Transfusion burden following reduced intensity allogeneic hematopoietic cell transplantation: Impact of donor type.

BACKGROUND: Transfusions are essential for allogeneic hematopoietic cell transplant (HCT), yet they are influenced by graft, donor, and other factors. STUDY DESIGN: We analyzed transfusions in 165 adult reduced intensity HCTs (2016-2019): HLA matched sibling donor (MSD) (n = 59), matched URD (n = 25), UCB (n = 33), and haploidentical (haplo, n = 48) detailing the cumulative incidence of platelet and RBC transfusion independence, total transfusions (day-10 to day+100) plus transfusion densities (per week) over 110 days. RESULTS: Platelet recovery to 20 × 109 /L by 6 months occurred in 39/48 (81.25%) haplo recipients (median 33 [range, 0-139]) days vs. 58/59 (98.3%) MSD (median 10 [0-37]), 21/25 (84%) matched URD (median 20 [0-153]), and 29/33 (87.87%) UCB (median 48 [29-166]) days, p < .01. Regression analysis demonstrated a lower likelihood of prompt platelet recovery in matched URD, UCB, or haplo HCTs vs. MSD. Recovery to platelet independence was quickest in MSD (median 8 days [range 0-94]), vs. URD (median 16 days [0-99]), UCB (median 57 [0-94]), or haplo (median 45 [12-97]) days, p < .01. Platelet needs were unaffected by age, conditioning, or acute GVHD. RBC transfusion independence was achieved in 78% of MSD, 64% URD, and 82% UCB, though less frequent (58%) and slowest in haplo recipients, p < .01. All haplo and UCB recipients required platelet transfusions vs. only 51% of MSD and 76% of URD. RBC needs were highest in UCB and haplo HCTs. DISCUSSION: The transplant donor influences the transfusion burden with greater platelet and RBC needs in haplo and UCB HCT which directly contributes to increased cost of care.

Posttransplant Outcomes for cPRA-100% Recipients Under the New Kidney Allocation System.

BACKGROUND: There is concern in the transplant community that outcomes for the most highly sensitized recipients might be poor under Kidney Allocation System (KAS) high prioritization. METHODS: To study this, we compared posttransplant outcomes of 525 pre-KAS (December 4, 2009, to December 3, 2014) calculated panel-reactive antibodies (cPRA)-100% recipients to 3026 post-KAS (December 4, 2014, to December 3, 2017) cPRA-100% recipients using SRTR data. We compared mortality and death-censored graft survival using Cox regression, acute rejection, and delayed graft function (DGF) using logistic regression, and length of stay (LOS) using negative binomial regression. RESULTS: Compared with pre-KAS recipients, post-KAS recipients were allocated kidneys with lower Kidney Donor Profile Index (median 30% versus 35%, P < 0.001) but longer cold ischemic time (CIT) (median 21.0 h versus 18.6 h, P < 0.001). Compared with pre-KAS cPRA-100% recipients, those post-KAS had higher 3-year patient survival (93.6% versus 91.4%, P = 0.04) and 3-year death-censored graft survival (93.7% versus 90.6%, P = 0.005). The incidence of DGF (29.3% versus 29.2%, P = 0.9), acute rejection (11.2% versus 11.7%, P = 0.8), and median LOS (5 d versus 5d, P = 0.2) were similar between pre-KAS and post-KAS recipients. After accounting for secular trends and adjusting for recipient characteristics, post-KAS recipients had no difference in mortality (adjusted hazard ratio [aHR]: 0.861.623.06, P = 0.1), death-censored graft failure (aHR: 0.521.001.91, P > 0.9), DGF (adjusted odds ratio [aOR]: 0.580.861.27, P = 0.4), acute rejection (aOR: 0.610.941.43, P = 0.8), and LOS (adjusted LOS ratio: 0.981.161.36, P = 0.08). CONCLUSIONS: We did not find any statistically significant worsening of outcomes for cPRA-100% recipients under KAS, although longer-term monitoring of posttransplant mortality is warranted.

Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients with life-threatening disorders. Well-designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans, and graft source selection. In this perspective, we summarize evidence supporting criteria for the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. These standardized criteria for graft source selection have been adopted by the BMT CTN to enhance the interpretation of clinical findings within and among future clinical protocols.

