Antibody-mediated Humoral Rejection Research Articles

P37 DIAGNOSIS AND TREATMENT OF HUMORAL REJECTION IN HEART–TRANSPLANT PATIENTS: SINGLE CENTER EXPERIENCE

Abstract Introduction Heart Transplantation remains the gold standard treatment for Advanced Heart Failure patients. Antibody–mediated humoral rejection (AMR) is one of the main causes of medium and long–term morbility and mortality. Success, therefore, is strictly connected to the possibility of modulating immune response in the recipient through innovative diagnostic approaches of immunosuppression–therapy tailoring. Method Since 2019, San Camillo Hospital’s Heart Transplant Center in Rome has adopted a new integrated protocol for early diagnosis and treatment for humoral rejection which consists of clinical, instrumental and laboratory monitoring through Solid Phase Flow Cytometric Techniques in order to identify Donor Specific Anti–HLA antibodies (DSA) both fixing and not fixing complement (cytotoxicity). Results 113 transplant patients were studied, resulted negative in prospective crossmatch at the time of surgery. Post–transplant DSA production has been monitored according to ISHLT guidelines in 1, 3, 6, 12 months’–time and, afterwards, once a year or after evidence of clinical symptoms or echocardiographic signs of graft disfunction associated always with biopsy. During the monitored period, 32 patients showed post–transplant DSA: 2 pz (6%) Class I, 16 (50%) Class II, DSA and the last 14 patients (44%) both Class I and II DSA. The capability of fixing complement (cytotoxicity) was evaluated in 19 patients. In 13 cases (68%) DSAs resulted positive for the specific test used (LSA–C1Q). In the aforementioned subgroup AMR incidence was of 23%; no AMR cases were found in the DSA C1q negative group. 3 patients showed clinical–functional deterioration and echocardiographic and bioptical alterations. Usage of apheretic treatment and re–modulation of immunosoppression therapy (FK, MMF or Everolimus) resulted in important reduction in DSAs amount, clinical recovery and echocardiocraphic signs of improvement. Conclusions The adopted protocol for monitoring and diagnosis of humoral rejection resulted in early identification of patients at higher risk of early graft failure. This leads to specific diagnostic and therapeutic strategies to improve long–term outcome.

Lung transplantation : Histomorphological diagnosis and clinical aspects

The function of pulmonary allografts is regularly impaired by alloimmune reactions with quite variable clinical outcomes, different involved effector cells and molecules, as well as affected anatomical compartments. Acute rejection of grafts after lung transplantation (LuTx) is not only associated with the subsequent development of acute graft dysfunction, but can also contribute - among other immunological and nonimmunological factors - to the development of chronic lung allograft dysfunction (CLAD), which is the main reason for the limited long-term survival after LuTx. In addition to ACR and analogous to other solid organ transplants, the importance of antibody-mediated (humoral) rejection (AMR) in LuTx has also been recognized. There are currently no specific laboratory, radiological, or clinical tests available for either ACR or AMR. Only by the synoptic examination of histopathological changes and interpretation against the background of microbiological, virological, serological, and functional findings, can adequate sensitivity and specificity be achieved in the diagnostics of rejection. In this article, the current criteria for histopathological diagnostics of rejection following LuTx are summarized and the most important differential diagnoses are discussed.

Anatomía patológica del trasplante renal

In order to make an objective assessment of the histopathology of a renal biopsy during a kidney transplant, all the various elements involved in the process must be understood. It is important to know the characteristics of the donor organ, especially if the donor is older than 65. The histopathological features of the donor biopsy, especially its vascular status, are often related to an initial poor function of the transplanted kidney. The T lymphocyte inflammatory response is characteristic in acute cellular rejection; the degree of tubulitis, together with the amount of affected parenchyme, are important factors. The proportion of cellular sub-populations, such as plasma cells and macrophages, is also important, as they can be related to antibody-mediated humoral rejection. Immunofluorescent or immunohistochemical studies are necessary to rule out C4d deposits or immunogloblulins. The presence of abundant deposits of C4d in tubular basement membranes supports a diagnosis of humoral rejection, as does the presence of capillaritis, glomerulitis which, together with vasculitis, are typical diagnostic findings in C4d negative cases. Interstitial fibrosis, tubular atrophy and glomerular sclerosis, although non-specific, imply a chronic phase. Transplant glomerulopathy and multilamination in more than 6 layers of the tubular and glomerular basement membranes are quasi-specific characteristics of chronic humoral rejection. Electron microscopy is essential to identify of these pathologies as well as to demonstrate the presence of other glomerular renal diseases.

