Effect of blood transfusion post kidney transplantation on de novo human leukocytes antigen donor-specific antibody development and clinical outcomes in kidney transplant recipients: A systematic review and meta-analysis
Kang ZY, Ma S, Liu W, Liu C
Transplant immunology. 2023;:101801
The relationship between blood transfusion following kidney transplantation (KT) and the development of de novo donor-specific antibodies (dnDSA) is controversial. This was investigated by conducting a meta-analysis of studies on patients who underwent KT with or without blood transfusion, and by evaluating the effect of post-KT blood transfusion on clinical outcomes of kidney transplant recipients. Relevant studies in the PubMed, EMBASE, and Cochrane Library databases were identified from inception to July 1, 2022. Two reviewers independently extracted data from the selected articles and estimated study quality. A fixed effects or random effects model was used to pool data according to the heterogeneity among studies. Data included in the meta-analysis were derived from 11 studies with a total of 19,543 patients including 6191 with and 13,352 without blood transfusion post-KT. We assessed the pooled associations between blood transfusion and occurrence of dnDSA and clinical outcomes of transplant recipients. Blood transfusion was strongly correlated with the development of dnDSA (relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.17-1.67; P < 0.05). Patients with blood transfusion had a higher risk of developing anti-human leukocyte antigen (HLA) class I dnDSA than non-transfused patients (RR = 1.75, 95% CI: 1.14-2.69; P < 0.05) as well as significantly higher rates of antibody-mediated rejection (AMR) (RR = 1.41, 95% CI: 1.21-2.35; P < 0.05) and graft loss (RR = 1.75, 95% CI: 1.30-2.35; P < 0.05). There were no statistically significant differences between the two groups in the development of anti-HLA antibodies, anti-HLA class II dnDSA, and anti-HLA class I and II dnDSA; delayed graft function; T cell-mediated rejection; acute rejection; borderline rejection; or patient death. Our results suggest that blood transfusion was associated with dnDSA development in KT recipients. The findings of this systematic review also suggest that post-KT blood transfusion recipients have a higher risk of AMR, and graft loss compared with non-transfused patients. Evidence from this meta-analysis indicates that the use of blood transfusion post-KT is associated with a significantly higher risk of immunological sensitization. More and higher quality results from large randomized controlled trials are still needed to inform clinical practice.
Epidemiological and clinical features, therapeutic strategies and outcomes in patients with hyperhaemolysis: A systematic review
Jacobs JW, Stephens LD, Allen ES, Binns TC, Booth GS, Hendrickson JE, Karafin MS, Tormey CA, Woo JS, Adkins BD
British journal of haematology. 2023
Hyperhaemolysis syndrome (HHS), a severe form of delayed haemolytic transfusion reaction most commonly described in patients with sickle cell disease (SCD), involves destruction of both donor and recipient red blood cells (RBCs). As the epidemiology and underlying pathophysiology have yet to be definitively elucidated, recognition can be challenging. We systematically reviewed PubMed and EMBASE to identify all cases of post-transfusion hyperhaemolysis and characterized the epidemiological, clinical and immunohaematological characteristics and treatments of HHS. We identified 51 patients (33 females and 18 males), including 31 patients with SCD (HbSS, HbSC and HbS/β-thalassaemia). The median haemoglobin nadir (3.9 g/dL) occurred a median of 10 days post-transfusion. 32.6% and 45.7% of patients had a negative indirect anti-globulin test and a negative direct anti-globulin test, respectively. The most common therapies included corticosteroids and intravenous immune globulin. 66.0% of patients received ≥1 supportive transfusion, which was associated with a longer median hospital stay/time to recovery (23 days vs. 15 days; p = 0.015) compared to no supportive transfusion. These findings illustrate that HHS that often results in marked anaemia 10 days post-transfusion is not restricted to patients with haemoglobinopathies, and additional transfused RBCs may be associated with a longer time-to-recovery.
Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Geneen, L. J., Dorée, C., Estcourt, L. J.
The Cochrane Database of Systematic Reviews. 2023;3(3):Cd012349
BACKGROUND Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence. OBJECTIVES To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia. SEARCH METHODS We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022). SELECTION CRITERIA For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion. DATA COLLECTION AND ANALYSIS For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding. AUTHORS' CONCLUSIONS The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Red Blood Cell Alloimmunizations in Thalassaemia Patients With Regular Transfusion in China: a Systematic Review and Meta-Analysis
Zhang X, Li Y, Yan B, Li X, Gui S, Sun A
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine. 2023
OBJECTIVE The development of red blood cell alloimmunization intensifies transfusion complication in thalassaemia patients. The purpose of this paper is to evaluate the existing evidence on the prevalence of erythrocyte alloimmunization in China by meta-analysis. We systematically searched cross-sectional studies regarding the alloimmunization of thalassaemia patients with regular blood transfusion in China from year 2000 to May 2021 in the Cochrane library, PubMed, EMBASE, Web of Science, and Chinese databases including CNKI, Wanfang Data, Vip and CBM. Data extraction and quality evaluation of the included studies were performed. Meta-analysis was performed using the DerSimonian and Laird random-effects models with inverse variance weighting. The presence of publication bias was tested by Egger's test, and the methodological quality of each included article was evaluated by the criteria specific to prevalence studies. RESULTS A total of 1874 patients and 263 alloantibodies from 11 studies were identified and included in the meta-analysis. The proportion of alloantibodies against antigens belonging to the Rh, MNSs and Kidd systems were as high as 70.3%, 17.9%, and 6.5%, respectively. Meta-analysis showed that the overall prevalence of alloimmunization among transfusion-dependent thalassaemia patients in China is 11.4% (95%CI: 7.2%∼16.3%). CONCLUSIONS The characteristics of red blood cell alloimmunization among thalassaemia patients with regular transfusion in China differ greatly from those in other countries. Therefore, transfusion strategies shall be actively adapted in line with thalassaemia patients in China to minimize the risk of alloimmunization.
