Search

Objective: The objective of this study was to determine the fate of patients who attempted to donate organs after circulatory death (DCD) using a standardized DCD protocol. Background: Successful donation is not always possible after attempted DCD. Methods: Data were collected for all DCD donors between 1/2011 and 9/ 2014. DCDs were carried out using a uniform protocol at a single-center organ procurement organization. Results: During the timeframe considered, DCD donation was attempted in 169 patients. In 46 patients (27.2%), no organs were recovered because the patients did not die within 2 hours. Successful donation was more likely if withdrawal of support occurred in the operating room versus the intensive care unit (P = 0.006). Time from extubation to death was available for 161/169 donors (95.3%). Of 161 donors, 111 (66.9%) died in under 1 hour. The mean time from withdrawal of support to patient death for unsuccessful donations was 33 hours, 37 minutes (range, 24 minutes-242 hours) versus 29 minutes (range, 5 minutes-2 hours, 4 minutes) for successful donations. Twenty-seven patients who unsuccessfully donated (67.5%) died within 24 hours. Were unsuccessful donations converted to successful donations, as many as 837 abdominal transplants could have been carried out in the United States, during the study period. Conclusions: DCD is an important form of organ donation. A large number of abdominal transplants are not possible due to unsuccessful DCD organ donation. It may be useful to explore DCD donor family satisfaction to identify other options for improving DCD donation. [ABSTRACT FROM AUTHOR]

Background: Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear., Methods: We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients., Results: B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1β correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population., Conclusions: In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The first simultaneous pancreas and kidney (SPK) transplant was performed in 1966. Early procedures were associated with significant morbidity and mortality and were performed in very low numbers in select patients., Methods: This study includes all recipients of an SPK at the University of Wisconsin-Madison between 1986 and 1993, who were actively followed and had a functional pancreas allograft for >25 years as of October 31, 2018., Results: A total of 291 SPK were performed during the study period; of these, 39 patients still had a functional graft at last follow up and 9 (18.8%) pancreas grafts were lost due to patient death or graft failure after >25 years. At last follow up, all 39 patients with functional pancreas graft had at least one comorbidity, such as hypertension, hyperlipidemia, or coronary artery disease. Twenty-seven required enteric conversion; 11 patients experienced renal allograft failure (10 underwent a repeat kidney transplant); and 6 required amputation of part of the lower extremity. In the Cox regression analysis, bladder drained pancreas was associated with lower probability of prolonged pancreas graft survival (hazard ratio: 0.52; confidence interval: 0.32-0.85; P = 0.01)., Conclusions: With careful and detailed follow-up and attention to complications, some recipients of pancreas grafts have outstanding outcomes. As the number of pancreas recipients with prolonged graft survival may be rising, healthcare providers should be aware of the management of complications associated with this unique group of patients.

Background: Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy., Methods: C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 10 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 μg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot., Results: APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups., Conclusions: APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.

Purpose of Review: Pancreas transplantation in type 2 diabetes mellitus (T2DM) candidates remains disproportionately lower than in type 1 diabetes mellitus (T1DM); however, outcomes in carefully selected patients mirrors that of T1DM. Despite the 2014 United Network for Organ Sharing (UNOS) eligibility criteria for simultaneous pancreas/kidney transplant (SPK) transplantation in T2DM patients, an expected increase in the number of transplants was not observed., Recent Findings: In an updated International Pancreas and Transplant Registry (IPTR) analysis, 1514 primary deceased donor pancreas transplants were performed in T2DM recipients [1995-2015, SPK 88%, pancreas after kidney (PAK) 9%, pancreas transplant alone (PTA) 3%]. In contrast to the declining number of SPK transplants for T1DM, the number of primary SPK transplants in T2DM patients is increasing over time in the USA. Improvement over time was noted for T2DM SPK patient and graft survival, and the rate of technical failures decreased, paralleling similar overall trends for pancreas transplants in general. Long-term follow-up data of pancreas outcomes in C-peptide positive vs. negative demonstrate noninferior outcomes. BMI does not appear to impact outcomes in carefully selected T2DM candidates., Summary: The current UNOS regulations that currently limit access of T2DM to pancreas transplantation based on strict BMI criteria and C-peptide levels need to be liberated.

β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.