ABO-incompatible living donor liver transplantation is suitable in patients without ABO-matched donor

ABO-incompatible liver transplantation is usually contraindicated because of the risk of antibody-mediated humoral rejection of the graft. We describe 22 successful cases of patients who had living donor liver transplantation (LDLT) from ABO-incompatible donors. The immunosuppressive protocol consisted of rituximab and plasmapheresis prior to LDLT. Plasmapheresis was planned for up to 2 weeks after LDLT aiming at maintaining levels of anti-ABO titers below 1:32. The median age of recipients was 54 years and the median MELD score was 13. The initial range of isoagglutinin IgM and IgG titers were 1:8-1:1024 and 1:2-1:1024, respectively. Preoperative isoagglutinin IgM and IgG titers were achieved less than or equal to 1:8 by performing therapeutic plasma exchange (TPE). While the median number of TPE was 4 (range, 2-18) in all patients, it was 4 (range, 2-8) in the initial low titer group (<1:256) and 8 (range, 6-18) in the high titer group (≥ 1:256). There were no statistically significant differences for liver function tests in the first 2 weeks after transplantation between the groups having high MELD score (≥ 20) vs. low MELD score (<20), local graft infusion vs. systemic infusion, or high initial isoagglutinin titer (≥ 1:256) vs. low initial isoagglutinin titer (<1:256). Patient and graft survival was 100% and there was no acute humoral rejection in recipients at a mean follow-up of 10months (range, 3-21). ABO-incompatible LDLT can be safely performed when rituximab and TPE are used, and may be proposed when ABO-compatible donors are not available.

Long-Term Recurrence-Free Survival After Liver Transplantation from an ABO-Incompatible Living Donor for Treatment of Hepatocellular Carcinoma Exceeding Milano Criteria in a Patient With Hepatitis B Virus Cirrhosis: A Case Report

The early results of liver transplantations (OLT) in patients with advanced hepatocellular carcinoma (HCC) were poor because of frequent tumor recurrence. However, OLT has significant, theoretical advantage that it removes both the tumor and the organ that is at a risk of malignancy. The Japanese law on organ transplantation limited the availability of cadaveric liver donors until its revision on July 17, 2011. ABO-incompatible OLT was formerly contraindicated because performed anti-A/B antibodies on recipient endothelial cells raised the risk of antibody-mediated humoral graft rejection. We have herein described four successful cases of steroid withdrawal among adult patients who underwent living donor OLT from ABO-incompatible donors. In addition, we transplanted a liver from a living donor into an ABO-incompatible recipient on August 9, 2004. The 55-year-old man with HCC due to hepatitis B virus (HBV) a cirrhosis had a Child-Pugh score of C, and Model for End-stage Liver Disease score of 22. Two tumors greater than 5 cm, exceeded the Milan criteria. His des-gamma-carboxy prothrombin level was 6 mAu/mL, and alpha-fetoprotein, 18.78 ng/mL. Antirejection therapy included multiple perioperative plasmaphereses and splenectomy; with an immunosuppressive regimen consisting of tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, we used intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1). The patient had complications of portal vein thrombosis, hepatic artery thrombosis, and acute myocardial infarction, which were treated by interventional radiology in the posttransplantation period. We controlled the HBsAb titer by administering hepatitis B immunoglobulin and lamivudine (200 IU/L doses) for 1 year after OLT and 100 IU/L doses thereafter. As a result, the patient achieved long-term, disease-free graft survival without steroids. He currently has good liver function and leads a normal lifestyle. Our results suggested the feasibility of controlling antibody-mediated humoral rejection and other complications in living donor liver transplantations into ABO-incompatible adults via intrahepatic arterial PG E1 infusion splenectomy, and plasmapheresis with regular immunosuppression. Withdrawal of steroids, HBV vaccination, and lamivudine, an nucleoside analog reverse transcriptase inhibitor, have achieved long-term (7 years) survival without recurrent HBV infection or tumor.