Validez diagnóstica de antígenos leucocitarios humanos para el diagnóstico de la enfermedad de Behcet / Diagnostic validity of human leukocyte antigens for the diagnosis of Behcet's disease

INTRODUCCIÓN: La enfermedad de Behcet (EB) es una vasculitis sistémica de etiología desconocida, caracterizada por ulceraciones orales y genitales recurrentes asociadas y compromiso ocular. En la actualidad, el diagnóstico se realiza por medio de grupos de criterios diagnósticos. Aunque existe una asociación entre HLA-B51 y EB, no se ha considerado aún el uso de los HLA como prueba diagnóstica. OBJETIVO: Evaluar si existe un papel para los antígenos leucocitarios humanos, en particular los denominados HLA 15, 108, 105, 109 y 119, en el diagnóstico de pacientes con EB. MÉTODOS: Se realizó una búsqueda de revisiones sistemáticas de estudios de validez diagnóstica publicadas en los últimos cinco años en Cochrane Database of Systematic Reviews, DARE y MEDLINE, así como una búsqueda de estudios primarios sobre validez diagnóstica en MEDLINE (1966 a la fecha), EMBASE (1982 a la fecha), LILACS (1982 a la fecha), de referencias entre los estudios encontrados y consulta a expertos temáticos, productores y comercializadores de la tecnología; la tecnología de interés fue el uso de HLA para el diagnóstico de EB; como estándar de referencia se consideraron diferentes criterios clínicos (International Study Group (ISG), International Criteria For Behcet Disease (ICBD), entre otros). Dos evaluadores de manera independiente, tamizaron las referencias obtenidas, resolviendo las discrepancias por medio de un tercer autor. RESULTADOS: No es posible establecer conclusiones acerca del papel de los antígenos leucocitarios humanos en el diagnóstico de EB dado que, hasta la fecha, no se han publicado estudios sobre sus características operativas. En Colombia se requieren estimaciones de la frecuencia de alelos HLA y su asociación con EB que puedan sugerir su posible valor diagnóstico.(AU)

The effect of HLA disparity on clinical outcome after HLA-haploidentical blood and marrow transplantation.

The relative importance of various human leukocyte antigen (HLA) loci has not been established for unmanipulated HLA-mismatched/haploidentical transplantation. To address this question, we analyzed the impact of HLA-A, HLA-B, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5 on the outcome of HLA-haploidentical transplantation. Four hundred and eighty-one donor-recipient pairs were fully typed before transplantation. In univariate analysis, HLA-B mismatch not only demonstrated significant adverse effects on acute graft-versus-host disease (GVHD) and transplant-related mortality but also was associated with reduced overall survival and leukemia-free survival (LFS). In multivariate analysis, HLA-B mismatch remained the independent risk factor for acute GVHD and transplant-related mortality. The high risk of disease and the female donor were found to be significant factors for reduced overall survival and LFS. Furthermore, multiple mismatch of the HLA locus was found to have no synergistic adverse effect on outcomes. Our results suggest that prospective matching of patients and donors for HLA-B antigen in the unshared HLA haplotype is warranted for HLA-mismatched/haploidentical transplantation.

Quantitation of HLA proteins incorporated by human immunodeficiency virus type 1 and assessment of neutralizing activity of anti-HLA antibodies.

