Journal articles on the topic 'Donor and recipient'
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1
Ozieranski, Piotr, Marcell Csanádi, Emily Rickard, and Shai Mulinari. "Under-reported relationship: a comparative study of pharmaceutical industry and patient organisation payment disclosures in the UK (2012–2016)." BMJ Open 10, no. 9 (September 2020): e037351. http://dx.doi.org/10.1136/bmjopen-2020-037351.
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ObjectivesTo examine the under-reporting of pharmaceutical company payments to patient organisations by donors and recipients.DesignComparative descriptive analysis of payments disclosed on drug company and charity regulator websites.SettingUK.Participants87 donors (drug companies) and 425 recipients (patient organisations) reporting payments in 2012–2016.Main outcome measuresNumber and value of payments reported by donors and recipients; differences in reported payments from/to the same donors and recipients; payments reported in either dataset but not the other one; agreement between donor–recipient ties established by payments; overlap between donor and recipient lists and, respectively, industry and patient organisation data.ResultsOf 87 donors, 63 (72.4%) reported payments but 84 (96.6%) were mentioned by recipients. Although donors listed 425 recipients, only 200 (47.1%) reported payments. The number and value of payments reported by donors were 259.8% and 163.7% greater than those reported by recipients, respectively. The number of donors with matching payment numbers and values in both datasets were 3.4% and 0.0%, respectively; for recipients these figures were 7.8% and 1.9%. There were 24 and 3 donors missing from industry and patient organisation data during the entire study period, representing 38.1% and 3.6% of those in the respective datasets. The share of donor–recipient ties in which industry and patient organisation data agreed about donors and recipients was 38.9% and 68.4% in each dataset, respectively. Of 63 donors reporting payments, only 3 (4.8%) had their recipient lists fully overlapping with patient organisation data. Of 200 recipients reporting industry funding, 102 (51.0%) had their donor lists fully overlapping with industry data.ConclusionsBoth donors and recipients under-reported payments. Existing donor and recipient disclosure systems cannot manage potential conflicts of interest associated with industry payments. Increased standardisation could limit the under-reporting by each side but only an integrated donor–recipient database could eliminate it.
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Beal, Eliza W., Dmitry Tumin, Lanla F. Conteh, A. James Hanje, Anthony J. Michaels, Don Hayes, Sylvester M. Black, and Khalid Mumtaz. "Impact of Recipient and Donor Obesity Match on the Outcomes of Liver Transplantation: All Matches Are Not Perfect." Journal of Transplantation 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/9709430.
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There is a paucity of literature examining recipient-donor obesity matching on liver transplantation outcomes. The United Network for Organ Sharing database was queried for first-time recipients of liver transplant whose age was ≥18 between January 2003 and September 2013. Outcomes including patient and graft survival at 30 days, 1 year, and 5 years and overall, liver retransplantation, and length of stay were compared between nonobese recipients receiving a graft from nonobese donors and obese recipient-obese donor, obese recipient-nonobese donor, and nonobese recipient-obese donor pairs. 51,556 LT recipients were identified, including 34,217 (66%) nonobese and 17,339 (34%) obese recipients. The proportions of patients receiving an allograft from an obese donor were 24% and 29%, respectively, among nonobese and obese recipients. Graft loss (HR: 1.27; 95% CI: 1.09–1.46;p=0.002) and mortality (HR: 1.38; 95% CI: 1.16–1.65;p<0.001) at 30 days were increased in the obese recipient-obese donor pair. However, 1-year graft (HR: 0.83; 95% CI: 0.74–0.93;p=0.002) and patient (HR: 0.84; 95% CI: 0.74–0.95;p=0.007) survival and overall patient (HR: 0.93; 95% CI: 0.86–1.00;p=0.042) survival were favorable. There is evidence of recipient and donor obesity disadvantage early, but survival curves demonstrate improved long-term outcomes. It is important to consider obesity in the donor-recipient match.
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Gibson, Christopher J., Haesook T. Kim, Lin Zhao, H. Moses Murdock, Bryan Hambley, Alana Ogata, Rafael Madero-Marroquin, et al. "Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation." Journal of Clinical Oncology 40, no. 2 (January 10, 2022): 189–201. http://dx.doi.org/10.1200/jco.21.02286.
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PURPOSE Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. PATIENTS AND METHODS We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. RESULTS CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations. CONCLUSION Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome–associated mutations or germline predisposition in donors.
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Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (October 15, 1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.3090.
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Abstract Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Fast, LD, CR Valeri, and JP Crowley. "Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease." Blood 86, no. 8 (October 15, 1995): 3090–96. http://dx.doi.org/10.1182/blood.v86.8.3090.bloodjournal8683090.
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Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.
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Tan, Susanna K., Chunhong Huang, Malaya K. Sahoo, Jenna Weber, Jason Kurzer, Margaret R. Stedman, Waldo Concepcion, et al. "Impact of Pretransplant Donor BK Viruria in Kidney Transplant Recipients." Journal of Infectious Diseases 220, no. 3 (March 14, 2019): 370–76. http://dx.doi.org/10.1093/infdis/jiz114.
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Abstract Background BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients. Methods We prospectively collected pretransplant plasma and urine samples from living and deceased kidney donors and performed BKV polymerase chain reaction (PCR) and immunoglobulin G (IgG) testing on pretransplant and serially collected posttransplant samples in kidney transplant recipients. Results Among deceased donors, 8.1% (17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4% (6/39) of living donors and 8.5% (4/47) of deceased donors of recipients at our institution (P = .50). BKV VP1 sequencing revealed identical virus between donor–recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6% vs 7.8%; P < .001) and viremia (66.6% vs 8.9%; P < .001) with a shorter time to onset (log-rank test, P < .001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pretransplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (P = .31, P = .75, and P = .51, respectively). Conclusions Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at risk for BKV complications.
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Ueda, Masumi, Lan Beppu, Judy Campbell, Mary E. D. Flowers, Jerald P. Radich, and Rainer Storb. "Clonal Hematopoiesis in Donor-Recipient Pairs after Allogeneic Hematopoietic Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 702. http://dx.doi.org/10.1182/blood-2019-126979.
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After allogeneic hematopoietic cell transplantation (HCT), a relatively small number of donor hematopoietic cells must reconstitute the entire recipient hematopoietic system, while the donor is left with a near normal pool of hematopoietic cells. We hypothesized that the increased replicative demand on donor cells in the recipient after allogeneic HCT will accelerate telomere shortening and magnify the genetic alterations that are associated with normal aging, including clonal hematopoiesis. We aimed to compare mutation frequency in genes associated with clonal hematopoiesis of indeterminant potential (CHIP) and myeloid diseases between donors and recipients, with a focus on transplant pairs with older donors. We obtained contemporary blood samples from 10 related donor-recipient pairs surviving a median of 36.6 years (range 6.6-45.7 years) after HCT. Information on donor-recipient pairs is summarized in Table 1. Variant libraries were prepared from bulk peripheral blood mononuclear cells (PBMCs) using Archer Dx VariantPlex Myeloid panel of 75 myeloid disease-associated genes (ArcherDx, Boulder, CO). Sequencing was completed on the Illumina HiSeq system. Variants with allelic frequency (AF) ≥2% were detected in donors (median number of variants 50.5, range 35-107) and recipients (median number of variants 50, range 32-109). In all pairs, there was significant overlap in the variants detected, although some were unique to donors or recipients (Figure 1). Two of the 3 donor-recipient pairs with >25 years difference in donor age (84 and 71 years) and recipient age (47 and 42 years) showed an increase in the shared variant AF in the recipient in DNMT3A (nonsense and frameshift mutations) of 5 to 18% and 5 to 16%, respectively. All other shared variants in CHIP-associated genes (DNMT3A, ASXL1, TET2) detected in 6 pairs did not show significant difference in AF (Table 2). Among other shared variants of non-CHIP genes, 7 pairs showed mutations with ≥5% difference in AF, but the difference was small (mean difference 5.3%, range 4.5-7.4%) (Table 3). In conclusion, our results suggest that even decades after transplantation and high replicative demand, most donor variants, at the level of detection of this assay, do not preferentially expand in the recipient. Donor-recipient pairs with older donors and ~30-year difference in age with the recipient showed a modest expansion in DNMT3A clones. Future studies will compare contemporary samples to historical samples from the time of transplant. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding.
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O'Hara, Jerome F., Katrina Bramstedt, Stewart Flechner, and David Goldfarb. "Ethical Issues Surrounding High-Risk Kidney Recipients: Implications for the Living Donor." Progress in Transplantation 17, no. 3 (September 2007): 180–82. http://dx.doi.org/10.1177/152692480701700304.
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Evaulating patients for living kidney donor transplantation involving a recipient with significant medical issues can create an ethical debate about whether to proceed with surgery. Donors must be informed of the surgical risk to proceed with donating a kidney and their decision must be a voluntary one. A detailed informed consent should be obtained from high-risk living kidney donor transplant recipients as well as donors and family members after the high perioperative risk potential has been explained to them. In addition, family members need to be informed of and acknowledge that a living kidney donor transplant recipient with pretransplant extrarenal morbidity has a higher risk of a serious adverse outcome event such as graft failure or recipient death. We review 2 cases involving living kidney donor transplant recipients with significant comorbidity and discuss ethical considerations, donor risk, and the need for an extended informed consent.
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Gibson, Christopher J., Haesook T. Kim, H. Moses Murdock, Bryan Hambley, Lin Zhao, Lisa Green, Mark Fleharty, et al. "DNMT3A clonal Hematopoiesis in Older Donors Is Associated with Improved Survival in Recipients after Allogeneic Hematopoietic Cell Transplant." Blood 136, Supplement 1 (November 5, 2020): 26. http://dx.doi.org/10.1182/blood-2020-142925.