Neue Entwicklungen in der Nierentransplantation

Renal transplantation has become an established option for renal replacement therapy in many patients with end stage renal disease. Living donation is a possibility for timely transplantation, hampered in 20 % of all possible donors and recipients byincompatible blood groups. AB0-incompatible renal transplantation overcomes this hurdle with acceptable allograft survival compared to conventional living-donor renal transplantation. During the last 10 years, the number of patients awaiting renal transplantation older than 65 years has nearly doubled. The decision to transplant those patients and their medical treatment is a growing challenge in transplantation. On the other hand donor age is increasing with potential negative consequences for long-term outcome of organ function. Antibody-mediated humoral rejection have been identified lately as an important cause for allograft failure during long-term follow up of renal transplant patients. New immunological methods to detect donor-specific antibodies, like solid-phase assays (Luminex®), have increased the knowledge and understanding of humoral rejection processes. This will lead hopefully to modified immunosuppressive strategies to minimize organ failure due to chronic rejection.

Successful Deceased-Donor Kidney Transplantation in Crossmatch-Positive Patients With Peritransplant Plasma Exchange and Rituximab

Sensitized patients awaiting renal transplantation have a markedly reduced probability of receiving a crossmatch (XM)-negative renal allograft, and, even if transplanted with a negative complement-dependent cytotoxicity (CDC)-XM, they are at an increased risk of antibody-mediated humoral rejection with early graft loss. We report here for the first time on the effectiveness of a single pretransplant plasma exchange session in rendering a positive complement-dependent cytotoxicity-XM negative and, in combination with anti-CD20 therapy, allowing successful renal transplantation in two sensitized deceased-donor kidney allograft recipients. In a third patient with high donor-specific reactivity, the therapy was unsuccessful. Plasma exchange treatments were continued during the posttransplant period until stable allograft function was achieved. Both patients showed good graft outcome at 27 and 21 months after transplantation with serum creatinine values of 1.60 and 1.25 mg/dL, respectively.

Effects and Problems of Adult ABO-Incompatible Living Donor Liver Transplantation Using Protocol of Plasma Exchange, Intra-arterial Infusion Therapy, and Anti-CD20 Monoclonal Antibody Without Splenectomy: Case Reports of Initial Experiences and Results in Korea

Introduction Adult ABO-incompatible liver transplantation is associated with a high risk of graft failure due to antibody-mediated humoral rejection (AMR). We evaluated the effects of a protocol using preoperative removal of isohemagglutinin, rituximab prophylaxis, and intrahepatic arterial infusion (HAI) therapy for ABO-incompatible adult living donor liver transplantation (LDLT). Patients and Methods Between March 2005 and September 2007, we performed 94 adult LDLTs, including 3 ABO-incompatible cases. All ABO-incompatible LDLT patients underwent administration of 375 mg/m 2 rituximab on preoperative days 15 and 8 without splenectomy, as well as preoperative removal of isohemagglutinin using plasma exchange, and HAI therapy for postoperative 21 days. Results Postoperative anti-donor blood-type antibody titer and B-cell level were effectively suppressed by early rituximab prophylaxis in all patients. HAI therapy was effective to prevent AMR and even resolved mild AMR. However, all patients suffered bacterial infections, and 1 died of septicemia with good graft function. Another subject died of late-onset AMR that occurred after discontinuation of HAI therapy. Conclusion An ABO-incompatible LDLT protocol using plasma exchange, rituximab prophylaxis, and intra-HAI therapy effectively suppressed anti-A/B antibody and prevented AMR. But this protocol should be further improved to reduce infectious complications and late onset of AMR.

ABO-Incompatible Adult Living Donor Liver Transplantation for Hepatocellular Carcinoma

Living donor liver transplantation (LDLT) offers timely transplantation for patients with hepatocellular carcinoma (HCC). If ABO-incompatible LDLT is feasible, the need for pretransplantation treatment may be eliminated, which may reduce overall morbidity. In this article, we have described 8 adult HCC patients who successfully underwent LDLT from ABO-incompatible donors. Antirejection therapy included multiple preoperative plasmaphereses, splenectomy, and an immunosuppressive regimen with tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of the ABO-identical cases. In addition, we also performed intrahepatic arterial infusion of prostaglandin E1. In 5 patients, we administered a single dose of rituximab, a chimeric CD20 monoclonal antibody. As a result of this treatment, 6/8 patients are still alive. Our experience has shown that it is possible to control antibody-mediated humoral rejection and other complications in adult ABO-incompatible LDLT.

