S plantation has become an accepted therapy for endstage

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1 HLA Histocompatibility Affects Cardiac Transplant Rejection and May Provide One Basis for Organ Allocation Verdi J. DiSesa, MD, Paul C. Kuo, MD, Keith A. Horvath, MD, Gilbert H. Mudge, MD, John J. Collins, Jr, MD, and Lawrence H. Cohn, MD Departments of Surgery and Medicine, Brigham and Women s Hospital, Boston, Massachusetts Prospective human lymphocyte antigen (HLA) typing is not performed for heart transplantation, and the relation between HLA matching and cardiac graft rejection is unclear. Recipient and donor HLA matching were analyzed retrospectively in 51 patients undergoing orthotopic cardiac transplantation. Immunosuppression was based on cyclosporine and prednisone. During the mean follow-up of 34 months (range, 16 to 63 months), the 46 operative survivors had an average of 3.95 rejection episodes (range, zero to 11 episodes). Twenty-one patients had steroid-resistant rejection requiring treatment with polyclonal or monoclonal antithymocyte globulin. Human lymphocyte antigen typing was available for 44 patients, and antigens were grouped in broad specificities. Patients with two or more HLA-A or HLA-B matches had a reduced number of rejection episodes (3/10 versus 19/34) and a lower incidence of steroid-resistant rejection (1/10 versus 18/34; p = 0.01). Inclusion of HLA-DR matches did not alter the findings. There was a strong correlation between the increased frequency of rejection and the incidence of steroid-resistant rejection (p < ). Four of six late deaths occurred in patients with steroid-resistant rejection; four were due to acute rejection and two to graft atherosclerosis. Although not currently done, prospective HLA matching is feasible with present typing methods. Our results suggest a rationale for prospective histocompatibility testing in cardiac transplantation with allocation of donor hearts to patients with two or more HLA matches. ( 1990;49:2204) ince the introduction of cyclosporine, cardiac trans- S plantation has become an accepted therapy for endstage cardiac dysfunction. Cardiac transplant recipient survival during the first year after transplantation approaches 90% [l-31. However, rejection remains a major cause of morbidity and death. Rejection has been implicated as the cause of death in 30% to 50% of late deaths [4-61. In other fields of organ transplantation, attention has focused on the impact of the human lymphocyte antigen (HLA) system on graft survival and rejection. A number of large multicenter studies have demonstrated For editorial comment see page 177. that class I and class I1 HLA mismatching plays a dominant role in determining long-term renal allograft survival [7,8], and this result has justified organ allocation based on histocompatibility testing. In contrast, little is known about the influence of HLA matching on results of cardiac transplantation although preliminary data (unpublished) from the collaborative study coordinated by Opelz in Heidelberg suggest a relation between matching and survival. In an attempt to determine the importance of HLA histocompatibility, we retrospectively examined the effect Presented at the Twenty-fifth Anniversary Meeting of The Society of Thoracic Surgeons, Baltimore, MD, Sep 11-13, Address reprint requests to Dr DiSesa, Brigham and Women s Hospital, 75 Francis St, Boston, MA of HLA-A, HLA-B, and HLA-DR matches and mismatches on cardiac transplant survival and the incidence of rejection. We also examined the incidence of steroidresistant rejection, that is, histological rejection not responding to a steroid pulse and requiring polyclonal antithymocyte globulin or OKT3 monoclonal antibody. In our series, HLA matches affected the incidence of rejection and steroid-resistant rejection. Because HLA typing of donors can now be accomplished in less than six hours [9], our results suggest a rationale for prospective histocompatibility testing with allocation of donor hearts to patients with two or more HLA matches. Material and Methods Between February 1984 and February 1988, 51 orthotopic cardiac transplantations were performed at Brigham and Women s Hospital. The mean age of the recipients was 39.6 years. No early deaths were due to rejection. Thirtyday mortality was 10% (5/51). Causes of early death included multisystem organ failure (2 patients), right heart failure, arrhythmia, and pancreatitis (1 patient each), and death occurred on postoperative day 0 to day 27 (mean, day 15). Patients discharged from the hospital were followed for a mean of 34 months. During this interval, recipients were treated for zero to 11 episodes of rejection (mean, 3.95 episodes). There were six late deaths, occurring 1 to 46 months (mean time, 8 months) postoperatively. Four late deaths were due to rejection and 2 to graft atherosclerosis by The Society of Thoracic Surgeons /90/$3.50

