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Ann Thorac Surg 2004;78:1703-1709
© 2004 The Society of Thoracic Surgeons
a The Congenital Heart Institute of Florida, All Children's Hospital, University of South Florida, St. Petersburg, Florida, USA
Accepted for publication March 8, 2004.
* Address reprint requests to Dr Jacobs, The Congenital Heart Institute of Florida, Pediatric Cardiac Surgery, All Children's Hospital, University of South Florida School of Medicine, Cardiac Surgical Associates, 603 7th St S, Suite 450, St. Petersburg, FL 33701, USA
jeffjacobs{at}msn.com
Presented at the Fiftieth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 13–15, 2003.
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Abstract |
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METHODS: Sixty consecutive children (median age = 130.5 days) underwent heart transplantation. Diagnoses included hypoplastic left heart syndrome (HLHS) (30 patients), cardiomyopathy (18 patients), and postoperative complex congenital heart disease (CCHD) (12 patients). Standard induction immunosuppressive therapy included pulse steroids, gamma globulin, and polyclonal rabbit antithymocyte globulin. Initial immunosuppression is a calcinurin inhibitor and an antiproliferative agent. Eight children exhibited elevated PRA (group P). Fifty-two exhibited nonelevated PRA (group N). Immunosuppression was modified in group P as follows: preoperative intravenous immunoglobulin G (IVIG) and/or cyclophosphamide or mycophenolate mofetil and preoperative and postoperative exchange transfusions or plasmapheresis. In group P, cyclophosphamide was the initial antiproliferative agent.
RESULTS: Group P = 4 HLHS patients (all status post [s/p] prior cardiac surgery) and 4 postoperative CCHD patients. Group N = 26 HLHS patients (4 patients s/p prior cardiac surgery), 18 cardiomyopathy patients, and 8 postoperative CCHD patients. Group P patients were older and weighed more than group N patients. Waiting time for donor heart, cardiac ischemic time, and length of hospital stay were similar in both groups. Thirty-day mortality for group P was 25% and for group N it was 7.9% (p = 0.178). Overall mortality for group P was 50% and for group N it was 15.4% (p = 0.043).
CONCLUSIONS: Although heart transplantation can offer children with end-stage heart failure and elevated PRA their only chance of survival, these patients remain high risk despite aggressive immunosuppression.
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Introduction |
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| Dr Jacobs discloses that he has a financial relationship with CardioAccess, Inc.
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Elevated panel reactive antibody (PRA) may be considered a risk factor precluding orthotopic heart transplantation (OHT) in adults [1], but the significance is uncertain in children. Immunosuppression strategies regarding pediatric heart transplantation continue to evolve. Efforts to expand the donor pool and to increase donor organ usage are ongoing. These current areas of investigation are especially relevant when evaluating children with elevated PRA for possible cardiac transplantation. Elevated PRA may be considered a risk factor precluding OHT in some children.
The PRA test combines the potential recipient's serum with samples of antigen-containing cells taken from 60 different individuals within the community, representative of the potential donor pool. The percentage PRA is the percentage of these 60 combinations that react positively. Recipients are more prone to have preformed reactive antibodies to the human leukocyte antigens (HLA) of other individuals after previous blood transfusions, pregnancies, transplantations, or even exposure to allograft material.
The PRA screen has been used to identify sensitized patients awaiting transplantation [1]. An increase in early mortality after cardiac transplantation may be associated with donor T-lymphocyte HLA specific antibodies, an elevated PRA, or a positive posttransplant retrospective crossmatch [1–3]. The most common threshold for considering PRA as elevated is a level greater than or equal to 10% [1, 4]. Adult patients with a PRA greater than 10% are considered to be at a more substantial risk for the development of not only acute cellular and humoral rejection but also increased mortality when compared with nonsensitized patients posttransplantation [1]. An increase in the frequency of acute allograft rejection and an increase in the incidence of transplant vasculopathy have also been reported in sensitized adult patients [5–9].
In this manuscript, we will present our contemporary management strategy and outcome data for children undergoing OHT with high PRA (> 10%) at The Congenital Heart Institute of Florida (CHIF) at the All Children's Hospital campus (Saint Petersburg, FL).
