Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor-Specific Anti-HLA Antibodies

I. Ferrandiz; N. Congy-Jolivet; A. Del Bello; B. Debiol; K. Trébern-Launay; L. Esposito; D. Milongo; G. Dörr; L. Rostaing; N. Kamar


American Journal of Transplantation. 2016;16(9):2661-2669. 

In This Article


In addition to a history of previous organ transplantation or pregnancy, blood transfusion is a well-known risk factor for the development of anti-HLA antibodies in candidates for kidney transplantation.[4] To facilitate access to kidney transplantation, it is recommended to avoid blood transfusion before kidney transplantation. Very few studies, however, have assessed the effects of posttransplant blood transfusion on the development of anti-HLA antibodies,[10–12] especially DSAs, which can cause AMR and decrease graft and patient survival rates.[9] This was the aim of our study.

To avoid confounding factors, only pretransplant non–HLA-sensitized patients who had received an ABO-compatible kidney transplant, who had not previously or simultaneously received a nonkidney transplant, who had a functioning graft at 1 mo, and who had not undergone allograft nephrectomy were included in this study. Because increased anti-HLA sensitization is observed after allograft nephrectomy,[14–16] we excluded patients who had undergone allograft nephrectomy within the first year after transplantation. None of these patients had developed DSAs before the nephrectomy. We used the sensitive Luminex SA assay to assess anti-HLA antibodies.

Our findings were fourfold: (i) Nearly 65% of kidney transplant patients received an RBC transfusion within the first year after transplantation, (ii) the 1-year incidence of DSAs was significantly higher in patients who needed a transfusion (7.2% vs. 0.7% of patients with no transfusion), (iii) blood transfusion was an independent predictive factor for the formation of de novo DSAs but not for AMR, and (iv) patients who received a transfusion and developed DSAs were more often treated with cyclosporin A than tacrolimus.

Anemia is commonly observed after kidney transplantation and often requires erythropoietin-stimulating agents and/or a blood transfusion. In our study, the proportion of patients who required a blood transfusion was high, at 64.1%, which is similar to the 52% reported by Scornik et al.[10] Similarly, the majority of blood transfusions were performed within the first month after transplantation: 94.8% in our study and 78% in the report by Scornik et al.[10] In a cohort of 143 anemic kidney transplant patients, Favardeh et al observed that 72% of patients also needed a transfusion within the first month after transplantation.[12] In both previous studies and in ours, the majority of patients received fewer than three blood transfusions.[10–12]

In the present study, patients who required a blood transfusion had significantly lower hemoglobin levels at transplantation than those that did not. Polyclonal antibodies, which are well known to have a myelotoxic effect, were also used significantly more frequently in patients who required a blood transfusion. Most of these patients received a transfusion within the perioperative period because their hemoglobin levels were <10 g/dL.

Little is known about the impact of posttransplant blood transfusion on anti-HLA antibodies and DSA formation. It has been suggested that, in contrast to the increased risk of anti-HLA formation observed in candidates for a kidney transplant, the risk of anti-HLA sensitization is low in transplant patients because of the use of immunosuppressive therapies.[13] In the present study, 32 kidney transplant patients (12.8%) developed anti-HLA antibodies after a blood transfusion versus only two patients (1.4%) who did not receive a blood transfusion (p < 0.0001). Eighteen patients (7.2%) in the transfusion group but only one patient (0.7%) from the nontransfusion group developed DSAs (p < 0.0001). Of these 18 patients, all patients developed anti–class II DSAs, and eight developed both anti–class I and II DSAs. We found that blood transfusion was an independent predictive factor for DSA formation. In univariate analyses, but not in multivariate analyses, blood transfusion was associated with the occurrence of AMR.

