Blood transfusion is common during the peri-transplantation period. The incidence of immunological reactions to blood transfusion after kidney transplantation and their consequences on graft outcomes have not been extensively studied.

To examine the risk of graft rejection and loss in patients who received blood transfusion in the immediate peri-transplantation period.

We conducted a single-center retrospective cohort study of 105 kidney recipients, among them 54 patients received leukodepleted blood transfusion at our center between January 2017 and March 2020.

This study included 105 kidney recipients, of which 80% kidneys were from living-related donors, 14% from living-unrelated donors, and 6% from deceased donors. Living-related donors were mostly first-degree relatives (74.5%), while the rest were second-degree relatives. The patients were divided into transfusion (n = 54) and non-transfusion (n = 51) groups. The average hemoglobin level at which blood transfusion was commenced was 7.4 ± 0.9 mg/dL. There were no differences between the groups in terms of rejection rates, graft loss, or death. During the study period, there was no significant difference in creatinine level progression between the two groups. Delayed graft function was higher in the transfusion group; however, this finding was not statistically significant. A high number of transfused packed red blood cells was significantly associated with increased creatinine levels at the end of the study.

Leukodepleted blood transfusion was not associated with a higher risk of rejection, graft loss, or death in kidney transplant recipients.

Anemia is common in the early post-kidney transplant period[1-3]. The causes of this anemia are multiple and may include blood loss during the surgical operation, erythropoietin deficiency, iron deficiency as a result of previous end-stage renal disease along with delayed graft function (DGF), and adverse reactions to immunosuppressive agents. In some cases, blood transfusion is an essential life-saving practice. Blood transfusion is widely used in the early post-transplantation period following surgery[2].

However, blood transfusion is not without risks. Exposure to non-self human leukocyte antigens (HLAs) can lead to the formation of anti-HLA antibodies or allosensitization[2-4]. Donor-specific antibodies (DSAs) can develop in kidney recipients after receiving a blood transfusion[2]. HLA sensitization may have negative clinical impacts, including, an increased risk of rejection, and graft loss. Despite these risks, clinical guidelines do not provide specific recommendations for blood transfusion during the perioperative period[4]. This uncertainty could be due to the assumption that post-kidney transplant patients receive immunosuppressive agents, which could reduce the possibility of allosensitization[4,5].

The incidence of immunological reactions to blood transfusion after kidney transplantation and their consequences on graft outcomes have not been extensively studied. Our study aimed to examine the risk of graft rejection and graft loss in patients who receive a blood transfusion in the immediate post-transplantation period and those who were on immunosuppressive therapy.

A total of 124 kidney transplant surgeries were performed at Al-Hada Armed Forces Hospital during the study period (between January 2017 and March 2020). Nineteen patients were excluded they were < 18 years (three recipients), had a previous kidney transplant (five recipients), required desensitization prior to surgery (nine recipients), had ABO incompatibility (1 recipient), and lacked sufficient information (one recipient). The final analysis included data from 105 recipients. The patients were divided into two groups: Blood transfusion (54 recipients) and non-transfusion (51 recipients) groups (Table 1). The transplant recipients in our cohort had a higher prevalence of male sex (77 recipients: 73%), and most kidney transplantations were from living-related (84 recipients, 80%) than living-unrelated (15 recipients, 14%) donors or from deceased-donor kidney transplantation (six recipients; 6%). The median number of HLA mismatches was three in both groups. Basiliximab was the most commonly used agent for induction (62 recipients; 59%). All the recipients in our cohort received a tacrolimus-based regimen with an average tacrolimus level during the study time of 7 ng/mL (6-8 ng/mL).

