Heart transplantation has significantly improved survival in patients with end-stage heart failure. One, 5, and 10-year survival in heart transplant recipients has been reported to be 81%, 64%, and 42%, respectively
. Up to 85% of the transplant recipients report improvement in quality of life and approximately 50% return to work after heart transplantation (1) . In patients awaiting heart transplantation, dysfunction of a second organ may occasionally occur that requires consideration of simultaneous multiorgan transplantation. Heart-lung transplants have been successfully performed for patients with cardiac failure, usually of right ventricle, secondary to severe pulmonary disease, or for patients with congenital abnormalities in whom isolated heart transplantation alone is not feasible. Despite technical advances, survival after heart-lung transplantation is substantially lower than for isolated heart or lung transplantation (2) . However, large studies describing the outcome of cardiac transplant recipients who also undergo simultaneous transplantation of an extra-thoracic organ have not been reported, presumably due to the limited experience at individual centers. The kidney is the most common extra-thoracic transplant to be combined with heart transplantation, because patients with intrinsic renal disease have the added burden of a low cardiac output, which can lead to progressive renal dysfunction. Outcome data in combined transplant recipients are needed to define the optimal utilization of scarce donor resources. (3)
To evaluate outcomes in multiorgan transplantation, a multi-institutional study was undertaken in collaboration with the International Society of Heart and Lung Transplantation and United Network for Organ Sharing (UNOS
). We analyzed 82 patients who underwent 84 combined heart and kidney transplantations during the past 7 years. In this retrospective observational study, the incidence of allograft rejection, actuarial recipient survival, and cardiac allograft rejection-free survival in the combined heart-kidney allograft recipients were compared with those reported for isolated heart transplant recipients. * METHODS
Data from UNOS Scientific Registry (UNOS-SR) database were used to identify all combined heart-kidney transplants performed in the United States since UNOS began collecting data in October 1987. Eighty-four such transplants involving 82 recipients were identified through May 1995. Patient demographics, indications for heart and kidney transplants, and survival statistics for all 82 patients were provided by UNOS. A questionnaire was sent to 42 centers, which had performed at least one combined heart-kidney transplantation. The study and the questionnaire format were approved by the UNOS-Scientific Advisory Committee. The questionnaire requested detailed information on serial cardiac biopsies, incidence and description of every episode of the treated rejection in either organ, immunosuppressive regimens, and allograft failure, as well as complications and concurrent illnesses. All centers were contacted by the investigators on at least three occasions, to provide and validate data. All questionnaire results were kept confidential. Complete clinical data on 56 transplants were obtained from 29 centers
(Appendix 1). Cardiac or renal allograft rejection was defined as any rejection episode that resulted in augmentation of immunosuppressive therapy. Biopsy verification of rejection in either organ was not required.
Data on the overall recipient survival after combined heart-kidney transplantation as provided by the UNOS-SR) was compared with 14,340 isolated heart transplant recipients transplanted during the same period
. Incidence of cardiac allograft rejection in combined heart-kidney recipients and their rejection-free survival was compared with the multi-institutional data on the incidence of cardiac allograft rejection and allograft rejection frequency in isolated heart transplant recipients obtained from previously published data by the Transplant Cardiologists' Research database (TCRD) (1) . All analyses were performed using SAS statistical software (4) . Fisher's exact test and the chi-square statistic were used for comparison of rates and proportions. Freedom from cardiac allograft rejection and actuarial patient survival were computed using the Kaplan-Meier method. Survival distributions for heart-kidney recipients and isolated heart recipients were compared by the log-rank test. (5) P<0.05 was used to indicate statistical significance. RESULTS
Patient characteristics. The 84 combined heart-kidney transplants represent 0.5% of the total number of the heart transplants performed in the United States during the same period. There were 59 male patients (72%) and 23 female patients (28%). The recipients' ages ranged from 8 to 65 years (mean ± SEM, 42±13). All transplants were performed simultaneously using the same donor for both organs.
The most frequent pretransplant cardiac diagnosis was idiopathic dilated cardiomyopathy in 31 patients (38%), followed by ischemic cardiomyopathy in 26 patients (32%). Reasons listed for simultaneous renal transplantation included a variety of intrinsic renal diseases exacerbated by end-stage heart failure, with the most common diagnoses being juvenile diabetes mellitus (17%) and chronic glomerulonephritis (11%). The cause of renal failure was not reported in 10 patients (12%).
Twenty-nine centers responded to the survey and provided verified information on 56 patients (68%). Of these 56 patients, 43 were males (77%) and 13 were females (23%). Their ages ranged from 11 to 65 years. The duration of posttransplant follow-up was 780±744 days, with a minimum follow-up of 2 days and a maximum follow-up of 2525 days. After transplantation, the majority of these patients have received triple-drug immunosuppression, including prednisone (89%), cyclosporine (92%), and azathioprine (64%); 4% of patients have received cyclophosphamide. OKT3 or ATG was used for induction cytolytic treatment or for treatment of an acute rejection episode in 62% of the double-transplant recipients. The majority of rejection episodes were treated with methylprednisolone or an increase in oral prednisone, but total lymphoid irradiation (2%) or plasmapheresis (6%) were occasionally used for more severe episodes of acute rejection. The patients' most recent serum cyclosporine trough levels were less than 100 ng/dl in 8%, 101-150 ng/dl in 24%, 151-200 ng/dl in 18%, and more than 200 ng/dl in 49% of patients.