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Material and Methods |
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Operative technique involves bicaval cannulation and anastamoses with continuous low flow bypass and short periods of circulatory arrest for aortic arch reconstruction in HLHS. The bicaval implantation technique is used with a superior vena caval reconstruction with a spatulated sliding cavoplasty to prevent narrowing. Initial reperfusion of the donor heart uses glutamate and aspartate substrate enriched white blood cell filtered cardioplegia. Mechanical circulatory support is used when necessary as a bridge to transplantation and to support marginal donor hearts.
Our standard immunosuppression protocol is as follows: induction immunosuppressive therapy includes pulse steroids for 4 days, gamma globulin, and polyclonal rabbit antithymocyte globulin. Initial immunosuppression is a double dose regimen: a calcinurin inhibitor (cyclosporine A or tacrolimus [Prograf], usually cyclosporine A) and an antiproliferative agent (either azathioprine [Imuran] or mycophenolate mofetil [MMF-CellCept (Roche Laboratories, Nutley, NJ) to target levels of 2–4]).
Rejection surveillance is conducted by echocardiography and echocardiographically guided endomyocardial biopsy, as previously described [10–14]. Echocardiographic surveillance of systolic and diastolic function predicts biopsy abnormalities and decreases the number of cardiac catheterizations. Biopsy is performed when the echocardiogram is suspicious for rejection. Rejection is defined as intensification of immunosuppression associated with an abnormal biopsy (greater than the International Society of Heart and Lung Transplantation [ISHLT] grade 3) and/or new-onset hemodynamic abnormalities confirmed by echocardiography. Posttransplant retrospective crossmatching was performed on all patients. No prospective crossmatching is performed in our program.
Eight children exhibited elevated pretransplant PRA (group P). Fifty-two children did not exhibit elevated pretransplant PRA (group N). Although elevated PRA is defined as a PRA level greater than or equal to 10%, the pretreatment PRA level for group P ranged from 44%–95% with a median of 88%. PRA measurements were assessed using cytotoxic PRA assay and dithiothretol (DTT) treated assay to factor out immune globulin M (IgM) and measure the highest immune globulin G (IgG). We are now also beginning to employ a flow PRA assay.
Immunosuppression was modified in group P as follows: preoperative intravenous immunoglobulin G (IVIG) was given weekly and/or preoperative cyclophosphamide (Cytoxan) or MMF was given daily from the time of listing until the time of transplantation. Preoperative and postoperative (up to 5 days) exchange transfusions (infants, n = 2) or plasmapheresis (children, n = 6) was used. Also in group P, cyclophosphamide (Cytoxan) (1 mg/kg/d) was the initial antiproliferative agent with conversion to MMF when oral intake was established.
A registry and database (a component of the CardioAccess International Clinical Outcomes Database: Comprehensive Cardiovascular and Thoracic Module, CardioAccess Inc, Saint Petersburg, FL and Fort Lauderdale, FL: http://www.cardioaccess.com) has been prospectively maintained on all patients and has been utilized for data collection and analysis. Informed consent was obtained in all cases.
Statistical comparisons between group P versus group N are made utilizing either the Fisher's exact test when comparing mortality data or the one-way analysis of variance when comparing the remainder of the data. The statistical analysis was performed using JMP—The Statistical Discovery Software (SAS Institute, Inc., Chicago, IL). A p value of less than 0.05 is considered to be significant.
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Results |
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Group P included 4 HLHS patients (2 s/p Norwood but no Fontan, 1 s/p Norwood and also s/p Fontan, 1 s/p biventricular repair) and 4 postoperative CCHD patients. Seven out of 8 patients in group P were status 1A at the time of transplant. Thirty-day mortality for group P was 25% (2 out of 8 patients). Follow-up for group P ranged from 295–453 days with 2 late deaths (2 out of 8 = 25%) and a mean of one rejection episode per patient.
Group N included 26 HLHS patients (22 without prior Norwood, 3 s/p Norwood but no Fontan, 1 s/p Norwood and also s/p Fontan), 18 cardiomyopathy patients, and 8 postoperative CCHD patients. Thirty-day mortality for group N was 7.69% (4 out of 52 patients). Follow-up for group P ranged from 17–2844 days with 4 late deaths (4 out of 52 = 7.69%) and a mean of 0.66 rejection episode per patient.
If one considers a p value of less than 0.05 to be significant, group P was older and of greater weight as compared with group N. Group P exhibited more prior median sternotomies. No significant difference existed between group P and group N with regard to waiting duration for the donor heart to become available, donor heart ischemic time, or posttransplant length of hospital stay.
