In a patient who developed antibodies approximately 1 year after transplantation, along with an increase in serum creatinine and subsequent failure at 5 years (42), the antibodies produced reacted with DQ4, 7, 8, and 9 single antigen beads (Fig. 2). Although we may have earlier thought this antibody was multispecific, the antibody reacts to a single amino acid substitution, epitope #2014 at the four possible locations indicated on the molecule (52).
It is a common observation and “complaint” that some patients with HLA antibodies have excellent kidney graft function. The exact frequency of this occurrence has been documented to be about 20% in studies of 2658 patients with functioning grafts (59) Thus, at any transplant center roughly 20% of patients would likely have antibodies and good function. According to prospective studies, when 158 patients with antibodies were followed for as long as 4 years, their graft survival was 58% as compared with 81% for 806 patients without antibodies (59).
Significantly, the presence of antibodies did not foretell immediate or certain graft failure. Studies by Worthington et al. (60) have shown that the mean time from antibody development to failure for class I antibodies was 2.7 years and 3.9 years for class II antibodies. Additionally, antibodies causing humoral rejection may not appear until as many as 13 years (61), or even after 26 years (62) posttransplant.
The reason for this long interval between antibody appearance and graft failure is the time needed for the endothelial walls of arteries to hypertrophy and close the lumen, or for the tubules to disappear because of peritubular capillary damage produced by antibodies (63). In both instances, defense mechanisms could be triggered as the endothelium is damaged and repair mechanisms are triggered (64). For instance, in a recent extensive analysis, transplant glomerulopathy was characterized by double contours of glomerular basement membranes and was a characteristic of late antibody-mediated kidney allograft rejection (65–67). Of 41 patients with transplant glomerulopathy HLA antibodies were seen in 73% of biopsies.
In protocol biopsies the incidence of C4d staining has been shown to be about 2% and in indication biopsies about 10% in a large multicenter trial of 551 protocol and 377 indication biopsies (68). One interpretation is that C4d in biopsies is transient, and at any moment, may be undetectable, because complement can be further degraded, past the C4d stage.
The strength of antibodies in 39 patients whose grafts subsequently failed was markedly higher than that in the sera of 26 patients who continued to have good graft function (P<0.0084). In the failure group, there were nine patients with DSA with MESF (molecules of equivalent soluble fluorochrome) values which were very significantly different from the functioning transplants (P=0.00000027) (69). This highlights the importance of examining and reporting antibody strength. To express the “titer” of antibodies converting the fluorescence intensity to MESF values taken at only one dilution was shown to be adequate.
Transplants are routinely performed despite HLA incompatibilities between the donor and recipient. Because HLA antigens are the main difference between donors and recipients, it is logical that the immunologic response is directed against the mismatched HLA antigens. There exist many organ specific antigens such as those specific for the heart, kidney, and liver, but these are shared among all humans. The only unique aspect of an allograft is that the donor and recipient HLA and other histocompatibility antigens are different. HLA is therefore the naturally expected target. Many would argue that cellular rather than humoral immunity against these differences causes rejection. Despite the existence of many in vitro tests, such as mixed lymphocyte culture, cell mediated lympholysis, and cytotoxic precursor assays measuring cellular immunity, using these tests, few studies of actual patients demonstrate that a cellular reaction against donor specific mismatches is associated with graft failure (70).
Many publications show that in experimental animals antibodies cause graft rejection. For example, among mice with aortic grafts, those deficient in helper T cells and humoral response did not develop neointimal concentric proliferation (71). In another study, intimal proliferation was induced in aortic grafts in rats by humoral antibody transfer (72). One very convincing finding from animal studies is that passive transfer of antibodies causes rejection of heart grafts (73). From the very early experiments with skin grafts (74), a separate review will be required to cover the animal experiments in the intervening 40 years.
