Acute transplant rejection induced by blood transfusion reaction to the Kidd blood group system

Stephen Holt1, Helen Donaldson2, Geoffrey Hazlehurst2, Zac Varghese3, Marcela Contreras2, Edward Kingdon1, Paul Sweny3 and Aine Burns3

1 Renal Unit, Brighton and Sussex University Hospitals, Royal Sussex County Hospital, Brighton BN2 5BE, 2 Blood Transfusion Department and 3 Renal Unit, Royal Free Hospital, Pond Street, London NW3 2QG, UK

Correspondence and offprint requests to: Stephen Holt, Renal Unit, Brighton and Sussex University Hospitals, Royal Sussex County Hospital, Brighton BN2 5BE, UK. Email: steve.holt{at}bsuh.nhs.uk



   Abstract
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 Abstract
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Many renal transplant centres now try to avoid blood transfusion prior to renal transplantation, to avoid alloimmunization due to antibody production against donor antigens usually present on contaminating white cells. Post- or peri-operative transfusions are usually not considered to present problems, since the patient is heavily immunosuppressed. We present a patient who suffered a rare transfusion reaction, that we believe may have initiated a severe vascular rejection of a kidney transplant, probably mediated by Kidd blood group antigens.

Keywords: blood transfusion; Kidd blood group antigens; rejection; renal transplantation



   Case
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A 29-year-old female was referred for a live related renal transplant from her sister. At the age of 11, she had developed an embryonal rhabdomyosarcoma of the palate, and at presentation she had developed lung metastases. She was treated with radiotherapy and myeloablative chemotherapy followed by an autologous bone marrow transplant (BMT). During her BMT, she received blood transfusions from her father. On routine follow-up, she developed hypertension and was found to have small multicystic kidneys. She developed progressive renal impairment despite medical management of her blood pressure and she was referred for live related transplant, with her mother and her sister offering themselves as potential donors. The patient was blood group A Rhesus positive and, although her mother had a compatible blood group, she had a positive cross-match and was therefore not suitable as a donor. However, her sister was blood group A Rhesus negative, and a one haplotype match. The donors tissue type was HLA A2, A26(10), B55(22), B44(12), DR12(5), DR16(2), and the recipient was HLA A2, A26(10), B7, B44(12), DR12(5), DR14(6). The FACS and CDC cross-matching were negative for both B and T cells, so a transplant was scheduled.

The transplant proceeded as planned, but the patient required temporary haemodialysis and was given erythropoietin for a few weeks pre-operatively. However, her renal function improved quickly post-operatively. Immunosuppression was obtained using prednisolone and cyclosporin (Neoral) and levels were in the target therapeutic range. The donor was cytomegalovirus (CMV) positive while the recipient was CMV negative, so she was also given intravenous ganciclovir as primary CMV prophylaxis.

Despite pre-operative erythropoietin therapy, her haemoglobin had been low pre-operatively but she was not transfused peri-operatively. Post-operatively, her anaemia was delaying her recovery, since she was breathless on exertion and mobilizing only slowly, and she was transfused with three units of packed red cells. Within 2 h of the transfusion, she developed a fever and her urine output slowed. Blood samples were taken for investigation of the suggested transfusion reaction. The graft function began to deteriorate (Figure 1) and she was given methylprednisolone and broad spectrum antibiotics, and a renal biopsy was performed. This showed some evidence of rejection, with mild and patchy interstitial lymphocytic aggregates and some patchy interstitial haemorrhage seen. She was given further methylprednisolone and changed from cyclosporin to tacrolimus. As her graft function showed no sign of improvement, she underwent a second biopsy and commenced a 10 day course of anti-thymocyte globulin (Meriuex rabbit ATG) at treatment doses for rejection. The cross-match was re-checked and remained negative. Anti-platelet antibodies, anti-endothelial cell antibodies and monocyte cross-match were negative. The second biopsy showed severe interstitial haemorrhage and severe cellular and vascular rejection. Daily plasma exchange and radiotherapy to the graft were given, but intravenous immunoglobulin was not administered. Local radiotherapy was given as the graft remained swollen despite the ATG and there were concerns about over-immunosuppression from systemic therapy that she had been given. Despite this aggressive anti-rejection regime, her graft failed to improve. The CMV polymerase chain reaction (PCR) was checked every other day and remained negative throughout. An HLA class I antibody against HLA B17 was identified ~1 month after the transplant, but otherwise the cross-match remained negative. However, it is interesting that HLA B17 was not a mismatched antigen on the donor kidney. This antibody was not present on further cross-match samples and was considered to have been a transient IgM antibody, again from blood transfusion at the time of transplantation.