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Background: Clonal hematopoiesis (CH) is an age-related condition in which somatic mutations can be detected in the blood of healthy individuals. In the non-transplant setting, CH is associated with an elevated risk of developing hematologic malignancy and an increased risk of non-hematologic outcomes due to altered inflammatory signaling. During hematopoietic cell transplantation (HCT), CH in older donors can engraft in recipients and could therefore influence outcomes through effects on graft immunologic function or by causing donor cell leukemia. A definitive link between donor CH and recipient outcomes has not been established. We therefore evaluated the impact of CH in donors aged 40 years or older on recipient clinical outcomes in 1727 donor-recipient pairs. Methods: We performed targeted, error-suppressed sequencing of 46 genes on 1727 samples from donors age 40 and older. We defined CH as pathogenic mutations at variant allele fraction (VAF) 0.005 or greater. Median donor age was 51 (range 40-80) and median recipient age was 55 (range 1-78). There were 889 matched related donors (51.5%), 454 haploidentical donors (26.3%), 273 matched unrelated donors (15.8%), 71 mismatched unrelated donors (4.1%), and 38 mismatched related donors (2.2%). 929 recipients (53.8%) had myeloid malignancies, 718 (41.6%) had lymphoid malignancies, and 80 (4.6%) had non-malignant diseases. 1022 (59.2%) recipients received peripheral blood stem cell products and 703 (40.7%) received bone marrow. 672 recipients (38.9%) received post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. Median follow-up for survivors was 6.0 years. Results: We identified CH in 388 of 1727 (22.5%) donor samples. Mutations in DNMT3A were most common (302 mutations in 253 donors), followed by TET2 (96 mutations in 89 donors), ASXL1 (n=22) and PPM1D (n=14). No other genes were mutated in more than 10 donors (0.5%). The presence of donor CH was independently associated with older donor age, but not with donor sex, donor-recipient relatedness, graft source, or recipient disease. The presence of donor CH at VAF 0.01 or greater was associated with improved progression-free survival (PFS) in a multivariable model that included donor and recipient age, HCT-CI, disease category, Disease Risk Index score, conditioning intensity, and donor type (HR for death or relapse 0.81, 95% CI 0.68-0.97, P=0.019). This effect was driven by DNMT3A mutations, which were independently associated with improved overall survival (HR for death 0.75; 0.59-0.95, P=0.016) and reduced risk of relapse (sHR 0.76; 0.59-0.97, P=0.029) in the same model. CH involving other gene mutations, including TET2 and genes other than DNMT3A/TET2, was not significantly associated with any recipient outcome. Smaller clones (VAF 0.005-0.01) had no effect on any outcome. The association between donor DNMT3A-CH and recipient outcomes was limited to those who did not receive PTCy for GVHD prophylaxis (Figure 1A-C). In the model described above, donor DNMT3A-CH in the absence of PTCy was independently associated with improved PFS (HR 0.61; 0.45-0.84, P=0.002), reduced risk of relapse (sHR 0.59; 0.39-0.9, P=0.014) and an elevated risk of chronic GVHD (sHR 1.36; 1.01-1.83, P=0.042) compared to those without DNMT3A-CH. In recipients who received PTCy, there was no significant effect of donor DNMT3A-CH on PFS, relapse, or cGVHD (1D). Eight recipients developed donor cell leukemia (DCL), for a cumulative incidence of 0.7% at 10 years. In seven of these cases, we identified gene mutations in the corresponding donor products that matched the mutations found in the subsequent DCL, including 2 with TP53 mutations, 3 with splicing factor mutations, and 2 with germline DDX41 mutations that were present in both donor and recipient. No recipients who received products with sole DNMT3A-CH developed DCL. Conclusions: In HCT donors age 40 or older, the presence of DNMT3A clonal hematopoiesis at VAF >/= 0.01 is independently associated with prolonged overall and progression-free survival in transplant recipients. This effect is driven by reduced risk of disease relapse and confined to recipients who do not receive PTCy, suggesting that it is mediated at least in part by effects on donor T cells. The risk of direct evolution of DNMT3A-CH to donor cell leukemia is low, and most DCLs were traced to atypical donor CH involving MDS-associated genes or germline risk alleles. Disclosures Nikiforow: Novartis: Honoraria; Nkarta Therapeutics: Honoraria; Kite/Gilead: Honoraria. DeZern:MEI: Consultancy; Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria. Ritz:Rheos Medicines: Consultancy; Infinity Pharmaceuticals: Consultancy; Amgen: Research Funding; Equillium: Research Funding; Kite Pharma: Research Funding; Avrobio: Consultancy; Falcon Therapeutics: Consultancy; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; LifeVault Bio: Consultancy. Soiffer:VOR Biopharma: Consultancy; Kiadis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; alexion: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Rheos Therapeutics: Consultancy. Lindsley:Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding; Bluebird Bio: Consultancy.
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Gandhi, Maher K., Mark R. Wills, Georgina Okecha, Elizabeth K. Day, Ray Hicks, Robert E. Marcus, J. G. Patrick Sissons, and Andrew J. Carmichael. "Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation." Blood 102, no. 9 (November 1, 2003): 3427–38. http://dx.doi.org/10.1182/blood-2002-12-3689.
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Abstract To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.
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Tong, Li, Xiao-Guang Hu, Fa Huang, Shun-Wei Huang, Li-Fen Li, Zhao-Xia Tang, Ji-You Yao, et al. "Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China." Journal of Infectious Diseases 221, Supplement_2 (March 16, 2020): S164—S173. http://dx.doi.org/10.1093/infdis/jiz591.
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Abstract Background Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents’ characteristics and cases outcomes. Methods A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. Results Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025–.529). Conclusions When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.
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Onishchenko, N. A., A. O. Nikolskaya, Z. Z. Gonikova, L. A. Kirsanova, M. Yu Shagidulin, and V. I. Sevastianov. "Regenerative and hepatospecific activity of total RNA from xenogenic bone marrow cells." Russian Journal of Transplantology and Artificial Organs 23, no. 1 (April 10, 2021): 43–48. http://dx.doi.org/10.15825/1995-1191-2021-1-43-48.
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Objective: to study the peculiarities of the induction effect of total RNA (tRNA) from xenogenic bone marrow cells (BMCs) on regeneration processes in the recipient's native liver with extensive liver resection using an adoptive transfer model. Materials and methods. The study was carried out on an adoptive transfer model using male Wistar rats (n = 20) and guinea pigs (n = 17). The donors were rats (n = 10). 12 hours after extensive liver resection (70-75%), tRNA was isolated from BMCs and injected into intact (non-operated) recipients intraperitoneally at a dose of 30 μg/100 g of weight. The induction effect of the tRNA on operated rats was studied in 3 groups of recipients: Group 1 (control, n = 5) - administration of saline to guinea pigs; Group 2 (control, n = 10) - administration of tRNA from a donor rat to a recipient rat (allogeneic transfer); Group 3 (experiment, n = 12) - administration of tRNA from a donor rat to a recipient guinea pig (xenogeneic transfer). In histological preparations of recipient livers, after 48, 72 hours and 7 days, we studied the mitotic activity of hepatocytes and the features of the microscopic picture of the liver. The significance of differences in the compared groups was assessed using the parametric Student's t-test. Results. The ability of BMC tRNA to tissue-specifically activate regenerative and immune responses in the liver after extensive resection was found to depend on the donor and recipient species identity. Introduction of allogeneic donor tRNA in the recipient's liver resulted in predominant enhancement in hepatocyte mitotic activity (p < 0.05). The use of xenogeneic donor tRNA leads to enhanced activity of only immuno-inflammatory reactions in the recipient's liver, such as sinusoidal cell activation, lymphocytic infiltration into sinusoids, and portal tract infiltration by inflammatory cells. Conclusion. To induce regenerative processes in the liver, tRNA obtained from allogeneic BMCs should be used.
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Wimperis, J. Z., M. K. Brenner, H. G. Prentice, E. J. Thompson, and A. V. Hoffbrand. "B cell development and regulation after T cell-depleted marrow transplantation." Journal of Immunology 138, no. 8 (April 15, 1987): 2445–50. http://dx.doi.org/10.4049/jimmunol.138.8.2445.
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Abstract Antibody secreting B lymphocytes from immunized donors can be adoptively transferred after T cell-depleted marrow transplantation to produce protective levels of antibody in the recipient. We have investigated whether these transferred lymphocytes remain subject to continued clonal selection and subsequently became memory B cells even in the initial absence of T cells. Twenty-eight donor/recipient pairs were randomized pretransplant to be immunized or not with tetanus toxoid (TT). The recipients were then vaccinated with TT at 3, 6, and 12 mo posttransplant, and the anti-TT antibody response (IgG and IgM) was measured. Only when both donor and recipient were immunized pretransplant could the recipient respond to antigen challenge within the first year posttransplant. Examination of the spectrotype pattern of the recipient anti-TT antibody shows that selection of B cell clones continues, so that T cell depletion does not prevent the appearance of oligoclonal antibody responses. However, because the spectrotype pattern of the recipient did not match the donors, B cell regulatory mechanisms in donor and recipient are nonidentical. These data contrast with observations made in recipients of non-T cell-depleted marrow and serve to illustrate the role of T lymphocytes in the induction and regulation of secondary antibody responses in man. The results also suggest that optimal humoral responses to any antigen after T cell depletion can only occur when both donor and recipient are immunized pretransplant, a prediction borne out by studies on the influence of donor cytomegalovirus status on the severity of cytomegalovirus infection in the recipient.
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Martin, Paul J., David M. Levine, Barry E. Storer, Sarah C. Nelson, Xinyuan Dong, and John A. Hansen. "Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 14 (July 20, 2020): 3224–33. http://dx.doi.org/10.1182/bloodadvances.2020001927.
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Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.
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Lepeytre, Fanny, Catherine Delmas-Frenette, Xun Zhang, Stéphanie Larivière-Beaudoin, Ruth Sapir-Pichhadze, Bethany J. Foster, and Héloïse Cardinal. "Donor Age, Donor-Recipient Size Mismatch, and Kidney Graft Survival." Clinical Journal of the American Society of Nephrology 15, no. 10 (August 25, 2020): 1455–63. http://dx.doi.org/10.2215/cjn.02310220.
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Background and objectivesSmall donor and/or kidney sizes relative to recipient size are associated with a higher risk of kidney allograft failure. Donor and recipient ages are associated with graft survival and may modulate the relationship between size mismatch and the latter. The aim of this study was to determine whether the association between donor-recipient size mismatch and graft survival differs by donor and recipient age.Design, setting, participants, & measurementWe performed a retrospective cohort study of first adult deceased donor kidney transplantations performed between 2000 and 2018 recorded in the Scientific Registry of Transplant Recipients. We used multivariable Cox proportional hazards models to assess the association between donor-recipient body surface area ratio and death-censored graft survival, defined as return to dialysis or retransplantation. We considered interactions between donor-recipient body surface area ratio and each of recipient and donor age.ResultsAmong the 136,321 kidney transplant recipients included in this study, 23,614 (17%) experienced death-censored graft loss over a median follow-up of 4.3 years (interquartile range, 1.9–7.8 years). The three-way donor-recipient body surface area ratio by donor age by recipient age interaction was statistically significant (P=0.04). The magnitude of the association between severe size mismatch (donor-recipient body surface area ratio <0.80 versus ≥1.00) and death-censored graft survival was stronger with older donor age and recipient age. In all recipient age categories except the youngest (18–30 years), 5- and 10-year graft survival rates were similar or better with a size-mismatched donor aged <40 years than a nonsize-mismatched donor aged 40 years or older.ConclusionsThe association of donor-recipient size mismatch on long-term graft survival is modulated by recipient and donor age. Size-mismatched kidneys yield excellent graft survival when the donor is young. Donor age was more strongly associated with graft survival than size mismatch.
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Burroughs, Thomas E., Amy D. Waterman, and Barry A. Hong. "One Organ Donation, Three Perspectives: Experiences of Donors, Recipients, and Third Parties with Living Kidney Donation." Progress in Transplantation 13, no. 2 (June 2003): 142–50. http://dx.doi.org/10.1177/152692480301300212.