During the 12th International Histocompatibility workshop, a multicenter prospective study was initiated to test patients with functioning kidney transplants once for HLA antibodies posttransplantation. The 806 patients without HLA antibodies, had a subsequent 4 year graft survival of 81%, compared with 58% for 158 patients with HLA antibodies (59). These results were obtained from 21 centers world-wide with many variables, but recently three large individual centers independently reported their own survival statistics. Among 512 patients followed for 1 year posttesting in Sao Paulo, 12% of antibody positive patients lost their grafts, whereas graft failure occurred in only 5.5% of those without HLA antibodies (P=0.03) (75). These results have been updated, demonstrating that at 3 years posttransplantation, patients without HLA antibodies had a 94% survival rate compared with 79% for those with HLA class II antibodies (76). Figure 3 provides results from independent studies from Perth (77), and from 1043 patients transplanted in Berlin (78). In these three studies the half lives of patients without HLA antibodies were similar to that of HLA identical siblings (Fig. 3), and may be considered to be relatively “safe” from rejection.
Results of frequent intervals of monitoring over a 16-year period, were quite similar (79). The 16-year graft survival of 375 patients without DSA was 80% compared with 14% in 73 patients who developed DSA.
The final evidence of the humoral theory would be to demonstrate that eliminating de novo antibodies resulted in long-term graft survival. This will require some time.
Studies have repeatedly shown that about 20% of patients have antibodies, despite current immunosuppressive therapy (59). This means that the drugs effectively suppress antibodies in 80% of patients (80). When de novo antibodies are first detected, the immunosuppressants could be increased or changed to other common immunosuppressants. Switching from azathioprine to mycophenolate mofetil has been shown to reduce antibody levels, and is associated with longer graft survival (81).
Many studies have investigated removal of presensitized antibody existing before transplantation, or antibody during acute rejection. In an extensive study of 67 patients with DSA present before transplantation and treated with plasmapheresis and intravenous immunoglobulin (IVIGG), antibodies could be removed in 53% of patients (82). The most important factors affecting removal were antibody strength and specificity. Among 32 patients treated with IVIGG, plasmapheresis, and CD20 antibodies, successful desensitization was directly correlated with the titer of the preformed antibody, as measured by antiglobulin crossmatch (83), indicating that desensitization depends entirely on treating patients under a certain threshold of antibody strength. This may also be true for the use of IVIGG (84).
If detected early, antibodies will likely be of lower strength and be more readily removed than if detected after many antibody producing clones have become active and high titers of antibodies are present. Relatively frequent monitoring, for example, every 4 months, may be required for timely detection of de novo antibody formation. Monitoring for antibody formation might also be the ideal means of checking for noncompliance to medication, estimated as high as 22% in adult renal patients (85). If no antibodies have formed, the patient may not need immunosuppression; if antibodies are present, obviously compliance should be enforced.
One important unknown is whether once removed, antibodies will again return. There is no evidence in the literature demonstrating that antibodies can be removed for long sustained periods. Possibly clones are continually regenerated, and cannot be removed permanently. If the half life of grafts is 10 years, one might estimate that clones are regenerated with a half life of 10 years.
Conventional wisdom is that cumulative damage from numerous possible factors such as ischemic injury damages the kidney leading to interstitial fibrosis and tubular atrophy (37). Reviews such as this by Nankivell and Chapman, can be cited as a “balanced” view of chronic rejection, emphasizing that there are many causes of chronic rejection. However, we conclude that ample evidence points to antibodies as the main cause of chronic rejection and that the criteria needed to argue for causation are essentially fulfilled. According to the humoral theory, this one main factor—antibody—triggers an attack on blood vessel endothelium, causing a loss of blood supply, ultimately leading to transplant glomerulopathy and tubular atrophy. But are antibodies the cause? Clearly, there exist other causes of failure such as drug toxicity to the kidney, recurrence of disease, senescence, so forth. However, based on the arguments above, HLA antibodies are one major cause (86%, Table 1) of chronic rejection.
If antibody removal eliminates chronic failures, antibodies can be said to conclusively cause rejection. Just as many years were needed to demonstrate that the reduction in smoking led to a lower lung cancer incidence, some time will be needed to obtain this information. In the meantime, there is now sufficient evidence to stop smoking … or stop antibodies produced de novo.