Human anti-human leukocyte antigen (HLA) antibodies were assessed for neutralizing activity against human immunodeficiency virus type 1 (HIV-1) carrying HLA alleles with matching specificity. Multiparous women carrying anti-HLA antibodies were identified. Plasma samples from those women were confirmed as having antibodies that specifically bound to HLA proteins expressed on the peripheral blood mononuclear cells (PBMCs) of their husbands. A primary HIV-1 isolate was cultured in the husband's PBMCs so that the virus carried matching HLA alleles. To determine the HIV-1-neutralizing activity of anti-HLA antibodies, the infectivity of the virus for GHOST cells (which express green fluorescent protein after HIV infection) was investigated in the presence of a plasma sample positive for the respective anti-HLA antibody. A neutralization assay was also performed using purified immunoglobulin G (IgG) from two plasma samples, and two plasma samples were investigated in the presence of complement. The prerequisite for anti-HLA antibody-mediated neutralization is incorporation of HLA proteins by HIV-1. Therefore, the extent of incorporation of HLA proteins by the primary HIV-1 isolate was estimated. The ratios of HLA class I protein to HIV-1 capsid (p24) protein cultured in the PBMCs of two healthy individuals were 0.017 and 0.054. These ratios suggested that the HIV-1 strain used in the assay incorporated more HLA proteins than gp160 trimers. Anti-HLA antibody-positive plasma was found to contain antibodies that specifically reacted to HIV-1 carrying cognate HLA alleles. However, incubation of HIV-1 with anti-HLA antibody- positive plasma or purified IgG did not show a reduction in viral infectivity. HIV-1-neutralizing activity was also not detected in the presence of complement. This study shows that HIV-1 primary isolates cultured in PBMCs contain significant amounts of HLA proteins. However, the binding of antibodies to those HLA proteins does not mediate a reduction in viral infectivity.

[Clinical results of the various replacement therapies for chronic renal failure: haemodialysis and renal transplantation]. / Risultati clinici delle diverse terapie sostitutive dell'insufficienza renale cronica: emodialisi e trapianto renale.

Results from recent studies have demonstrated that kidney-transplanted patients have better expectation and quality of life than dialysis patients on a waiting list for kidney transplant. Moreover, the scientific literature has conclusively shown that the survival of the patient and of the kidney graft are better in patients who received a kidney from a living donor, than in patients who received a cadaveric kidney. The main factors that may have a negative influence on the kidney transplant are: the recipient's age, diabetes mellitus, smoking and the time spent on dialysis before the transplant. The shortage of cadaveric kidneys and the small number of living kidney transplant are the main obstacles to a more widespread use of kidney transplantation. Kidney transplant from living donors needs to be implemented because it represents the best treatment for patients with kidney failure and it can decrease or even avoid the need for dialysis before kidney transplantation.

Diabetes mellitus after kidney transplantation in the United States.

New onset diabetes is a major complication after kidney transplantation. However, the incidence, risk factors and clinical relevance of post-transplant diabetes mellitus (PTDM) vary among reports from single-center observational studies and clinical trials. Using data from the United Renal Data System we identified 11 659 Medicare beneficiaries who received their first kidney transplant in 1996-2000. The cumulative incidence of PTDM was 9.1% (95% confidence interval = 8.6-9.7%), 16.0% (15.3-16.7%), and 24.0% (23.1-24.9%) at 3, 12, and 36 months post-transplant, respectively. Using Cox's proportional hazards analysis, risk factors for PTDM included age, African American race (relative risk = 1.68, range: 1.52-1.85, p < 0.0001), Hispanic ethnicity (1.35, range: 1.19-1.54, p < 0.0001), male donor (1.12, range: 1.03-1.21, p = 0.0090), increasing HLA mismatches, hepatitis C infection (1.33, range: 1.15-1.55, p < 0.0001), body mass index >or=30 kg/m2 (1.73, range: 1.57-1.90, p < 0.0001), and the use of tacrolimus as the initial maintenance immunosuppressive medication (1.53, range: 1.29-1.81, p < 0.0001). Factors that reduced the risk for PTDM included the use of mycophenolate mofetil, azathioprine, younger recipient age, glomerulonephritis as a cause of kidney failure, and a college education. As a time-dependent covariate in Cox analyses that also included multiple other risk factors, PTDM was associated with increased graft failure (1.63, 1.46-1.84, p < 0.0001), death-censored graft failure (1.46, 1.25-1.70, p < 0.0001), and mortality (1.87, 1.60-2.18, p < 0.0001). We conclude that high incidences of PTDM are associated with the type of initial maintenance immunosuppression, race, ethnicity, obesity and hepatitis C infection. It is a strong, independent predictor of graft failure and mortality. Efforts should be made to minimize the risk of this important complication.