Approximately 85 (69%) recipients in our cohort had anemia [hemoglobin (Hb) of < 12 g/dL]; however, only 57 (54%) recipients received blood transfusions. Among the 57 recipients who received blood transfusion 31 recipients (54%) received only 1 unit, 15 (26%) received two units, 7 (12%) received three units, 3 (5%) received four units, and only 1 (2%) received nine units of blood. The average Hb at the time of transplantation was significantly higher in the non-transfusion group (11.2 mg/dL vs 9.8 mg/dL, P < 0.001) (Table 2). In the transfusion group, the average Hb level at which blood transfusion was initiated was 7.4 ± 0.9 mg/dL. There were no significant differences in infectious and non-infectious complications between the two groups (Table 3). Additionally, there was no significant difference in graft loss or all-cause death between the two groups (Table 4, Figures 1 and 2). There was no significant difference in creatinine level progression between the two groups during the study period (Figure 3).

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Figure 1 Comparison in the outcomes between the blood transfusion vs non-blood transfusion groups. DGF: Delayed graft function.

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Figure 2 Progression of the mean creatinine between the blood transfusion vs non-blood transfusion groups.

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Figure 3 Progression of the mean creatinine between the blood transfusion vs non-blood transfusion groups. Total patients in non-transplantation group are 51. Total patients in transplantation group are 54 patients.

Rejection occurred in five recipients in our cohort; three had cellular rejection and two had antibody-mediated rejections (Table 5). All rejection episodes were biopsy-proven, and three occurred in the transfusion group; nevertheless, there was no significant difference in the rate of rejection between the two groups. Additionally, during the study period, there was an improvement in serum creatinine levels in all the patients with rejection in both groups. None of the recipients with allograft rejection lost their grafts during the study period. However, one of the recipients died due to coronavirus disease 2019 pneumonia with a functioning graft. There were no statistically significant differences in age, sex, type of transplantation, HLA mismatch, induction therapy, or CNI levels between patients who developed rejection and those who did not.

The incidence of DGF was higher in the transfusion group; however, this difference was not statistically significant. In contrast, analysis of the predictors of DGF using multivariate logistic regression showed that age [adjusted odds ratio, 1.06, 95% confidence interval (CI): 1.012-1.111; P = 0.014] and blood transfusion (adjusted odds ratio 5.649, 95%CI: 1.106-28.848; P = 0.037) were significant independent risk factors for DGF. There were no significant differences in graft loss or all-cause death mortality between the two groups.

We conducted a multiple linear regression analysis to examine the association between creatinine change (the difference between creatinine at the end of the study and baseline creatinine) as a dependent variable and eligible study variables as independent variables. We found that a higher number of transfused packed red blood cells was significantly associated with increased creatinine levels at the end of the study (B = 20.14; SE = 6.99; P = 0.004), whereas a higher creatinine level at discharge was associated with milder creatinine increase over the study period (B = -0.79; SE = 0.12; P < 0.001) (Table 6).

Anemia is a common condition during the peri-transplantation period. The rate of anemia during this period varies significantly. In a retrospective cohort study, Vanrenterghem et al[1] reported an anemia rate of 38% in a transplant population[1]. However, in a recent prospective study, 64% of the study cohort had anemia that requiring blood transfusion in the first month after transplantation[2]. The transfusion rate post-transplantation has been repeatedly reported to be between 37%-75%[4,6-8]. This high prevalence of transfusion has also been observed in pediatric populations. For instance, Richards et al[7] reported that the prevalence of transfusion was approximately 50% with a higher prevalence in younger children[7]. In our study, the anemia rate was toward the higher end of the above mentioned range at 69% however, only 54% of our cohort required blood transfusion.

Anemia carries significant risk in kidney transplant recipients. A drop of Hb level > 30% of its pre-transplant level was reported to be associated with higher all-cause graft failure and longer length of hospital stay, with a greater risk in those who required blood transfusion of > 3 units and those with longer cold ischemia time[9]. However, the effect of peri-transplantation blood transfusion on graft outcome have not been well established. For instance, in a study by Daloul et al[4], blood transfusion was not associated with a greater risk of worse graft outcomes[4]; however, Massicotte-Azarniouch et al[6] revealed that blood transfusion is associated with a greater risk of graft loss[6]. This is also supported by the findings form a recent study that included more than 1000 recipients, which showed that early blood transfusion post-transplantation didn’t lead to de novo DSAs formation[10]. Our study did not find any association between blood transfusion and graft loss or mortality. The link between blood transfusion and graft or patient loss might be a cofounding factor because patients with advanced allograft dysfunction are commonly anemic. Similarly, sick patients with multiple comorbidities are usually anemic and may require blood transfusions.

