Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.     

Dissociation of Depletional Induction and Posttransplant Lymphoproliferative Disease in Kidney Recipients Treated With Alemtuzumab

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.     

Liver transplantation from controlled non-heart-beating donors

BACKGROUND: The use of organs from non-heart-beating donors (NHBDs) has been proposed as one way to increase the donor pool. However, few centers have transplanted livers from NHBDs. We report here the results of 19 liver transplants from controlled NHBDs. METHODS: From January 1993 through August 1999, 364 liver transplantations were performed from heart-beating donors (HBDs) and 19 liver transplantations were performed from NHBDs. Donor and recipient characteristics, posttransplant complications, and patient and allograft survival were compared. RESULTS: No differences in hepatic artery, portal vein, or biliary complications were noted between the groups. However, the rate of primary nonfunction was higher in recipients of livers from NHBDs (10.5% vs. 1.3%; P = .04). No difference in patient survival was seen between recipients of NHBDs or HBDs (72.6% vs. 84.8%; P =.36); however, allograft survival was lower in recipients who received livers from NHBDs (53.8% vs. 80.9%; P =.007). CONCLUSIONS: Liver transplantation from controlled NHBDs results in similar patient survival and post-transplant complications. However, primary nonfunction was higher and allograft survival was less in recipients of livers from NHBDs. The results of liver transplantation from controlled NHBDs are encouraging and should continue to be cautiously pursued as one way to help alleviate the current shortage of donor livers.     

Performance trends in 3000 m open-water age group swimmers from 25 to 89 years competing in the FINA World Championships from 1992 to 2014

We investigated trends in participation, performance and sex difference in performance in 3000 m freestyle in age groups swimmers (25–29 to 85–89 years) competing in the Fédération Internationale de Natation World Masters Championships between 1992 and 2014. During this period, participation increased in women and men. Women and men improved race times across years in all age groups. Women were slower in age groups 25–29 to 70–74 years. In age groups 75–79 and 85–89 years, however, race times were similar for both women and men. Sex difference in performance remained unchanged across years. In summary, performance improved across years in all age groups, men were faster than women up to the age group 70–74 years and women were not able to reduce the sex difference in performance to men across years. For athletes and coaches, an increase in participation and a continuous improvement in performance can be expected in these age group athletes.     

Elite triathletes in ‘Ironman Hawaii’ get older but faster

The age of peak performance has been well investigated for elite athletes in endurance events such as marathon running, but not for ultra-endurance (>6 h) events such as an Ironman triathlon covering 3.8 km swimming, 180 km cycling and 42 km running. The aim of this study was to analyze the changes in the age and performances of the annual top ten women and men at the Ironman World Championship the ‘Ironman Hawaii’ from 1983 to 2012. Age and performances of the annual top ten women and men in overall race time and in each split discipline were analyzed. The age of the annual top ten finishers increased over time from 26 ± 5 to 35 ± 5 years (r² = 0.35, P < 0.01) for women and from 27 ± 2 to 34 ± 3 years (r² = 0.28, P < 0.01) for men. Overall race time of the annual top ten finishers decreased across years from 671 ± 16 to 566 ± 8 min (r² = 0.44, P < 0.01) for women and from 583 ± 24 to 509 ± 6 min (r² = 0.41, P < 0.01) for men. To conclude, the age of annual top ten female and male triathletes in the ‘Ironman Hawaii’ increased over the last three decades while their performances improved. These findings suggest that the maturity of elite long-distance triathletes has changed during this period and raises the question of the upper limits of the age of peak performance in elite ultra-endurance performance.     

Review: chemokines in transplantation

The alloimmune response in solid organ transplantation is characterized by antigen presentation, activation of the recipient's immune system, and an effector response. Chemokines are chemotactic cytokines and play a role in all 3 components of the alloimmune response. Early studies showed an effectiveness of chemokine receptor blockade in experimental transplant models; chemokine receptor blockers will become more widely available because of their development for other applications. This review intends to summarize the available experimental evidence surrounding chemokines in transplantation. It will first describe the inflammatory chemokine/receptor pairs IP-10/CXCR3, Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCR5, and MCP-1/CCR2 and then cover studies regarding dendritic cell trafficking, memory cell trafficking, and regulatory cell trafficking, as well as the role of chemokines in the innate immune system. The role of S1P receptors and its antagonist FTY720 will be covered because it exemplifies the importance of trafficking for the immune response. Especially as subsets of lymphocytes and dendritic cells will be better defined as far as their regulatory and memory function is concerned, chemokine targeting strategies will be important in transplantation.     

Cytokine kinetics profiling in pediatric renal transplant recipients

Niederhaus SV, Bloom DD, Chang Z, Hu H, Bartosh SM, Knechtle SJ. Cytokine kinetics profiling in pediatric renal transplant recipients.
Pediatr Transplantation 2010: 14:636–645. © 2010 John Wiley & Sons A/S. Abstract: Pediatric renal transplant recipients experience side effects of immunosuppression. Few immunoassays exist which can assess the adequacy of immunosuppression. We developed a CKT, whereby cytokine levels are measured in a five‐day mixed lymphocyte reaction. We describe the in vitro cytokine responses to donor and third‐party antigen in a pilot study of nine children after living‐donor renal transplantation. The CKT identified five patterns of IFN‐γ secretion relative to donor and third‐party alloantigen: no response to alloantigen (n = 2), hypo‐response to donor (n = 3), equal response (n = 1), hyper‐response to donor (n = 1), and intermediate response (n = 2). IL‐2 and IL‐13 patterning correlated with IFN‐γ expression. Two of nine subjects had acute rejection, which correlated with intermediate and hyper‐responsive profiles. No rejection occurred during immunosuppression or donor‐specific hypo‐responsiveness. Significant immunosuppression was universal early after transplantation. Two of four children showed strong pretransplant responses to donor, which were regained three months post‐transplant, and associated with rejection in one subject. The CKT reflects the level of immunosuppression and may offer a method to assess the adequacy of immunosuppression. A pattern of complete non‐responsiveness or hypo‐responsiveness correlated with lack of acute rejection. The CKT may prove useful in titrating immunosuppression and in improving live donor selection.