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Fig. 1. The time course of the rejection can be seen by the annotated diagram of the serum creatinine. HD = haemodialysis; ATG = anti-thymocyte globulin; PLEX = plasma exchange; DXT = radiotherapy; TxN = transplant nephrectomy; MP = methylprednisolone; CyA = cyclosporin; TAC = tacrolimus.

 
Eventually she underwent a graft nephrectomy and recommenced haemodialysis before being transferred onto peritoneal dialysis where she remains in good health.

The investigation of the transfusion reaction revealed a positive direct antiglobulin test at around day 12 post-operatively. Patient red cells were coated with IgG and C3D complement. An eluate from the patients’ cells was found to have anti-Jka (Kidd) specificity, suggesting that this was an acute blood transfusion reaction. Prior to the transplant, the patient (who was Jka–b+) had no anti-Jka antibodies detectable within the serum and, 2 weeks after detection, the antibody level again became undetectable. The antibodies detected were a mixture of IgM and IgG, suggesting that this was a secondary response. Further questioning revealed exposure to the Jka antigen previously, when she had been given transfusions from her father (Jka+b+) at the age of 11 years.

The transfusion reaction was rather early and vigorous, starting within hours of the transfusions. Anti-Jka antibodies usually cause a delayed transfusion reaction (at ~5–10 days). Thus, this is rather early for a reaction. However, we feel that it is still reasonable to suspect anti-Jka as the cause of the fever and rejection in this case as anti-Jka levels may already have been increasing in response to the presence of Jka antigen due either to the antigen present on the donor kidney or to Jka-positive passenger red cells. The transfusion would then have acted as a second stimulus to an already nascent immune response. This reaction could then have caused her acute transfusion reaction and may have also caused acute severe rejection of the donor kidney. There is evidence that Kidd antigens are expressed on endothelial cells within the renal medulla of the kidney and we went on to look for evidence that Kidd antibodies could bind, by performing anti-Kidd staining in renal biopsy sections from patients whose Kidd phenotype was known. Polyclonal fluorescent antibodies raised to Jka and Jkb antigens were applied to kidney sections (Figure 2). This showed that antibodies could bind to Jka-positive kidney sections, but only to tubular epithelial cells and not endothelial cells. Tissue from patients who were homozygous for the antigens Jka or Jkb failed to show staining with antibodies to Jkb or Jka, respectively (negative controls).



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Fig. 2. A section of kidney from a Jka-positive patient stained with a fluorescently tagged antibody directed towards the Jka antigen. Fluorescence is present but is in the tubular epithelial cells, not the endothelial cells.

 


   Discussion
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 Case
 Discussion
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We report a case of transfusion reaction that we believe led directly to an antibody-mediated hyperacute graft rejection caused by complement-fixing antibody to the Jka antigen of the Kidd blood group system. These antibodies may cross-react with urea transporters within the transplanted kidney, completing the mechanistic link to support our assertion.

ABO compatibility has been considered more or less a prerequisite for successful kidney transplantation for many years, incompatible grafts being rejected by pre-formed complement-fixing antibody within minutes or hours (hyperacute rejection). Lenhard et al. analysed the influence of incompatibility in the ABO, Rhesus, Lewis, MN, Ss, P, Kell and Duffy blood groups [1]. Their results indicated that of the minor blood group antigens, only Lewis played a major role in graft survival. Nevertheless, several simultaneously present mismatched antigens are associated with poor graft survival.