Group P tended to exhibit a higher 30-day mortality although this was not statistically significant (p = 0.178). Group P also tended to exhibit more rejection episodes per patient but this was not statistically significant either (p = 0.178). Group P did endure an overall survival less than group N (p = 0.0434).
Only 1 patient in group P died from rejection. Group P sustained 2 early deaths (1 death caused by acute rejection on posttransplant day 9 and 1 death caused by brain injury and eventual brain death in a child supported pretransplant with extracorporeal membrane oxygenation [ECMO] for 5 days who also died on posttransplant day 9). The 2 late deaths in group P were secondary to pulmonary vein stenosis on posttransplant day 628 and secondary to an unclassified T-cell immunodeficiency and subsequent fungal pneumonia on posttransplant day 727.
Plasmapheresis was continued for 5 days posttransplant in 5 out of 6 children. In 1 child, plasmapheresis was discontinued on posttransplant day 1 after the preliminary posttransplant retrospective crossmatch was revealed to be negative; this patient is the child who died from acute rejection on postoperative day 9. In this child, the final posttransplant retrospective crossmatch subsequently was found to be positive.
Posttransplant retrospective crossmatching was performed on all patients in group P and was negative in 5 patients and positive in 3 patients. Of the 5 patients with negative posttransplant retrospective crossmatch, 3 of the patients are still alive and 2 of the patients have died. Of the 2 expired patients with negative posttransplant retrospective crossmatch, one is the child who died from brain death on posttransplant day 9 and the other one is the child who died from pulmonary vein stenosis on posttransplant day 628. Of the 3 patients with positive posttransplant retrospective crossmatch, 1 is still alive, and 2 are deceased. Of the 2 deceased patients with positive posttransplant retrospective crossmatch, one is the child who died from acute rejection on posttransplant day 9 and the other one is the child who died from an unclassified T-cell immunodeficiency and subsequent fungal pneumonia on posttransplant day 727. (Addendum: Since the time of the submission of this article, the third child with positive posttransplant retrospective crossmatch also died, most likely from rejection [but the biopsy was grade 1B] on posttransplant day 399.)
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Comment |
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Several reasons explain why children may exhibit elevated PRA and why more children may exhibit elevated PRA in the future. Common risk factors and predisposing factors for elevated PRA in the pediatric population include previous blood transfusions, previous exposure to allograft material [15–19], and previous transplantations. The increased use of mechanical circulatory support with its commonly associated transfusion requirement ensures that the leukocyte-induced HLA antibodies and positive prospective crossmatches will become more common [1]. As the population of children undergoing pediatric cardiac transplantation matures, more and more will require retransplantation.
In children, cryopreserved valved allografts are known to induce a marked HLA alloantibody response that increases to broad panel reactivity within 3 months postimplantation [15]. This HLA sensitization can potentially cause deleterious effects on allograft function and limit future heart transplantation opportunities in patients who receive cryopreserved valved allografts [15]. Shaddy and colleagues [15] demonstrated that after allograft implantation, PRA increased from 3.2% ± 2.7% preoperatively to 63.3% ± 12% at 25 ± 2 days postoperatively and 99.7% ± 0.3% at 3.4 ± 0.3 months postoperatively. Control patients indicated no increase in PRA over time: 1.6% ± 1% preoperatively, 3.2% ± 1% at 28 ± 5 days postoperatively, and 1.7% ± 1% at 2.7 ± 0.3 months postoperatively. Pompilio and colleagues demonstrated that the immune reaction to cryopreserved allograft aortic valve implantation is a long-lasting response that occurs in a great majority of recipients. Furthermore, this immune response was associated with midterm valve failure [19]. They demonstrated that the sera of all patients before allograft implantation were PRA negative. Seventeen patients out of 19 receiving allografts (89.4%) developed significant (>10%) PRA levels, which peaked at 6 months postoperatively, declined from 6 to 24 months and slowly decreased afterwards. A strong immunization (persistence of PRA > 70% and peak PRA > 80%) was detected in 31.5% and 36.8% of the recipients, respectively. In 14 out of 19 patients (73.6%), donor-specific HLA antibodies were identified.