The authors thank Dr. Richard Glassock for suggesting the use of the Bradford Hill criteria for this review.
1. McKenna RM, Takemoto SK, Terasaki PI. Anti-HLA antibodies after solid organ transplantation. Transplantation
2000; 69: 319.
2. Terasaki PI. Humoral theory of transplantation. Am J Transplant
2003; 3: 665.
3. Terasaki PI, Cai J. Humoral theory of transplantation: Further evidence. Curr Opin Immunol
2005; 17: 541.
4. Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. BMJ
1950; 4682: 739.
5. Doll R, Hill AB. The mortality of doctors in relation to smoking habits; a preliminary report. BMJ
1954; 4877: 1451.
6. Hill AB. The environment and disease: Association or causation? Proc R Soc Med
1965; 58: 295.
7. Morris PJ, Williams GM, Hume DM, et al. Serotyping for homotransplantation. XII. Occurrence of cytotoxic antibodies following kidney transplantation in man. Transplantation
1968; 6: 392.
8. Morris PJ, Mickey MR, Singal DP, et al. Serotyping for homotransplantation. XXII. Specificity of cytotoxic antibodies developing after renal transplantation. BMJ
1969; 1: 758.
9. Jeannet M, Pinn VW, Flax MH, et al. Humoral antibodies in renal allotransplantation in man. N Engl J Med
1970; 282: 111.
10. Xydas S, Yang JK, Burke EM, et al. Utility of post-transplant anti-HLA antibody
measurements in pediatric cardiac transplant recipients. J Heart Lung Transplant
2005; 24: 1289.
11. Cardarelli F, Pascual M, Tolkoff-Rubin N, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int
2005; 18: 532.
12. Mizutani K, Terasaki P, Bignon JD, et al. Association of kidney transplant
failure and antibodies against MICA. Hum Immunol
2006; 67: 683.
13. Palomar R, Lopez-Hoyos M, Pastor JM, et al. Impact of HLA antibodies on transplant glomerulopathy. Transplant Proc
2005; 37: 3830.
14. Panigrahi A, Deka R, Bhowmik D, et al. Functional assessment of immune markers of graft rejection: A comprehensive study in live-related donor renal transplantation. Clin Transplant
2006; 20: 85.
15. Panigrahi A, Gupta N, Siddiqui JA, et al. Post transplant development of MICA and anti-HLA antibodies is associated with acute rejection episodes and renal allograft loss. Hum Immunol
2007; 68: 362.
16. Sun Q, Liu Z, Yin G, et al. Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: A report of three cases. Transplantation
2005; 79: 1759.
17. Vasilescu ER, Ho EK, Colovai AI, et al. Alloantibodies and the outcome of cadaver kidney allografts. Hum Immunol
2006; 67: 597.
18. Zhang Q, Liang LW, Gjertson DW, et al. Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction. Transplantation
2005; 79: 591.
19. Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet
2005; 365: 1570.
20. Collins AB, Chicano SL, Cornell LD, et al. Putative antibody-mediated rejection with C4d deposition in HLA-identical, ABO-compatible renal allografts. Transplant Proc
2006; 38: 3427.
21. Cai J, Terasaki PI, Bloom DD, et al. Correlation between human leukocyte antigen antibody production and serum creatinine in patients receiving sirolimus monotherapy after Campath-1H induction. Transplantation
2004; 78: 919.
22. Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol
2005; 16: 2804.
23. Tambur AR, Buckingham M, McDonald L, et al. Development of donor-specific and non-donor-specific HLA-DP antibodies post- transplant: The role of epitope sharing and epitope matching. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 399.
24. Tambur AR, Pamboukian SV, Costanzo MR, et al. The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome. Transplantation
2005; 80: 1019.
25. McKay M, Pinney S, Gorwara S, et al. Anti-human leukocyte antigen antibodies are associated with restenosis after percutaneous coronary intervention for cardiac allograft vasculopathy. Transplantation
2005; 79: 1581.