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Although living kidney donors' experiences with donation have been studied, questions of potential bias in retrospective donor reports remain. This study examined the experience of living kidney donation from 3 perspectives: those of the donor, the recipient, and a third party involved with the donation (ie, a donor triad). Surveys were completed with 174 donor triads to examine triad members' perceptions of donors' concerns before transplantation, whether these concerns came true after transplantation, the donors' experiences with surgery and recovery, and whether they would make the same decision again today. Triad members all agreed that donors were highly satisfied with their donation experience and that the relationship between recipient and donor improved after transplantation. Although recipients and third parties correctly identified the donors' primary concerns, they underestimated the prevalence of 16 of 18 donor concerns, including the donors' willingness to make the same decision again. Recipients also overestimated how painful and difficult the surgery and recovery were for donors. The results suggest that retrospective studies of donors may not be marred by significant misreporting or memory biases and that better education about the donation experience for the entire donor triad might provide better social support for donors, reduce recipients' guilt about donors' pain, and increase donation rates overall.
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Goldfarb, David A. "Laparoscopic Donor Nephrectomy : Recipient Surgeon's Perspective." Japanese Journal of Urology 96, no. 2 (2005): 49–51. http://dx.doi.org/10.5980/jpnjurol.96.49.
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Suddaby, Elizabeth C., Margaret J. Schaeffer, Lori E. Brigham, and Timothy R. Shaver. "Analysis of Organ Donors in the Peripartum Period." Journal of Transplant Coordination 8, no. 1 (March 1998): 35–39. http://dx.doi.org/10.1177/090591999800800108.
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This study was a retrospective review of 252 brain-dead potential donors from 1990 to 1996, including 5 organ donors in the peripartum period. The purpose of the study was to determine the effects of pregnancy on organ donor management and recipient outcome. Case analysis of 5 pregnant donors identified problems with hemodynamic stability and electrolyte abnormalities, including hypernatremia, hyperchloremia, and hypocalcemia. In addition, blood glucose was frequently elevated. Two donors were treated for diabetes insipidus. All 5 donors produced organs for 20 transplant recipients. Five heart recipients (including 1 heart-lung), 4 liver recipients, 4 kidney recipients, and 4 pancreas-kidney recipients have reported excellent outcomes. The use of organs from brain-dead organ donors in the peripartum period has minimal impact on donor management and recipient outcome.
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Birch, Thomas D. "Basic Needs: Paternalistic Government Welfare Policy with Distortionary Taxation." Public Finance Quarterly 15, no. 3 (July 1987): 298–321. http://dx.doi.org/10.1177/109114218701500304.
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This article analyzes government welfare policy in a general equilibrium setting with distortionary taxation. Government welfare policy is in accordance with the preferences of donor-taxpayers who want the consumption-leisure bundle of recipients to satisfy “basic needs.” The main focus is on the optimal level of employment for a destitute welfare recipient from the donor-taxpayer's perspective. This optimal level depends on the distortionary cost of taxation, whether the donor regards leisure or work as a basic “need,” and the distribution of the recipient's income if work is required. It is argued that donor appropriation of income resulting from mandatory recipient work in the private sector is not necessarily superior to either letting recipients retain their income or having the government appropriate the recipient's income from mandatory public sector employment.
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Nguyen, Yume, Abed Al-Lehibi, Elizabeth Gorbe, Ellen Li, Michael Haagenson, Tao Wang, Stephen Spellman, Stephanie J. Lee, and Nicholas O. Davidson. "Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease–associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation." Blood 115, no. 17 (April 29, 2010): 3625–31. http://dx.doi.org/10.1182/blood-2009-09-243840.
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Abstract Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% having both donor and recipient variants. Twenty-three percent of both donors and recipients had variant IRGM SNPs. None of the 3 IBD-associated alleles showed a statistically significant association with any adverse clinical outcomes. Our results do not support an association between the 3 IBD-associated SNPs and adverse outcomes after matched unrelated donor hematopoietic cell transplantations in US patients.
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Brucker, Sara Yvonne, Thomas Strowitzki, Florin-Andrei Taran, Katharina Rall, Dorit Schöller, Markus Hoopmann, Melanie Henes, et al. "Living-Donor Uterus Transplantation: Pre-, Intra-, and Postoperative Parameters Relevant to Surgical Success, Pregnancy, and Obstetrics with Live Births." Journal of Clinical Medicine 9, no. 8 (August 3, 2020): 2485. http://dx.doi.org/10.3390/jcm9082485.
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Uterus transplantation (UTx) can provide a route to motherhood for women with Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS), a congenital disorder characterized by uterovaginal aplasia, but with functional ovaries. Based on our four successful living-donor transplantations and two resulting births, this analysis presents parameters relevant to standardizing recipient/donor selection, UTx surgery, and postoperative treatment, and their implementation in routine settings. We descriptively analyzed prospectively collected observational data from our four uterus recipients, all with MRKHS, their living donors, and the two newborns born to two recipients, including 1-year postnatal follow-ups. Analysis included only living-donor/recipient pairs with completed donor/recipient surgery. Two recipients, both requiring ovarian restimulation under immunosuppression after missed pregnancy loss in one case and no pregnancy in the other, each delivered a healthy boy by cesarean section. We conclude that parameters crucial to successful transplantation, pregnancy, and childbirth include careful selection of donor/recipient pairs, donor organ quality, meticulous surgical technique, a multidisciplinary team approach, and comprehensive follow-up. Surgery duration and blood vessel selection await further optimization, as do the choice and duration of immunosuppression, which are crucial to timing the first embryo transfer. Data need to be collected in an international registry due to the low prevalence of MRKHS.
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Schreiber, Peter W., Verena Kufner, Kerstin Hübel, Stefan Schmutz, Osvaldo Zagordi, Amandeep Kaur, Cornelia Bayard, et al. "Metagenomic Virome Sequencing in Living Donor and Recipient Kidney Transplant Pairs Revealed JC Polyomavirus Transmission." Clinical Infectious Diseases 69, no. 6 (December 2, 2018): 987–94. http://dx.doi.org/10.1093/cid/ciy1018.
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AbstractBackgroundBefore kidney transplantation, donors and recipients are routinely screened for viral pathogens using specific tests. Little is known about unrecognized viruses of the urinary tract that potentially result in transmission. Using an open metagenomic approach, we aimed to comprehensively assess virus transmission in living-donor kidney transplantation.MethodsLiving kidney donors and their corresponding recipients were enrolled at the time of transplantation. Follow-up study visits for recipients were scheduled 4–6 weeks and 1 year thereafter. At each visit, plasma and urine samples were collected and transplant recipients were evaluated for signs of infection or other transplant-related complications. For metagenomic analysis, samples were enriched for viruses, amplified by anchored random polymerase chain reaction (PCR), and sequenced using high-throughput metagenomic sequencing. Viruses detected by sequencing were confirmed using real-time PCR.ResultsWe analyzed a total of 30 living kidney donor and recipient pairs, with a follow-up of at least 1 year. In addition to viruses commonly detected during routine post-transplant virus monitoring, metagenomic sequencing detected JC polyomavirus (JCPyV) in the urine of 7 donors and their corresponding recipients. Phylogenetic analysis confirmed infection with the donor strain in 6 cases, suggesting transmission from the transplant donor to the recipient, despite recipient seropositivity for JCPyV at the time of transplantation.ConclusionsMetagenomic sequencing identified frequent transmission of JCPyV from kidney transplant donors to recipients. Considering the high incidence rate, future studies within larger cohorts are needed to define the relevance of JCPyV infection and the donor’s virome for transplant outcomes.
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Ebad, Chaudhry Adeel, David Brennan, Julio Chevarria, Mohammad Bin Hussein, Donal Sexton, Douglas Mulholland, Ciaran Doyle, et al. "Is Bigger Better? Living Donor Kidney Volume as Measured by the Donor CT Angiogram in Predicting Donor and Recipient eGFR after Living Donor Kidney Transplantation." Journal of Transplantation 2021 (July 9, 2021): 1–6. http://dx.doi.org/10.1155/2021/8885354.
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Background. The role of kidney volume measurement in predicting the donor and recipient kidney function is not clear. Methods. We measured kidney volume bilaterally in living kidney donors using CT angiography and assessed the association with the donor remaining kidney and recipient kidney (donated kidney) function at 1 year after kidney transplantation. Donor volume was categorized into tertiles based on lowest, middle, and highest volume. Results. There were 166 living donor and recipient pairs. The mean donor age was 44.8 years (SD ± 10.8), and donor mean BMI was 25.5 (SD ± 2.9). The recipients of living donor kidneys were 64% male and had a mean age of 43.5 years (SD ± 13.3). Six percent of patients experienced an episode of cellular rejection and were maintained on dialysis for a mean of 18 months (13–32) prior to transplant. Kidney volume was divided into tertiles based on lowest, middle, and highest volume. Kidney volume median (range) in tertiles 1, 2, and 3 was 124 (89–135 ml), 155 (136–164 ml), and 184 (165–240 ml) with donor eGFR ml/min (adjusted for body surface area expressed as ml/min/1.73 m2) at the time of donation in each tertile, 109 (93–129), 110 (92–132), and 101 ml/min (84–117). The median (IQR) eGFR in tertiles 1 to 3 in kidney recipients at 1 year after donation was 54 (44–67), 62 (50–75), and 63 ml/min (58–79), respectively. The median (IQR) eGFR in tertiles 1 to 3 in the remaining kidney of donors at 1 year after donation was 59 (53–66), 65 (57–72), and 65 ml/min (56–73), respectively. Conclusion. Bigger kidney volume was associated with better eGFR at 1 year after transplant in the recipient and marginally in the donor remaining kidney.
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Bellini, Maria Irene, Mikhail Nozdrin, Liset Pengel, Simon Knight, and Vassilios Papalois. "How good is a living donor? Systematic review and meta-analysis of the effect of donor demographics on post kidney transplant outcomes." Journal of Nephrology 35, no. 3 (January 24, 2022): 807–20. http://dx.doi.org/10.1007/s40620-021-01231-7.