Confusion about C4d and Humoral Rejection: See 4 Yourself

Cellular (T-cell), humoral (antibody), and innate (natural killer cell) immunity all potentially initiate graft rejection, although most attention and treatment strategies have focused on cellular rejection. Antibody-mediated (humoral) rejection (AMR) has been implicated in ‘‘hyperacute’’ and ‘‘accelerated’’ rejection, which have become rare in the modern transplantation era. Recent evidence, however, indicates that AMR is involved in both acute and chronic rejection. The major risk for humoral rejection is presensitization, usually due to prior transplantation, transfusion, or pregnancy, the latter likely accounting for higher reported rates in women. However, most patients with AMR had a negative cross-match at the time of transplantation. Other associations with humoral rejection include cytomegalovirus seropositivity, OKT3 prophylaxis, and the use of mechanical circulatory assist devices in cardiac transplant patients. The incidence of AMR varies and depends, in part, on the rate of presensitization in the population at each transplant center, but also on diagnostic criteria. Antibody-mediated rejection is usually caused by antibodies to either human leukocyte antigen (HLA) class I or class II donor antigens and local activation of the complement cascade. The capillary endothelium is the major target of circulating HLA antibodies. Non-HLA antibodies, such as in ABO incompatible grafts and, uncommonly, antibodies against tissue-specific or organ-specific antigens, have also been implicated (examples in Table 1).

Long‐term follow‐up ABO‐incompatible adult living donor liver transplantation in cirrhotic patients

ABO-incompatible liver transplantation is usually contraindicated. The presence in the recipient of preformed anti-A/B antibodies located on endothelial cells raises the risk of antibody-mediated humoral rejection of the graft. We describe four successful cases of steroid withdrawal in adult patients who had living-donor liver transplantation from ABO-incompatible donors. Antirejection therapy included multiple perioperative plasmapheresis, splenectomy, and a triple immunosuppressive regimen with tacrolimus, methylprednisolone (MPSL), and cyclophosphamide or mycophenolate mofetil (MMF). The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1) was used. As a result, all four patients were able to achieve long-term graft survival without steroid use. They all have good liver function and are leading normal lifestyles. Our experience with these four patients suggests the feasibility of controlling humoral rejection and other complications in adult ABO-incompatible living donor liver transplantations with intrahepatic arterial infusion of PGE1, splenectomy, and plasmapheresis with a regular base of immunosuppression protocol to prevent antibody-mediated humoral rejection.

Humoral Rejection in Pediatric Orthotopic Heart Transplantation

Pediatric heart transplant grafts may fail without evidence of cellular rejection or transplant coronary artery disease. The role of antibody-mediated humoral rejection (HR) in graft failure has not yet been described in the pediatric population. We reviewed the medical records of 103 pediatric heart transplantations performed at our institution from July 1997 to June 2004. Biopsy specimens were evaluated for HR histologically and by immunoperoxidase and immunofluorescence staining. Risk factors for HR were determined by statistical analysis. Graft survival curves were constructed and compared for patients testing negative or positive for HR. A total of 358 endomyocardial biopsies (EMBs) from 103 pediatric heart transplant patients (age 3 weeks to 20 years; 52% males) were analyzed for HR. Thirty-six grafts (32%) showed evidence of HR. Grafts with a history of HR during the first year after transplant had a 47% failure rate over 3 years, compared with 29% of those hearts with no evidence of HR (p = 0.06). Although patients with congenital heart disease (CHD) appeared to be at greatest risk for developing HR (p = 0.01), patients with positive donor-specific crossmatch data showed a trend toward more significant risks for HR (p = 0.055). Hemodynamic data (including pulmonary capillary wedge pressure [PCWP] and cardiac index [CI]), left ventricular ejection fraction (LVEF), gender matching, recipient age, race of recipient vs donor and pre-transplant panel-reactive antibody (PRA) were not predictive of HR. Patients with a pathologic diagnosis of HR have increased graft failure rates and overall mortality. Patients with congenital heart disease and positive cross-match results may be at increased risk for HR.

