximately 70% of these transplants proceeded without the performance of any FCXM. Incidence rates of AMR were low (9.63 per 1000 person-months), which compared favorably with the incidence rate of AMR during the 3-y period preceding the policy (4.82 per 1000 person-months, P = 0.21). Conclusions: Our results suggest that moving away from retrospective FCXM and relying exclusively on the virtual crossmatch is safe and efficient for kidney allocation.

Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis.

Introduction: Studies on complement activation have implicated a combination of the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) in triggering the terminal pathway (TP) for each common autoimmune glomerulonephritis (GN). Evaluating different pathways simultaneously may help identify whether one is preferentially activated and, consequently, which is best to target for each disease. Methods: We followed 112 patients with focal segmental glomerular sclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), and antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) for a median duration of 22 (12-52) months. At the time of greatest clinical activity, we simultaneously evaluated urinary C3a (C3 convertase activity), C5a and sC5b-9 (TP), MASP-1 and MASP-2 (LP), C1q (CP), C4a (CP/LP), and Ba and Bb (AP). We evaluated the relation between activation fragments of the AP and CP/LP with the TP. Results: Urinary complement biomarkers for each pathway were associated with the severity of proteinuria. Fragments of the TP were higher among patients with FSGS and MN compared with patients with IgAN, LN, and AAV. For the AP, urinary Ba level was lower in those with IgAN and LN compared with those with FSGS. For the CP/LP, urinary C4a, MASP-1, and MASP-2 levels were similar between diseases whereas urinary C1q levels were lower in those with LN. For each GN, independent associations existed between the activation markers of the AP and CP/LP with the degree of TP activation, except for the AP in AAV, although perhaps underpowered. Conclusion: The AP and CP/LP contribute individually to the TP activation in autoimmune GN, and both seem to be valid potential therapeutic targets.

Kidney transplant candidates' and recipients' perspectives on the decision-making process to accept or refuse a deceased donor kidney offer: Trust and graft survival matter.

BACKGROUND: The decision to accept a kidney from a deceased donor can be a difficult one. This study aims to capture the perspectives of transplant candidates (TCs) and kidney transplant recipients (KTRs) on the decision-making process when a deceased kidney is offered. METHODS: We conducted six focus groups with KTRs and TCs. The content of the focus groups was analyzed using the qualitative thematic method. RESULTS: KTRs reported that the experience of being offered a kidney could be difficult because of the circumstances of the offer and unpreparedness to participate in the discussion. Both KTRs and TCs trusted the medical expertise. Age and having experience with dialysis could influence the decision to accept an offer. In order to engage in the discussion, patients wanted to obtain estimates of expected graft survival. Patients did not express interest for a web-based calculator for patient use, but expected transplant physicians to summarize and explain the information that would impact graft survival time. CONCLUSION: TCs and KTRs wanted to be involved in the decision to accept a deceased donor kidney. Tools that can help physicians communicate the risks and benefits of accepting an offer could improve patient participation in the decision-making process.

Clinical Use of Complement, Inflammation, and Fibrosis Biomarkers in Autoimmune Glomerulonephritis.

INTRODUCTION: Complement activation, inflammation, and fibrosis play central roles in the mechanisms of injury in autoimmune glomerulonephritis (GN) but they are seldom assessed in epidemiologic studies. The measurement of urinary biomarkers of these pathways of injury could parallel disease activity and add clinical value beyond proteinuria. METHODS: We performed a prospective cohort study of 100 patients with focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), and membranoproliferative GN (MPGN) followed for 33 (18-54) months. Repeated urinary samples were collected throughout their follow-up to determine proteinuria, urinary sC5b-9, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta 1 (TGF-ß1), expressed as creatinine ratios. We identified 177 periods of active and inactive disease based on current remission definitions for each disease. RESULTS: Urinary sC5b-9, MCP-1, and TGF-ß1 were present in each disease. In periods leading to a remission, the reduction of urinary sC5b-9 was 91%, greater than for proteinuria with 76%. During inactive periods, those who did not experience a relapse maintained lower levels of biomarkers compared with those who relapsed. At that time, the increase in urinary sC5b-9 was significantly greater than the rise in proteinuria (8.5-fold increase compared with 3.2-fold) and urinary MCP-1 and TGF-ß1. Using current remission definitions for each disease, thresholds for each biomarker were determined using receiver operating characteristic curves. Individuals who averaged levels below these cutoffs during their follow-up had better renal outcomes. CONCLUSION: In autoimmune glomerular diseases, urinary sC5b-9, MCP-1, and TGF-ß1 are present and parallel disease activity and outcomes. Urinary sC5b-9 appears to be a more discerning marker of immunologic remissions and relapses.

Impact of updated recommendations on acetylsalicylic acid use for primary prevention of cardiovascular disease in Canada: a population-based survey.

BACKGROUND: The debate over acetylsalicylic acid (ASA) therapy for primary prevention of cardiovascular disease (CVD) has recently resurfaced, but scarce data are available on prophylactic ASA use in Canada for this purpose. This study aimed to evaluate the prevalence and factors associated with ASA use, and the potential impact of implementing the most recent (2016) US Preventive Services Task Force recommendations for primary CVD prevention in a Canadian setting. METHODS: We performed a cross-sectional analysis using data from the CARTaGENE study, which included a representative sample (n = 20 004) of the 2018 general population of the province of Quebec. We assessed eligibility for ASA treatment using US Preventive Services Task Force criteria (age 50-69 yr, no past history of myocardial infarction or stroke, and 10-year risk of CVD of at least 10%). We extrapolated to the entire 2018 Quebec population the number of people who would need to start ASA treatment. RESULTS: A total of 6231 respondents in the CARTaGENE study (54.2% of those aged 50-69 yr with no prior history of CVD) were found to be potentially eligible for ASA use for primary CVD prevention. Of the 6231, 1379 (22.1%) were receiving prophylactic ASA treatment. Factors found to be related to ASA use included age, male sex, regular medical visits, lower education level, obesity, hypertension, diabetes and dyslipidemia. Income and smoking status were not found to be significantly associated with ASA use. Our results indicate that 885 261 people would potentially have started ASA treatment if the US Preventive Services Task Force recommendations had been implemented in Quebec in 2018. INTERPRETATION: Prevalent ASA use for primary CVD prevention was low. Implementation of the 2016 US Preventive Services Task Force recommendations would require initiating ASA treatment in a substantial proportion of people, with undetermined potential benefits.

TGFß Programs Central Memory Differentiation in Ex Vivo-Stimulated Human T Cells.

The adoptive transfer of ex vivo-expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGFß during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFß suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4+ and CD8+ T-cell subsets. The T cells stimulated in the presence of TGFß expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo-stimulated T cells into immunodeficient mice confirmed that TGFß-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versus-host disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor-expressing T cells generated in the presence of exogenous TGFß were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFß in memory T-cell differentiation and indicates that TGFß signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.