There is emerging interest in the application of mesenchymal stem cells (MSC) for the prevention and treatment of autoimmune diseases, graft‐versus‐host disease and allograft rejection. It is, ...however, unknown how inflammatory conditions affect phenotype and function of MSC. Adipose tissue‐derived mesenchymal stem cells (ASC) were cultured with alloactivated peripheral blood mononuclear cells (PBMC) (mixed lymphocyte reaction: MLR), with proinflammatory cytokines interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 or under control conditions, and their full genome expression and function examined. Proinflammatory cytokines mainly increased indoleamine‐2,3‐dioxygenase expression, whereas ASC cultured with MLR showed increased expression of COX‐2, involved in prostaglandin E₂ production. Both conditions had a stimulatory, but differential, effect on the expression of proinflammatory cytokines and chemokines, while the expression of fibrotic factors was decreased only in response to proinflammatory cytokines. Functional analysis demonstrated that inflammatory conditions affected morphology and proliferation of ASC, while their differentiation capacity and production of trophic factors was unaffected. The immunosuppressive capacity of ASC was enhanced strongly under inflammatory conditions. In conclusion, ASC showed enhanced immunosuppressive capacity under inflammatory conditions, while their differentiation capacity was preserved. Therefore, in vitro preconditioning provides ASC with improved properties for immediate clinical immune therapy.
The Declaration of Istanbul is the first document that has been established by the international transplant community that defines and prohibits transplant commercialism and organ trafficking. Its ...Custodian Group has successfully led various countries to implement legislation against trafficking and commercialism. The question arises, however, whether efforts to prohibit organ trade are realistic and effective. The Declaration differentiates trafficking from commercialism, yet it does not mention how both acts should be approached by policy. Policies that address transplant commercialism work differently from policies that tackle organ trafficking. There is considerable room for improvement in the current prohibitive approach to commercialism and organ trafficking. The Custodian Group and World Health Organization (WHO) should address commercialism by encouraging the expansion of living donation in the same manner as they encourage deceased donation. Furthermore, the Custodian Group and the WHO can improve their strategy to combat organ trafficking by raising awareness for enforcement. To achieve a consistent and effective prohibition of trafficking, legislation and law enforcement must go hand in hand. Ideally, this can best be achieved by close collaboration between the medical field and (international) criminal justice agencies.
This personal viewpoint expresses the opinion of the authors on how prohibition of organ trade can be improved. See editorial by Glazier and Delmonico on page 515.
Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease ...and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B-cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19(+) CD27(high) CD38(high) antibody-producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B-cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10-producing CD19(+) CD24(high) CD38(high) B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B-cell response in immune disease.
In this Phase 2b study, 331 low‐to‐moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of ...tofacitinib (CP‐690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy‐proven acute rejection (BPAR) with a serum creatinine increase of ≥0.3 mg/dL and ≥20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6‐month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side‐effects at the doses evaluated.
The authors present the results of a phase 2b trial of tofacitinib in renal transplantation.
Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized‐controlled study investigated ...whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10–15 ng/mL) at first steady‐state. Two hundred forty living‐donor, renal transplant recipients were assigned to either receive a standard, body‐weight‐based or a CYP3A5 genotype‐based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard‐dose and genotype‐based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.
This randomized trial shows that in living donor kidney transplant recipients, a tacrolimus starting dose based on the CYP3A5 genotype does not increase the proportion of patients reaching the tacrolimus target concentration range at day 3 posttransplant.
Background. We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression ...and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. Methods. From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and ‘doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up’ was used. Results. In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005. The mean tacrolimus concentration for controls 7.4 (± 2.9) ng/mL and for failures 6.9 (± 2.5) ng/mL was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. Conclusions. This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.
Therapeutic drug monitoring (TDM) for tacrolimus (Tac) is universally applied. However, the concentration–effect relationship for Tac is poorly defined. This study investigated whether Tac ...concentrations are associated with acute rejection in kidney transplant recipients. Data from three large trials were pooled. We used univariate and multivariate analysis to investigate the relationship between biopsy‐proven acute rejection (BPAR) and Tac predose concentration at five time points (day 3, 10 and 14, and month 1 and 6 after transplantation). A total of 136/1304 patients experienced BPAR, giving an overall incidence of 10.4%. We did not find any significant correlations between Tac predose concentrations and the incidence of BPAR at the different time points. In the multivariate analysis, only delayed graft function (DGF) and the use of induction therapy were independently correlated with BPAR, with an odds ratio of 2.7 95% CI: 1.8–4.0; p < 0.001 for DGF and 0.66 95% CI: 0.44–0.99; p = 0.049 for induction therapy. The other variables, including the Tac predose concentrations, were not statistically significantly associated with BPAR. We did not find an association between the Tac predose concentrations measured at five time points after kidney transplantation and the incidence of acute rejection occurring thereafter. Based on this study it is not possible to define the optimal target concentrations for Tac.
