It is widely accepted that blood transfusions can cause allosensitization, but it is often reported that new human leukocyte antigen (HLA) antibodies are nonspecific and transient. This study explores the effect of blood transfusion on allosensitization in waitlisted transplant patients including the development of transfusion-specific antibodies (TSAs), both while they remain on the waiting list, and following subsequent transplantation. A total of 105 blood donors of transfusions received by 50 patients on the transplant waiting list were HLA typed. De novo HLA antibodies developed in 62% of patients following transfusion, with 34% of patients having at least 1 TSA. TSAs developed in 23% of patients with no circulating HLA antibodies at the time of transfusion and in 50% of patients with circulating HLA antibodies. This was associated with an average increase in calculated reaction frequency of 16.4%. Of the 34 patients who underwent transplantation, the majority received a kidney with at least 1 shared HLA specificity with a transfusion donor. After transplantation, 14.7% had a newly detected TSA within 3 months. These patients had higher rates of rejection, specifically antibody-mediated rejection, at 3 years. The use of HLA-selected blood for waitlisted patients, where transfusion is unavoidable, could therefore improve transplant outcomes.

Human leukocyte antigen (HLA) sensitization remains an impediment to successful solid organ transplantation, whether it be chances of receiving a transplant offer or subsequent transplant longevity. Current treatments targeting HLA antibodies lack long-term effectiveness; therefore, preventing HLA sensitization should remain a priority in all potential wait-list candidates and transplant recipients. Recent advances in the management of anemia in patients with chronic kidney disease may reduce the need for red cell transfusions. However, data from several anemia intervention studies of novel therapeutic agents have shown that a need for transfusion will remain. It has also been increasingly recognized that blood transfusions following kidney transplantation, especially in the peri-operative period, are common. Routine data on transfusion incidence, indications, and outcomes are not captured by most kidney and transplant registries across the globe. This restricts the evidence to inform both clinicians and patients on the clinical effects of transfusion, which have been considered both an allogeneic stimulus and to be immunomodulatory.This review aims to provide an update on what is currently known about transfusion-induced HLA sensitization in wait-list candidates and transplant recipients, summarizes where evidence is lacking, and demonstrates the distinct need for patient blood management guidelines in the field of kidney transplantation.

In many fields of clinical medicine and blood transfusion, the human leukocyte antigen (HLA) system is crucial. Alloimmunization happens as a result of an immune response to foreign antigens encountered during blood transfusion. This gives rise to alloantibodies against red blood cells (RBCs), HLA, or human platelet antigen (HPA). HLA alloimmunization following allogeneic transfusion was shown to be a result of contaminating white blood cells (WBCs) present in the product. It is a common complication of transfusion therapy that leads to difficulties in clinical intolerance and refractoriness to platelet transfusion during patient management. Single-donor platelets, prophylactic HLA matching, leukoreduction, and irradiation of cellular blood products are some of the mechanisms to prevent HLA alloimmunization during a blood transfusion. Now, the best approach to reduce the occurrence of primary HLA alloimmunization is the removal of WBCs from the blood by filtration.

Previous blood product exposures may result in the development of antibodies to human leukocyte antigens (HLA). Pediatric heart transplant recipients who have these antibodies experience increased morbidity and mortality after transplantation. In this study, our aims were to confirm the association of previous allogeneic blood product exposures with the formation of anti-HLA antibodies, determine which blood components pose the greatest risk of developing antibodies, and assess differences in outcomes after transplantation between patients who had anti-HLA antibodies and those who did not.

This retrospective investigation included all children who underwent cardiac transplantation at Children's Healthcare of Atlanta from January 1, 2015 through December 31, 2018. Chart reviews were performed to collect pertinent data. Anti-HLA antibodies were detected by single antigen bead testing. Antibody burden was tabulated using the calculated panel reactive antibody (cPRA) score immediately prior to transplantation. Statistical analyses were conducted to examine differences based on HLA antibody status and identify associations with outcomes of interest.