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Abstract Background and Aims Living donor kidneys are considered the best quality organs. In the attempt to expand the donor pool, the donor’s age, sex and body mass index (BMI) might be considered as potential determinants of the kidney transplant outcomes, and thus guide recipient selection. We aimed to investigate the effects of donor demographics on kidney function, graft and recipient survival, delayed graft function (DGF) and acute rejection (AR). Methods Systematic review and meta-analysis. EMBASE, MEDLINE, Web of Science, BIOSIS, CABI, SciELO and Cochrane were searched using algorithms. NHBLI tools were used for risk of bias assessment. Mean difference (MD), standardized mean difference (SMD), and risk ratio (RR) were calculated in Revman 5.4 Results Altogether, 5129 studies were identified by the search algorithm; 47 studies met the inclusion criteria and were analyzed. No significant difference in recipient 1-year survival was found between recipients of donors aged < 50 vs donors aged > 50 (RR = 0.65 95% CI: 0.1–4.1), and recipients of donors aged < 60 vs donors aged > 60 (RR = 0.81 95% CI: 0.3–2.3). Graft survival was significantly higher in recipients of grafts from donors aged < 60. Risk of AR (RR = 0.62 95% CI: 0.5–0.8) and DGF (RR = 0.28 95% CI: 0.1–0.9) were significantly lower in recipients of grafts from donors aged < 60. One-year serum creatinine was significantly lower in recipients from donors aged < 60 years compared to donors aged > 60 years (MD = 0.3 mg/dl 95% CI: 0.1–0.9), although there was high heterogeneity. Recipients of grafts from male donors had lower 1-year serum creatinine (MD = 0.12 mg/dl 95% CI: 0.2–0.1) and higher eGFR compared to recipients of female donors (p < 0.00001). Donor obesity increased the incidence of delayed graft function but not acute rejection (RR = 0.66 95% CI: 0.32–1.34). Conclusions Older donor age was associated with worse post-transplant outcomes and recipients of male donors had better 1-year eGFR. Donor obesity affects the incidence of delayed graft function, but not the incidence of acute rejection in recipients. Graphical Abstract
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Nepali, Rabin, Dibya S. Shah, Prem R. Gyawali, Uttam Sharma, and Pawan R. Chalise. "Donor Factors Affecting Short Term Graft Outcome in Live Donor Kidney Transplantation." Journal of Institute of Medicine Nepal 41, no. 2 (December 3, 2019): 4–7. http://dx.doi.org/10.3126/jiom.v41i2.26539.
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Introduction: Since the beginning of renal transplant, the objective has been to increase the patient and graft survival, both short term and long term. Data relating to donor factors affecting short term survival at 6 months in live donor kidney transplantation has been scarce. This single center study tries to examine the predictors of short term graft outcome at six months in recipients of live donor kidney transplants and explore which donor characteristics are the most useful in predicting the post-transplant graft function in Nepalese population.
Methods: All patients who underwent kidney transplantation between May 2015 to July 2016 were included in the study. The patients who expired during follow were excluded. The clinical and laboratory parameters of the donors we rerecorded. The recipients were followed up for six months post transplantation. The eGFR of the recipients and the occurrence of rejection were recorded at the end of six months post transplantation.
Results: A total of 82 donor-recipient pairs underwent living donor renal transplantation at our hospital during the studyperiod. One recipient who expired during follow up was excluded. The mean age of donor was 45.20 ± 11.226years of which 55 (67.9%) were female and 26 (32.1 %) were male. The mean eGFR of the donor calculated from Cockcroft Gault equation was 81.98 ± 18.11. The eGFR of the recipient at the end of six months post transplantation calculated form the MDRD equation was 67.76 ± 20.94. A total of 7 patients (8.6%) had rejection that were biopsy proven. Only donor eGFR was found to be significantly associated with eGFR of the recipient at six months post transplantation (p=0.034). Body mass index of the donor was significantly associated with rejection in the recipient at six months post transplantation (p=0.011).
Conclusion: Our study demonstrates that the donor eGFR and body mass index are independent and important factors affecting the short term graft outcome at six months post transplantation.
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Shiba, Hiroaki, Shigeki Wakiyama, Yasuro Futagawa, Tomonori Iida, Michinori Matsumoto, Koichiro Haruki, Yuichi Ishida, Takeyuki Misawa, and Katsuhiko Yanaga. "Assessment of Graft Selection Criteria in Living-Donor Liver Transplantation: The Jikei Experience." International Surgery 100, no. 7-8 (November 1, 2015): 1229–32. http://dx.doi.org/10.9738/intsurg-d-14-00300.1.
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In living-donor liver transplantation, graft selection is especially important for the safety of the live donor and an acceptable outcome for the recipient. The essential medical requirements for living liver donation at Jikei University Hospital are as follows: an adult aged 65 years or younger, in good general condition, with partial liver volume of more than 35% of the standard liver volume (SLV) for the recipient, and without severe liver steatosis. Based on our criteria, we performed 13 living-donor liver transplantations between 2007 and 2013, including 1 retransplantation. Three cases were outside our standard donor criteria, including age (18 and 66 years) and 33% graft volume (GV) to SLV ratio for the recipient on preoperative volumetry using computed tomography. In 2 cases, the actual GV to SLV ratio at transplantation was less than 35%. Median postoperative hospital stay was 11 days for the donors, and 29 days for the recipients. All donors returned to their preoperative status, and all recipients were discharged in good condition. Our medical requirements for living liver donation seem to be acceptable because of the good outcome.
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Qiu, Wenxian, Yan Jiang, Jianyong Wu, Hongfeng Huang, Wenqing Xie, Xishao Xie, Jianghua Chen, and Wenhan Peng. "Simple Cysts in Donor Kidney Contribute to Reduced Allograft Function." American Journal of Nephrology 45, no. 1 (December 2, 2016): 82–88. http://dx.doi.org/10.1159/000453078.
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Background: Simple renal cysts may be an early marker of renal disease. We investigated whether simple cysts in donor kidney are associated with the decline of allograft function in living donor kidney transplantation. Methods: We retrospectively reviewed records of donors and recipients from 716 living donor kidney transplants performed between April 2007 and April 2015 in our hospital. Ninety-one donors with renal cysts and 64 recipients with cysts in donor kidney were noted. We compared these 64 cases to 128 no cyst-bearing controls matched for the donor gender, recipient gender, donor baseline serum creatinine (sCr), donor/recipient body surface area ratio, donor age, recipient age and the date of kidney transplantation in turn. Results: The presence of cysts was interrelated with age, gender and renal function independently in donors. Pathological findings of time-zero biopsy revealed that donor kidney harboring cysts existed more glomerular sclerosis compared with no cyst-bearing controls (p = 0.040). The estimating glomerular filtration rate levels of recipients were 80.82 ± 26.61 vs. 88.21 ± 23.12, 66.95 ± 17.42 vs. 72.15 ± 16.42 and 60.92 ± 22.17 vs. 68.72 ± 14.43 ml/min· 1.73 m2 in cyst-bearing and no cyst-bearing group on day 7, month 6 and year 5, respectively, after surgery (p < 0.05). The mean sCr were 112.14 ± 48.32 vs. 98.75 ± 29.71 and 126.28 ± 42.32 vs. 115.05 ± 26.35 μmol/l on the 7th day and a half year after transplant, respectively (p < 0.05). The 2 groups did not significantly differ in terms of the other characteristics. Conclusion: Simple cysts in donor kidney can influence the early and long-term allograft function. In living donor transplantation, kidney presenting cysts should be considered carefully at the time of donor selection.
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Udomkarnjananun, Suwasin, Natavudh Townamchai, Pajaree Chariyavilaskul, Kroonpong Iampenkhae, Krit Pongpirul, Boonchoo Sirichindakul, Kamol Panumatrassamee, et al. "The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity." American Journal of Nephrology 47, no. 3 (2018): 182–90. http://dx.doi.org/10.1159/000487857.
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Background: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes. Methods: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode. Results: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient’s genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005). Conclusion: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity.
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Enghofer, Michael, Jörg Bojunga, Ralf Ludwig, Anke Oldenburg, August Bernd, Klaus Henning Usadel, and Klaus Kusterer. "Lymphocyte transfer in streptozotocin-induced diabetes: adhesion of donor cells to islet endothelium." American Journal of Physiology-Endocrinology and Metabolism 274, no. 5 (May 1, 1998): E928—E935. http://dx.doi.org/10.1152/ajpendo.1998.274.5.e928.
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The interaction between intravenously transferred lymphocytes derived from spleens of multiple low-dose streptozotocin-diabetic mice with islet, exocrine pancreatic, and gastric mucosal endothelium of nondiabetic recipient mice was investigated by in vivo microscopy. Donor lymphocytes were stained with acridine red in vitro. The adoptive transfer of these cells from diabetic donor animals resulted in significantly increased lymphocyte rolling (4.46 ± 1.32%, P < 0.05) and adhesion (3.86 ± 1.04%, P < 0.05) in islets of nondiabetic recipients that had been pretreated with a single subdiabetogenic dose of streptozotocin. No increased endothelial interaction was noted in nonpretreated recipients or in experiments with nondiabetic donors. Rolling (1.19 ± 0.61 to 2.71 ± 0.62%) and adhesion (0.61 ± 0.33 to 2.80 ± 0.97%) of donor lymphocytes were low in exocrine pancreatic and gastric mucosal control tissue. It is concluded that, in this animal model, lymphocytes from diabetic donors interact preferentially with recipient islet endothelium. However, additional stimulation of recipient islet endothelium by exogenous factors is necessary to enable transferred cells to adhere to pancreatic islets.
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Kato, S., H. Yabe, M. Yabe, M. Kimura, M. Ito, F. Tsuchida, K. Tsuji, and M. Takahashi. "Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient." Blood 75, no. 3 (February 1, 1990): 806–9. http://dx.doi.org/10.1182/blood.v75.3.806.806.
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Abstract The transfer of antigen-specific cellular immunity in human bone marrow transplantation (BMT) was studied in 49 donor-recipient pairs, using a varicella-zoster-virus (VZV) specific lymphoproliferative response (LPR) assay. Posttransplant VZV-LPR could be serially measured in 31 long-term surviving recipients. VZV-specific T-cell immunity was detected in the early posttransplant period in 4 of 16 recipients who were, and whose donors were, immune to VZV before BMT, but two of those positive responses diminished in the first 100 days posttransplant. No positive response was detected in the immediate posttransplant period when either only the recipient or the donor was immune to VZV pretransplant. Herpes zoster or chickenpox developed in the recipients depending on a history of pretransplant VZV infection when the VZV-LPR became negative, and recovery from VZV infection was always followed by quick conversion of VZV-LPR. Long-lasting positive VZV-LPR was observed in the two recipients who experienced VZV infection in the immediate pretransplant period and received marrow graft from an immune donor. Our results indicate that a simple or direct transfer of VZV-specific cellular immunity from a marrow donor to a recipient cannot be expected in usual clinical bone marrow transplantation and that there might be a collaboration or recruitment of immune responses involving both donor and recipient that permits the VZV-LPR to remain positive posttransplant.
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Kato, S., H. Yabe, M. Yabe, M. Kimura, M. Ito, F. Tsuchida, K. Tsuji, and M. Takahashi. "Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient." Blood 75, no. 3 (February 1, 1990): 806–9. http://dx.doi.org/10.1182/blood.v75.3.806.bloodjournal753806.