To date, there are few data relating to the influence of the Kidd antigens. This system is named after a patient described in 1951. Mrs Kidd delivered a baby with a haemolytic disease of the newborn associated with an antibody directed against a new antigen (Jka) [2]. Two years later, antibodies directed against the JKb antigen were described in a patient with a transfusion reaction [3]. The alleles for this gene are located on chromosome 18q12–q21 exon 11, which is distributed over 30 kb and codes for a 45 kDa, 10 domain, membrane-spanning glycoprotein. A single base transition is responsible for the two alleles, giving three potential genotypes, the heterozygote, JkaJkb (with a gene frequency of ~50% in Caucasians) and homozygotes, JkaJka (~25%) and JkbJkb (~25%). One further phenotype has been described named Jka–b– (Jk3). This is a null phenotype and has been detected in people from Asian populations but is exceptionally rare in Caucasians [4]. Complement-fixing antibodies may be detected against the Jka, Jkb (and rarely Jk3) antigens causing transfusion reactions in sensitized patients. One of the characteristics of these antibody reactions is that they retain a strong memory response. A vigorous production of IgG or IgG and IgM antibody occurs when stimulated, but antibody titres are very low or undetectable at other times.

What makes these antigens particularly interesting in kidney transplantation is that there is almost complete homology between the Kidd antigens and a urea transporter protein within the kidney. Kidd antigens appear to function as urea transport proteins on red cells. Patients with the Kidd-null phenotype have red cells that are relatively resistant to hyperosmolar urea stress, but have normal permeability to other substances [5]. Identification and cloning of the gene that produces this urea transporter have suggested that it is highly conserved between species. The human equivalent of this urea transporter protein in erythrocytes was initially named HUT11, but has now been renamed hUT-B1. A number of organs have been shown to produce mRNA for this gene. Human renal tissue expression has been determined by raising polyclonal antibodies to the protein, showing that it is expressed in endothelial cells of the vasa recta in the kidney [6].

A protein (HUT11a) has been produced that is functionally identical to the Kidd blood group locus A, by a gene identical to hUT-B1 except for a base pair substitution (Lys44->Glu) and a Val–Gly deletion [7], suggesting that the Kidd antigen and the HUT11a proteins are the same.

In this report, we have shown Kidd antigen expression was present in kidney sections and that it was possibly the target for the intense probably humorally mediated aggressive rejection seen. Interestingly, this expression was on tubular epithelium rather than the endothelium. We speculate that urea transporters in endothelial cells may be glycosylated differently and that the antibodies designed for picking up Kidd antigens may have had a lower stringency binding. In addition, this work was carried out on fresh tissue biopsies selectively looking at cortical tissue for rejection. Inner medullary tissue would only have been obtained inadvertently and so we might have been seeing a sampling artefact. It is also possible that Kidd antigens are indeed expressed in tubular epithelial cells, or those antibodies were cross-reacting with a homologous urea-transporting protein.

We believe that there is enough circumstantial evidence to implicate Jka antibodies in the pathogenesis of the devastating rejection experienced by this patient. It is therefore possible that high dose intravenous immunoglobulin after the plasma exchange may have been useful. Nevertheless, these patients are rare and there are few reports of cross-reacting transfusion reactions in the literature, and we believe they require further investigation. We remain optimistic that we will be able to retransplant this patient with an identically Kidd-matched donor at some point in the near future.



   Acknowledgments
 
We would like to acknowledge the help of the national Blood Service South West, Bristol who kindly donated the anti-Jk antibodies.

Conflict of interest statement. None declared.



   References
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 Abstract
 Case
 Discussion
 References
 

  1. Lenhard V, Hansen B, Roelcke D et al. Influence of the Lewis and other blood group systems in kidney transplantation. Proc EDTA 1982; 19: 432–437
  2. Allen FH, Diamond LK, Niedziela B. A new blood group antigen. Nature 1951; 167: 482
  3. Plaut G, Ikin EW, Mourant AE, Sanger R, Race RR. A new blood group antibody JKb. Nature 1953; 171: 431
  4. Sinor LT, Eastwood KL, Plapp FV. Dot and blot purification of the Kidd blood group. Med Lab Sci 1987; 44: 294–296[ISI][Medline]
  5. Heaton DC and Mcloughlin K. Jk(a–b–) red blood cells resist urea lysis. Transfusion 1982; 22: 70–71[ISI][Medline]
  6. Xu Y, Olives B, Bailly P et al. Endothelial cells of the kidney vasa recta express the urea transporter HUT11. Kidney Int 1997; 51: 138–146[ISI][Medline]
  7. Sidoux-Walter F, Lucien N, Olives B et al. At physiological expression levels the Kidd blood group/urea transport protein is not a water channel. J Biol Chem 1999; 24: 30228–30235[CrossRef]
Received for publication: 27. 2.04
Accepted in revised form: 30. 4.04





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