In a sensitized patient, waiting for a compatible (crossmatch negative) donor may prolong wait time and increase wait list morbidity and cost of care [1]. Furthermore, in sensitized patients, in many instances a negative crossmatched donor will rarely be available [1]. Therefore, we have opted to list sensitized patients and to pretreat them with plasmapheresis in older patients or preoperative and intraoperative exchange transfusions in infants. We continue the plasmapheresis or exchange transfusions for up to 5 days posttransplant. The immunosuppression protocol is also modified so that the initial antiproliferative agent is cyclophosphamide (Cytoxan) dosed at 1 mg/kg/d.
The management of sensitized patients remains controversial. Concerns persist regarding the short- and long-term effects of sensitization in relation to rejection, development of transplant vasculopathy, and short- and long-term survival [1]. Singh and colleagues reported 6 cardiac transplant patients with a PRA greater than 10%; 4 of these patients exhibited a positive crossmatch and died [2]. Kobashigawa and colleagues compared patients exhibiting a PRA greater than or equal to 11% with patients exhibiting a PRA less than or equal to 10% and reported that the 3-year actuarial survival was lower in the high PRA group. Moreover, in the high PRA group, 86% of deaths occurred within the first 3 months of transplant. They also reported a trend toward earlier time to first rejection and more severe rejection requiring anti-CD3 monoclonal antibody (OKT3) therapy in the high PRA group [9].
Success has been reported in the adult cardiac transplant population with elevated PRA using single pretransplant plasmapheresis followed by intravenous immunoglobulin G [1]. Sixteen out of 118 patients awaiting cardiac transplantation were found to be sensitized and these patients underwent plasmapheresis followed by 20 gm of IVIG immediately before cardiac transplantation. There was no statistically significant difference between the high PRA group and the remaining 102 patients (with a PRA < 10%) in length of stay or mortality at a mean follow-up of 21.6 ± 15.0 months. There was no difference in the occurrence of mild, moderate, or severe cellular rejection or humoral rejection in these sensitized patients when compared with the control patients [1].
Loh and colleagues followed 120 patients for 10 years and documented no difference in survival after OHT based on peak PRA [3]. However, if the PRA at the time of transplantation was greater than 25%, they did demonstrate a statistically significant decrease in survival and a trend favoring death caused by rejection.
Many centers require prospective crossmatching pretransplantation. This requirement can create a longer waiting time and, for many, can eliminate their chance of ever being transplanted [1]. The effect of elevated PRA or positive crossmatch on morbidity and mortality after cardiac transplantation in children is controversial and unclear. Our protocol using plasmapheresis or exchange transfusions coupled with cyclophosphamide (Cytoxan) has strong support in the literature. Similar protocols have been successfully used in adult cardiac transplant recipients with high PRA [1]. During acute rejection, plasmapheresis has been used successfully to remove HLA in both kidney and heart transplant recipients [20–22]. Theoretically plasmapheresis can induce B-cell proliferation [1]; therefore various protocols combine pretransplant and posttransplant plasmapheresis with cyclophosphamide or antilymphocyte globulin to prevent rejection caused by resynthesis of HLA antibodies [22].
Prospective crossmatching is difficult with cardiac transplantation and may increase waiting list mortality. The Pediatric Heart Transplant Study Group reports that longer waiting time to transplant and increased pretransplant mortality are both associated with an elevated PRA, presumably related to the usage of prospective crossmatching [23].
It is unknown whether matching of donor-recipient HLA improves outcome. In one review of 448 cyclosporine-treated heart transplant recipients, survival for well-matched and poorly matched recipients were comparable and not markedly different, although well-matched recipients experienced substantially fewer rejection episodes [24]. This study later concluded that poorly matched recipients might benefit from more aggressive immunosuppression in an attempt to prevent early rejection [24]. Other studies suggest that HLA compatibility does manifest a positive impact on graft survival [25–27].
Because of the potential for increased waiting list mortality with prospective crossmatching, we have elected not to require a prospective crossmatch. We have also not followed posttreatment and posttransplant PRA levels because our treatment protocol is not PRA driven. PRA simply reveals reactivity to the potential donor community and not to the specific donor. Donor-specific antibody titer would be an ideal quantitative measurement to guide immunosuppression posttransplantation in patients with elevated PRA; however, this test is not yet available. In the meantime, our treatment is empirically based on a high pretreatment PRA. We do not adjust this treatment based on posttransplant PRA or posttransplant retrospective crossmatching, especially after the case of acute rejection that occurred in a child in whom we discontinued the plasmapheresis on posttransplant day 1 after the preliminary posttransplant retrospective crossmatch was negative.