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The transfer of antigen-specific cellular immunity in human bone marrow transplantation (BMT) was studied in 49 donor-recipient pairs, using a varicella-zoster-virus (VZV) specific lymphoproliferative response (LPR) assay. Posttransplant VZV-LPR could be serially measured in 31 long-term surviving recipients. VZV-specific T-cell immunity was detected in the early posttransplant period in 4 of 16 recipients who were, and whose donors were, immune to VZV before BMT, but two of those positive responses diminished in the first 100 days posttransplant. No positive response was detected in the immediate posttransplant period when either only the recipient or the donor was immune to VZV pretransplant. Herpes zoster or chickenpox developed in the recipients depending on a history of pretransplant VZV infection when the VZV-LPR became negative, and recovery from VZV infection was always followed by quick conversion of VZV-LPR. Long-lasting positive VZV-LPR was observed in the two recipients who experienced VZV infection in the immediate pretransplant period and received marrow graft from an immune donor. Our results indicate that a simple or direct transfer of VZV-specific cellular immunity from a marrow donor to a recipient cannot be expected in usual clinical bone marrow transplantation and that there might be a collaboration or recruitment of immune responses involving both donor and recipient that permits the VZV-LPR to remain positive posttransplant.
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Poldervaart, Rosalie A., Mirjam Laging, Tessa Royaards, Judith A. Kal-van Gestel, Madelon van Agteren, Marry de Klerk, Willij Zuidema, Michiel G. H. Betjes, and Joke I. Roodnat. "Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation." Journal of Transplantation 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/748102.
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Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n=101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs.Genetically unrelateddonors (486) were primarily partners.Genetically relateddonors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P<0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P<0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate.
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Isaacman-Beck, Jesse, Emilia A. Hermann, Yanjie Yi, Sarah J. Ratcliffe, Joseph Mulenga, Susan Allen, Eric Hunter, Cynthia A. Derdeyn, and Ronald G. Collman. "Heterosexual Transmission of Human Immunodeficiency Virus Type 1 Subtype C: Macrophage Tropism, Alternative Coreceptor Use, and the Molecular Anatomy of CCR5 Utilization." Journal of Virology 83, no. 16 (June 10, 2009): 8208–20. http://dx.doi.org/10.1128/jvi.00296-09.
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ABSTRACT Human immunodeficiency virus type 1 transmission selects for virus variants with genetic characteristics distinct from those of donor quasispecies, but the biological factors favoring their transmission or establishment in new hosts are poorly understood. We compared primary target cell tropisms and entry coreceptor utilizations of donor and recipient subtype C Envs obtained near the time of acute infection from Zambian heterosexual transmission pairs. Both donor and recipient Envs demonstrated only modest macrophage tropism, and there was no overall difference between groups in macrophage or CD4 T-cell infection efficiency. Several individual pairs showed donor/recipient differences in primary cell infection, but these were not consistent between pairs. Envs had surprisingly broad uses of GPR15, CXCR6, and APJ, but little or no use of CCR2b, CCR3, CCR8, GPR1, and CXCR4. Donors overall used GPR15 better than did recipients. However, while several individual pairs showed donor/recipient differences for GPR15 and/or other coreceptors, the direction of the differences was inconsistent, and several pairs had unique alternative coreceptor patterns that were conserved across the transmission barrier. CCR5/CCR2b chimeras revealed that recipients as a group were more sensitive than were donors to replacement of the CCR5 extracellular loops with corresponding regions of CCR2b, but significant differences in this direction were not consistent within pairs. These data show that sexual transmission does not select for enhanced macrophage tropism, nor for preferential use of any alternative coreceptor. Recipient Envs are somewhat more constrained than are donors in flexibility of CCR5 use, but this pattern is not universal for all pairs, indicating that it is not an absolute requirement.
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Gibson, Christopher J., James A. Kennedy, Sarah Nikiforow, John E. Dick, Jerome Ritz, Robert J. Soiffer, Joseph H. Antin, and R. Coleman Lindsley. "Donor Chip Causes Donor-Derived Clonal Hematopoiesis As an Early Complication of Allogeneic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 987. http://dx.doi.org/10.1182/blood.v128.22.987.987.
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Background Allogeneic stem cell transplantation (HSCT) involves the transfer of healthy donor hematopoietic cells, including hematopoietic stem cells (HSCs) and mature immune effector cells, to recipients with high-risk hematologic malignancies. The success of HSCT is fundamentally dependent on engraftment of normal donor-derived hematopoiesis. Rarely, donor-derived cells undergo transformation to myeloid leukemia as a late complication of HSCT (donor cell leukemia, DCL), a process linked in some cases to pre-existing mutations in donor hematopoietic stem cells (HSCs). In healthy older adults, HSC mutations can cause clonal hematopoiesis of indeterminate potential (CHIP), which is associated with increased risk of hematologic malignancy and an increased risk of all-cause mortality. Among donors over age 40, the frequency of donor CHIP can be estimated to be 5 to 20-fold higher than the frequency of donor cell leukemia, suggesting that non-leukemic endpoints of donor derived clonality may be more prevalent and consequential than previously recognized. Methods We performed targeted next generation sequencing in patients who developed peripheral cytopenias or myeloid neoplasms in the context of 100% donor cell chimerism after allogeneic HSCT. We also prospectively sequenced potential donors who had abnormal CBC parameters, including WBC differential and RBC indices. To determine whether the mutations detected in recipients were of donor derivation, and to assess clonal evolution over time, we performed ultra-deep genotyping at 30,000-100,000X or droplet digital PCR (ddPCR) in the donor stem cell product and serial post-SCT samples. Results We identified four allogeneic SCT recipients with 100% chimerism who met inclusion criteria, two with late-onset hematologic malignancy (latency 23 and 10 years) and two with progressive cytopenias but no evidence of hematologic malignancy on bone marrow examination (latency 18 and 13 months). In each of these patients, sequencing of bone marrow or peripheral blood specimens revealed at least one somatic mutation (SF3B1 K666Q; U2AF1 S34F; DNMT3A T868N; DNMT3A Q356X) that could be used to assess the possibility of donor derivation. In all patients, we identified at least one mutation present in both the diagnostic post-HSCT recipient sample and the pre-HSCT banked donor stem cell product. Figure 1 shows post-HSCT clonal evolution from one case. In another case, we evaluated contemporaneous samples from the donor and recipient obtained at the time of diagnosis of DCL in the recipient (23 years after HSCT). We identified two key findings: 1) a shared SF3B1 K666 mutation in donor and recipient, and 2) divergent clonal evolution, with ASXL1 C789X in the donor, and ASXL1 G642fs, SETBP1 D868N, and SUZ12 D605E in the recipient (Figure 2). In this context, the recipient had a morphologic diagnosis of MDS/MPN overlap, while the donor had abnormal RBC indices but no cytopenias. Since CHIP is associated with subtle abnormalities in hematologic parameters even in the absence of overt cytopenias, we evaluated potential donors with non-exclusionary CBC abnormalities, such as abnormal white blood cell differential or elevated MCV. In two cases, we prospectively identified DNMT3A mutations (R736Cand R882H, variant allele fractions 11.5% and 2%, respectively), consistent with donor CHIP. In one case, the donor with CHIP was used for transplantation. At 90 days after HSCT, donor cell chimerism was 99%; sequencing of recipient peripheral blood revealed the donor-derived DNMT3A mutation and the recipient remained persistently anemic, macrocytic, and thrombocytopenic. Conclusion We identified healthy stem cell donors with clonal hematopoiesis, marked by mutations in canonical genetic drivers of myeloid malignancies. In each instance, the aberrant clone engrafted in the transplant recipient, underwent selective expansion, and caused development of abnormal hematopoietic function. Our findings suggest that donor-derived clonal hematopoiesis may be common, especially in grafts from older donors, and that donor CHIP may confer an unrecognized and increased risk of leukemic and non-leukemic endpoints. We further demonstrate that donor CHIP can be identified prospectively, thus highlighting an emerging challenge in HSCT that may influence donor selection strategies as the clinical significance of donor CHIP is systematically elucidated. Disclosures Ritz: Kiadis: Membership on an entity's Board of Directors or advisory committees. Soiffer:Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lindsley:MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy.
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Mitus, AJ, JH Antin, CJ Rutherford, CJ McGarigle, and MA Goldberg. "Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs." Blood 83, no. 7 (April 1, 1994): 1952–57. http://dx.doi.org/10.1182/blood.v83.7.1952.1952.
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Abstract In an attempt to reduce or eliminate homologous red blood cell transfusion requirements during allogeneic bone marrow transplantation (BMT), we instituted a novel program whereby recombinant human erythropoietin was administered to pairs of BMT donors and recipients. Eleven recipients and their HLA-matched donors were enrolled. Donors treated with recombinant human erythropoietin (rHuEPO) were phlebotomized a median of 6 U (range, 4 to 11 U) of blood over a 5-week period. This donor-derived blood was available to the BMT donor or recipient as needed. Transplant recipients were also treated with rHuEPO post-BMT to hasten erythropoiesis. Five of 11 BMT recipients underwent transplant receiving only donor-derived red blood cell transfusion, compared with 0 of 11 concomitant control recipients (P = .04). In addition, the time to absolute reticulocyte count > or = 10(4)/microL was statistically shorter in the rHuEPO-treated recipient group. This study serves as a paradigm for hematopoietic growth factor use in allogeneic BMT to decrease or eliminate homologous transfusion exposures and to possibly hasten hematopoietic engraftment.
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Mitus, AJ, JH Antin, CJ Rutherford, CJ McGarigle, and MA Goldberg. "Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs." Blood 83, no. 7 (April 1, 1994): 1952–57. http://dx.doi.org/10.1182/blood.v83.7.1952.bloodjournal8371952.
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In an attempt to reduce or eliminate homologous red blood cell transfusion requirements during allogeneic bone marrow transplantation (BMT), we instituted a novel program whereby recombinant human erythropoietin was administered to pairs of BMT donors and recipients. Eleven recipients and their HLA-matched donors were enrolled. Donors treated with recombinant human erythropoietin (rHuEPO) were phlebotomized a median of 6 U (range, 4 to 11 U) of blood over a 5-week period. This donor-derived blood was available to the BMT donor or recipient as needed. Transplant recipients were also treated with rHuEPO post-BMT to hasten erythropoiesis. Five of 11 BMT recipients underwent transplant receiving only donor-derived red blood cell transfusion, compared with 0 of 11 concomitant control recipients (P = .04). In addition, the time to absolute reticulocyte count > or = 10(4)/microL was statistically shorter in the rHuEPO-treated recipient group. This study serves as a paradigm for hematopoietic growth factor use in allogeneic BMT to decrease or eliminate homologous transfusion exposures and to possibly hasten hematopoietic engraftment.
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Seo, Sachiko, Michael Boeckh, Barry E. Storer, Mark M. Schubert, Marcello Rotta, Brenda M. Sandmaier, and Marco Mielcarek. "The Effect Of Donor and Recipient Statin Treatment On Infections After Allogeneic Hematopoietic Cell Transplantation." Blood 122, no. 21 (November 15, 2013): 4548. http://dx.doi.org/10.1182/blood.v122.21.4548.4548.