Our results show a significant association between pretransplant blood product exposures and HLA antibody status. Children with a pretransplant blood product exposure had 7.98 times the odds of developing an anti-HLA antibody compared to those without a pretransplant blood product exposure (p = .01). We also found a significant association between a previous red blood cell (RBC) exposure and HLA antibody status (p = .01) which was not found for other blood component exposures. Patients who were HLA antibody positive were more likely to develop a donor-specific antibody (DSA) after transplantation (p = .04).

Exposure to previous allogeneic blood products affects the development of anti-HLA antibodies in children presenting for heart transplantation. Previous RBC exposures resulted in HLA antibody positivity more than other blood component exposures. Importantly, the presence of HLA antibodies was associated with the development of DSAs post-transplantation. Developing transfusion strategies to reduce allogeneic blood product exposures in children who may need future cardiac transplantation should be a high priority.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

De novo HLA donor-specific antibodies (DSA) following transplantation are associated with alloimmune injury and allograft failure. Blood transfusions are allogeneic, and when given posttransplant (PTBT) they may independently increase the risk of HLA antibody development. This study aims to analyze the development of HLA transfusion-specific antibodies (TSA) to blood donors of transfusions given posttransplant and examine the impact on clinical outcomes. A total of 244 blood donors of transfusions received by 86 transplant patients (46 who developed a DSA post transfusion and 40 who remained DSA negative) were HLA typed. De novo TSA developed against 150/244 (61.5%) blood donors. In 70/150 (46.7%) cases the TSA was of shared HLA antibody specificity with a DSA response in the recipient (DSA+ = TSA+). This occurred when there was a greater overall HLA match between the blood and transplant donor. DSA+ = TSA+ patients had increased risk of allograft failure (P = .0025) and AMR (P = .02) compared with the DSA+ ≠ TSA+ patients. To conclude, PTBT may elicit de novo HLA antibodies. Enhanced HLA matching between the blood and transplant donor is more likely to result in a DSA and TSA of shared antibody specificities. Transfusion avoidance or the use of HLA matched or selected blood may reduce this risk and improve outcomes.

Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non-HLA-sensitized patients who had received an ABO-compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

Optimal selection of blood donors is critical for ensuring the safety of blood products. The current selection process is concerned principally with the safety of the blood donor at the time of donation and of the recipient at the time of transfusion. Recent evidence suggests that the characteristics of the donor may affect short- and long-term transfusion outcomes for the transfused recipient. We conducted a systematic review with the primary objective of assessing the association between blood donor characteristics and red blood cell (RBC) transfusion outcomes. We searched MEDLINE, EMBASE, and Cochrane Central databases and performed manual searches of top transfusion journals for all available prospective and retrospective studies. We described study characteristics, methodological quality, and risk of bias and provided study-level effect estimates and, when appropriate, pooled estimates with 95% confidence intervals using the Mantel-Haenszel or inverse variance approach. The overall quality of the evidence was graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. From 6121 citations identified by our literature search, 59 studies met our eligibility criteria (50 observational, 9 interventional). We identified the evaluation of association of 17 donor characteristics on RBC transfusion outcome. The risk of bias and confounding of the included studies was high. The quality of evidence was graded as very low to low for all 17 donor characteristics. Potential associations were observed for donor sex with reduced survival at 90 days and 6 months in male recipients that receive donated blood from females (hazard ratio 2.60 [1.09, 6.20] and hazard ratio 2.40 [1.10, 5.24], respectively; n = 1), Human Leukocyte Antigen - antigen D Related (HLA-DR) selected transfusions (odds ratio [OR] 0.39 [0.15, 0.99] for the risk of transplant alloimmunization, n = 9), presence of antileukocyte antibodies (OR 5.84 [1.66, 20.59] for risk of transfusion-related acute lung injury, n = 4), and donor RBC antigens selection (OR 0.20 [0.08, 0.52] for risk of alloimmunization, n = 4). Based on poor quality evidence, positive antileukocyte antibodies, female donor to male recipients, HLA-DR selected RBC transfusion, or donor RBC antigen selection may affect RBC transfusion outcome. Our findings that donor characteristics may be associated with transfusion outcomes warrant establishing vein-to-vein data infrastructure to allow for large robust evaluations. PROSPERO registration number: CRD42013006726.

