Altruistic Donor Triggered Domino‐Paired Kidney Donation for Unsuccessful Couples from the Kidney‐Exchange Program

Between January 2000 and July 2009, 132 individuals inquired about altruistic kidney donation to strangers. These donors were willing to donate to genetically and emotionally unrelated patients. Some altruistic donors wished to donate to a specific person, but most wished to donate anonymously. In domino‐paired donation, the altruistic donor donates to the recipient of an incompatible couple; the donor of that couple (domino‐donor) donates to another couple or to the waiting list. In contrast to kidney‐exchange donation where bilateral matching of couples is required, recipient and donor matching are unlinked in domino‐paired donation. This facilitates matching for unsuccessful couples from the kidney‐exchange program where blood type O prevails in recipients and is under‐represented in donors. Fifty‐one altruistic donors (39%) donated their kidney and 35 domino‐donors were involved. There were 29 domino procedures, 24 with 1 altruistic donor and 1 domino‐donor, 5 with more domino‐donors. Eighty‐six transplantations were performed. Donor and recipient blood type distribution in the couples limited allocation to blood type non‐O waiting list patients. The success rate of domino‐paired donation is dependent on the composition of the pool of incompatible pairs, but it offers opportunities for difficult to match pairs that were unsuccessful in the kidney‐exchange program.     

Donor pre-treatment with tacrolimus reduces transplant vasculopathy

We tested whether transplant arteriosclerosis can be reduced by pre-treatment of the donor with immunosuppressive agents, using a rat allogeneic aorta transplantation model.Donor rats received no pre-treatment, or tacrolimus, methylprednisolone, rapamycin, or mycofenolate mofetil (MMF) 16 and 2 h before explantation of the grafts. Eight weeks after transplantation, aorta allografts were harvested. Percent intima area/intima + media area (I/I + M), inflammatory cells and in situ MMP-2 and -9 activity were determined. In pre-transplantation biopsies, MMP-2 and -9 ratio, and mRNA levels for genes of interest were determined.In pre-transplantation biopsies we found no differences in MMP-2/9 ratio, and Bcl-2, Bax, TGF-β, HO-1, p21, and HIF-1α mRNA expression between the groups.Aorta allografts, pre-treated with tacrolimus, showed significantly lower I/I + M ratio compared to untreated controls (p < 0.01). Pre-treatment with methylprednisolone, rapamycin or MMF did not significantly reduce I/I + M ratio. In situ MMP-2/MMP-9 activity was significantly reduced in grafts treated with tacrolimus and rapamycin compared to controls (p < 0.05). Immunohistochemistry revealed a high number of CD4+ cells and high CD4/CD8 ratio in grafts pre-treated with tacrolimus.Donor pre-treatment with tacrolimus significantly reduces transplant arteriosclerosis and is associated with reduced in situ MMP-2/MMP-9 activity and increased number of CD4+ cells.     

Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor

Even though other γδ T-cell subsets exhibit antitumor activity, adoptive transfer of γδ Tcells is currently limited to one subset (expressing Vγ9Vδ2 T-cell receptor (TCR)) due to dependence on aminobisphosphonates as the only clinically appealing reagent for propagating γδ T cells. Therefore, we developed an approach to propagate polyclonal γδ T cells and rendered them bispecific through expression of a CD19-specific chimeric antigen receptor (CAR). Peripheral blood mononuclear cells (PBMC) were electroporated with Sleeping Beauty (SB) transposon and transposase to enforce expression of CAR in multiple γδ T-cell subsets. CAR⁺γδ T cells were expanded on CD19⁺ artificial antigen-presenting cells (aAPC), which resulted in >10⁹ CAR⁺γδ T cells from <10⁶ total cells. Digital multiplex assay detected TCR mRNA coding for Vδ1, Vδ2, and Vδ3 with Vγ2, Vγ7, Vγ8, Vγ9, and Vγ10 alleles. Polyclonal CAR⁺γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19⁺ tumor cell lines compared with CAR^negγδ T cells. CD19⁺ leukemia xenografts in mice were reduced with CAR⁺γδ T cells compared with control mice. Since CAR, SB, and aAPC have been adapted for human application, clinical trials can now focus on the therapeutic potential of polyclonal γδ T cells.     

Tinidazole in treatment of acute amoebic dysentery in children

The excellent results obtained in this trial indicate that tinidazole is a drug worthy of extensive evaluation in the treatment of amoebiasis, as three single daily doses is a simple form of treatment. The drug was well tolerated and free from any toxic effects.     