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Background Recent studies have reported that statin use is associated with improved outcomes in immunocompetent patients with bacterial sepsis and respiratory virus disease. We have reported previously that statin use in donors or recipients was associated with reduced risks of severe acute graft-versus-host disease (GVHD) or chronic GVHD, respectively, after allogeneic hematopoietic cell transplantation (HCT). In the present study, we analyzed the influence of donor and recipient statin use on the incidence of infections and infection-outcomes after allogeneic HCT. Patients and Methods A previously reported cohort of HCT recipients (BBMT 16:1463-6, 2010) was used for the analyses. The cohort included 1206 allogeneic HCT recipients (no statin treatment: n=1130; statin treatment: n=76) transplanted between 2001 and 2008 at the Fred Hutchinson Cancer Research Center. Recipients were considered “statin-treated” when a statin was used to treat hyperlipidemia before and after HCT-conditioning. In addition, for all 567 sibling donors in the same cohort, the statin treatment status at the time of stem cell donation was assessed by review of medical records (no statin treatment: n=480, statin treatment: n=87; Blood 115:1288-95, 2010). The associations between statin use and risks of incident infections or infection-related mortality were evaluated using Cox proportional hazards models. Results Among 1206 HCT recipients, the following proportions experienced first infectious events within 100 days after HCT: bacteremia, 23% (n=275); CMV reactivation, 23% (n=277); respiratory viral infection with upper and/or lower respiratory tract involvement, 8.0% (n=97), and with only lower respiratory tract involvement (LRI), 1.8% (n=22). Within 1 year after HCT, 13% (n=153) developed invasive fungal infections and 3.7% (n=45) developed CMV disease. The overall incidences of bacteremia, invasive fungal infection, CMV reactivation, CMV disease, and LRI were not impacted by recipient or donor statin use. Recipient statin-use, however, was associated with a significantly increased cumulative incidence of gram-negative bacteremia (adjusted HR 2.15 [95% CI, 1.1-4.1], p=0.02), an association not observed with donor statin use. The risk of 30-day mortality attributable to gram-negative bacteremia was not significantly affected by recipient or donor statin use. Finally, the risk of respiratory viral infections was increased in recipients transplanted from statin-treated donors compared with those transplanted from donors not treated with a statin (adjusted HR 2.7 [95% CI, 1.3-5.6], p=0.01). There were no progressions to LRI among recipients transplanted from statin-treated donors (0% vs. 15%, p=0.15). Conclusions Recipient or donor statin use did not alter incidence of most infections after allogeneic HCT. However, while recipient statin use was associated with an increased risk of gram-negative bacteremia, donor statin use was associated with an increased risk of recipient respiratory viral infections without affecting mortality or progression to LRI. The mechanisms underlying these associations remain unknown. Validation of the findings in other large cohorts and, ultimately, randomized trials are needed. Disclosures: Boeckh: Merck: Consultancy, Research Funding.
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Grubbs, Allison, Jaqueline Meadow, J. Richard Thistlethwaite, and Lainie F. Ross. "Attitudes of Lay Stakeholders and Transplant Professionals About Disclosure to Living Kidney Donors in Exchanges and Chains." Progress in Transplantation 26, no. 4 (September 20, 2016): 299–308. http://dx.doi.org/10.1177/1526924816663515.
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Background: Current policies require very limited informational disclosure between living kidney donors and recipients regardless of the relationship type. No specific policies exist to suggest that exchange/chain donors and their recipients should be treated differently. We surveyed transplant professionals (surgeons and nephrologists) and members of the National Kidney Foundation (NKF) to determine their support for disclosing to donors the health, health behavior, and social information of their exchange/chain donors and exchange/chain recipients. Methods: Twenty questions regarding disclosing to donors information about both their exchange/chain donors and exchange/chain recipients were included in 2 larger surveys on disclosure about kidney transplantation. Survey A was sent electronically to NKF list-servs, and survey B was sent to transplant professionals both electronically and by postal mail. Results: Survey A yielded 236 valid surveys from NKF donors and recipients (lay stakeholders). Survey B yielded 111 valid surveys from transplant professionals. Both sets of stakeholders support disclosing to donors some health and health behavior information of their exchange/chain donor and exchange/chain recipient, and mostly oppose disclosure of social information. Lay stakeholders favored disclosing significantly more information than transplant professionals. Among lay stakeholders, donor respondents were more supportive than recipient respondents in disclosing to donors health information about the exchange/chain recipient. Among transplant professionals, surgeons were more supportive than nephrologists in disclosing to donors information about the exchange/chain recipient that may impact graft survival. Conclusions: There is broad stakeholder support for disclosing some health and health behavior information to donors about their exchange/chain donors and recipients.
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Heeger, Peter S., Neil S. Greenspan, Shannon Kuhlenschmidt, Cora Dejelo, Donald E. Hricik, James A. Schulak, and Magdalena Tary-Lehmann. "Pretransplant Frequency of Donor-Specific, IFN-γ-Producing Lymphocytes Is a Manifestation of Immunologic Memory and Correlates with the Risk of Posttransplant Rejection Episodes." Journal of Immunology 163, no. 4 (August 15, 1999): 2267–75. http://dx.doi.org/10.4049/jimmunol.163.4.2267.
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Abstract While matching for MHC Ags improves renal allograft survival, closely matched grafts sometimes fail due to rejection, and poorly matched allografts are often well tolerated by the recipient. The severity of the rejection process may partially depend on the presence of environmentally primed T cells in the recipient that cross-react with donor Ags. To test for the presence of primed, donor-specific T cells in humans before transplantation, we used an enzyme-linked immunospot assay for detection of allospecific cytokines produced by individual human PBLs. We demonstrate that this approach detects cytokine production at single cell resolution and detects production of IFN-γ only when there is defined immunologic priming, thus representing a measure of primed donor-specific immunity. Because the environmental Ag exposure of the recipient is not a function of the HLA mismatch between donor and potential recipient, the number of HLA mismatches may not correlate with the frequency of pretransplant, donor-specific IFN-γ-producing PBLs. Studies of donor-specific IFN-γ-producing lymphocytes in a cohort of patients being evaluated for renal transplantation corroborated this hypothesis. Moreover, for recipients of both living and cadaver renal allografts, the pretransplant frequency of donor-specific memory cells correlated with the posttransplant risk of developing acute rejection episodes. This improved ability to define the strength of the allospecific immune response by enzyme-linked immunospot assay may allow improved pairing of recipients with donors and identification of kidney allograft donor-recipient pairs at high risk for acute rejection, thus permitting targeted interventions aimed at prolonging graft survival.
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Ralph, Angelique F., Phyllis Butow, Jonathan C. Craig, Germaine Wong, Steve J. Chadban, Grant Luxton, Talia Gutman, Camilla S. Hanson, Angela Ju, and Allison Tong. "Living kidney donor and recipient perspectives on their relationship: longitudinal semi-structured interviews." BMJ Open 9, no. 4 (April 2019): e026629. http://dx.doi.org/10.1136/bmjopen-2018-026629.
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Background and objectivesMany donors and recipients report an improved bond posttransplantation; however, unexpected conflicts and tension may also occur. Insights into the lived experiences of the donor–recipient relationship can inform strategies for interventions and support. We aimed to describe donor and recipient expectations and experiences of their relationship before and after living kidney donor transplantation.Design, setting and participantsSemistructured interviews were conducted with 16 donor–recipient pairs before the transplant and 11–14 months post-transplant. Transcripts were analysed thematically.ResultsWe identified seven themes (with respective subthemes): donation as enacting familial responsibility for care; analytical decision making to mitigate regret (avoiding anticipated regret and maintaining control, removing emotional impulsivity); strengthened interpersonal ties (gaining a deeper appreciation among family members, stronger empathy for each other, improving social participation); instability of relational impacts (anger and aggression threatening dynamics, unanticipated stress and emotional lability, triggering familial tension); renegotiating social roles (unexpected continuation of caregiving responsibilities, inability to relinquish the caregiving role, disappointment with unfulfilled renewal of intimacy, dissatisfaction over discrepant energy levels); guilt over unmet expectations and inevitability of the gift relationship (vague and transient indebtedness, expectation of reciprocity, transferring kidney ownership).ConclusionsDonor–recipient relationships may be improved through increased empathy, appreciation, and ability to participate in life together; however, unfulfilled expectations and behavioural and emotional changes in recipients (a side effect related to immunosuppression) remain unresolved consequences of living kidney donor transplantation. Education and counselling to help donors and recipients adjust to potential changes in relationship dynamics may help protect and foster relational stability postdonation.
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Heinemann, Jack A., Heidi E. Scott, and Meredith Williams. "Doing the Conjugative Two-step: Evidence of Recipient Autonomy in Retrotransfer." Genetics 143, no. 3 (July 1, 1996): 1425–35. http://dx.doi.org/10.1093/genetics/143.3.1425.
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Abstract Bidirectional exchange of genetic information, called retrotransfer, during bouts of bacterial conjugation has drawn the interest of those concerned with the risk of releasing genetically engineered microbes, the fluidity of genes among species, and the mechanism of DNA transport between cells. The phenomenon has generated two models in explanation, both of which yield highly testable predictions. The first model, called the one-step, predicts that the flow of genes from recipient bacteria to donor bacteria is mechanistically distinct from, but dependent on, conjugation between donors and recipients. The second model, called the two-step, predicts that the same genetic requirements and mechanistic constraints apply to the process of gene flow from recipients to donors as for gene flow from donors to recipients. The requirement for expression of at least 10 plasmid-encoded genes in recipients, sensitivity of the reverse flow (recipient to donor) to restriction of DNA transferring from the donor, and the requirement of an additional 30–90 min for DNA to flow from recipients back to donors are predictions of the two-step model and directly refute the one-step model. Retrotransfer of genes to donors during conjugation remains genetically and physically indistinguishable from two successive rounds of conjugation between neighbors.
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Tangpanithandee, Supawit, Charat Thongprayoon, Caroline C. Jadlowiec, Shennen A. Mao, Michael A. Mao, Pradeep Vaitla, Napat Leeaphorn, et al. "Clinical Phenotypes of Dual Kidney Transplant Recipients in the United States as Identified through Machine Learning Consensus Clustering." Medicina 58, no. 12 (December 12, 2022): 1831. http://dx.doi.org/10.3390/medicina58121831.
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Background and Objectives: Our study aimed to cluster dual kidney transplant recipients using an unsupervised machine learning approach to characterize donors and recipients better and to compare the survival outcomes across these various clusters. Materials and Methods: We performed consensus cluster analysis based on recipient-, donor-, and transplant-related characteristics in 2821 dual kidney transplant recipients from 2010 to 2019 in the OPTN/UNOS database. We determined the important characteristics of each assigned cluster and compared the post-transplant outcomes between clusters. Results: Two clinically distinct clusters were identified by consensus cluster analysis. Cluster 1 patients was characterized by younger patients (mean recipient age 49 ± 13 years) who received dual kidney transplant from pediatric (mean donor age 3 ± 8 years) non-expanded criteria deceased donor (100% non-ECD). In contrast, Cluster 2 patients were characterized by older patients (mean recipient age 63 ± 9 years) who received dual kidney transplant from adult (mean donor age 59 ± 11 years) donor with high kidney donor profile index (KDPI) score (59% had KDPI ≥ 85). Cluster 1 had higher patient survival (98.0% vs. 94.6% at 1 year, and 92.1% vs. 76.3% at 5 years), and lower acute rejection (4.2% vs. 6.1% within 1 year), when compared to cluster 2. Death-censored graft survival was comparable between two groups (93.5% vs. 94.9% at 1 year, and 89.2% vs. 84.8% at 5 years). Conclusions: In summary, DKT in the United States remains uncommon. Two clusters, based on specific recipient and donor characteristics, were identified through an unsupervised machine learning approach. Despite varying differences in donor and recipient age between the two clusters, death-censored graft survival was excellent and comparable. Broader utilization of DKT from high KDPI kidneys and pediatric en bloc kidneys should be encouraged to better address the ongoing organ shortage.