2 1990;49:22C-4 DISESA ET AL 221 I- z W V a W n 0 ALL PATIENTS 0 OPERATIVE SURVIVORS YEARS Fig 1. Actuarial probability of survival for all patients and for patients surviving 30 days and discharged from the hospital (operative survivors). Actuarial survival at 5 years was 74% for all patients and 82% for patients discharged from the hospital (Fig 1). Donor-recipient pairs were selected on the basis of size and ABO blood group compatibility. Also, a lymphocyte crossmatch was used if preoperative screening indicated greater than 10% sensitization to a random panel. Immunosuppressive therapy consisted of cyclosporine (serum level, 100 to 200 ng/ml) and prednisone (tapered to 0.15 mg/kg). Azathioprine (1 to 2 mgkg) was added for patients with azotemia or persistent rejection. Episodes of rejection, detected by periodic endomyocardial biopsies, were defined as lymphocytic infiltrate plus myocyte necrosis, and were treated with corticosteroid pulse therapy (methylprednisolone, 1 g intravenously for three days). Rejection episodes with persistent myocyte necrosis on follow-up biopsy despite steroid pulses (steroid resistant) were treated with antithymocyte globulin or OKT3 monoclonal antibody. Severe rejection with vasculitis and hemorrhage was treated simultaneously with steroids and either antithymocyte globulin or OKT3. Twenty-one patients had at least one episode of steroid-resistant rejection or severe rejection requiring treatment with antithymocyte globulin. Complete HLA-A, HLA-B, and HLA-DR data were available for 44 donors and patients. No attempt was made to prospectively match donor-recipient pairs based on HLA histocompatibility. For purposes of tabulating HLA matches and mismatches, the A, B, and DR antigens were grouped into broad specificities (Table 1) [lo]. An antigen present in both donor and recipient was considered a match, and an antigen present in the donor and not in the recipient was considered a mismatch. The study population was stratified into the following groups: 0 to 1 or 2 to 3 HLA-A and HLA-B matches and 0 to 1 or 2 to 3 HLA-A, HLA-B, and HLA-DR matches. Similarly, the patients were grouped into 0 to 2 or 3 to 4 HLA-A and HLA-B mismatches and 0 to 3 or 4 to 6 HLA-A, HLA-B, and HLA-DR mismatches. Patients were also segregated based on the occurrence of three or fewer or more than three rejection episodes. Correlations were examined by the Wilcoxon test, the Fisher exact test, or the Mantel-Haenszel 2 test. Significant differences were considered to exist when calculated p values were less than Table 1. Human Lymphocyte Antigen Specijkities Broad Specificities A Locus A1 A2 A3 A9 A10 Awl9 B Locus B5 B B B21 Bw B Bw41 Bw46 Bw67 Bw70 Bw71 Bw72 Bw73 Cross-reacting Antigens Aw36 A28, Aw68, Aw69 All A23, A24 A25, A26, Aw34, Aw43, Aw66 A29, A30, A31, A32, Aw33 B51, Bw52 Bw73 Bw59 844, B45 Bw64, Bw65 Bw62, Bw63, , 839 Bw57, Bw58 849, Bw50 Bw42, Bw54, Bw55, Bw56 Bw53 Bw60, Bw61 Bw47, Bw48 Bw71, Bw72 Results The relationship between HLA matching and cardiac transplant rejection is shown in Table 2. Frequent (more than three) rejection episodes were associated with fewer Table 2. Human Lymphocyte Antigen Matching and Frequency of Rejection No. of HLA Three Rejections More Than Matches or Fewer Three Reiections A and B 0 or A, B, and DR 0 or or 3 12 a Significance: p = by Mantel-Haenszel 2 test. = by Mantel-Haenszel 2 test. HLA = human lymphocyte antigen. 19 3" 15 7b Significance: p

3 222 DISESA ET AL 1990;49:22M Table 3. Human Lymphocyte Antigen Matching and Steroid- Resistant Rejection No. of HLA Matches No Rejection Rejection A and B 0 or A, B, and DR 0 or or 3 15 a Significance: p = 0.01 by Mantel-Haenszel,$ test by Mantel-Haenszel,$ test. HLA = human lymphocyte antigen. 