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Keywords:

  • ABO-incompatibility;
  • hemolytic uremic syndrome;
  • lung transplantation;
  • thrombotic microangiopathy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References

With ABO blood group incompatibility (ABOi) between donor and recipient becoming a part of mainstream living-donor renal transplantation, the applicability of ABOi to other areas of transplantation is being reconsidered. Here we present a case of inadvertent ABOi lung retransplantation managed successfully with initial plasmapheresis, antithymocyte globulin and intravenous immunoglobulin; and subsequently with oral cyclophosphamide and sirolimus in addition to tacrolimus and prednisolone. Interestingly, in the setting of solid levels of tacrolimus and sirolimus, the patient developed a fatal thrombotic microangiopathy of uncertain origin subsequent to the cessation of cyclophosphamide at 9 years posttransplant. It is apparent that ABOi lung transplantation can result in surprisingly successful long-term outcomes. Low pretransplant antibody titers likely aid this and, in pediatric neonatal or infant cases, this may not be uncommon. We must proceed cautiously as there are significant risks. Understanding the monitoring, prevention and treatment of lung transplant antibody-mediated rejection, while avoiding the long-term complications of overimmunosuppression, will be the keys to the success of future cases.


Abbreviations
ABOi

ABO blood group incompatibility

ATG

antithymocyte globulin

BOS

Bronchiolitis Obliterans Syndrome

HUS

hemolytic uremic syndrome

IVIG

intravenous immunoglobulin; LTx, lung transplantation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References

Paediatric lung transplantation (LTx) is challenged by the limited number of size appropriate blood group compatible donor organs available. Strategies under consideration to increase organ availability include the use of donation-after-cardiac death donors, extended-criteria donors, living-related donors, larger donors cut-down to size and blood group-incompatible (ABOi) donors [1-4].

Although ABOi is well recognized as a successful strategy in renal transplantation [5, 6], only two planned ABOi cases with very short-term follow-up, and several inadvertent clerical error cases with limited follow-up, are described in the LTx literature [7-10]. This report details an additional LTx case following clerical error. In this case long term, follow-up provides insights into ABOi LTx complications, clinical dilemmas, mechanisms of allograft acceptance and potential wider application to clinical LTx.

Case

At 13 years of age in March 1996 a blood group O male child received a blood group-matched bilateral lung transplant for a primary problem of pulmonary fibrosis. His course was initially uncomplicated and his immunosuppression included cyclosporine, azathioprine and prednisolone. However, at months 5 and 35 posttransplant he had biopsy-proven acute rejection and was changed from cyclosporine to tacrolimus. With a continued refractory fall in lung function, he was ultimately diagnosed with Bronchiolitis Obliterans Syndrome (BOS) [11] and treated with horse antithymocyte globulin (ATG) in March 1999. Symptomatic, and with poor allograft function, he was relisted for a second LTx, which was performed in April 2000. A clerical error saw him transplanted with blood group B organs. Two sessions of postoperative plasmapheresis, a course of rabbit ATG and intravenous gamma-globulin (IVIG) were administered in addition to tacrolimus, azathioprine and prednisolone. Of interest, anti-B antibody levels were low prior to these therapies (see Figure 1 and legend). Again the patient's post-LTx course was initially uneventful. However, during months 3 and 4 posttransplant lung function fell from an FEV1 of 70% predicted to 50% despite augmented steroid therapy. A normal trans-bronchial biopsy and a slight rise in anti-B titer led to suspicion of antibody-mediated rejection, culminating in a further course of rabbit ATG, two sessions of plasmapheresis and monthly courses of intravenous cyclophosphamide and IVIG. These changes saw a slow improvement in lung function back to baseline. Cyclophosphamide was subsequently ceased but was associated with a deterioration in lung function. This prompted a further bronchoscopy in February 2002 that demonstrated Grade A3 acute rejection and C1 chronic rejection [11]. Following further steroids and rabbit ATG, the patient's lung function stabilized at 43% predicted. The monthly intravenous cyclophosphamide was eventually changed to a daily oral route in August 2002, sirolimus was substituted for azathioprine while IVIG continued indefinitely in addition to the tacrolimus and prednisolone.