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Loren, Alison Wakoff, Greta R. Bunin, Christian Boudreau, Richard E. Champlin, Avital Cnaan, Mary Horowitz, Fausto Loberiza, and David L. Porter. "Impact of Prior Pregnancy on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation." Blood 104, no. 11 (November 16, 2004): 1638. http://dx.doi.org/10.1182/blood.v104.11.1638.1638.
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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) can cure adults with hematologic malignancies, but results in significant morbidity and mortality. Graft-vs.-host disease (GVHD) is a major complication; attempts to reduce the risk of GVHD include selecting donors based on several characteristics, including parity, a criterion which has been controversial. This retrospective cohort study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) is the first multi-center analysis of the effects of donor and recipient parity on outcomes of HSCT in the modern transplant era. Methods: We studied patients at least 18 years old who received a non-T-cell-depleted, myeloablative HLA-identical sibling HSCT between 1995 and 1999, for acute lymphoblastic or myelogenous leukemia or chronic myelogenous leukemia. The study endpoints included acute and chronic GVHD, overall survival, and relapse. There were 2,626 patients who met inclusion criteria and had complete information on both donor and recipient pregnancy status. Donors and recipients were categorized as: males, nulliparous females, or parous (one or more pregnancies) females. Analysis: We compared all possible combinations of donor and recipient pregnancy status (9 groups in total); the reference group was male donor/male recipient pairs. Multivariate Cox proportional hazards regression was used to adjust for other prognostic factors. Because multiple groups were compared, significant p-values were considered to be less than or equal to 0.006. Results: After controlling for important patient-, disease-, and transplant-related covariates, the risk of chronic GVHD was significantly increased in parous female donor/male recipient pairs (HR 1.56, 95% CI 1.23 – 1.94, p < 0.0001). Neither donor nor recipient parity had an impact on overall survival, acute GVHD, or relapse risk. Conclusions: This multi-center retrospective registry study showed that parous female donors resulted in a significantly increased risk of chronic GVHD in male recipients, but without concomitant reduction in relapse. Thus, H-Y antigens may be important targets of GVHD, but not of a graft-versus-leukemia effect. As when selecting unrelated donors, avoidance of parous female donors, particularly for male patients, in HLA-identical sibling transplants is recommended when possible.
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DiGuardo, Maggie A., Sarah J. Kester, Victor J. Mahaffey, Scott A. Hammel, Katelyn K. Heaser, Christopher D. Hofich, Craig D. Tauscher, et al. "Does Transfusion of Red Blood Cells Impact Germline Genetic Test Results?" Journal of Personalized Medicine 10, no. 4 (December 9, 2020): 268. http://dx.doi.org/10.3390/jpm10040268.
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Purpose: molecular testing is often indicated for recently transfused patients. However, there are no guidelines regarding the potential interference from donor DNA or whether it is necessary to wait for a period of time post-transfusion prior to genetic testing. While the majority of patients are transfused in the non-trauma setting using leukoreduced (LR) red blood cell products, the degree of leukoreduction varies among centers and is not universally practiced. Methods: whole blood units collected from anonymous donors were used in an in vitro transfusion model. One unit was split: half being leukoreduced simulating a leukopenic recipient and half left untreated. Donors were simulated by leukoreduced, partially leukoreduced (PLR), or non-leukoreduced units, transfused in 2, 5, or 16 unit equivalents. DNA from the combinations were subjected to short tandem repeat (STR) analysis for chimerism detection. Results: donor DNA was not detectable in any of the LR combinations, but detected in the PLR combinations, ranging from 0.1 to 1.5% donor DNA in the immunocompetent recipient and 6.3–27.8% in the leukopenic recipient. Non-LR donor DNA was also detected (13–95%). Conclusion: donor-derived DNA from leukoreduced blood products is unlikely to interfere with the interpretation of germline genetic testing in immunocompetent recipients but may interfere in immunocompromised recipients.
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Landfried, Karin, Martin Hausmann, Gerhard Rogler, Daniel Wolff, Anne M. Dickinson, Matthew Collin, Juergen Finke, Ernst Holler, and Reinhard Andreesen. "“ATG16 L1 a Additional Risk Factor for TRM After allogeneic Stem Cell Transplantation”." Blood 114, no. 22 (November 20, 2009): 1155. http://dx.doi.org/10.1182/blood.v114.22.1155.1155.
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Abstract Abstract 1155 Poster Board I-177 Introduction A genome wide association scan of DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16 L1 as a new genetic risk factor of Crohn's disease. As our group had previously reported SNPs of another innate immunity receptor important in Crohn's disease, NOD2/CARD15, as a risk factor of severe graft-versus-host disease (GvHD) and treatment related mortality (TRM) following allogeneic stem cell transplantation (SCT), we now assessed the role of ATG16L in complications following SCT. Material and Methods A total of 127 HLAidentical sibling donor/recipient pairs were included. DNA from donors and recipients were analyzed for the ATG16L1 polymorphism and presence or absence of NOD2/CARD15 variants as previously published. Results of ATG16L1 and NOD2/CARD15 were correlated with clinical characteristics and outcome data, which were documented in a SPSS 17 database. The role of polymorphisms in GvHD III/IV was assessed by cross tabs, treatment related mortality (TRM) and overall survival were assessed by Kaplan Meier analysis. All patients and donors gave informed consent to analysis of genetic risk factors of GvHD. Results In 15 (12%) both recipient and donor were wildtype ATG16L1, in 25 (19%) either donor or recipient had the variant; and in 87 (69%) both donor and recipient had the variant. In 34 pairs, additional NOD2/CARD15 SNPs were observed. Severe GvHD occured in 6%, if both donor and recipient were ATG16L1 wildtype but increased to 22% if donor or recipient had the variant. Treatment related mortality increased in the presence of a donor variant (16% versus 46%, p 0.03) or if both; recipient and donor had variants (21% vs 48%, p 0.03). There seemed to be a gene dose effect for TRM, which was 13% if both were wildtype, 27% in the presence of either a donor or recipeint varaint and 48% if both had the variant (p≤ 0.05). Overall survival was not significantly different between these groups. In multivariate analysis, presence of ATG16L1 variant in both, donor and recipient was an independent risk factor for treatment related mortality when compared with age and stage of underlying disease (Hazard ratio 2.5, 95% confidence interval 1.1 – 6.1). Additional presence of NOD2/CARD15 variants seemed to be additive: TRM rose from 36% in recipients with ATG16L1 variant to 59% in the presence of additional recipient NOD2/CARD15 variants and from 34% in donors with ATG16L1 variants to 64%, if donors had additional NOD2/CARD15 SNPs. Conclusions As reported ATG16L1 polymorphism is a genetic risk factor for inflammatory bowel disease. In our work ATG16L1 polymorphism seems also to contribute to increased TRM in patients receiving allogeneic SCT. An accurate analysis of the causes of death is still accomplished. Altogether the data underline the role of the innate immunity and the disturbed antibacterial defense in the pathophysiology of transplant-associated complications. Disclosures No relevant conflicts of interest to declare.
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Torreggiani, Massimo, Ciro Esposito, Elena Martinelli, Thomas Jouve, Antoine Chatrenet, Lionel Rostaing, Marco Colucci, et al. "Outcomes in Living Donor Kidney Transplantation: The Role of Donor’s Kidney Function." Kidney and Blood Pressure Research 46, no. 1 (2021): 84–94. http://dx.doi.org/10.1159/000512177.
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Introduction: Living donor kidney transplant (LDKT) is one of the best therapeutic options for end-stage kidney disease (ESKD). Guidelines identify different estimated glomerular filtration rate (eGFR) thresholds to determine the eligibility of donors. The aim of our study was to evaluate whether pretransplant donor eGFR was associated with kidney function in the recipient. Methods: We retrospectively studied LDKT recipients who received a kidney graft between September 1, 2005, and June 30, 2016 in the same transplant center in France and that had eGFR data available at 3, 12, 24, and 36 months posttransplant. Results: We studied 90 donor-recipient pairs. The average age at time of transplant was 51.47 ± 10.95 for donors and 43.04 ± 13.52 years for recipients. Donors’ average eGFR was 91.99 ± 15.37 mL/min/1.73 m2. Donor’s age and eGFR were significantly correlated (p < 0.0001, r2 0.023). Donor’s age and eGFR significantly correlated with recipient’s eGFR at 3, 12, and 24 months posttransplant (age: p < 0.001 at all intervals; eGFR p = 0.001, 0.003, and 0.016, respectively); at 36 months, only donor’s age significantly correlated with recipient’s eGFR. BMI, gender match, and year of kidney transplant did not correlate with graft function. In the multivariable analyses, donor’s eGFR and donor’s age were found to be associated with graft function; correlation with eGFR was lost at 36 months; and donor’s age retained a strong correlation with graft function at all intervals (p < 0.001). Conclusions: Donor’s eGFR and age are strong predictors of recipient’s kidney function at 3 years. We suggest that donor’s eGFR should be clinically balanced with other determinants of kidney function and in particular with age.
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Francus, T., Y. W. Chen, L. Staiano-Coico, and J. M. Hefton. "Effect of age on the capacity of the bone marrow and the spleen cells to generate B lymphocytes." Journal of Immunology 137, no. 8 (October 15, 1986): 2411–17. http://dx.doi.org/10.4049/jimmunol.137.8.2411.
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Abstract The effect of age on the regeneration of the B cell population was studied by cell transfer methods, using the allotype-congenic mouse strains BALB/c (Igha) and C.B-17 (Ighb) as donors of old and young bone marrow (BM) and spleen cells, and C.AL-20 (Igho) as recipients. This design allowed us to identify the origin of the sIgD+ B cells present in the recipients. It was found that in a simple cell transfer, BM cells or spleen cells of aged donors could reconstitute the peripheral B cell population of irradiated, thymectomized recipients essentially as effectively as could BM or spleen cells from young donors. However, when BM cells from aged donors and from young donors were mixed and were used to reconstitute a single recipient, the cells from the aged donor were less efficient than were the cells from the young donor. We found that sIgD+ B cells of young donor origin predominated in the peripheral B cell population of the recipient at 3 to 6 wk after cell transfer. In the BM of the recipients, however, there was no difference in the incidence of sIgD+ B cells derived from the young and the old donors. When recipients were reconstituted with a mixture of spleen cells from old and young mice, the sIgD+ cells of young donor allotype showed a tendency to predominate in the peripheral B cell population, although this predominance was not statistically significant. Under such competitive conditions, the spleen cells of aged donors were less efficient than the BM of aged donors in reconstituting the sIgD+ B cell population of the recipient's BM, but were more efficient in reconstituting the splenic sIgD+ cells. Thus, a subtle defect in the B cell precursor population of the BM and the spleen of aged mice has been demonstrated. The role of T cells in the generation of sIgD+ cells was also analyzed.