Evaluation of C4d Staining in Liver and Small Intestine Allografts

Antibody-mediated humoral rejection in kidney and heart allografts is well recognized and is often associated with poor outcome. C4d deposition in allograft biopsy specimens occurs at sites of antibody-mediated complement activation and has become one of the histopathologic criteria for diagnosis of humoral rejection in the kidney and the heart. To study immunohistochemical C4d staining as a potential diagnostic marker in liver and small intestine allograft biopsy specimens. Thirty-six small intestine and 71 liver specimens, including native specimens, allografts with and without histologic features of acute cellular rejection, and explants, were stained with antisera to C4d using an immunohistochemical method on formalin-fixed, paraffin-embedded tissue. In small intestine, C4d labeled capillaries in 27% of cases with no evidence of rejection, 36% of cases with evidence of acute rejection, and 2 (28%) of 7 specimens of native normal small intestine. In liver allograft biopsy specimens, C4d stained endothelium of veins, arteries, and/or sinusoids in 2 (8%) of 25 cases of acute rejection with central vein involvement; C4d staining was negative in biopsy specimens with no evidence of rejection. C4d stained the endothelium in a subset of explanted liver allografts with ductopenic rejection or chronic vascular rejection and strongly stained 1 explant with features of hyperacute rejection. The clinical utility of C4d staining in solid organ transplantation may vary by organ. Our data show C4d is unlikely to have utility in small intestine allograft biopsy specimens; however, further study in liver allografts, in conjunction with donor-specific antibody testing, is warranted.

Effect of Yunnan-cobra venom factor in overcoming acute humoral rejection after allograft cardiac transplantation in presensitized recipients: experiment with rats

To investigate the effect of Yunnan-cobra venom factor (Y-CVF) in overcoming acute humoral rejection after allograft cardiac transplantation in presensitized recipients. Fifteen Lewis rats received the transplantation of full-thickness skin graft of BN rats three times so as to be presensitized. Fifteen pairs of Lewis rat, as recipients of heart, and BN rat, as heart donors, were randomly divided into 2 groups: experimental group (n = 8), and control group (n = 7). The Lewis rats in the experimental group received heart transplantation of the heart of the BN rat 7 approximately 10 days after the third skin transplantation, and were injected with Y-CVF 80 microg/kg 24 hours before the heart transplantation. The Lewis rat in the control group received only the heart transplantation without Y-CVF injection. Blood samples were collected from all rats before pre-sensitization and 7 days after the third skin transplantation so as to determine the titer of anti-BN rat lymphocyte antibody. 0 and 24 hours, and 6 and 8 days after Y-CVF injection blood samples were collected from the Lewis rats to determine the total complement activity with the complement activity before Y-CVF injection defined as 100%. The survival time of the transplanted heart was observed. After the transplanted hearts stopped to beat, they were resected and underwent HE staining and microscopy. Immunohistochemistry was used to examine the deposition of IgG and complement 3 (C3). The titer of anti-BN rat lymphocyte antibody was 0 before the pre-sensitization, and increased to 1:1028 - 1:2056 7 days after the third skin pre-sensitization. The serum total complement activity of the Lewis rats decreased to 0 twenty-four hours after the Y-CVF injection, recovered to 2.01% - 15.41% 6 days after, and returned to the normal level (89.61% - 109.46%) 8 days after. The mean survival time of the transplanted hearts of the control group was 12.71 +/- 13.94 hours (with a range of 1.5 - 15 hours), significantly shorter than that of the experimental group (99.50 +/- 38.72 hours, with a range of 23 - 153 hours, P < 0.01). Pathological examination showed that the acute humoral rejection in the control group was mainly complement-dependent antibody-mediated humoral rejection characterized by intravascular thrombosis, and that in the experimental group was mainly cellular rejection, characterized by extensive infiltration of mononuclear cells. Immunohistochemistry showed that remarkable IgG deposition was seen in the cardiac muscle cells and vascular endothelial cells in both groups; however, C3 deposition in vascular endothelial cells could be seen only in the control group. Administration of CVF is effective in overcoming the acute humoral rejection after allograft cardiac transplantation in presensitized recipients.