Quantitative assessment of human leukocyte antigen-G protein in amniotic fluid by a double-determinant enzyme-linked immunosorbent assay using anti-human leukocyte antigen-G-specific antibody '87G'.

PROBLEM: The objective of this study was to establish an enzyme-linked immunosorbent assay (ELISA) system, in an attempt to quantify the amount of human leukocyte antigen (HLA)-G protein in amniotic fluid. METHOD OF STUDY: We established a double-determinant ELISA system using the anti-HLA-G specific mouse monoclonal antibody '87G' as a capture antibody and the horseradish-peroxidase labeled rabbit anti-human beta2-microglobulin antibody as a detection antibody. We then measured the concentration of HLA-G protein in amniotic fluid samples from nine normal second-trimester pregnant women and in serum samples from eight normal males. RESULTS AND CONCLUSION: HLA-G protein was detected in amniotic fluid at a concentration of 275 ng/ml (197-343 ng/ml) (median value and 95% confident range), whereas the concentration of HLA-G protein in male serum was below the minimum detection level.

Culture of ascitic ovarian cancer cells as a clinically-relevant ex vivo model for the assessment of biological therapies.

There are few in vitro models of human ovarian cancer suitable for the assessment of biological therapies. We have established short-term cultures of ovarian carcinoma cells from ascites, maintained in suspension in ascitic fluid to help preserve the original tumor cell microenvironment. We assessed the effects of a potential biological therapeutic agent, interferon-alpha (IFN alpha), on ovarian cell phenotype. In total, eight cultures were established from seven patients. Quantitative changes in cell surface phenotype were determined by flow cytometry for HLA-ABC, HLA-DR, TAG72, CA125, HMFG1 and HMFG2 antigens. The amount of CA125 antigen shed into the culture media was also assessed. Variations in cell surface phenotype between specimens probably reflected the specific cytokine milieu of the ascites as well as idiotypic differences between tumors. Nevertheless, there were consistent phenotypic responses to IFN alpha, with up-regulation of MHC Class I but down-regulation of the HMFG1 and HMFG2 antigens from the cell surface. The results suggest that this approach may be useful in patient selection and for optimizing biological therapies, as it enables patients' individual tumor responses to exogenous cytokine to be studied against the background of the endogenous cytokine milieu.

Distribution of HLA and haplotypes of Colombian and Jamaican black populations.

To investigate the genetic background of the black populations of Colombia and Jamaica, we determined HLA types of 78 Colombian and 98 Jamaican blacks from 2 different socioeconomic groups (Jamaican #1 and Jamaican #2) and estimated the frequencies of HLA genes and haplotypes. A phylogenetic tree based on the HLA gene frequencies revealed that Jamaican #1 and Jamaican #2 were distinct from each other, Jamaican #1 being closely related to the Colombian blacks and the Jamaican #2 being closely related to Senegalese and Zairean populations. Three-locus HLA haplotypes of Colombian and Jamaican #1 blacks were an admixture between Africans and Caucasians or South American Indians, while Jamaican #2 blacks were relatively homogeneous and appeared to conserve African lineages. The major five-locus HLA haplotypes were not shared among Colombian, Jamaican #1 and Jamaican #2 blacks. These results indicated that the black populations of Colombia and Jamaican were originated from African blacks and admixed variably with Caucasians and South American Indians to make genetic subpopulations in Colombia and Jamaica.

Kidney transplants in black recipients. HLA matching and other factors affecting long-term graft survival.

Primary kidney transplants from living related and cadaveric donors to black recipients failed twice as rapidly as those to white recipients in data reported to the United Network for Organ Sharing Scientific Renal Transplant Registry between 1987 and 1991. The projected half-life for 132 HLA-identical sibling donor transplants in blacks was 15 years versus 29 years for 1,033 whites (P < 0.001). For recipients of cadaveric grafts, the half-lives were 5 years for blacks (n = 5,282) and 10 years for whites (n = 14,917). The 1-year graft survival rates and half-lives improved with HLA matching in both blacks and whites, but the 2-fold difference in long-term survival rates persisted even among recipients of well-matched grafts. With a zero HLA-A,B-mismatched donor, blacks had an 8-year half-life, compared with 17 years for whites (P < 0.001). The racial difference was most marked in young adults, with a 15-20% disparity at 3 years between blacks and whites aged 16-30. Pediatric and older black patients had 3-year graft survival rates similar to those of whites. Antilymphocyte globulin or OKT3 prophylaxis improved graft survival by 2% at 1 year and 5% at 2 years among blacks, but the half-life remained 5.6 years. In contrast to these findings in the United States, 63 blacks transplanted in Canada had the same short- and long-term graft survival as whites, suggesting an important long-term influence of the health care system and socioeconomic factors. In addition to improved access to health care and improved HLA typing of blacks, more black donors are needed to provide better matched transplants for blacks awaiting transplants.