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Marcondes, A. Mario Q., Ekapun Karoopongse, Marina Lesnikova, Sabina Janciauskiene, Charles A. Dinarello, and H. Joachim Deeg. "Donor Treatment with α1 Anti-Trypsin (AAT) Mitigates Gvhd and Increases Survival While Sparing GVL Effects." Blood 120, no. 21 (November 16, 2012): 1889. http://dx.doi.org/10.1182/blood.v120.21.1889.1889.
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Abstract Abstract 1889 Background: Graft-versus-host disease (GVHD) is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). While cytolytic effector function of donor-derived CD8+ cytotoxic T lymphocytes (CTLs) is critical for the elimination of the underlying malignant disease, the goal is to achieve this graft-versus-leukemia (GVL) effect without inducing GVHD. We and others showed in murine models that administration of AAT in the peri-transplant period decreased GVHD incidence and mortality. Concurrently, levels of pro-inflammatory cytokines were suppressed compared to albumin-treated recipients. Since both GVHD and GVL effects are initiated by donor cells, we asked whether donor treatment with AAT would modify GVHD or GVL effects in recipients. Of concern was the observation that AAT enhanced expression of heme oxygenase-1 (HMOX-1) which, via generation of carbon monoxide, enables the transcription factor Nrf2 to bind to the promoters of IL10 and IL1Ra, which might interfere with GVL activity. Methods: We determined the effect of donor AAT treatment on GVHD and GVL in two murine transplant models: C3H/SW(H-2Kbc) into C57Bl/6(H-2Kb) (minor mismatch), and C57Bl/6(H-2Kb) into BALB/C (H-2Kd) (major mismatch). Four regimens of donor and recipient treatment were studied: 1) Donor albumin /recipient albumin; 2) donor albumin/recipient AAT; 3) donor AAT/recipient albumin; 4) donor AAT /recipient AAT. AAT and albumin were given to donors at 3 μg/ dose every 72 hours for two weeks before cell harvesting. Recipients received 3 μ/dose every 72 hours following total body irradiation with 800 cGy. On day 4, recipients were injected with 5 × 106 T cell-depleted bone marrow (TCD-BM) plus 5 × 105 CD4+/CD8+ splenic T cells to induce acute GVHD. To test our hypothesis that donor AAT treatment would interfere with the GVL effect, BALB/C (H-2Kd) recipients were injected i.v. with 20 × 103 A-20 lymphoma cells containing a luciferase reporter construct (A20-luc/yfp; H-2Kd), following TBI. The infusion of TCD-BM and T cells from C57Bl/6(H-2Kb) donors was delayed until day 4 to allow the tumor to home and get established. Results: RT-PCR analysis of donor BM and T cells prior to transplantation showed up-regulation of HMOX-1 and Nrf2 (10 and 15 log2 increase, respectively), and enhanced transcription of IL-10 and IL-1Ra (50 and 10 log2, respectively, compared to albumin treated donors). In contrast, TNFa, was down-regulated (7 log2 decrease in comparison to albumin-treated donors) in both unsorted bone marrow and in CD8+/CD4+spleen cells from AAT pre-treated donors. FACS analysis revealed a 4-fold increase in frequency of CD56+NK cells, and a 5-fold increase in CD4+/CD24+FoxP3+ Treg cells, associated with a 3 fold increase in CD8+/CD205+ APCs/ DC in comparison to albumin treated donors. Mice transplanted with cells from AAT-treated donors showed lower clinical GVHD scores and decreased mortality (Figure 1) in comparison to mice transplanted from albumin-treated donors. BALB/C (H-2Kd) animals transplanted from AAT-treated donors showed significantly lower A-20 tumor signal (luciferase) intensity (over the first 3 weeks post-HCT) than did mice transplanted from albumin-treated donors (n=6, mean 4.8 × 106 (AAT) versus,7 × 106 (albumin) photons/sec/mouse, P =.03). Summary and conclusions: These data suggest that pre-transplant in vivo AAT exposure of donor cells results in protection against acute GVHD. Tumor growth was not increased in mice transplanted from AAT treated donors and, in fact, appeared to be suppressed, presumably related to a significant increase in NK cells. Further studies on donor pre-treatment or direct administration of AAT to the transplant recipients are warranted. Disclosures: No relevant conflicts of interest to declare.
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Sucheston-Campbell, Lara E., Leah Preus, Marcelo C. Pasquini, Philip L. McCarthy, Kenan Onel, Xiaochun Zhu, Stephen R. Spellman, et al. "Combined Donor and Recipient Non-HLA Genotypes Show Evidence of Genome Wide Association with Transplant Related Mortality (TRM) after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (URD-BMT) (DISCOVeRY-BMT study)." Blood 126, no. 23 (December 3, 2015): 61. http://dx.doi.org/10.1182/blood.v126.23.61.61.
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Abstract Transplant-related mortality (TRM) is the largest limiting factor to successful URD-BMT as curative therapy. Identification of non-HLA genetic factors in either recipients or donors could improve BMT outcomes through better matching at these loci. We performed a genome-wide association study (GWAS), named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of 1-year TRM in 3,532 patients treated for AML, ALL or MDS (recipients) reported to CIBMTR from 2000-2011 and their HLA-matched URD (donors); donor DNA was available for 98% of HCT recipients. Cohort 1 includes 2,240 donor-recipient pairs; patients received a 10/10 HLA URD-BMT from 2000-08. Cohort 2 includes 823 donor-recipient pairs; patients received either a 10/10 HLA URD-BMT from 2009-11 or 8/8 (but <10/10) HLA URD-BMT. Genotyping of recipient and donor DNA was performed using the Illumina HumanOmniExpress-24 BeadChip containing 729,293 single nucleotide polymorphisms (SNPs) at University of Southern California. Due to the small number of non-European individuals, we report analyses of European American recipients only. After quality control, Cohort 1 includes 2,052 donor-recipient pairs and Cohort 2 includes 763 donor-recipient pairs typed at 637,655 SNPs. For each SNP, a shared genotype variable was created to capture donor-recipient allele sharing. The shared genotype was assigned a value of 0 if the recipient and donor have the same genotype at a given SNP and a value of 1 if they differ by 1 or 2 alleles. This idea, that a "matched" genotype can impact risk of TRM, is similar to the idea behind HLA matching. For all survival analyses we accommodated the competing risk of death due to disease; covariates including age, body mass index, and graft type (blood or marrow) were included in all analyses. Analyses of the shared genotype variable with TRM were run for all diseases together and excluding ALL (AML+MDS). P-values for each cohort were combined using METAL software with weights proportional to the square root of the number of cases. We report on results for combined P-value (Pmeta) <5 x 10-8. In analyses of AML+MDS donor-recipient pairs four typed SNPs, rs9884653, rs16850885, rs1246576 and rs10014791, spanning 865,040 base pairs in and near MTHFD2L and EPGN on chromosome 4q13.3 were significant at Pmeta <5 x 10-8; several SNPs in this region approach genome wide significance level. The most significant SNP, rs16850885 (P=7.6 x 10-7 in Cohort 1, P=6 x10-3 in Cohort 2, Pmeta =1.8 x 10-8) at 74,304,423 bp, places recipients who differ from their donors by at least one allele (5.2% of patients in Cohort 1 and 3.9% in Cohort 2) at a 2.6 fold increased risk of TRM (Tables 1 and 2). It is in perfect linkage disequilibrium (r2=1) with rs9884653 at 74,280,426 and rs10014791 at 75,145,466; rs1246576 is in strong linkage disequilibrium with rs16850885 (r2 =.91). All four SNPs shows hazard ratios (HRs) of similar magnitude across both cohorts for patients who differ from their donors by at least 1 allele. These SNPs are not associated with death due to disease in either cohort. The difference was not allele specific; of those patients who died of TRM with at least one allele difference approximately 50% of the donors provided the less common A allele (donor A/G or A/A with recipient G/G) and 50% of the recipients had the A allele (recipient A/G with a G/G donor). Analyses of the donors and recipients separately each show some evidence of association with the minor allele A at rs16850885 (Table 2), but it is patients who differ from their donors at this locus who have greatest risk of TRM. A previous GWAS showed that individuals with at least one copy of the A allele at rs16850885 have lower levels of secreted IL-1β following small pox vaccination compared with those who are homozygous GG (P=7.3 x 10-9). IL-1β, a pro-inflammatory cytokine secreted early in the inflammatory response, may be contributing to the risk of TRM through the combination of initiation and maintenance of host tissue inßammation and donor cell inßammatory response. Our study, DISCOVeRY-BMT, is the largest GWAS of TRM HLA-matched URD-BMT. Further confirmation of these findings in a third cohort may aid in donor selection. Disclosures Sucheston-Campbell: NIH/NHLBI: Research Funding. McCarthy:The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:NIH/NHLBI: Research Funding; Novartis: Equity Ownership.
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Rotta, Marcello, Barry E. Storer, Rainer F. Storb, Paul J. Martin, Shelly Heimfeld, Amanda Peffer, David G. Maloney, et al. "Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation." Blood 115, no. 6 (February 11, 2010): 1288–95. http://dx.doi.org/10.1182/blood-2009-08-240358.
Full textAbstract:
Abstract We retrospectively analyzed outcomes among 567 patients with hematologic malignancies who had hematopoietic cell transplantation from human leukocyte antigen-identical sibling donors between 2001 and 2007 for a correlation between statin use and risk of graft-versus-host disease (GVHD). Compared with allografts where neither the donor nor recipient was treated with a statin at the time of transplantation (n = 464), statin use by the donor and not the recipient (n = 75) was associated with a decreased risk of grade 3-4 acute GVHD (multivariate hazard ratio, 0.28; 95% confidence interval, 0.1-0.9). Statin use by both donor and recipient (n = 12) was suggestively associated with a decreased risk of grade 3 or 4 acute GVHD (multivariate hazard ratio, 0.00; 95% confidence interval, undefined), whereas statin use by the recipient and not the donor (n = 16) did not confer GVHD protection. Risks of chronic GVHD, recurrent malignancy, nonrelapse mortality, and overall mortality were not significantly affected by donor or recipient statin exposure. Statin-associated GVHD protection was restricted to recipients with cyclosporine-based postgrafting immunosuppression and was not observed among those given tacrolimus (P = .009). These results suggest that donor statin treatment may be a promising strategy to prevent severe acute GVHD without compromising immunologic control of the underlying malignancy.