26. Girnita AL, Duquesnoy R, Yousem SA, et al. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant
2005; 5: 131.
27. Masson E, Stern M, Chabod J, et al. Hyperacute rejection after lung transplantation caused by undetected low-titer anti-HLA antibodies. J Heart Lung Transplant
2007; 26: 642.
28. Ionescu DN, Girnita AL, Zeevi A, et al. C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody. Transpl Immunol
2005; 15: 63.
29. Muro M, Marin L, Miras M, et al. Liver recipients harbouring anti-donor preformed lymphocytotoxic antibodies exhibit a poor allograft survival at the first year after transplantation: Experience of one centre. Transpl Immunol
2005; 14: 91.
30. Kato T, Mizutani K, Terasaki P, et al. Association of emergence of HLA antibody
and acute rejection in intestinal transplant recipients: A possible evidence of acute humoral sensitization. Transplant Proc
2006; 38: 1735.
31. Melcher ML, Olson JL, Baxter-Lowe LA, et al. Antibody-mediated rejection of a pancreas allograft. Am J Transplant
2006; 6: 423.
32. Mohanakumar T, Narayanan K, Desai N, et al. A significant role for histocompatibility in human islet transplantation. Transplantation
2006; 82: 180.
33. Mizutani K, Terasaki PI, Shih RN, et al. Frequency of MIC antibody in rejected renal transplant patients without HLA antibody
. Hum Immunol
2006; 67: 223.
34. Suarez-Alvarez B, Lopez-Vazquez A, Diaz-Pena R, et al. Post- transplant soluble MICA and MICA antibodies predict subsequent heart graft outcome. Transpl Immunol
2006; 17: 43.
35. Suarez-Alvarez B, Lopez-Vazquez A, Gonzalez MZ, et al. The relationship of anti-MICA antibodies and MICA expression with heart allograft rejection. Am J Transplant
2007; 7: 1842.
36. Zou Y, Heinemann FM, Grosse-Wilde H, et al. Detection of anti-MICA antibodies in patients awaiting kidney transplantation, during the post-transplant course, and in eluates from rejected kidney allografts by Luminex flow cytometry. Hum Immunol
2006; 67: 230.
37. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: Current concepts and future directions. Transplantation
2006; 81: 643.
38. El-Awar N, Terasaki PI, Lazda V, et al. Almost all patients who are waiting for a regraft of a kidney transplant
have anti HLA antibodies. Transplant Proc
2002; 34: 2531.
39. Mizutani K, Terasaki P, Rosen A, et al. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant
2005; 5: 2265.
40. Mizutani K, Shibata L, Ozawa M, et al. Detection of HLA and MICA antibodies before kidney graft failure. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 255.
41. Kinukawa T, Kato M, Terasaki P, et al. Retrospective antibody analysis of thirty patients with kidney graft failure. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 291.
42. Ozawa M, Rebellato L, Terasaki P, et al. Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 265.
43. Van den Berg-Loonen E, Terasaki P, Kohanof S, et al. Longitudinal testing of seventy-six renal allograft patients of HLA antibodies: Maastricht experience. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 305.
44. Supon P, Constantino D, Hao P, et al. Prevalence of donor-specific anti-HLA antibodies during episodes of renal allograft rejection. Transplantation
2001; 71: 577.
45. Gibney EM, Cagle LR, Freed B, et al. Detection of donor-specific antibodies using HLA-coated microspheres: Another tool for kidney transplant
risk stratification. Nephrol Dial Transplant
2006; 21: 2625.
46. Lenaers JI, Christiaans MH, Voorter CE, et al. Relevance of posttransplant flow cytometric T- and B-cell crossmatches in tacrolimus-treated renal transplant patients. Transplantation
2006; 82: 1142.
47. Pei R, Lee JH, Shih NJ, et al. Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities. Transplantation
2003; 75: 43.
48. El-Awar N, Lee JH, Tarsitani C, et al. HLA class I epitopes: Recognition of binding sites by mAbs or eluted alloantibody confirmed with single recombinant antigens. Hum Immunol
2007; 68: 170.