Background: Many strategies regarding timing of native nephrectomies exist for patients with symptomatic polycystic kidney disease (PCKD)., Methods: This is a single-center, retrospective study of 594 adults with PCKD who had renal transplants from 1994 to 2014. Three groups were analyzed: renal transplant-only recipients (tx alone), recipients of simultaneous bilateral nephrectomies and transplant (simultaneous), and recipients with pretransplant bilateral nephrectomies (pre). The primary outcome was graft survival. Secondary outcomes included postoperative complications., Results: Five hundred sixty-five adults with PCKD received kidney transplants (303 tx alone, 161 simultaneous, 27 pre). Ten-year posttransplant graft survival was 68.5%, 63.6%, and 65.7% for tx alone, simultaneous, and precohorts (P = 0.86). No statistically significant differences were observed in rates of postoperative ileus, deep vein thrombosis, small bowel obstruction, urinary stricture, urine leak, hernia formation, and delayed graft function. More wound complications were seen in prepatients (25.9% vs 11.1% tx alone, 5.1% simultaneous; P = 0.03), whereas simultaneous patients had a lower incidence of lymphocele (1.3% vs 11.1% pre, 10.2% tx-alone; P = 0.002). Importantly, simultaneous patients had more renal vascular thromboses (4.4% vs 1.3% tx alone, 0% pre; P = 0.04). 16.3% of renal transplant alone patients required nephrectomy at 10 years follow-up. Twenty-nine patients were referred for transplant having had nephrectomies and were ultimately not transplanted. In 4 of these patients who had data available for analysis, the mean panel-reactive antibody significantly increased after nephrectomy was performed., Conclusions: Simultaneous bilateral nephrectomy can be safely performed at the time of renal transplantation, however, carries a significantly increased risk of renal vascular thrombosis.

Background: Hemoglobin A1C (HbA1c) levels are often obtained in potential pancreas graft donors to assess the overall long-term functional glycemic control or the possibility of unrecognized diabetes. Although routinely measured, the impact of donor HbA1c levels on pancreas graft outcomes has not been reported. Here, we researched the relationship between donor HbA1c levels and postoperative pancreas graft survival., Methods: Data from 266 pancreas transplant patients including 182 simultaneous kidney-pancreas and 84 pancreas alone transplants were reviewed for the study. The patients were separated into groups according to their HbA1c levels (5 groups: HbA1c < 5.0, 5.0-5.4, 5.5-5.9, ≥6.0 % and not available, or 2 groups: HbA1c <5.7, ≥5.7%). Overall, death-censored and technically successful pancreas graft survival and rejection rates of each group were compared. In the case of technically successful graft survival, graft losses due to technical problems in the first 60 days were excluded., Results: All groups were similar with regard to donor variables including age, sex, ABO blood type, ethnicity, donor type and recipient variables including recipient age, sex, induction agents and maintenance treatment. Mean follow-up time was 4.2 ± 1.97 years. The overall graft survivals and death censored graft survivals among groups were not statistically different from one other (P > 0.05). Additionally, excluding early technical losses in 18 patients did not reveal any differences in graft survivals. Patient survival and biopsy-proven acute rejections were statistically similar among HbA1c strata., Conclusions: This univariate retrospective analysis of a single center/organ procurement organization use of HbA1c shows that donor HbA1c levels between 3.5 and 6.2 in otherwise transplantable pancreata are not associated with different short-term outcomes.

Background: There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) toxicity while effectively preventing antibody-mediated rejection (AMR)., Methods: We tested the efficacy of an investigational proteasome inhibitor, ixazomib, alone and in a CNI minimization strategy in a rat kidney transplant model of transfusion-elicited acute AMR. Nonsensitized (naïve) and sensitized allograft recipients were randomized into 4 treatment groups (8 groups total, n = 3 to 6 in each group) and treated for 1 week. Groups included: no treatment, full dose cyclosporine (CsA, 10 mg/kg per day), ixazomib (0.25 mg/kg on days -5, -2 and +2) alone, and half dose CsA (5 mg/kg per day) + ixazomib., Results: Compared to untreated animals, ixazomib alone or in combination with ½ dose CsA reduced donor-specific antibody, intragraft transcripts for chemokines CCL-21 and CXCL-13, and CD19 expression in both sensitized and naïve transplants. Compared to full dose CsA, the CNI minimization strategy with ixazomib inhibited AMR and allograft injury as evidenced by reduced C4d staining in peritubular capillaries, microcirculation inflammation, splenic plasma cells, circulating B cell activating factor, and intragraft transcripts for major histocompatibility complex class II, Toll-like receptors (TLR-1, TLR-10, and TLR-12) and CCL-21 and CXCL-13 in sensitized animals, indicating downregulation of B cell activation, antigen presentation and T-cell and B-cell signaling., Conclusions: These studies suggest that CNI minimization strategies including ixazomib are effective to prevent AMR including in sensitized kidney allograft recipients. Clinical studies are needed to determine the role of novel proteasome inhibitors for the prevention and treatment of AMR.