image

Figure 1. Anti-blood group B titers and therapeutic strategies versus time from transplant. Note broken axis. Anti-ABO antibody titers reported in this case were assayed using an indirect antiglobulin test with Commonwealth Serum Laboratories (Parkville, Australia) Coombs Reagent—monovalent anti-IgG, using the NICE method [5, 22]. Agglutination was scored using the Marsh 0–12 scoring system and the titer was recorded as the reciprocal of the highest doubling dilution at which a reaction was noted [21]. ATG, antithymocyte globulin; CyP, cyclophosphamide; IVIG, intravenous immunoglobulin; LTx, lung transplantation; PP, plasmapheresis.

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Over the next 7 years the patient had recurrent bronchitis and his FEV1 slowly fell to 29% predicted, notwithstanding he was otherwise comfortable, employed and essentially remained out of hospital. In late February 2009 macroscopic hematuria was noted at routine follow-up and as a result the cyclophosphamide was ceased and urological investigations planned—suspecting malignancy. At this visit, the tacrolimus and sirolimus trough levels were 13.1 μg/L and 6.3 μg/L, respectively (Abbott Diagnostic, Sydney, Architect CMIA). Over subsequent weeks the patient became increasing unwell presenting with anemia, thrombocytopenia, renal failure and respiratory distress (Figure 2). Although there was a wide range of diagnostic possibilities, investigations determined a primary diagnosis of thrombotic microangiopathy: Hemolytic Uremic Syndrome (HUS) variant. Importantly, the anti-B titer was undetectable, while the anti-A titer was normal at 1:64. Tacrolimus and sirolimus were ceased [noting these were possible associations [12]] and dialysis, assisted ventilation, plasmapheresis, intravenous corticosteroids, blood transfusion and IVIG were commenced. With continued confusion and respiratory failure it transpired the patient was not able to wean from ventilation. Although the hematuria continued, cystoscopy noted no specific bladder lesion. Small bowel perforation with ischemic colitis was the terminal event.

image

Figure 2. Final admission: key laboratory measures during final admission versus time. Hb, hemoglobin; normal range 135–175 g/L. Plt, platelets; normal range 150–400×109/l. Cr, creatinine; normal range 50–120 μmol/L. LDH, lactate dehydrogenase; normal range 110–230 U/L. CyP, cyclophosphamide; IVIG, intravenous immunoglobulin; PP, plasmapheresis.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References

At 9 years this case represents the longest survival of an ABOi LTx, with the 4 previously cases reports describing survival to 6 months [3], 9 months [1], 3 years [7] and 6 years [9]. As a second time LTx, the current case is remarkable. The initial 18 months were challenging, reflecting the very limited knowledge of ABOi transplants in general, and ABOi LTx in particular, at that time. The nonspecific nature of symptomatic antibody-mediated LTx rejection, and its poorly characterized pathological phenotype (true even today) [11], further hampered management.

With hindsight, the low anti-B titers seen initially here were likely conducive to acceptance of a B graft (anti-A titers at this time are not known)—rather than the specific immunosuppressive strategies chosen (5). It is unknown, but potentially possible the immunosuppression associated with the patient's first LTx immunosuppression, or even the presence of chronic lung disease per se, may have surreptitiously reduced anti-B titers. We note the two intentional ABOi LTx [1, 3] both used preoperative interventions to achieve this state. In ABOi renal transplantation titers less that 1:64 seem to predict a successful outcome [5, 6]. The unrecordable anti-B titer 9 years on (and normal anti-A titer) might suggest a mechanism of immune tolerance, rather than accommodation. It is also possible that the low serum titers observed related to chronic binding of antibody within the allograft (contributing to its chronic dysfunction). Accommodation to the graft, manifest by good function in the setting of a high titer, is the pattern seen most commonly after ABOi renal transplantation [6]. Donor-specific B cell tolerance via persistent exposure to donor antigens or increased expression of complement regulator proteins are alternative explanations [3, 13].