A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes
Oliva, E. N., Huey, K., Deshpande, S., Turner, M., Chitnis, M., Schiller, E., Tang, D., Yucel, A., Hughes, C., Shah, F.
Journal of Clinical Medicine. 2022;11(3)
Anemia is the most common form of cytopenia in patients with myelodysplastic syndromes (MDS), who require chronic red blood cell transfusions and may present high serum ferritin (SF) levels as a result of iron overload. To better understand the potential effects of high SF levels, we conducted a systematic literature review (SLR) to identify evidence on the relationship between SF levels and clinical, economic, or humanistic outcomes in adult patients with MDS. Of 267 references identified, 21 were included. No studies assessing SF levels and their relationship with humanistic or economic outcomes were identified. Increased SF levels were an indicator of worse overall survival and other worsened outcomes; however, the association was not consistently significant. SF levels were a significant prognostic factor for relapse incidence of MDS and showed a significant positive correlation with number of blood units transfused but were not associated with progression to acute myeloid leukemia or the time to transformation. Higher SF levels were also an indicator of a lower likelihood of leukemia-free survival, relapse-free survival, and event-free survival. The SLR suggests that SF levels are associated with clinical outcomes in MDS, with higher levels correlated with number of blood units transfused, frequently indicating worse outcomes.
Deferasirox versus deferoxamine in managing iron overload in patients with Sickle Cell Anaemia: a systematic review and meta-analysis
The Journal of international medical research. 2022;50(12):3000605221143290
OBJECTIVES To examine the efficacy of deferasirox (DFX) by comparison with deferoxamine (DFO) in managing iron overload in patients with sickle cell anaemia (SCA). METHODS Online databases were systematically searched for studies published from January 2007 to July 2022 that had investigated the efficacy of DFX compared with DFO in managing iron overload in patients with SCA. RESULTS Of the 316 articles identified, three randomized clinical trials met the inclusion criteria. Meta-analysis of liver tissue iron concentration (LIC) showed that iron overload was not significantly higher in the DFX group compared with DFO group (WMD, -1.61 mg Fe/g dw (95% CI -4.42 to 1.21). However, iron overload as measured by serum ferritin was significantly lower in DFO compared with DFX group (WMD, 278.13 µg/l (95% CI 36.69 to 519.57). Although meta-analysis was not performed on myocardial iron concentration due to incomplete data, the original report found no significant difference between DFX and DFO. CONCLUSION While limited by the number of studies included in this meta-analysis, overall, the results tend to show that DFX was as effective as DFO in managing iron overload in patients with SCA.
Efficacy and Tolerability of Twice-Daily Dosing Schedule of Deferasirox in Transfusion-Dependent Paediatric Beta-Thalassaemia Patients: A Randomized Controlled Study
Panachiyil GM, Babu T, Sebastian J, Ravi MD
Journal of pharmacy practice. 2022;:8971900211038301
BACKGROUND Deferasirox has proved good efficacy and acceptable safety for the management of thalassaemia patients. However, some patients are unresponsive or intolerant to once-daily administration of deferasirox even at a high dose. The current study evaluated the effectiveness and tolerability of twice-daily dosing of deferasirox among transfusion-dependent paediatric beta-thalassaemia patients. METHODS This prospective randomized single-blinded parallel study included all transfusion-dependent paediatric beta-thalassaemia patients prescribed with deferasirox, who visit the study site for their regular blood transfusions and follow-up. The enrolled patients were randomized into intervention and control groups by using a simple block randomization method. In the intervention group, the once-daily dosing of deferasirox was changed to twice-daily dosing with the same total daily dose. Whereas, in the control group, the patients continued with the once-daily deferasirox dosing. The serum ferritin levels of both groups were determined on the enrolment day and after 6 months of follow-up. RESULTS Forty-one patients were included for analysis. A statistically significant mean decrease in serum ferritin levels was detected in the intervention group, while the serum ferritin levels of the control group significantly increased from baseline. The twice-daily dosing of deferasirox was better tolerated by the thalassaemia patients when compared to once-daily dosing. CONCLUSION This study concludes that twice-daily dosing of deferasirox with the same total daily dose significantly enhances the iron chelation efficacy and tolerability among transfusion-dependent paediatric beta-thalassaemia patients when compared to once-daily regimen.