Our success with this more intensive immunosuppression protocol has encouraged us to be more aggressive in other aspects of our transplant program as well. We have begun a program that lists infants for ABO-incompatible donor hearts following the Toronto Hospital for Sick Children Protocol [28]. Recently, we successfully performed our first and only ABO-incompatible transplant to date in a recipient of blood type O (the universal donor with limited conventional recipient options) who received a heart from a donor with blood type AB (the universal recipient with limited conventional donor options).
As immunosuppression strategies for pediatric heart transplantation evolve, more aggressive strategies may both expand the donor pool and increase donor organ usage. These intensive immunosuppressive protocols can facilitate both transplantation in children with elevated PRA and possibly infants receiving ABO incompatible transplants.
As immunosuppression options improve, outcomes for transplantation of critically ill children with terminal heart failure but elevated PRA are also likely to improve. Nevertheless, the higher risks warrant careful discussions with both recipients and their families in order to obtain informed consent. Our data does establish that the children in group P remain at high risk for cardiac transplantation. The etiology of this risk is in all likelihood multifactorial. In addition to elevated PRA, group P also was older and had undergone more previous cardiac surgeries. The older age may be associated with less immune tolerance and the multiple prior operations may increase surgical risk. Still, it is clear that the subgroup of children with elevated PRA remain at a higher risk than those with nonelevated PRA. Patients undergoing staged palliation are most likely at higher risk for cardiac transplantation after one or more stages of their palliation than before these surgical interventions. Thus, although patients and families can be offered transplantation as a rescue option during the course of failing staged palliation, they should be aware from the beginning that this rescue option will be a higher risk than primary cardiac transplantation. Furthermore, given the extreme shortage of pediatric heart donors, an overall survival rate of only 50% in the high PRA group can lead to several ethical questions regarding optimal donor organ usage.
Our comparison of children with elevated PRA to those without elevated PRA reveals that overall survival after OHT seems to be worse for those patients with an elevated PRA. Still it must be understood that OHT represents the only treatment option offering potential long-term survival for these challenging patients. Although 30-day mortality is not statistically different in patients with elevated PRA versus nonelevated PRA (p = 0.178), the trend is for higher 30-day mortality in children with elevated PRA. Meanwhile, overall survival is decreased in patients with elevated PRA (p = 0.0434). Mortality seems to be higher in patients having positive posttransplant retrospective crossmatch compared with those having negative posttransplant retrospective crossmatch. In light of this information, it may be more important to consider the prospective crossmatching of patients with high PRA. A rapid prospective crossmatch or rapid donor-specific antibody test would certainly make prospective crossmatching more feasible. Clearly, additional follow-up of this group is required to assess the actual long-term outcomes of these patients and further study is necessary to improve the treatment of presensitized patients. Although heart transplantation can offer children with end-stage heart failure and elevated PRA their only chance of survival, this subgroup of patients remains at high risk despite aggressive immunosuppression.
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DISCUSSION |
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I have a few questions. You have demonstrated a reasonable approach to these patients when they have high panel reactive antibodies (PRAs). Have you crossed the ABO blood compatibility barrier with any of your patients?
You have used double the doses of immunosuppressive agents. If you are doing that, can you tell us a little bit about the renal failure that you might have encountered in these kinds of patients? Also, it appears from your patients that you are fairly aggressive with some of them who are on extracorporeal membrane oxygenation (ECMO). What is your policy when you put someone on ECMO in anticipation of a heart transplant? Do you try to wake them up to find out if they have brain function and then do you go ahead and do the transplant?
This is a very excellent paper and I was delighted to hear it and I look forward to your comments.
DR JACOBS: Thank you, Dr Mavroudis. As you know, you and I had discussed this manuscript previously. In fact, it was your idea for our team to put this series together and generate this manuscript. I thank you for that.
It is a great honor for me to present this data at the 50th Anniversary Annual Meeting of The Southern Thoracic Surgical Association (STSA). Dr Hooshang Bolooki, an active member of the STSA, founded the cardiac transplant program at the University of Miami. The first heart transplant I observed as a medical student was performed by Dr Bolooki. Later, as a cardiac surgery resident, the first heart transplant I performed was under Dr Bolooki's leadership and instruction. I am truly grateful to Dr Bolooki for these wonderful opportunities.