18 1" 15 4b Significance: p = HLA-A and HLA-B matches and HLA-A, HLA-B, and HLA-DR matches, although the differences were not significant (p = and p = 0.153, respectively). No significant relationship was found between HLA mismatching and the incidence of rejection. The number of HLA matches did correlate with the incidence of steroid-resistant rejection (Table 3). Steroidresistant rejection occurred in 18 of 34 patients with 0 or 1 HLA-A and HLA-B matches but only 1 of 10 with 2 such matches (p = 0.01). Similarly, steroid-resistant rejection occurred in 15 of 25 patients with 0 or 1 HLA-A, HLA-B, and HLA-DR matches as opposed to 4 of 19 wih 2 or more (p = 0.009). In comparison, HLA mismatching was not associated with an increased incidence of steroid-resistant rejection. There was a strong correlation between the incidence of steroid-resistant rejection and the frequency of rejection episodes (Table 4). Steroid-resistant rejection occurred in 19 of 20 patients with more than three rejection episodes but in only 4 of 26 with three or fewer instances of rejection (p < ). There was no significant correlation between HLA matching and survival, but 4 of the 6 patients dying late had sustained at least one episode of steroid-resistant rejection. No other variable examined, including age and sex, had any effect on survival or incidence or severity of rejection. Comment Despite progress in transplant survival associated with the use of cyclosporine, the role of HLA class I and class I1 antigen compatibility in cardiac transplant rejection and Table 4. Steroid-Resistant Rejection and Frequency of Rejection Steroid- Resistant More than Three Rejections Rejection Three Rejections or Fewer Present Absent 19= 1 a Significance: p < by Fisher's exact test survival is poorly defined and plays no role in organ allocation. Human lymphocyte antigen histocompatibility clearly does affect results of renal transplantation, and kidneys from cadaveric donors are preferentially transplanted in well-matched recipients. In renal transplantations, studies have focused on HLA mismatching and graft survival. Takiff and co-workers [8] showed a 5% renal allograft survival advantage in patients with no HLA-A and HLA-B mismatches. Similarly, Opelz [7] noted a 10% allograft survival advantage with no HLA-A and HLA-B mismatches. The role of HLA-DR histocompatibility remains controversial. Both Takiff [8], Opelz [7], and their associates have demonstrated increased renal allograft survival in cyclosporine-treated recipients with no HLA-A and HLA-B mismatches. Although several studies [ll, 121 have suggested that the deleterious effects of HLA-DR mismatching are negated with the use of cyclosporine, prospective tissue typing including HLA-DR matching remains an important determinant of organ allocation in renal transplantation. In our review of patients with cardiac transplants, there was an association between HLA matching and the frequency of graft rejection but significance was not reached. Frist and colleagues [lo] reviewed the experience at Stanford, and were also unable to demonstrate any relationship between HLA matching and transplant rejection, although an impact on survival and incidence of infection was seen. As noted, preliminary data from the collaborative heart transplant study (Opelz) suggest that HLA matching may have the same impact on results of cardiac transplantation as has been observed in patients with renal allografts from cadaveric donors. In our study, HLA-A and HLA-B matching and HLA-A, HLA-B, and HLA-DR matching correlated with the incidence of more serious steroid-resistant rejection. In addition, patients who had at least one episode of steroidresistant rejection usually had an increased number of rejection episodes and were at increased risk of rejectionrelated late death. This analysis was based on HLA histocompatibility defined by grouping antigens in broad specificities. The heterogeneity of antigenic loci within a single broad specificity and antigenic heterozygosity were not considered. This study suggests that HLA-A and HLA-B matches and HLA-A, HLA-B, and HLA-DR matches are associated with a decreased incidence of steroid-resistant rejection in cardiac transplant patients using cyclosporine and steroid immunosuppression. Prospective HLA matching of heart donors and recipients can be accomplished in a matter of hours as has been the practice with lymphocyte crossmatches. The reagents and techniques required to perform HLA matching should be familiar to tissue-typing laboratories affiliated with most large organ-procurement agencies. Typing can be done on donor tissue or even blood and need not be carried out in the donor hospital, just as lymphocyte cross-matching and HLA typing for kidney allocation are performed in centralized tissuetyping laboratories. Our results suggest a rationale for organ allocation based on HLA matching and, especially as techniques of myocardial preservation improve, truly national sharing of hearts for transplantation.