CLINICO-PATHOLOGICAL CHARACTERISTICS OF RENAL TRANSPLANTS AFTER ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION

O77 Aims: Both anti-HLA antibody and anti-blood group antibody are responsible for antibody-mediated humoral rejection. Clinicopathological characteristics of acute humoral rejection after ABO-compatible renal transplantation are well investigated, recently. However, those of ABO-incompatible renal transplantation are still unclear; especially in terms of correlation with concomitant ordinary (T-lymphocyte dependent) rejection and graft dysfunction. The precise pathogenesis occurred in acute rejection after ABO-incompatible renal transplantation is important. Methods: We studied the significance of C4d deposition in peritubular capillaries (PTC) as a sensitive indicator of humoral rejection and concomitant cellular rejection in renal allograft biopsies of ABO-incompatible renal transplantation. We analyzed 63 graft biopsy specimens from 27 patients with ABO-incompatible living recipients within 90 days after renal transplantation. Only diffuse and bright stain of C4d was consider as a positive finding of acute humoral rejection and severity of acute cellular rejection was classified by Banff scheme. Results: No graft was lost by acute rejection. Acute humoral rejection was noted in 14 graft biopsies; pure type in 8 and 6 combined with cellular rejection. Positive C4d was noted in all 14 graft biopsies. Ordinary cellular rejection was diagnosed in 14 biopsies. The diffuse C4d deposition in PTC was noted in 4 of 16 biopsies with acute tubulo-interstitial rejection of Grade I and no morphological findings of humoral rejection. Furthermore in the well functioning grafts with no morphologic findings of both humoral and cellular rejection, we found 3 diffuse and 2 focal and bright C4d positive biopsies. Focal and weak positive C4d is often noted in grafts without episode of graft dysfunction. No positive C4d deposition was noted in one-hour biopsy during transplant operation. Conclusions: Strong C4d deposition in PTC is valuable as a relatively specific and sensitive indicator for acute humoral rejection. However, the meaning of positive C4d is still unclear and requires further study after ABO-incompatible renal transplantation.

Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease

Background Acute cellular rejection is the mechanism of most immune-related injury in cardiac transplant recipients. However, antibody-mediated humoral rejection (HR) has also been implicated as an important clinical entity following orthotopic heart transplantation. Humoral rejection has been reported to play a role in graft dysfunction in the early post-transplant period, and to be a risk factor for the development of transplant coronary artery disease. Some involved in transplantation pathology doubt the existence of clinically significant humoral rejection in cardiac allografts. Those who recognize its existence disagree on its possible role in graft dysfunction or graft coronary artery disease. In this study, we report clinical features of patients with the pathologic diagnosis of HR at our institution since July 1997, when we began systematic surveillance for humoral rejection. Methods We reviewed medical records of patients with the pathologic diagnosis of HR without concurrent cellular rejection between July 1997 and January 2001. Diagnosis was based on routine histology (“swollen cells” distending capillaries, interstitial edema and hemorrhage) and immunofluorescence (capillary deposition of immunoglobulin and complement with HLA-DR positivity), or immunoperoxidase staining of paraffin-embedded tissue (numerous CD68-positive macrophages and fewer swollen endothelial cells distending capillaries). Results A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent cellular rejection at autopsy or on one or more biopsies. Although females comprised only 26% of our transplant population, 23 patients (52%) with HR were female. A positive peri-operative flow cytometry T-cell crossmatch was observed in 32% of HR patients compared with 12% of controls ( p = 0.02). Hemodynamic compromise consisting of shock, hypotension, decreased cardiac output/index and/or a rise in capillary wedge or pulmonary artery pressure was observed in 47% of patients at the time of diagnosis of HR. Six patients (5 females) died (14% mortality) with evidence of HR at or just before autopsy, 6 days to 16 months after transplantation. The incidence of transplant coronary artery disease was 10% greater at 1 year, and 36% greater at 5 years, in patients with HR when compared with non-HR patients. Conclusion Humoral rejection was associated with acute hemodynamic compromise in 47% of patients, and was the direct cause of death in 6 patients (13%). Humoral rejection is a clinicopathologic entity with a high incidence in women and is associated with acute hemodynamic compromise, accelerated transplant coronary artery disease and death.