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Tong A.,University of Sydney | Tong A.,Center for Kidney Research | Brown M.A.,University of Sydney | Winkelmayer W.C.,Baylor College of Medicine | And 3 more authors.
American Journal of Kidney Diseases | Year: 2015

Background Women with chronic kidney disease (CKD) often have difficulty achieving pregnancy and are at increased risk for adverse pregnancy outcomes. Given the medical, ethical, and emotional complexities of pregnancy in CKD, the clinical approach should involve explicit consideration of women's values, for which there are sparse data. This study aims to describe the beliefs, values, and experiences of pregnancy in women with CKD to inform prepregnancy counseling and pregnancy care. Study Design Qualitative study. Setting & Participants 41 women (95% response rate) aged 22 to 56 years with CKD stages 3 to 5 (n = 5), receiving dialysis (n = 5), or received a kidney transplant (n = 31) from 2 renal units in Australia. Methodology Semistructured interviews. Analytical Approach Transcripts were analyzed thematically. Results 6 themes were identified: bodily failure (conscious of fragility, noxious self, critical timing, and suspended in limbo), devastating loss (denied motherhood, disempowered by medical catastrophizing, resolving grief, barriers to parenthood alternatives, and social jealousy), intransigent guilt (disappointing partners, fear of genetic transmission, respecting donor sacrifice, and medical judgment), rationalizing consequential risks (choosing survival, avoiding fetal harm, responding to family protectiveness, compromising health, decisional ownership, and unjustifiable gamble), strengthening resolve (hope and opportunity, medical assurance, resolute determination, and reticent hope), and reorientating focus (valuing life and gratitude in hindsight). Limitations Only English-speaking women were recruited, which may limit transferability of the findings. Conclusions Decisions surrounding pregnancy in the context of CKD require women to confront uncertainties about their own survival, disease progression, guilt toward their family and kidney donor, the outcomes of their offspring, and genetic transmission. Communicating the medical risks of pregnancy to women with CKD must be carefully balanced with their values of autonomy, hope, security, and family. Informed and shared decision making that addresses women's priorities as identified in this study may help contribute to improved pregnancy, health, and psychosocial outcomes in this vulnerable population. © 2015 National Kidney Foundation, Inc. Source

Hope C.M.,Central Northern Adelaide Renal and Transplantation Service CNARTS | Hope C.M.,Center for Clinical and Experimental Transplantation | Krige A.J.,Central Northern Adelaide Renal and Transplantation Service CNARTS | Barratt A.,Central Northern Adelaide Renal and Transplantation Service CNARTS | And 2 more authors.
Transplant International | Year: 2015

Few data exist on how immunosuppression is altered in kidney transplant recipients (KTR) following a diagnosis of cancer. This study investigated how immunosuppression was altered in KTR after cancer diagnosis and its effect on patient and graft survival. All KTR diagnosed with cancer at our centre from 1990 to 2012 were assessed. Drug regime and serum creatinine levels were recorded 1 year before, at time of, and 1 year after cancer diagnosis. Of 87 KTR who developed cancer (7.3% of transplanted population, n = 1189), 30 developed haematological malignancies and 57 developed solid organ cancers (SOC). In total, 38% of KTR presented with nodal or metastatic disease and 23 of 87 (26%) KTR died within 6 months of cancer diagnosis. Fifty-five KTR had records of pre- and postcancer diagnosis drug regimes. Thirty-six KTR had a (>50%) dose reduction or cessation of 1 or more immunosuppressive agents, and 19 no reduction in immunosuppression. In total, 2 of 36 (6%) of KTR who underwent a dose reduction suffered acute rejection that was reversed with methylprednisolone. Dose reduction/cessation of immunosuppression did not impair graft function, but also did not affect cancer free survival. Further larger prospective studies are needed to determine whether dose reduction alters relapse free cancer survival in KTR. © 2015 Steunstichting ESOT. Source