4 ~ ~~~~~~ 1990;49:22&4 DISESA ET AL 223 We thank Elizabeth Allred, MS, for assistance with the statistical analysis. References Slater AD, Klein JB, Gray LA. Clinical orthotopic cardiac transplantation. Am J Surg 1987;153: Bolman RM, Olivari MT, Saffitz J, et al. Current results with triple therapy for heart transplantation. Transplant Proc 1987;19:249@1. Hofflin JM, Potasman I, Baldwin JC, et al. Infectious complications in heart transplant recipients receiving cyclosporine and corticosteroids. Ann Intern Med 1987;106: Baumgartner WA, Borkon AM, Achuff SC, et al. Organization, development and early results of a heart transplant program. Chest 1986;89: Utah Cardiac Transplant Team. Heart transplantation at the Utah transplantation affiliated hospitals. J Heart Transplant 1986;5:367. Painvin G, Okereke OUJ, Frazier OH, Kahan BD, Van Buren CT, Cooley DA. Cardiac transplantation: current results of cyclosporine-treated patients at the Texas Heart Institute. Transplant Proc 1985;17: Opelz G. Correlation of HLA matching with kidney graft survival in patients with or without cyclosporine treatment. Transplantation 1985;40:24G3. 8. Takiff H, Cook DJ, Himaya NS, Mickey MR, Terasaki PI. Dominant effect of histocompatibility and ten year kidney transplant survival. Transplantation 1988;45:41&5. 9. Zachary AA, Braun WE, eds. American Association for Clinical Histocompatibility Testing laboratory manual. 1st ed. New York, 1981: Frist WH, Oyer PE, Baldwin JC, Stinson EB, Shumway NE. HLA compatibility and cardiac transplant recipient survival. 1987;44: Taylor RJ, Andrews W, Rosenthal JT, Carpenter 8, Hakala TR. Influence of DR matching in cadaveric renal transplants performed with cyclosporine. Transplantation 1984;38:61& Koyle MA, Rajfer J, Mickey MR, Glassock RJ, Ward HJ. The current role of pre-transplant blood transfusions and tissue typing in cadaveric renal transplantation. J Urol 1987;138: DISCUSSION DR JACK G. COPELAND (Tucson, AZ): I congratulate DiSesa and associates for raising again the issue of tissue typing in cardiac transplantation, where currently ABO compatibility is most often the only matching. There is no doubt that a biological relationship exists between goodness of matching for human lymphocyte antigens (HLA) and survival after solid organ transplantation. Of the class I antigens (polypeptides), which are located on the surfaces of all nucleated cells, those produced by the A and B loci evoke strong immune responses including formation of antibodies and cytotoxic T cells. Class I1 antigens, glycoproteins found on B lymphocytes, monocytes, endothelial cells and Langerhans cells (of the skin), are produced by the D locus and are felt to play a most important role in rejection by activating T helper cells. Current immunosuppressive therapy tends to neutralize this relationship of HLA matching to success. We have analyzed HLA class I matching (for A and B antigens) in 146 consecutive patients treated with rabbit antithymocyte globulin induction, followed by triple therapy consisting of cyclosporine, azathioprine, and prednisone, and found an insignificant trend toward improved freedom from rejection and a small (5%) but significant ( p < 0.05) improvement in survival, but no improvement in freedom from death from rejection and a possibly significant (p < 0.10) improvement in freedom from infection (27% at 6 months, 16% at 1 year, 10% at 2 years). We would therefore consider the present HLA matching advantage to be small at best. DiSesa and associates have shown a reduction in steroidresistant rejection and a reduction in the number of recipients with over three rejection episodes with retrospective matching. It must be pointed out that the weaker the immunosuppressive regimen, the more likely HLA matching has a favorable effect. For instance, with our immunosuppressive protocol, which would be considered stronger, the survival at 1 year was 94% for all patients, compared with 80% in the report by DiSesa and associates, and we have seen very few steroid-resistant rejections in over 150 consecutive patients. Our mean number of rejections has been 1.24 per patient at 1 year and 1.27 per patient at 3 years, compared with 3.95 episodes per patient at 32 months in the study by DiSesa and associates. Dr DiSesa, do you think donor sharing based on HLA matching is worthwhile, assuming