Second renal transplantations. Ethical issues clarified by outcome; outcome enhanced by a reliable crossmatch.

OBJECTIVE: To determine whether the appropriate use of scarce donor resources has been accomplished by renal retransplantation by reviewing the initial and long-term outcomes of second-renal transplant recipients at the Massachusetts General Hospital, Boston. PATIENTS AND RESULTS: With a mean follow-up of nearly 5 years following transplantation, 54 (68%) of 80 second-transplant recipients had functioning allografts (allograft failure was defined by patient death or a return to dialysis). Rejection was the most common cause of failure (14 [54%] of 26 patients). The 1-, 3-, and 5-year actuarial allograft survival rates were 86%, 78%, and 69%, respectively, which were not significantly different from the survival rates of primary allografts at this center. These results support the continued approach of providing both cadaver-donor and living-donor renal allografts for recipients whose primary renal allograft has failed. The antiglobulin crossmatch may have contributed to the successful outcome by accurately determining compatibility and by averting early rejection failures. CONCLUSIONS: Health care policy reviewers should clearly distinguish the prospects for successful second renal transplants from the outcomes of extrarenal retransplantation. Moreover, because excellent second-renal allograft survival is attainable and comparable to primary-renal allograft survival and because the costs are comparable, restricting suitable patients to subsequent lifelong dialysis becomes unethical.

Immunogenetic marrow donor search for 1012 patients: a retrospective analysis of strategies, outcome and costs.

To analyse strategies, outcome and costs of immunogenetic marrow donor search 1012 patients were enrolled in a retrospective single centre study covering the period from January 1990 to December 1992. An HLA-compatible donor was identified for 562 of the patients (55.4%). Core family donor search (CFDS) provided a donor for 39%, extended family donor search (EFDS) for 6.4% and unrelated marrow donor search (UMDS) for 10% of the patients. During the period analysed, UMDS success rate increased from 13.3% to 47.8%, while mean search length decreased from 7.2 to 4.8 months. The percentage of donors from German registries rose from 5% in 1990 to 50% in 1993. Search length was dependent on patient's HLA phenotype frequency, but even for patients with frequencies as low as < 1:3 000 000 a donor was found in 5 of 24 cases. The mean costs (DM) per donor identified by CFDS, EFDS and UMDS were 2921, 19 172 and 24 036, respectively. Thus, CFDS is the utmost effective type of search. In view of the clinical outcome of BMT, EFDS remains a meaningful strategy and should not be replaced by UMDS despite its increasing success rate.

Molecular techniques for typing unrelated marrow donors: potential impact of molecular typing disparity on donor selection.

HLA matching between a bone marrow recipient and donor is one of the major factors influencing transplant success. However, it is not possible to locate an HLA-identical donor for about 70% of patients who might benefit from bone marrow transplantation (BMT). New molecular biological methods for detection of HLA polymorphism currently provide an opportunity to improve HLA matching of unrelated donors as well as a research tool to investigate the relationship between HLA disparity and transplant complications. These molecular HLA typing methods include sequence-specific amplification, hybridization with oligonucleotide probes, heteroduplex formation and direct nucleotide sequencing. Molecular HLA typing is being utilized to address questions regarding the extent of HLA disparity between two unrelated individuals and the effect of HLA disparity that is not detected using conventional HLA typing methods. Accumulating data suggest some HLA disparities may be tolerated while others are very immunogenic. Use of more precise HLA typing may contribute to the success of future transplants utilizing alternative donors. A better understanding of the relationship between HLA disparity and transplant complications may make it possible to relax the stringency of donor matching to make BMT available to larger numbers of patients.