Background: The waiting time for deceased donor renal transplantation in the United States continues to grow. Retransplant candidates make up a small but growing percentage of the overall transplant waiting list and raise questions about the stewardship of scarce resources. The utility of renal transplantation among individuals with two prior renal transplants is not described in the literature, and we thus sought to determine the survival benefit associated with a third kidney transplant (3KT)., Methods: Multivariable Cox regression models were created to determine characteristics associated with 3KT outcomes and the survival benefit of 3KT among recipients wait listed and transplanted within the United States between 1995 and 2009., Results: A total of 4,334 patients were waitlisted for a 3KT and 2,492 patients received a 3KT. In a multivariate analysis, 3KT demonstrated an overall patient survival benefit compared to the waitlist (hazards ratio, 0.379; 95% confidence interval, 0.302-0.475; P<0.001) for those awaiting their first, second, or third kidney transplants, although an inferior graft outcome compared to first kidney transplants. The time to survival benefit did not accrue until 8 months after transplantation. In addition, we found that the duration of second graft survival was predictive of third graft survival, such that second graft survival beyond 5 years is associated with superior 3KT graft survival. Second graft loss in 30 days or less was not associated with inferior 3KT graft survival., Conclusion: A 3KT achieves a survival benefit over remaining on the waitlist, although is associated with inferior graft outcomes compared to first kidney transplants. Graft survival of the second transplant beyond 5 years is associated with superior 3KT graft survival.

We have established a cohort of 64 Natural Viral Suppressors (NVS) (similar to Elite Controllers/Elite Suppressors), 30 of which have chronic hepatitis C virus (HCV). We investigated T-cell phenotypic changes in association with HCV infection. NVS without HCV and normal controls had similar T-cell phenotypes. However, NVS with HCV had lower naive cell proportions (CD4 and CD8) compared with NVS without HCV (P = 0.0008 and P = 0.02) or normal controls (P = 0.0163 and P = 0.017). These results and previously reported data suggest that HCV coinfection increases immune activation and T-cell disturbances. Any associated T-cell functional changes or potential clinical consequences need further study.

CCR5 blockers inhibit CCR5-tropic (R5) HIV-1, including strains resistant to other antiretrovirals. We demonstrate that the CCR5 antibody HGS004 and the CCR5 antagonist maraviroc have potent antiviral synergy against R5 HIV-1, translating into dose reductions of more than 10-fold for maraviroc and more than 150-fold for HGS004. These data, together with the high barrier of resistance to HGS004, suggest that combinations of maraviroc and HGS004 could provide effective preventive and therapeutic strategies against R5 HIV-1.

Objective: HIV-1 natural viral suppressors (NVSs) demonstrate an intrinsic ability to control HIV-1 replication in the absence of antiretroviral therapy. The objective of this study was to investigate whether HIV-infected NVSs also demonstrate enhanced ability to control hepatitis C virus (HCV) infection, and whether HCV infection in the NVSs affects the degree of HIV control., Design and Methods: A cross-sectional study was undertaken to compare HCV-related parameters in the NVS to the two race-matched cohorts (HIV/HCV-coinfected or HCV-monoinfected patients). Within the NVS, HIV-related parameters were compared based on the presence or absence of chronic HCV., Results: NVS patients had a significantly higher clearance rate of HCV at 23.3% (seven of 30), compared to the 6.5% (23 of 350) of HIV/HCV-coinfected and 9.1% (32 of 350) of HCV-monoinfected patients (P = 0.005 and P = 0.024, respectively). Apart from the HCV clearance rate, there was no significant difference in HCV-related parameters such as HCV viral load or liver histology in the NVS with chronic HCV compared to HCV/HIV-coinfected patients or HCV-monoinfected patients. However, NVS patients with chronic HCV infection had statistically significant lower CD4 cell count and CD4%, and lower CD4/CD8 ratio compared to those NVSs without chronic HCV infection (P = 0.029, P = 0.046, and P = 0.062, respectively)., Conclusion: It appears that some NVS patients have the ability to effectively control multiple agents that can cause chronic viral infections. In addition, it appears that the presence of chronic HCV infection within the NVS adversely affects immunological parameters.