In a cohort of 199 kidney transplant patients who were tested for anti-HLA antibodies several months or years after transplantation, using a less sensitive immunological test than the Luminex SA assay, Scornik et al did not observe a significant difference between patients who had received a transfusion (17%) and those who had not (15%).[10] Interestingly, they observed that 57% of patients who produced DSAs and 20% who developed non-DSA anti-HLA antibodies had received a transfusion (p = 0.05).[10] In the present study, in transfused patients, 56.25% of de novo anti-HLA antibodies were directed against the kidney donor. Scornik et al also found that patients with chronic allograft dysfunction had undergone more transfusions than patients who had no acute or chronic rejection.[10]

Fidler et al showed that receiving a blood transfusion during the perioperative period in patients with preformed DSAs was associated with an increased risk of AMR.[11] More recently, Favardeh et al showed in a cohort of 143 kidney transplant patients with anemia that an increased number of transfusion episodes, regardless of the total number of blood transfusions given, was associated with a significantly increased risk of developing class II DSAs.[12] In the present study, the number of transfusion episodes was not associated with DSA formation; however, the total number of RBC units was associated with the development of DSAs but was not a predictive factor.

HLA molecules are expressed in different blood components. The antigen load is found in leukocytes, mainly in lymphocytes; however, HLA molecules are also expressed in monocytes, platelets and RBCs. Platelets are usually removed from RBC units. In fact, RBC units are leukodepleted, and the residual leukocyte count is below 1 × 106. Nevertheless, several studies have shown that leukodepletion does not prevent the risk of allosensitization.[5–8] In addition, HLA class I molecules are expressed constitutively on erythrocytes at low levels. Because there are 1000 more erythrocytes than leukocytes within a blood unit, the content of HLA within the blood units is sufficient to induce HLA class I sensitization.[13]

In the present study, the use of tacrolimus rather than cyclosporine A was an independent protective factor against DSA formation. Furthermore, at blood transfusion, the proportion of patients treated by cyclosporin A was greater among those who developed DSAs than among those that did not develop DSAs. Conversely, the proportion of patients treated by tacrolimus was lower in those who had developed a DSA. Several studies and meta-analyses have reported lower incidences of acute rejection in patients treated by tacrolimus compared with cyclosporine.[17–19] To the best of our knowledge, however, no study has compared the incidence of de novo DSAs in patients treated with tacrolimus versus cyclosporine A. Interestingly, at the time of blood transfusion, calcineurin inhibitor (CNI) levels, the proportion of patients who had a low CNI level, the use of mTOR inhibitors (and their levels), the use of MPA (and doses) and the use of steroids (and doses) did not differ between patients who developed and did not develop DSAs.

In addition, the proportions of patients who had a tacrolimus trough level of <5 ng/mL, an everolimus trough level of <5 ng/mL or a cyclosporine A C2 level <500 ng/mL at 1, 3, 6 or 12 mo after transplantation were relatively low. The data did not differ significantly between patients who received a blood transfusion and developed a DSA and those who did not develop a DSA after blood transfusion. Finally, anti-CD25 mAb induction therapy was more frequently given to patients who received a blood transfusion and developed DSAs. This was not the case when patients were given polyclonal antibody induction therapy. Several recent studies showed an increased risk of DSA development after early conversion from CNIs to mTOR inhibitors;[20–22] however, this was not observed in our study.

In the present study, cellular rejection was associated with de novo DSA formation in univariate analyses but not in multivariate analyses. This finding agrees with recent reports of an association between acute cellular rejection and the occurrence of later DSA formation.[23,24]

Because of its retrospective design, our study has several limitations. We could not exclude the effect of low exposure to immunosuppressant drugs at any time point during the study period, although this can facilitate DSA formation. Nevertheless, we assessed immunosuppressant doses and levels at the time of blood transfusion and did not observe any differences between patients who developed and did not develop DSAs. Proportions of patients who had low trough levels at 1, 3, 6, and 12 mo after transplantation were similar to those who received a blood transfusion and developed a DSA compared with those who did not develop a DSA after blood transfusion. It would have been useful to have had information on the blood donors' HLA types to help us understand the mechanisms of HLA sensitization. The use of HLA-matched blood can reduce HLA sensitization;[8,13] however, it is unlikely that the increased HLA sensitization induced by a blood transfusion was related only to the HLA mismatches. It could also have been caused by the immunostimulatory effect of a blood transfusion.

In conclusion, our study showed that a relatively high proportion of patients receive a blood transfusion soon after kidney transplantation. This is associated with an increased immunological risk, especially in underimmunosuppressed patients, and may be responsible for DSA formation, which can expose patients to the risk of AMR. Further larger studies are needed to better assess the risk of posttransplant blood transfusion.