Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It preferentially inhibits denovo pathway of guanosine nucleotide synthesis in T and B-lymphocytes and prevents their proliferation, thereby suppresses both cell mediated and humoral immune responses. Clinical trials in kidney transplant recipients have shown the efficacy of MMF in reducing the incidence and severity of acute rejection episodes. It also improves long term graft function as well as graft and patient survival in kidney transplant recipients. MMF is useful as a component of toxicity sparing regimens to reduce or avoid exposure of steroids or calcineurin inhibitor (CNI). Enteric-coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppressive agent in kidney transplant recipients with efficacy and safety profile similar to MMF

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.Design Systematic review and meta-analysis of individual patient data.Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.Results the search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. the most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. the benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.PfizerOttawa Hosp, Res Inst, Ottawa, ON K1H 7W9, CanadaUniv Ottawa, Ottawa, ON, CanadaCairo Univ, Cairo Kidney Ctr, Cairo, EgyptLimites Med Res, Vacallo, SwitzerlandUniv Manitoba, Dept Pediat & Childs Hlth, Winnipeg, MB, CanadaLund Univ, Dept Nephrol & Transplantat, Malmo, SwedenUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, São Paulo, BrazilAddenbrookes Hosp, Dept Renal Med, Cambridge, EnglandNorthwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USAMaastricht Univ, Med Ctr, Maastricht, NetherlandsSt Louis Hosp, Dept Nephrol, Paris, FranceHosp JW Goethe, Div Nephrol, Frankfurt, GermanyUniv Munich, Dept Surg, Munich, GermanyGoethe Univ Frankfurt, JW Goethe Clin, Clin Dermatol Venerol & Allergol, Frankfurt, GermanyInst Klin Expt Med, Dept Nephrol, Prague, Czech RepublicUniv Cambridge, Addenbrookes Hosp, Dept Surg, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 2QQ, EnglandUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, São Paulo, BrazilWeb of Scienc

Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients

BackgroundBelatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney transplant recipients. The use of Bela with early steroid withdrawal (ESW) and simultaneous CNI avoidance has not been formally evaluated. MethodsAt 3 months post-transplant, stable kidney transplant recipients with ESW on Tacrolimus (Tac) + mycophenolate (MPA) were randomized 1:1:1 to: 1) Bela+MPA, 2) Bela+low-dose Tac (trough goal <5 ng/mL), or 3) continue Tac+MPA. All patients underwent surveillance graft biopsies at enrollment and then at 12, and 24 months post-transplant. Twenty-seven recipients were included; 9 underwent conversion to Bela+MPA, 8 to Bela+low-dose Tac and 10 continued Tac+MPA. Serial blood samples were collected for immune phenotyping and gene expression analyses. ResultsThe Bela+MPA arm was closed early due to high rate of biopsy proven acute rejection (BPAR). The incidence of BPAR was 4/9 in Bela+MPA, 0/8 in Bela+low dose Tac and 2/10 in Tac+MPA, P= 0.087. The Bela+low-dose Tac regimen was associated with +8.8 mL/min/1.73 m(2) increase in eGFR compared to -0.38 mL/min/1.73 m(2) in Tac+MPA, P= 0.243. One graft loss occurred in the Bela+MPA group. Immunophenotyping of peripheral blood monocyte count (PBMC) showed that CD28(+)CD4(+) and CD28(+)CD8(+) T cells were higher in Bela+MPA patients with acute rejection compared to patients without rejection, although the difference did not reach statistical significance. ConclusionsOur data indicate that, in steroid free regimens, low-dose Tac maintenance is needed to prevent rejection when patients are converted to Bela, at least when the maneuver is done early after transplant

Pre-transplant T-cell clonal analysis identifies CD8+ donor reactive clones that contribute to kidney transplant rejection

IntroductionResponses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection.MethodsDRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4+ and CD8+ DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients.ResultsIn patients with an abnormal biopsy, the majority of CD8+ DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8+ DRTC were more abundant pre- and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples.DiscussionThe findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection

From Metastudies to Metaverse

The authors believe that the Metaverse is a paradigm shift infrastructure technology that may make 60% of universities irrelevant in the next 20 years if they don’t move away from the meta-studies model. Meta-studies refers to an archival, largely paper-based process of “teaching” what other people have written about, focused on the past, and supported by the “publish or perish” imperative. The Covid-19 pandemic has forced universities into adopting technologies that form a part of the Metaverse, but for the most part they have used these technologies to perpetuate the status quo. If universities cannot change their practices to become more agile, adopting design thinking, inquiring minds, and critical thinking not only for students but also for themselves as institutions, it will be commercial entities such as Meta and Microsoft who will decide what education will take place in the Metaverse, and students will go there whether universities are present or not. It is therefore important that universities change their own paradigms, and engage with this technology to discover how it can be used effectively in education, so as to foster principles and values for building knowledge and cementing ethical, sustainable practices.</jats:p

Higher Education and Globalization

In this chapter, the authors examine the forces influencing higher education in a digitally globalized, plurilingual, and intercultural world, and how they have already begun to change some traditional notions of what higher education is for, and how it should be adapted to fit new emergent social needs, which are currently under debate in the educational field (Mehaffy, 2012). They go on to propose a connectivist vision for the future of globalized higher education and provide three case studies that illustrate ways of achieving that vision. Each case study has a different orientation: resource orientation, process orientation, transformation orientation. All three of them have the same objective: innovation and adaptation to the new globalized paradigms that have placed higher education in an increasingly complex context. </jats:p