Objective: To evaluate Vgamma2Vdelta2 T cells in a group of HIV-infected patients who suppress HIV replication without antiretroviral therapy (natural viral suppressors, NVSs)., Design: : It is a cross-sectional study., Methods: We compared Vgamma2Vdelta2 T-cell frequency, T-cell repertoire, and responses to isopentenyl pyrophosphate stimulation between NVSs (n = 21) and HIV-uninfected controls (n = 27) and between NVSs and HIV-infected patients taking HAART with suppressed viral replication (HIV-P; n = 25)., Results: NVSs had a mean frequency of 1.06 +/- 0.82% CD3Vdelta2+ cells among total lymphocytes, which was significantly higher than both control groups (HIV-negative: 0.50 +/- 0.53%, P = 0.042; HIV-P: 0.34 +/- 0.37%, P = 0.002). The proportion of Vgamma2 chains correlating with the Vgamma2-Jgamma1.2 rearrangement was reduced among NVSs compared with HIV-negative controls (0.57 +/- 0.06 vs. 0.32 +/- 0.04; P = 0.016) but was increased compared with HIV-P patients (0.32 +/- 0.04 vs. 0.22 +/- 0.03; P = 0.03). NVSs had a similar baseline frequency of CD27/CD45RA effector cells (19.6 +/- 4.2%) compared with HIV-negative controls (20.8 +/- 12.9%; P = 0.35)., Conclusion: The altered gammadelta T-cell receptor repertoire among NVS was consistent with the known effect of HIV-1 on these cells. Uniquely among all HIV-infected groups, NVS reconstituted the gammadelta T-cell population, eventually reaching levels significantly above controls. This capacity to recover gammadelta T-cell numbers and function distinguishes individuals who control HIV-1 with and without HAART.

G1 cytostatic drugs reduce CCR5 co-receptor expression and enhance the antiviral activity of a CCR5 antagonist in vitro. The administration of rapamycin, a G1 cytostatic agent, to three cynomolgous macaques led to decreased CCR5 messenger RNA expression in peripheral blood mononuclear cells and cervicovaginal tissue. These results support further clinical evaluation of G1 cytostatic agents such as rapamycin targeting the downregulation of CCR5 expression as a strategy for both the prevention and treatment of HIV infection.

Objective and Design: Studies in cell lines have demonstrated that CCR5 coreceptor levels influence the replication efficiency and Enfuvirtide (T-20) susceptibility of R5 HIV-1 strains. At present, however, the role that CCR5 levels on primary CD4 T cells--which are markedly lower than in cell lines and vary only approximately fivefold among most donors--may play in virus replication levels or susceptibility to T-20 is not known. In the present study we evaluated the impact of differences in CCR5 levels among donor CD4 T cells on the infection efficiency and T-20 susceptibility of R5 HIV-1., Methods: CD4 and CCR5 density levels were determined by Quantitative FACS analysis. Virus infectivity assays were conducted in cell lines and primary cells. Associations between coreceptor density, virus replication and T-20 sensitivity were tested using the Spearman's correlation test., Results: We found a positive correlation (r, 0.55; P = 0.011) between CCR5 density levels on primary CD4 T cells and replication of R5 HIV-1. In cell lines expressing physiologically relevant levels of CD4 and CCR5, T-20 was significantly more potent in cells with low CCR5 levels. In addition, T20 50% inhibitory concentrations for R5 HIV-1 replication varied approximately 100-fold among primary cells from different donors and they were positively correlated with CCR5 density values (r, 0.84; P = 0.00004)., Conclusions: These results suggest that CCR5 density levels in HIV-1 patients may impact the activity of T-20 against R5 strains and that therapeutic approaches to alter CCR5 density may potentiate T-20.

The objective of this study was to identify and define a cohort of HIV-1-infected individuals with the ability to suppress HIV-1 replication naturally (patients with undetectable viral loads for at least 2 years without antiretroviral drugs). Proviral DNA ranged from one to 74 copies/10(6) peripheral blood mononuclear cells, with the mean value lower by 1-2 logs than long-term non-progressors. This ability to control HIV-1 viral replication naturally has led us to refer to them as natural viral suppressors.

We evaluated the effect of vitamin E in controlling HIV-1 production upon activation of the patients' reservoir of resting CD4 lymphocytes in tissue culture experiments. The addition of vitamin E to patients' cultures resulted in significantly reduced levels of p24 virus production (P = 0.0015). These results suggest that vitamin E supplementation may interfere with the emergence of drug-resistant HIV-1 variants archived in the resting cell reservoir and delay or limit virus rebound upon treatment interruptions.

Current treatment approaches cannot predict, ensure, or sustain the needed adherence required to achieve long-term successful therapy in many of our urban poor patients. The current treatment paradigm in the United States thus relies heavily on sequential therapy to maintain patient health. This approach is often unsuccessful in achieving viral durable suppression, increases the complexities of care, increases the costs of care, and can fail to improve patients' health. As the HIV epidemic shifts into the urban poor in the USA, the success of the current antiretroviral therapy approach to achieve durable viral suppression in this population remains under question. New treatment delivery programmes designed to address these concerns for the urban poor in the USA may represent models that can achieve high levels of treatment success in resource-limited countries.