Dr Mavroudis' first question regarding ABO incompatible transplants is very important. The series we just presented from our group shows that aggressive immunosuppressive strategies may allow cardiac transplantation in subgroups of patients who otherwise would not be candidates, such as those with high PRA. Similar to this subgroup, aggressive immunosuppressive strategies may increase donor organ utilization and increase the availability of donor hearts by crossing ABO barriers and using ABO-incompatible donor hearts.
Our group has followed the protocol from the Toronto Hospital for Sick Children, published in the New England Journal of Medicine. This Toronto manuscript reports a successful series of 10 infants 4 hours to 14 months old (median, 2 months) who had congenital heart disease or cardiomyopathy and who received heart transplants from donors of incompatible blood type between 1996 and 2000. At the Congenital Heart Institute of Florida at All Children's Hospital, we recently successfully performed our first and only ABO-incompatible transplant in a recipient of blood type O (the universal donor with limited conventional recipient options) who received a heart from a donor with blood type AB (the universal recipient with limited conventional donor options). We modified our blood transfusion regimen so that this patient received type O red blood products, that is, packed red blood cells and type AB yellow blood products, that is fresh frozen plasma, platelets, or cryoprecipitate. This transfusion protocol was modeled after the Toronto protocol and has been successful in our one patient. Now, this patient also received a fairly aggressive immunosuppressive strategy, which was quite similar to our high PRA strategy, utilizing intraoperative and postoperative plasmapheresis.
With regards to your second question about the immunosuppressive doses and renal failure, we have not seen a high incidence of renal failure in our cardiac transplantation patients. I think a lot of the credit for this accomplishment goes to Dr Robert J. Boucek, who is our Chief of Pediatric Cardiology and the Director of our Transplant Program. Dr Boucek guides and manages the immunosuppression. We have been able to avoid problems with nephrotoxicity because although Dr Boucek uses an aggressive immunosuppressive regimen, he watches the kidney function closely and selects non-nephrotoxic medicines when necessary.
The final question regarding ECMO I think is another very important question. Our group has been very aggressive with the utilization of ECMO as a bridge to transplantation, and we have a number of patients in our series who are now alive and doing well because of this strategy. We also have had patients who have used this strategy and have not survived. We always think it is very important to assess the neurological status before using a precious donor heart and certainly would never want to transplant a donor heart into a patient who is not neurologically viable. Therefore, we try to wake up all potential recipients. We do head ultrasounds, we do CAT scans, and we do an aggressive neurological evaluation before deciding to accept the donor organ.
DR KIRK R. KANTER (Atlanta, GA): I have one comment and two hopefully quick questions. The one comment is concerning the 30-day mortality of 25% in your high PRA group compared with the 30-day mortality of around 7% in your other group. Although this did not achieve statistical significance, it sounds clinically important and certainly not trivial.
The question I have is, did you look at retrospective cross- matches in these patients? Did all eight patients with high preformed antibodies have positive retrospective cross-matches and was that a predictor of a bad outcome if they did? And the other question is, I am a little suspicious of your rejection data since you did not routinely biopsy. Rather you just looked at echoes. That has been shown repeatedly in the literature that echoes are not the gold standard for rejection and I worry that you may have missed rejection in this group of patients.
DR JACOBS: Thank you, Dr Kanter. Clearly, you are an expert on this subject and I enjoyed your presentation earlier today.
To answer your questions, first, I certainly would not "blow off" the increase in early mortality. Children with elevated PRA are high-risk candidates for cardiac transplantation. This elevated risk is a very significant issue, you are right. What we need to remember is that without transplantation, these are patients who would be dead for sure. So I think it is reasonable to give them a chance as long as the families (and the patients, when appropriate) are aware of the elevated risk.
Regarding the retrospective cross-match, we have performed this test on all of our patients. The 7-minute time limit of this presentation did not give me the opportunity to present that data. The issue of retrospective cross-matching and the outcomes of our retrospective cross-matches are discussed in detail in the manuscript.
Finally, I would like to comment quickly on your question about rejection data and echocardiography. Robert Boucek, our Chief of Cardiology, and his brother, Mark Boucek, have published extensively on echocardiographic surveillance as a method of detecting rejection. I think they would both argue with your challenge of the accuracy of echocardiography to detect transplantation rejection.
I thank the Society for the opportunity to present this data.
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