that a stronger immunosuppressive protocol than yours is in effect? I would ask you to be a little bit more specific than you were in your concluding statement about the tremendous limitations of time, potential recipient acuity, donor availability, geography, and our crude techniques of long-term cardiac preservation, not to mention problems in communication and, in some cases, unhealthy competition. What new information or developments might lead to sharing of transplants based on HLA matching? DR DISESA: I appreciate Dr Copelands comments. He has certainly made a number of contributions to this field. His comments about our incidence of rejection are well-taken. There is always a balance in this area between the level of immunosuppression, rejection, and infection. We have a very low incidence of infection in our patients; in fact, in our series, which is now 95 patients, only 1 patient has died with infection as the primary cause. Certainly, you will see less rejection if you intensify the immunosuppressive regimen. In fact, in our later patients, we do use triple therapy based on long-term data that are available. I do not have any data to answer the question of whether a strong immunosuppressive regimen will mitigate the impact of HLA matching. I would turn it around to say that with better HLA matching immunosuppression need not be as strong, and therefore patients may not suffer the infectious complications that inevitably will ensue with more profound immunosuppression. The time limits that I referred to really concern how long we can store organs before revascularizing them. There are experimental techniques including autoperfusion or other methods that are presently too cumbersome, I think, for widespread use. The logistics of doing HLA tying are similar to the logistics of lymphocyte cross-matching, which is done routinely in many

5 224 DISESA ET AL 1990;49:220-4 centers. Therefore, the time limitations are within the span that we presently use, so that if we were set up to do pretransplant HLA typing, it could be done. I think the problem, though, is in identifying all the potential recipients who might be candidates for an HLA-typed heart and then getting the heart transported to a matched patient in a timely fashion. If, as in renal transplanta- tion, it were possible to harvest the heart, do the typing while the heart is in storage, then direct it to the best match, then it would be worth addressing the logistical problems. I certainly would not advocate setting it up until we had more definitive evidence that HLA matching is really going to have a substantial impact, but I think it is important to address this issue in an ongoing fashion. Notice From the Southern Thoracic Surgical Association The Thirty-seventh Annual Meeting of the Southern Thoracic Surgical Association will be held at the Hyatt Regency Cerromar Beach, Puerto Rico, November 8-10, There will be a $155 registration fee for nonmember physicians except for guest speakers, authors and coauthors on the program, and residents. There will be a $50 registration fee for attendees of the Postgraduate Course, which will be held the morning of Thursday, November 8, The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected primarily as a means to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. Members wishing to participate in the Scientific Program should submit an original abstract and one copy by May 15, 1990, to Donald C. Watson, Jr, MD, Program Chairman, Southern Thoracic Surgical Association, 111 East Wacker Drive, Chicago, IL Abstracts must be submitted on the Southern Thoracic Surgical Association abstract submission form. These forms may be obtained from the Association s office or in the March 1989 issue of The Annals of Thoracic Surgery. All slides used during the presentation must be 35 mm. Manuscripts of accepted papers must be submitted to The Annals of Thoracic Surgery prior to the 1990 meeting or to the Secretary-Treasurer at the opening of the Scientific Session. Applications for membership should be completed by July 1, 1990, and forwarded to Lenox Baker, Jr, MD, Membership Committee Chairman, Southern Thoracic Surgical Association, 111 East Wacker Drive, Chicago, IL Gordon F. Murray, MD Secretary-Treasurer Southern Thoracic Surgical Association 111 East Wacker Drive Chicago, 1L 60601