Immune Hemolysis Resulting From Passenger Lymphocyte Syndrome Derived Anti-Rh (D) Reactivity After Kidney Transplantation

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Immune-mediated hemolysis is a recognized complication in the context of red cell antigen mismatched solid organ or hemopoietic cell transplantation. Donor-derived memory B lymphocytes with antigen-specific activity against foreign red cell antigens are transferred with the transplanted organ. On exposure to recipient red blood cells, which express the target antigen, a secondary immune response is triggered, antibodies are produced, and hemolysis occurs. This is termed passenger lymphocyte syndrome (PLS). We report a case of significant hemolysis resulting from PLS-derived anti-D antibody after kidney transplantation. CASE REPORT A 51-year-old male patient, blood group B Rhesus-D positive, with diabetic nephropathy received a living kidney transplant from an O Rhesus-D negative 63-year-old female donor. The donor had anti Rhesus-D antibodies, which were presumed secondary to pregnancy. The recipient received induction immunosuppression with basiliximab and maintenance immunosuppression with prednisolone and trough level adjusted tacrolimus. The transplant operation was uneventful. Recipient’s serum creatinine improved from a pretransplant level of 600 μmol/L to less than 100 μmol/L within 72 hr of transplant. The recipient’s recovery was complicated by culture-proven Pseudomonas aeruginosa urinary tract infection (UTI) on day 9 posttransplantation. This was successfully treated with tazobactam and piperacillin. On day 15 postoperatively, hemoglobin unexpectedly declined to 59 g/L from a previous baseline of approximately 100 g/L in the absence of clinical and radiological evidence of bleeding. The following day, his hemoglobin level dropped further to 38 g/L. Additional investigations including blood film (showing spherocytes), lactate dehydrogenase (>1,800 IU/L), bilirubin (52 μmol/L), and haptoglobin (unrecordable) levels confirmed hemolysis as the sole cause for declining hemoglobin. A strongly positive Direct Anti-globulin Test with IgG (strongly positive 5+), C3d (4+), and weak IgM (1+) was detected by the NHS Blood & Transplant (UK) regional serology laboratory using gel agglutination technique. Anti-D (4+) was found in his serum and eluted from his red cells. Anti-B was not detected. A diagnosis of immune hemolysis resulting from passenger lymphocyte syndrome (PLS) was made. The patient was transfused with two units of O Rhesus-D negative blood each on postoperative days 16 and 18. No changes were made to immunosuppression or specific treatments for hemolysis were not instituted. Three months after transplantation, he had a normal hemoglobin (>130 g/L), no biochemical evidence of ongoing hemolysis, and barely detectable anti-D (1+). Graft function continued to be excellent with serum creatinine less than 100 μmol/L. DISCUSSION Immune hemolysis resulting from PLS secondary to mismatched ABO antigens after renal transplantation is well described and was recently reviewed by Nadarajah et al. (3). Anti–D-related PLS has been well described in the non-renal transplant setting (4–6) and likely reflects the increased lymphoid tissue transferred with the donor organ. In contrast, PLS resulting from anti-Rhesus-D following renal transplantation is relatively rare (Table 1).TABLE 1: Reported cases of passenger lymphocyte syndrome following renal transplantAlloimmunization of the donor to the Rhesus-D antigen, as documented in our report, is a risk factor and has been described previously (1, 7–9). Anti–D-related PLS appears more common when the donor is female (8, 9, 13). The risk of PLS is dependent on the likelihood of transfer of donor-derived lymphocytes and is more common in hemopoietic cell transplants followed by heart and lung, liver, and finally kidney transplants (2). Anti-D is characteristically an IgG antibody which causes extravascular hemolysis. Conversely, intravascular hemolysis is typically the result of an IgM antibody which can link two antigen sites on the red cell membrane and activate complement. To date, in previous cases of PLS after renal transplantation, only IgG anti-D has been identified on DAT testing, in keeping with extravascular hemolysis. In our case, in addition to IgG, C3d and IgM were detected, raising the possibility of intravascular hemolysis. Rarely, severe hemolytic reactions associated with anti-D have been reported in the setting of immune thrombocytopenia. Postulated mechanisms to explain the severe reactions include the overexpression of the D antigen on recipient red cells allowing IgG molecules to link and activate complement, the presence of trace amounts of IgM anti-D, or the overloading of the extravascular clearance mechanism allowing free hemoglobin to spill into the circulation (10). In our case, any of these mechanisms would seem possible and may have been augmented by P. aeruginosa UTI on postoperative day 9 (3). Although the presence of C3d on the red cell surface may have indicated an augmented hemolytic reaction as postulated above, conversely this may simply have reflected immune stimulation associated with his previous infection. Given the apparent rare occurrence of anti–D-mediated PLS, and equally importantly the self-limiting nature of the condition, in our opinion, routine screening of donors or risk stratification (if it were possible) of recipients is unlikely to have an acceptable risk-versus-benefit profile. Renal transplants can safely be performed in this scenario as long as the clinical teams caring for the patient are aware of the possibility of PLS as a self-limiting cause of anemia 7 to 14 days after transplantation with an ABO or Rhesus-D mismatched donor. Prashanth Karanth, MRCP 1 Janet Birchall, FRCPath2 Sarinder Day, Phd1 David J Unsworth, Phd1 Rommel Ravanan, MD1 1 Renal Transplant Centre Southmead Hospital Bristol, UK 2 NHS Blood & Transplant and North Bristol NHS Trust Bristol, UK

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