The vanishing importance of age in renal transplantation

BACKGROUND: The growing number of patients awaiting a kidney transplant raises questions about allocation of kidneys to the elderly and about the use of elderly donors. In all reported studies analyzing the influence of age on the outcome after renal transplantation, age is investigated as a categorical variable. METHODS: We studied age both as a categorical (Kaplan-Meier) and as a continuous (Cox) variable in a total of 509 cyclosporine-treated recipients of a primary cadaveric kidney graft who underwent transplantation between July 1983 and July 1997. For the Kaplan-Meier analysis, the population was divided into three comparably sized age groups: 17-43 years (n=171), 44-55 years (n=169), and 56-75 years (n=169). RESULTS: Patient survival was better and graft survival censored for death was worse in the younger patients. Overall graft survival (end point was death or graft failure) was not significantly influenced by age. In the Cox proportional hazards analysis, transplantation year turned out to be an important, independent variable influencing all end points. Because the influence was not linear, three periods were defined in which the relative risk remained stable: 1983-1990, 1991-1993, and 1994-1997. In the second period, the relative risk for transplant failure or death was 49% of that in the first period. In the third period, the relative risk had decreased to 22% of that in the first period. Recipient age and donor age were significant predictors of overall transplant failure. There was no interaction between these variables and transplantation year. Within each transplantation period, an increase in recipient age by 1 year increased the relative risk for overall graft failure by only 1.44%. The influence of donor age followed a J-shaped curve with a minimum at 30 years. The influence of increasing either recipient or donor age was counteracted by the improving results over time. CONCLUSION: Considering the improving results over time, there are, at this moment, no arguments for an age restriction for kidney transplant recipients or donors.     

Critical temperature and heating time for coagulation damage: implications for interstitial laser coagulation (ILC) of tumors.

BACKGROUND: Interstitial laser coagulation (ILC) is a method of local tissue destruction for solid tumors such as irresectable hepatic metastases from colorectal cancer. With the availability of new magnetic resonance (MR) techniques, which allow real time tissue temperature mapping, it is essential to know the critical temperature and exposure times leading to cell death. MATERIALS AND METHODS/STUDY DESIGN: Samples (8 mm(3)) of solid rat tumor (CC-531, syngenic to the WAG/Rij rat strain), were warmed in tubes for four different temperatures (40, 50, 60 or 80 degrees C) and four different exposure times (3, 6, 12, or 24 minutes). Combinations were replicated in five-fold. Cell viability was assessed with three methods: Trypan blue exclusion test in collagenase/dispase dissociated samples, NADH activity in snap frozen samples and outgrowth for 2 weeks under the renal capsule of WAG/Rij rats. RESULTS: Results of the three methods revealed that viability was not affected with heating at 40 and 50 degrees C except for 24 minutes at 50 degrees C. At higher temperatures cell death occurred at all exposure times. CONCLUSION: The temperature range resulting in sufficient tissue coagulation for cell death is between 50 degrees C and 60 degrees C for a short duration (<3 minutes). These data can be used to achieve complete tumor destruction and minimal surrounding tissue damage during real-time MR-controlled ILC.     

Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virus-inactivated plasma (ESDEP)

After the introduction of solvent/detergent-treated plasma (ESDEP) in our hospital, an increased incidence of hyperfibrinolysis was observed (75% vs 29%; P = 0.005) compared with the use of fresh frozen plasma for liver transplantation. To clarify this increased incidence, intraoperative plasma samples of patients treated with fresh frozen plasma or ESDEP were analyzed in a retrospective observational study. During the anhepatic phase, plasma levels of D-dimer (6.58 vs 1.53 microg/mL; P = 0.02) and fibrinogen degradation products (60 vs 23 mg/L; P = 0.018) were significantly higher in patients treated with ESDEP. After reperfusion, differences increased to 23.5 vs 4.7 microg/mL (D-dimer, P = 0.002) and 161 vs 57 mg/L (fibrinogen degradation products, P = 0.001). The amount of plasma received per packed red blood cell concentrate, clotting tests, and levels of individual clotting factors did not show significant differences between the groups. alpha(2)-Antiplasmin levels, however, were significantly lower in patients receiving ESDEP during the anhepatic phase (0.37 vs 0.65 IU/mL; P < 0.001) and after reperfusion (0.27 vs 0.58 IU/mL; P = 0.001). Analysis of alpha(2)-antiplasmin levels in ESDEP alone showed a reduction to 0.28 IU/mL (normal >0.95 IU/mL) because of the solvent/detergent process. Therapeutic consequences for the use of ESDEP in orthotopic liver transplantation are discussed in view of an increased incidence of hyperfibrinolysis caused by reduced levels of alpha(2)-antiplasmin in the solvent/detergent-treated plasma. IMPLICATIONS: The use of solvent/detergent virus-inactivated plasma is of increasing importance in the prevention of human immunodeficiency virus and hepatitis C virus transmission. Since the use of this plasma during orthotopic liver transplantation has increased, the incidence of hyperfibrinolysis was observed. Clotting analysis of the patients revealed small alpha(2)-antiplasmin concentrations because of the solvent/detergent process.