Protocolled Blood Transfusions in Recipients of a Simultaneous Pancreas–Kidney Transplant Reduce Severe Acute Graft Rejection

Pretransplant protocolled blood transfusions (PBT) have been associated with less acute rejections and improved graft survival after kidney and heart transplantation (1–3). Subsequent studies suggested that this effect was mediated by leukocytes in the blood product (4), which share a human leukocyte antigen (HLA)-DR with the patient (5). Although during the last decade deliberate PBT has been discontinued at most transplant centers, our center continued this procedure for simultaneous pancreas–kidney transplantation (SPKT). This retrospective study spanning 10 years investigated the effect of a PBT in patients who underwent SPKT and whether this effect is influenced by induction therapy with anti-T cell reagents. MATERIALS AND METHODS Between October 1996 and June 2005, 118 patients underwent SPKT for insulin dependent type 1 diabetes mellitus and end-stage renal failure. Before transplantation (median 220 days, range 31–1721 days), 49 patients received one unit of one HLA-DR matched, non-leukocyte depleted packed red blood cells, stored less than 24 hr. Sixty-nine patients received no PBT because of previous therapeutical (leukocyte-depleted) transfusions or pregnancy. Posttransplant maintenance immunosuppressive therapy consisted of standard regimens of calcineurin inhibitors, purine synthesis inhibitors, and corticosteroids. Induction therapy with polyclonal antithymocyte globulin (ATG)-Fresenius (ATGF; Fresenius AG, Bad Homburg, Germany) or humanized antibodies against the interleukin-2 receptor α-chain (daclizumab) was given from 1999 to 2005. Acute rejection episodes of the kidney (within 6 months posttransplant) were biopsy-proven. First-line treatment of rejection was 1 g methylprednisolone. Severe acute rejections (steroid resistant or second rejection episodes) were treated with ATG-Merieux (ATGM; Thymoglobulin; Genzyme Europe BV, Naarden, The Netherlands), which is different from the ATGF product to circumvent serum sickness. Cox proportional hazard regression analysis was applied to identify independent prognostic factors for occurrence of acute rejection episodes and its treatment with ATGM. RESULTS Characteristics of the study population are summarized in Table 1. With respect to transplantation outcome, occurrence of acute rejection at 6 months was similar in both groups. However, in patients with acute rejection a subsequent severe acute rejection episode requiring ATGM treatment occurred less frequently when they had received a PBT (P=0.002).TABLE 1: Characteristics of study population and outcomeMultivariate analysis identified immunosuppressive induction therapy and year of transplantation (comparing more recent 2-year cohorts with previous ones) as independent prognostic factors for reducing the number of patients with acute rejection episodes (induction therapy HR: 0.478, 95% CI: 0.274–0.835, P=0.010; year of transplantation HR: 0.784, 95% CI: 0.637–0.965, P=0.022; multivariate analysis adjusted for patient age, patient sex, diabetes duration, time on dialysis, PBT, organ donor age, and HLA-DR mismatch patient-organ donor). With respect to severe rejections, a PBT and year of transplantation were identified in a multivariate model as prognostic factors for decreasing the risk of developing a severe acute graft rejection (PBT HR: 0.385, 95% CI: 0.186–0.796, P=0.010; year of transplantation HR: 0.774, 95% CI: 0.610–0.983, P=0.036; multivariate analysis adjusted for patient age, patient sex, diabetes duration, time on dialysis, induction therapy, organ donor age, and HLA-DR mismatch patient-organ donor). As shown in Figure 1, a PBT decreased the proportion of severe acute rejections from 81% to 37.5% in patients without induction therapy (P=0.082) and from 76.5% to 38.9% in patients with induction therapy (P=0.033).FIGURE 1.: Patients with severe acute rejection episodes requiring ATGM treatment represented as percentage of patients with acute rejections after SPKT (n=64). This figure shows that a PBT reduced the incidence of severe acute rejections in patients without induction therapy (graph A; HR: 0.334, 95% CI: 0.097–1.151, P=0.082) and in patients with induction therapy (graph B; HR: 0.336, 95% CI: 0.145–0.923, P=0.033). Two patients (with induction and with PBT) died before a severe acute rejection had developed and were therefore not at risk for the full period. Statistics: Cox proportional hazard regression; SPSS version 14.0.DISCUSSION A beneficial effect of PBT was present irrespective of the use of induction therapy. A PBT was not associated with a reduction of acute rejections as also shown by others (6, 7), but prevented the need of ATGM treatment for more severe, refractory rejections, thereby reducing the risk of ATG side effects (8). The synergistic effect of induction therapy and PBT resulted in the lowest incidence of severe acute rejections in the group with combined therapy. A major flaw in our study is the difference in immunological risk profile between patients with and without a PBT, while the inclusion criteria for a PBT select predominantly untransfused males. Alloimmunization as detected by antibody formation was low and equal in both groups. However, excluded patients may have, by pregnancy and therapeutic transfusions induced, memory cells without detectable alloantibodies, which may play a role causing more aggressive rejections. On the other hand, residual leukocytes in a therapeutic blood transfusion and trafficking of fetal cells into the maternal circulation during pregnancy may have a similar beneficial effect as a PBT. The retrospective nature of our study allowed us to correct only for known risk factors in multivariate analysis, whereas unknown confounders for rejection may still be present. To investigate solely the effect of an HLA-DR shared PBT in present times of modern immunosuppressive drugs, a prospective, randomized controlled study in SPK patients is necessary. ACKNOWLEDGMENTS The authors thank Geert W. Haasnoot and Leo M.G. van de Watering for their assistance in the statistical analyses. Marloes M. Waanders Department of Immunohaematology and Blood Transfusion Leiden University Medical Center Sanquin Blood Bank Leiden, The Netherlands Dave L. Roelen Department of Immunohaematology and Blood Transfusion Leiden University Medical Center Leiden, The Netherlands Johan W. de Fijter Marko J. K. Mallat Department of Nephrology Leiden University Medical Center Leiden, The Netherlands Jan Ringers Department of Surgery Leiden University Medical Center Leiden, The Netherlands Ilias I. N. Doxiadis Department of Immunohaematology and Blood Transfusion Leiden University Medical Center Leiden, The Netherlands Anneke Brand Department of Immunohaematology and Blood Transfusion Leiden University Medical Center Sanquin Blood Bank Leiden, The Netherlands Frans H. J.