A Systematic Review on the Management of Transfusion-Related Acute Lung Injury in Transfusion-Dependent Sickle Cell Disease
Arzoun H, Srinivasan M, Adam M, Thomas SS, Lee B, Yarema A
The onset of respiratory distress and acute lung injury (ALI) following a blood transfusion is known as transfusion-related acute lung injury (TRALI), although its pathophysiology remains unknown. Even though sickle cell disease (SCD) has been studied for more than a century, few therapeutic and management strategies adequately address the emergence of TRALI. TRALI, an immune-mediated transfusion response that can result in life-threatening consequences, is diagnosed based on clinical signs and symptoms. Early detection and treatment increase the chances of survival and, in most cases, result in a complete recovery. Our objective is to provide a firm grasp of the present status of SCD-related TRALI care and therapy. After exploring multiple databases, this study offers evidence-based guidelines to aid clinicians and other healthcare professionals make decisions concerning transfusion assistance for SCD and the management of transfusion-related complications. Other risk factors for acute lung injury including sepsis aspiration should be ruled out throughout the diagnostic process. Several recent studies have shown that immunotherapy or immunological targets can effectively prevent these complications. Red cell transfusions, red cell antigen matching optimization, and iron chelation can also help reduce negative consequences. It is to be noted that poor clinical outcomes can be avoided by early detection and treatment of hemolytic transfusion reactions. Finally, preventing the onset of TRALI may be the most effective therapeutic strategy for SCD patients who rely on blood transfusions for survival.
Amlodipine: Can act as an antioxidant in patients with transfusion-dependent β-thalassemia? A double-blind, controlled, crossover trial
Darvishi-Khezri H, Khalilzadeh Arjmandi H, Aliasgharian A, Shaki F, Zahedi M, Kosaryan M, Karami H, Naeimayi Aali R, Salehifar E
Journal of clinical laboratory analysis. 2022;:e24752
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BACKGROUND AND AIM This study aimed to assess the antioxidant effects of amlodipine in transfusion-dependent β-thalassemia (TDT) patients. METHODS This crossover trial consisted of two sequences (AP and PA). In the AP sequence, nine cases received amlodipine 5 mg daily (phase I) and then were switched to placebo (phase II). In PA sequence, 10 patients took the placebo (phase I) and were shifted to amlodipine (phase II). The washout period was 2 weeks. The length of each phase was 6 months. Serum malondialdehyde (MDA, μmol/L), carbonyl (protein CO, μM/L), glutathione (GSH, nM/L), and total antioxidant capacity (TAC, μmol FeSO4/L) were measured in the beginning and at the end of phases I and II. The clinical significance was viewed as a minimum change difference of 5% for each outcome between amlodipine and placebo. RESULTS Seventeen cases completed the study. According to the baseline MDA values, the adjusted Hedges's g for MDA was -0.59, 95% confidence interval [CI] -1.26 to 0.08. After controlling the baseline protein CO values, Hedges's g computed for protein CO was -0.11, 95% CI -0.76 to 0.55. The estimated values of the adjusted Hedges's g for GSH and TAC were also 0.26, 95% CI -0.40 to 0.91, and 0.42, 95% CI -0.24 to 1.09, respectively. The change difference for MDA was 8.3% (protein CO 2.2%, GSH 3.1%, and TAC 12.9%). CONCLUSION Clinically, amlodipine therapy is an efficacious adjuvant treatment with conventional iron chelators for improving the levels of MDA and TAC in patients with TDT.
Adherence to Iron Chelation Therapy among Adults with Thalassemia: A Systematic Review
Locke M, Reddy PS, Badawy SM
Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassemia. However, the role that adherence to ICT plays in health-related outcomes is less well known. Our objectives were to identify adherence rates of ICT, and to assess methods of measurement, predictors of adherence, and adherence-related health outcomes in the literature published between 1980 and 2020. Of 543 articles, 43 met the inclusion criteria. Studies measured ICT adherence, predictors, and/or outcomes associated with adherence. Most studies were across multiple countries in Europe and North America (n = 8/43, 18.6%), recruited in clinics (n = 39/43, 90.7%), and focused on β-thalassemia (β-thal) (n = 25/43, 58.1%). Common methods of assessing ICT adherence included patient self-report (n = 24/43, 55.8%), pill count (n = 9/43, 20.9%), prescription refill history (n = 3/43, 7.0%), provider scoring (n = 3/43, 7.0%), and combinations of methods (n = 4/43, 9.3%). Studies reported adherence either in 'categories' with different levels of adherence (n = 24) or 'quantitatively' as a percentage of doses of medication taken out of those prescribed (n = 17). Adherence levels varied (median 91.7%, range 42.0-99.97%). Studies varied in sample size and methods of adherence assessment and reporting, which prohibited meta-analysis. Due to a lack of consensus on how adherence is defined, it is difficult to compare ICT adherence reporting. Further research is needed to establish guidelines for assessing adherence and identifying suboptimal adherence. Behavioral digital interventions have the potential to optimize ICT adherence and health outcomes.