HLA molecules in the blood products are known to cause HLA allosensitization for blood transfusion recipients[11-13]. Various strategies have been attempted to avoid HLA allosensitization after blood transfusion, including leuko-reduced (leuko-depleted) blood products[11,14], HLA-selected blood products[15], and autologous blood transfusion[16]. However, the protective effects of these strategies are not well established[11,14-19]. In our study, we decided to account only for leuko-depleted blood products because this is a widely used technique in our blood bank.

The effect of blood transfusion on DSA formation and antibody-mediated rejection are not well understood. Few studies have examined the development of de-novo HLA antibodies after blood transfusions in transplant populations. While some studies found that de-novo HLA antibodies and DSAs have a negative impact on the transplant[2,20], other studies have doubted the significance of HLA antibody development in the setting of immunosuppression therapy[3,8,11]. For instance, In Ferrandiz et al[2] reported that antibody-mediated rejection occurred in 6% of kidney transplant recipients who required blood transfusion post-surgery compared with 1.4% in a non-transfusion group (P = 0.04)[2]. In contrast, in a study by Jalalonmuhali et al[3] involving 699 patients, there was no differences in the development of HLA antibodies or de-novo HLA-DSA and rejection between the transfusion and none transfusion groups[3]. Similarly in our study, the rejection rate in the transfusion group was approximately 5%, with no difference between the two groups.

Multiple factors are associated with an increased risk of poor transplant outcomes after blood transfusion. In a previous prospective observational study, worse transplantation outcomes were linked to the number of transfusion episodes (pre and post-transplantation), regardless of the total number of transfusion units[20]. In another study, poor transplantation outcomes were linked to the number of transfusion units (> 3 units)[9]. In our study, creatinine levels tended to increase toward the end of the follow-up period in the transfusion group, but this finding was not statistically significant.

It is noteworthy that maintenance immunosuppression therapy in studies that found a significant increase in rejection risk after transfusion was cyclosporine-based[2,20] while studies in which the maintenance immunosuppression regimen was tacrolimus-based showed no significant increase in rejection rate between transfusion and non-transfusion groups[3,8]. Our study is consistent with this observation as rejection rate was not significantly different between the two groups in our tacrolimus-based study cohort.

Although blood transfusion after kidney transplantation did not have an impact on patient survival, a cross-sectional study of 1198 liver transplant recipients showed a significant increase in mortality rate in patients who received a large number of blood transfusion units. Average blood transfusion units in expired patients was 5.92 ± 5.91 compared to 3.74 ± 4.23 in alive patients (95%CI: 1.47–2.88)[21].

In this study, there was a tendency toward higher DGF rates in the transfusion group. Although this finding was not statistically significant, it was in line with that of MacIsaac et al[9], in which the rate of DGF in transplant patients was up to 26%[9]. Similarly, in a retrospective cohort study on 1258 kidney transplant recipients who were followed for a median of 1405 d, DGF was as high as 41% in a transfusion group vs 15% in a non-transfusion group (P < 0.0001)[6]. In a study by Fidler et al[20], DGF was associated with a higher risk of combined patient and graft loss at a hazard ratio of 2.5 (1.5-4.5) on univariate analysis; However, this difference disappeared on multivariate analysis. It’s difficult to determine whether DGF is a cause, or a result of blood transfusion based on the available literature.

This study has limitations. This was a single-center retrospective cohort study. The lack of routine DSA and allograft biopsy restricted the inclusion of clinically insignificant DSAs and non-apparent rejections. Moreover, our cohort was predominantly males, which limits the generalizability of our findings.

Leukodepleted blood transfusion in the peri-transplantation period was not associated with a higher risk of rejection, graft loss, or patient loss. Further investigations are needed to address the link between peri-transplantation blood transfusions, DGF and DSA formation.