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Chronic kidney disease (CKD) after liver transplantation (LT) is a major clinical problem that appears to be associated with nongenetic as well as genetic determinants. Calcineurin inhibitor (CNI) use is considered to play a major role in the development of CKD after LT. We studied the influence of single-nucleotide polymorphisms (SNPs) in the genes of the donor and recipient CNI-metabolizing enzyme CYP3A5 and the CNI-transporting ABCB1 on the development of CKD after LT.Tacrolimus (Tac) predose concentrations at different time-points after transplantation and the CYP3A5 6986A>G and ABCB1 3435C>T SNPs were determined in 125 LT recipients and their respective donors to study the influence of Tac predose levels and genetics on the development of CKD.After a median follow-up of 5.7±2.9 years, CKD developed in 47 patients (36%). The Tac predose levels were not correlated with the development of CKD. Neither did we find a correlation between the investigated SNPs in either donor or recipient ABCB1 and CYP3A5 genes (or combinations thereof) and the development of CKD. These genetic variations did not relate to Tac predose blood concentrations in our study.An individual’s risk of developing CKD after LT is not associated with genetic variation in either recipient or donor CYP3A5 or ABCB1 genotype status. [ABSTRACT FROM AUTHOR]

Background: Primary sclerosing cholangitis (PSC) is a chronic progressive pathological process, related to inflammatory bowel disease and subsequent bacterial translocation. Liver transplantation (LT) is the only curative therapy, but outcomes are compromised by recurrence of PSC (rPSC). The aim of the study was to investigate a potential link between intestinal bacteremia, fucosyltransferase-2 (FUT2), and rPSC after LT., Methods: LT recipients with PSC (n = 81) or without PSC (n = 271) were analyzed for clinical outcomes and positive bacterial blood cultures. A link between bacteremia and the genetic variant of the FUT2 gene was investigated., Results: The incidence of inflammatory bowel disease was significantly higher in PSC recipients but not associated with rPSC. Bacteremia occurred in 31% of PSC recipients. The incidence of rPSC was 37% and was significantly more common in patients with intestinal bacteremia versus no bacteremia (82% versus 30%; P = 0.003). The nonsecretor polymorphism of the FUT2 gene was identified as a genetic risk factor for both intestinal bacteremia and rPSC. Combined FUT2 genotype and intestinal bacteremia in recipients resulted in the highest risk for rPSC (hazard ratio, 15.3; P < 0.001)., Conclusions: Thus, in this article, we showed that bacterial translocation is associated with rPSC after LT and related to the FUT2 nonsecretor status., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intravenous immunoglobulins (IVIg) therapy is effective as a treatment for T-cell-mediated immune diseases, but whether and how IVIg suppress allogeneic T-cell responses is largely unknown., Methods: In vitro, human CD4(+), CD4(+)CD25(-), or CD4(+)CD25(+) T cells were stimulated with allogeneic antigen-presenting cells (APCs), and mouse CBA/Ca (H2(k)) CD4(+) or CD4(+)CD25(-) T cells were stimulated with C57BL/10 (H2(b)) splenocytes, in the presence or absence of IVIg. Proliferation, binding of IVIg, expression of activation markers, and ZAP70-phosphorylation were determined. In vivo, 1x10(5) CD4(+) or CD4(+)CD25(-) T cells of CBA/Ca mice were adoptively transferred into CBA/RAG1(-/-) mice, which were 1 day later transplanted with skin grafts of C57BL/10 mice. IVIg was administered intravenously and skin graft survival was determined., Results: IVIg bound to the surface of human and mouse CD4(+)Foxp3(+) regulatory T cells (Tregs). IVIg binding resulted in functional activation of Tregs, as detected by increased expression of surface activation markers, enhanced ZAP70-phosphorylation, and increased capacity to suppress allogeneic T-cell proliferation. IVIg inhibited allogeneic T-cell proliferation in the presence of Tregs, but this effect was abrogated on selective depletion of CD25(+) cells from responder T cells. IVIg prevented T-cell-mediated rejection of fully mismatched skin grafts in CBA/RAG1(-/-) mice reconstituted with CD4(+) T cells, but this effect was lost on selective depletion of CD4(+)CD25(+) cells from transferred T cells, indicating that IVIg induced dominant allograft protection mediated by Tregs., Conclusions: Our data show that IVIg suppress allogeneic T-cell responses by direct activation of Tregs. IVIg treatment, which has been proven safe, may have therapeutic potential in tolerance-inducing strategies in transplant medicine.

Background: CD4+FOXP3+ regulatory T cells (Treg) depend on interleukin (IL)-2 for their function and survival. By interfering with the IL-2 production, calcineurin inhibitors (CNI) may negatively affect Treg. Here, we describe the effects of conversion from CNI to mycophenolate mofetil (MMF) monotherapy on renal function, and on Treg frequency and phenotype in liver transplant recipients., Methods: Patients (n=16) with renal impairment on CNI were converted to MMF and received a single dose of IL-2-receptor blocking antibody (Daclizumab). Control patients (n=8) continued CNI treatment., Results: Renal function rapidly and significantly improved after conversion. Daclizumab treatment resulted in a 75% blocking of CD25 at 1 month causing a significant reduction in the percentage of CD4+CD25+ cells but not affecting the percentage of CD4+CD25+Foxp3+ cells. Six months after conversion to MMF, the percentage of CD4+CD25+Foxp3+ cells increased significantly by 125%. FOXP3 mRNA analysis of mononuclear cells confirmed the enrichment of Foxp3 in peripheral blood. Interestingly, the CD25 expression level on CD4+Foxp3+, but not CD4+Foxp3-, cells significantly increased compared with preconversion., Conclusion: Conversion to MMF increases the percentage and CD25 expression of CD4+FOXP3+ cells indicating that MMF therapy can overturn the repressive effect of CNI on circulating Treg levels and therefore may promote Treg-mediated suppression of alloreactivity.

Background: Differentiation between acute liver graft rejection and infection remains a clinical challenge during the early posttransplantation period. Although cytokines play a pivotal role in mediating allograft rejection, previous studies demonstrate that most cytokines are not specific for liver graft rejection or infections. However, other studies suggest that adhesion molecules and cytokines in bile reflect the immunologic activity within the liver more closely. Therefore, we postulated that by combining cytokine patterns in serum and bile, early recognition of acute liver graft rejection and differentiation from infectious complications can be improved., Methods: We performed a prospective study in 45 patients who were monitored daily for clinical events and cytokine patterns in serum and bile during the first month after liver transplantation., Results: Soluble intercellular adhesion molecule-1 (sICAM-1) in serum and interleukin-8 in bile were specifically increased at the onset of acute rejection (P<0.001), whereas serum soluble tumor necrosis factor-receptor II was also significantly increased in patients with infectious complications and serum interleukin-6 only in patients with rejection during infection. In 68% of patients with increased sICAM-1, acute rejection was diagnosed within 10 days, whereas rejection occurred in only 26% of patients with low serum levels of sICAM-1. In patients with increased sICAM-1, the relative risk for rejection was 4.8 (P=0.009)., Conclusions: Cytokine patterns in bile do not provide rejection markers with higher specificity compared with serum cytokines. Daily monitoring of sICAM-1 in serum could identify patients at risk for rejection; therefore, acute liver graft rejection may be recognized earlier in those patients.