The authors find no relationship between biopsy‐proven acute rejection and tacrolimus predose concentrations, and posit that it is not possible to define the optimal target concentrations for tacrolimus.
On Patients Who Purchase Organ Transplants Abroad Ambagtsheer, F.; Jong, J.; Bramer, W. M. ...
American journal of transplantation,
October 2016, 2016-10-00, 20161001, Letnik:
16, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The international transplant community portrays organ trade as a growing and serious crime involving large numbers of traveling patients who purchase organs. We present a systematic review about the ...published number of patients who purchased organs. With this information, we discuss whether the scientific literature reflects a substantial practice of organ purchase. Between 2000 and 2015, 86 studies were published. Seventy‐six of these presented patients who traveled and 42 stated that the transplants were commercial. Only 11 studies reported that patients paid, and eight described to what or whom patients paid. In total, during a period of 42 years, 6002 patients have been reported to travel for transplantation. Of these, only 1238 were reported to have paid for their transplants. An additional unknown number of patients paid for their transplants in their native countries. We conclude that the scientific literature does not reflect a large number of patients buying organs. Organ purchases were more often assumed than determined. A reporting code for transplant professionals to report organ trafficking networks is a potential strategy to collect and quantify cases.
In this systematic review, the authors find that of the 6002 patients reported as travelling abroad for transplantation, only 1238 were reported to have paid for their transplants, concluding organ purchases are more often assumed than determined.
Our aim was to develop and test an educational program to support well‐informed decision making among patients and their social network regarding living donor kidney transplantation (LDKT). One ...hundred sixty‐three patients who were unable to find a living donor were randomized to standard care or standard care plus home‐based education. In the education condition, patients and members of their social network participated in home‐based educational meetings and discussed renal replacement therapy options. Patients and invitees completed pre–post self‐report questionnaires measuring knowledge, risk perception, communication, self‐efficacy and subjective norm. LDKT activities were observed for 6 months postintervention. Patients in the experimental group showed significantly more improvements in knowledge (p < 0.001) and communication (p = 0.012) compared with the control group. The invitees showed pre–post increases in knowledge (p < 0.001), attitude toward discussing renal replacement therapies (p = 0.020), attitude toward donating a kidney (p = 0.023) and willingness to donate a kidney (p = 0.039) and a decrease in risk perception (p = 0.003). Finally, there were significantly more inquiries (29/39 vs. 13/41, p < 0.001), evaluations (25/39 vs. 7/41, p < 0.001) and actual LDKTs (17/39 vs. 4/41, p = 0.003) in the experimental group compared with the control group. Home‐based family education supports well‐informed decision making and promotes access to LDKT.
A home‐based family intervention is effective in increasing living donation rates and improving well‐informed decision making among patients and their families regarding renal replacement therapies.
The safety of older live kidney donors, especially the decline in glomerular filtration rate (GFR) after donation, has been debated. In this study we evaluated long‐term renal outcome in older live ...kidney donors. From 1994 to 2006 follow‐up data of 539 consecutive live kidney donations were prospectively collected, during yearly visits to the outpatient clinic. Donors were categorized into two groups, based on age: <60 (n = 422) and ≥60 (n = 117). Elderly had lower GFR predonation (80 vs. 96 mL/min respectively, p < 0.001). During median follow‐up of 5.5 years, maximum decline in eGFR was 38%± 9% and the percentage maximum decline was not different in both groups. On long‐term follow‐up, significantly more elderly had an eGFR <60 mL/min (131 (80%) vs. 94 (31%), p < 0.001). However, renal function was stable and no eGFR of less than 30 mL/min was seen. In multivariate analysis higher body mass index (HR 1.09, 95%CI 1.03–1.14) and more HLA mismatches (HR 1.17, 95%CI 1.03–1.34) were significantly correlated with worse graft survival. Donor age did not influence graft survival. After kidney donation decline in eGFR is similar in younger and older donors. As kidney function does not progressively decline, live kidney donation by elderly is considered safe.
Live kidney donation by the elderly is considered, demonstrating that the decline in eGFR is similar in younger and older donors.
PDF