49. Duquesnoy RJ, Askar M. HLAMatchmaker: A molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP. Hum Immunol
2007; 68: 12.
50. El-Awar N, Akaza T, Terasaki PI, et al. Human leukocyte antigen class I epitopes: Update to 103 total epitopes, including the C locus. Transplantation
2007; 84: 532.
51. Cai J, Kohanof S, Terasaki PI. HLA-DR antibody epitopes. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 103.
52. Deng CT, Cai J, Tarsitani C, et al. HLA class II DQ epitopes. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 115.
53. Piazza A, Poggi E, Ozzella G, et al. Public epitope specificity of HLA class I antibodies induced by a failed kidney transplant
: Alloantibody characterization by flow cytometric techniques. Transplantation
2006; 81: 1298.
54. Adeyi OA, Girnita AL, Howe J, et al. Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches. Transpl Immunol
2005; 14: 53.
55. Mao Q, Terasaki PI, Cai J, et al. Analysis of HLA class I specific antibodies in patients with failed allografts. Transplantation
2007; 83: 54.
56. Mao Q, Terasaki PI, Cai J, et al. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant
2007; 7: 864.
57. Cai J, Terasaki PI, Mao Q, et al. Development of nondonor-specific HLA-DR antibodies in allograft recipients is associated with shared epitopes with mismatched donor DR antigens. Am J Transplant
2006; 6: 2947.
58. Qiu J, Cai J, Terasaki PI, et al. Detection of antibodies to HLA-DP in renal transplant recipients using single antigen beads. Transplantation
2005; 80: 1511.
59. Terasaki P, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant
2007; 7: 408.
60. Worthington JE, McEwen A, McWilliam LJ, et al. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome. Transplantation
2007; 83: 398.
61. Kamimaki I, Ishikura K, Hataya H, et al. A case of allograft dysfunction with antibody-mediated rejection developing 13 yr after kidney transplantation. Clin Transplant
2007; 21(suppl 18): 60.
62. Weinstein D, Braun WE, Cook D, et al. Ultra-late antibody-mediated rejection 30 years after a living-related renal allograft. Am J Transplant
2005; 5: 2576.
63. Shimizu A, Yamada K, Sachs DH, et al. Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis. Kidney Int
2002; 61: 1867.
64. Jin YP, Jindra PT, Gong KW, et al. Anti-HLA class I antibodies activate endothelial cells and promote chronic rejection
2005; 79(3 suppl): S19.
65. Sis B, Campbell PM, Mueller T, et al. Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant
2007; 7: 1743.
66. Miura M, Ogawa Y, Kubota KC, et al. Donor-specific antibody in chronic rejection
is associated with glomerulopathy, thickening of peritubular capillary basement membrane, but not C4d deposition. Clin Transplant
2007; 21(suppl 18): 8.
67. Gloor JM, Sethi S, Stegall MD, et al. Transplant glomerulopathy: Subclinical incidence and association with alloantibody. Am J Transplant
2007; 7: 2124.
68. Mengel M, Bogers J, Bosmans JL, et al. Incidence of C4d stain in protocol biopsies from renal allografts: Results from a multicenter trial. Am J Transplant
2005; 5: 1050.
69. Mizutani K, Terasaki P, Hamdani E, et al. The importance of anti-HLA-specific antibody strength in monitoring kidney transplant
patients. Am J Transplant
2007; 7: 1027.
70. Jutte NH, Knoop CJ, Heijse P, et al. Cytotoxicity of graft-derived lymphocytes: Specific for donor heart endothelial cells? J Heart Lung Transplant
1997; 16: 209.
71. Shi C, Lee WS, He Q, et al. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci USA
1996; 93: 4051.
72. Alkhatib B, Freguin-Bouilland C, Litzler PY, et al. Antidonor humoral transfer induces transplant arteriosclerosis in aortic and cardiac graft models in rats. J Thorac Cardiovasc Surg
2007; 133: 791.