HLA matching: identification of permissible HLA mismatches.

Previous studies of mismatches for a single HLA antigen in kidney transplants have not demonstrated that any single HLA antigen was more immunogenic than another. Here we show that certain mismatched antigens are "permissible" to recipients of certain types and not to others. In this retrospective study of 1,273 living-donor kidney transplants, a mismatch for 27 different, single A,B,DR antigens was evaluated with respect to recipients of various types. Various combinations of donor/recipient incompatibilities were then classified as "permissible" or immunogenic, depending upon the fate of the transplant. This list was then evaluated with 1,905 patients who received cadaver-donor transplants mismatched for a single A,B,DR antigen. Cadaver-donor kidney transplants judged to have received a permissible mismatch in the A, B, or DR loci had graft survival rates equivalent to zero-A,B,DR-mismatched grafts. Among 425 patients with one-A,B,DR-permissible mismatches, one-year graft survival was 89% with a 14.1-year half-life, compared with 966 one-A,B,DR-mismatched grafts with an 89% one-year survival and an 18-year half-life. Based upon these results, we recommend the initiation of one permissible A,B,DR-mismatched transplants for national sharing. This will result in potentially 60% of shared transplants having high long-term graft survival rates.

HLA matching: maximizing the number of compatible transplants.

1. Less than 10% of the cadaver kidneys currently allocated have 0-B,DR mismatches. 2. Up to 15% of the kidneys could be regionally allocated using the UNOS algorithm to 0-B,DR-mismatched recipients with a projected 67% 5-year graft survival. 3. Twice the number (32%) of recipients can be identified with zero of 10 A,B residues mismatched with the same 67% 5-year survival. 4. Another doubling (68%) of compatible recipients can be identified with zero of 7 DR supertypic determinants (4 DQ and 3 DRB) and zero of the A,B residues mismatched with a 66% 5-year graft survival. 5. Compressing A,B, and DR antigens to supertypic determinants reduces the racial differences in HLA to the point that 90% of kidneys can be allocated to Black recipients with zero of 3 DRB and zero A,B residues mismatched.

Racial differences in the survival of cadaveric renal allografts. Overriding effects of HLA matching and socioeconomic factors.

BACKGROUND: The long-term survival of cadaveric renal allografts is lower in black recipients than in white recipients, although the one-year graft survival is similar in these racial groups. We sought to determine what factors account for this disparity. METHODS: We studied 100 consecutive recipients of primary cadaveric renal allografts (57 were black and 43 white) at least 1 year after transplantation (mean, 40 months); all had received identical immunosuppressive therapy. We evaluated differences in the cause and duration of end-stage renal disease, the number of pretransplantation transfusions, age, matching for HLA-A, B, and DR antigens, race of the donor, insurance coverage, and compliance to assess their effect on graft survival in both groups. RESULTS: Allograft survival after one year was significantly lower in black than in white patients (P = 0.025). According to univariate analysis, only the recipient's age at transplantation, the number of mismatches for HLA antigens, the type of insurance coverage, the source of referral for transplantation, and the degree of compliance correlated significantly with the rate of graft survival. The frequency of all variables that reduced graft survival was higher among the blacks. According to proportional-hazards analysis, the only factors contributing to a lower rate of graft survival were age of less than 30 years at transplantation (relative risk, 2.3; 95 percent confidence interval, 1.3 to 4.6), mismatches for all six HLA antigens as compared with three or fewer mismatches (relative risk, 5.6; 95 percent confidence interval, 3.3 to 9.6), and coverage by Medicaid or Medicare (relative risk, 2.2; 95 percent confidence interval, 1.5 to 3.2). Race had no additional effect. Noncompliance was more frequent among blacks (16 percent vs. 2 percent) and could substitute for insurance status in the model. CONCLUSIONS: When immunosuppression is equivalent in black and white transplant recipients, apparently race-related differences in the long-term survival of renal cadaveric allografts appear to be related to other factors that affect graft survival unfavorably, notably poor HLA matching and unfavorable socioeconomic factors.