Human leukocyte antigen (HLA) sensitisation occurs after transfusion of blood products and transplantation. It can also happen spontaneously through cross-sensitisation from infection and pro-inflammatory events. Patients who are highly sensitised face longer waiting times on organ allocation programmes, more graft rejection and therefore more side effects of immunosuppression, and poorer graft outcomes. In this review, we discuss these issues, along with the limitations of modern HLA detection methods, and potential ways of decreasing HLA antibody development. We do not discuss the removal of antibodies after they have developed.

The development of donor-specific HLA antibodies (DSA) is associated with worse renal allograft survival in adult patients. This study assessed the natural history of de novo DSA, and its impact on renal function in pediatric renal transplant recipients (RTR). HLA antibodies were measured prospectively using single-antigen-bead assays at 1, 3, 6 and 12 months posttransplant followed by 12-monthly intervals and during episodes of allograft dysfunction. Of 215 patients with HLA antibody monitoring, 75 (35%) developed DSA at median of 0.25 years posttransplant with a high prevalence of Class II (70%) and HLA-DQ (45%) DSA. DSA resolved in 35 (47%) patients and was associated with earlier detection (median, inter-quartile range 0.14, 0.09-0.33 vs. 0.84, 0.15-2.37 years) and lower mean fluorescence intensity (MFI) (2658, 1573-3819 vs. 7820, 5166-11 990). Overall, DSA positive patients had more rapid GFR decline with a 50% reduction in GFR at mean 5.3 (CI: 4.7-5.8) years versus 6.1 (5.7-6.4) years in DSA negative patients (p = 0.02). GFR decreased by a magnitude of 1 mL/min/1.73 m(2) per log10 increase in Class II DSA MFI (p < 0.01). Using Cox regression, independent factors predicting poorer renal allograft outcome were older age at transplant (hazard ratio 1.1, CI: 1.0-1.2 per year), tubulitis (1.5, 1.3-1.8) and microvasculature injury (2.9, 1.4-5.7). In conclusion, pediatric RTR with de novo DSA and microvasculature injury were at risk of allograft failure.

Little is known about the use of lung transplantation in the management of sickle cell disease-associated pulmonary arterial hypertension (SCD-PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD-PAH and pulmonary veno-occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD-associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD-PAH.

The detection of antibodies against the human leukocyte antigen (HLA) complex has become indispensable in every clinical practice. The development of solid-phase assays like the Luminex allows the standardized measurement of anti-HLA antibodies (HLAab) with high sensitivity, albeit the relevance for some clinical settings remains a matter of debate. In this review we aim to describe the principle of Luminex-based antibody detection, including two modifications that allow identifying solely complement-activating antibodies. We then describe three applications for Luminex: i) detection of HLAab preceding solid-organ transplantation and monitoring of donor-specific antibodies posttransplant as a risk factor for antibody-mediated rejection; ii) presence of HLAab in recipients as a risk for graft failure in hematopoietic stem cell transplantation, especially in haploidentical or mismatched transplantations; iii) role of HLAab in blood transfusion including refractory thrombocytopenia and selection of suitable platelet donors, transfusion-related lung injury after plasma transfusion, and immunization against HLA after red blood cell transfusion despite leukodepletion. Although the Luminex platform constitutes a potent technology for HLA antibody detection, some drawbacks require the well-educated analysis and interpretation of data in critical cases. In addition, Luminex has become an important tool to identify clinically relevant antibodies.