73. Russell PS, Chase CM, Winn HJ, et al. Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol
1994; 152: 5135.
74. Stetson CA Jr, Demopoulos R. Reactions of skin homografts with specific immune sera. Ann N Y Acad Sci
1958; 73: 687.
75. Campos EF, Tedesco-Silva H, Machado PG, et al. Post-transplant anti-HLA class II antibodies as risk factor for late kidney allograft failure. Am J Transplant
2006; 6: 2316.
76. Gerbase-DeLima M, Campos EF, Tedesco-Silva H, et al. Anti-HLA class II antibodies and chronic allograft nephropathy. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 201.
77. Langan LL, D'orsogna L, Park LP, et al. HLA antibodies and soluble CD30 are associated with poor renal graft outcome: Updated results of a single-center cross-sectional study. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 219.
78. Lachmann N, Terasaki P, Schonemann C. Donor-specific HLA antibodies in chronic renal allograft rejection: A prospective trial with a four-year follow-up. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 171.
79. Piazza A, Poggi E, Ozzella G, et al. Post-transplant donor-specific antibody production and graft outcome in kidney transplantation: Results of sixteen-year monitoring by flow cytometry. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 323.
80. Morales-Buenrostro L, Castro R, Terasaki PI. Impact of immunosuppression on HLA-antibodies formation. In: Terasaki P, ed. Clinical transplants 2006. Los Angeles, Terasaki Foundation Lab 2007, p 227.
81. Dudley C, Pohanka E, Riad H, et al. Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: The “creeping creatinine” study. Transplantation
2005; 79: 466.
82. Zachary AA, Montgomery RA, Leffell MS. Factors associated with and predictive of persistence of donor-specific antibody after treatment with plasmapheresis and intravenous immunoglobulin. Hum Immunol
2005; 66: 364.
83. Stegall MD, Gloor J, Winters JL, et al. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant
2006; 6: 346.
84. Jordan S. IVIG vs. plasmapheresis for desensitization: Which is better? Am J Transplant
2006; 6: 1510.
85. Hansen R, Seifeldin R, Noe L. Medication adherence in chronic disease: Issues in posttransplant immunosuppression. Transplant Proc
2007; 39: 1287.
86. Terasaki PI, Marchioro TL, Starzl TE. Sero-typing of human lymphocyte antigens: Preliminary trials on long term kidney homograft survivors. Washington, DC, National Academy of Science, 1965.
87. Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med
1969; 280: 735.
88. Kissmeyer-Nielsen F, Olsen S, Petersen VP, et al. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet
1966; 2: 662.
89. Williams GM, Hume DM, Hudson RP Jr, et al. “Hyperacute” renal-homograft rejection in man. N Engl J Med
1968; 279: 611.
90. Terasaki PI, Kreisler M, Mickey RM. Presensitization and kidney transplant
failures. Postgrad Med J
1971; 47: 89.
91. Zou Y, Stastny P, Susal C, et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med
2007; 357: 1293.
92. Gebel HM, Bray RA, Nickerson P. Pre-transplant assessment of donor-reactive, HLA-specific antibodies in renal transplantation: Contraindication vs risk. Am J Transplant
2003; 3: 1488.
93. Bray RA, Nolen JD, Larsen C, et al. Transplanting the highly sensitized patient: The emory algorithm. Am J Transplant
2006; 6: 2307.
94. Bray RA, Nickerson PW, Kerman RH, et al. Evolution of HLA antibody
detection: Technology emulating biology. Immunol Res
2004; 29: 41.
95. Cook DJ, Terasaki PI, Iwaki Y, et al. The flow cytometry crossmatch in kidney transplantation. Clin Transpl
96. Ogura K, Terasaki PI, Johnson C, et al. The significance of a positive flow cytometry crossmatch test in primary kidney transplantation. Transplantation
1993; 56: 294.
97. Yen E, Hardinger K, Brennan DC, et al. Cost-effectiveness of extending medicare coverage of immunosuppressive medications to the life of a kidney transplant
. Am J Transplant
2004; 4: 1703.