Sivanathan K.N.,University of Adelaide | Sivanathan K.N.,Center for Clinical and Experimental Transplantation | Gronthos S.,University of Adelaide | Rojas-Canales D.,University of Adelaide | And 3 more authors.
Stem Cell Reviews and Reports | Year: 2014

Bone marrow-derived mesenchymal stem cells (MSC) have unique immunomodulatory and reparative properties beneficial for allotransplantation cellular therapy. The clinical administration of autologous or allogeneic MSC with immunosuppressive drugs is able to prevent and treat allograft rejection in kidney transplant recipients, thus supporting the immunomodulatory role of MSC. Interferon-gamma (IFN-γ) is known to enhance the immunosuppressive properties of MSC. IFN-γ preactivated MSC (MSC-γ) directly or indirectly modulates T cell responses by enhancing or inducing MSC inhibitory factors. These factors are known to downregulate T cell activation, enhance T cell negative signalling, alter T cells from a proinflammatory to an anti-inflammatory phenotype, interact with antigen-presenting cells and increase or induce regulatory cells. Highly immunosuppressive MSC-γ with increased migratory and reparative capacities may aid tissue repair, prolong allograft survival and induce allotransplant tolerance in experimental models. Nevertheless, there are contradictory in vivo observations related to allogeneic MSC-γ therapy. Many studies report that allogeneic MSC are immunogenic due to their inherent expression of major histocompatibility (MHC) molecules. Enhanced expression of MHC in allogeneic MSC-γ may increase their immunogenicity and this can negatively impact allograft survival. Therefore, strategies to reduce MSC-γ immunogenicity would facilitate "off-the-shelf" MSC therapy to efficiently inhibit alloimmune rejection and promote tissue repair in allotransplantation. In this review, we examine the potential benefits of MSC therapy in the context of allotransplantation. We also discuss the use of autologous and allogeneic MSC and the issues associated with their immunogenicity in vivo, with particular focus on the use of enhanced MSC-γ cellular therapy. © 2014 Springer Science+Business Media New York. Source

Sivanathan K.N.,University of Adelaide | Sivanathan K.N.,Center for Clinical and Experimental Transplantation | Sivanathan K.N.,Center for Stem Cell Research and Robinson Institute | Rojas-Canales D.M.,University of Adelaide | And 12 more authors.
Stem Cells | Year: 2015

Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA-activated CD4+CD25- T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application. © 2015 AlphaMed Press. Source

Hope C.M.,Center for Clinical and Experimental Transplantation | Hope C.M.,University of Adelaide | Troelnikov A.,Center for Clinical and Experimental Transplantation | Troelnikov A.,University of Adelaide | And 8 more authors.
Kidney International | Year: 2015

Reducing immunosuppression has been proposed as a means of preventing cancer in kidney transplant recipients but this can precipitate graft rejection. Here we tested whether anti-tumor natural killer (NK) cell and allo-responsive T-cell function in kidney transplant recipients may predict cancer risk and define risk of rejection. NK cell function was measured by the release of lactate dehydrogenase and T-cell allo-response by interferon-γ quantification using a panel of reactive T-cell enzyme-linked immunospot (ELISPOT) in 56 kidney transplant recipients with current or past cancer and 26 kidney transplant recipients without cancer. NK function was significantly impaired and the allo-response was significantly lower in kidney transplant recipients with cancer. With prospective follow-up, kidney transplant recipients with poor NK cell function had a hazard ratio of 2.1 (95% confidence interval 0.97-5.00) for the combined end point of metastatic cancer, cancer-related death, or septic death. Kidney transplant recipients with low interferon-γ release were also more likely to reach this combined end point. Thus, posttransplant monitoring of allo-immunity and NK cell function is useful for assessing the risk of over immunosuppression for the development of malignancy and/or death from cancer or sepsis. © 2015 International Society of Nephrology. Source

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