We might now regard this patient as overimmunosuppressed from the ABOi perspective, putting him at risk of recurrent infections and malignancy. Indeed, recent renal studies suggest immune accommodation is a process that occurs within weeks, and physical antibody removal may actually be the only proven therapy, rather than complex regimens of long-term immunosuppression [5, 6, 14]. On the other hand, pathologically proven acute cellular rejection was seen late from transplant, and the patient had already lost his first allograft in the setting of late acute rejection.

Cyclophosphamide is an old-fashioned, relatively understudied but potentially useful, agent in ABOi. There is some suggestion that it may reduce both anti-HLA antibodies [15] and antiblood group antibodies [16]. We note the dramatic and unfortunately fatal episode of HUS coinciding with its withdrawal. HUS is a disease characterized by uncontrolled activation of the complement cascade leading to endothelial injury and microvascular thrombosis [17]. As noted, successful ABOi transplantation may often require alterations in complement regulation [3, 13]. Consistent with this theory, in one renal transplant series, HUS was also more common in ABOi [18]. HUS is most commonly associated with intercurrent infections, tacrolimus and sirolimus (typically at the time of high levels and in children) [18, 19] and these factors potentially may all have been contributors in this particular case.

Noting this case and a recent publication detailing surprisingly low ABO-antibody titers in a pediatric neonatal and infant prerenal transplant population (41% of cases had potentially acceptable and transplantable ABOi titers) [20], we explored the potential to perform planned ABOi LTx in four critically ill wait-listed patients aged 17–63 years, three of whom were already on long-standing immunosuppression. We measured their anti-ABO antibody titers using a BioVue card (Ortho Clinical Diagnostics, Raritan, NJ, USA) column agglutination technology [5] (Table 1). With a titer cut-off set at 1:64 [5, 6], it is apparent none of these cases would be able to proceed without significant peritransplant antibody depletion. Realistically, in addition, there is also a pressing need to have better tools and strategies to understand the monitoring, prevention and treatment of lung transplant antibody-mediated rejection before ABOi can become anything other than experimental.

Table 1. Lung transplant wait-listed patient's anti-ABO titers
Potential recipientBlood groupAgeGenderDiagnosisPre-LTx I/SAnti-A titerAnti-B titer
  1. COPD = chronic obstructive pulmonary disease; ILD = interstitial lung disease; I/S = immunosuppression; LTx = lung transplantation; OB = obliterative bronchiolitis.

1O63FCOPDYes1:2561:256
2O47FILDYes1:10241:128
3O63FILDYes1:2561:64
4O17FOBNo1:5121:128

In conclusion, this case confirms that satisfactory long-term outcomes have been seen after ABOi LTx. Combining the LTx ABOi cases and the renal transplant ABOi literature, therapeutic strategies are now clearer. Low anti-ABO titer recipients can be considered (and are probably not rare in the neonatal and wider pediatric population) [20], or alternatively antibody depletion and IVIG are plausible acute strategies. Longer-term immunosuppression can likely start with standard tacrolimus–based triple therapy [5, 6], although cyclophosphamide and long-term IVIG may still have a role. All cases need to be monitored via anti-ABO antibody titer [5, 21, 22], graft function and graft pathology [11]—areas that are under active debate and evolution in the wider LTX arena. The avoidance of harm via appropriate antiinfective strategies, cancer surveillance and consideration of risk factors for HUS are also important. Although we must proceed cautiously, more will be heard of intentional ABOi LTx—particularly if the emerging technique of ex vivo lung perfusion [3] can be combined with the pretransplant use of Abase [23], an enzyme to “condition” an incompatible organ by removing A and B antigens.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References

The authors wish to acknowledge the support of the Margaret Pratt Foundation and Anne Griffiths in the preparation of this manuscript.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Acknowledgments
  6. Disclosure
  7. References