Complications other than episodes of acute allograft rejection have included treated hypertension (73%), chronic liver disease (2%), malignancy (15%), hyperlipidemia (25%), and diabetes mellitus (27%). One or more infections requiring antibacterial or antiviral treatment have occurred in 62% of patients. Mild renal dysfunction has developed in the majority of patients. The most recent creatinine was below or equal to 1.0 mg/dl in 10%, 1.0-2.0 mg/dl in 63%, and >2.0 mg/dl in the remaining 27% of patients. The incidence of graft vasculopathy was assessed histologically in renal allografts and angiographically in cardiac allografts in 50 of the 56 patients. Three patients demonstrated evidence of renal vasculopathy (one mild and two severe) and seven patients showed distal pruning of one or more coronary arteries (five mild and two moderate).
Cause of death and actuarial recipient survival in dual-organ recipients. Twenty-three of 82 patients (28%) with combined heart-kidney transplantation have died. The cause of death in the 23 patients was reported as cardiac allograft failure (n=5; 21%, including acute rejection in two, primary graft failure in one), myocardial infarction (n=2; 9%), cardiac arrhythmias or cardiac arrest (n=2; 9%), renal failure (n=2; 9%), multiple organ failure (n=2; 9%), infections (n=7; 30%), and other (n=3; 13%).
Overall actuarial patient survival rates for the combined heart-kidney transplant recipients at 1, 3, 6, 12, and 24 months were 92.4 (95% confidence interval [CI], 86.6-98.3), 83.8 (75.4-92.2), 79.4 (70-88.7), 76.4 (66.5-86.3), and 66.5 (54.6-78.3), respectively
(Fig. 1). Actuarial survival rates for isolated heart transplant recipients enrolled in the UNOS-SR were similar at 92.0 (95% CI, 91.5-92.4), 88.2 (87.7-88.7), 85.9 (85.4-86.5), 82.8 (82.1-83.4), and 78.6 (77.9-79.3), respectively. A comparison of the study population and UNOS registry patients revealed no significant difference in survival ( P=0.2).
Occurrence of cardiac allograft rejection and rejection-free survival in dual-organ transplant recipients. Twenty-seven of 56 (48%) patients, in whom complete clinical data were available, have not had rejection of either organ. Of the remaining 29 patients (52%), 15 patients (27%) have had only cardiac rejection, eight patients (14%) had only renal allograft rejection, and six patients (11%) have developed at least one rejection episode in both organs (Table 1).
Thirty-five patients (63%) have not experienced any episode of cardiac allograft rejection. A total of 35 treated rejection episodes have been described in 21 of the remaining patients (38%); 11 patients (20%) had a single rejection episode and 10 patients (18%) were reported as having two or more treated rejection episodes
(Table 2). A description of the timing and histopathology of individual cardiac allograft rejection episodes is provided in Table 1. Frequency of rejection episodes in the published TCRD report of 911 isolated heart transplant recipients was substantially higher; 1 and ≥2 rejection episodes have occurred in 27% and 28%, respectively ( P=0.02; Table 2). On the other hand, renal allograft rejection occurred in 14 patients (25%), which was almost always suspected on a biochemical basis and usually confirmed by graft biopsy. There were a total of 24 rejection episodes: eight patients had one episode of renal allograft rejection and six patients suffered two or more treated rejection episodes.
The majority of cardiac allograft (30/35) and renal allograft (19/24) rejection episodes were independent of each other
(Fig. 2). Of 35 cardiac rejection episodes and 24 renal rejection episodes, only five episodes have occurred concurrently. Whenever a renal allograft rejection episode was treated, a report of endomyocardial biopsy was available within 1 week of the renal biopsy. On the other hand, whenever histology suggestive of cardiac allograft rejection was observed, renal biopsy was usually not performed and a decision regarding concurrent renal allograft rejection was based only on the biochemical parameters.
For heart-kidney recipients, freedom from cardiac rejection at 1, 3, 6, and 12 months averaged 88.4% (95% CI, 79.6-97.1), 73.6% (61.2-86), 71.4% (58.6-84.1), and 66.2% (52.5-79.9) of patients, respectively
(Fig. 3). In contrast, TCRD data indicate that isolated heart transplant recipients demonstrated absence of rejection rates during the same time periods of 64%, 44%, 44%, and 39%, respectively. Confidence intervals for the TCRD rejection data could not be obtained for statistical comparison. DISCUSSION
Actuarial survival and the freedom from cardiac allograft rejection. The present study is the first to demonstrate that no significant difference in short-and intermediate-term actuarial patient survival was observed between simultaneous heart-kidney and isolated heart transplantation. Cardiac allograft rejection episodes also seem to be less frequent in combined heart-kidney recipients, as compared with isolated heart recipients. Further, freedom from cardiac allograft rejection was more commonly observed in heart-kidney recipients for at least the initial 6 months after transplantation. Beyond 6 months, the incidences of rejection were similar.
The finding of decreased rejection at 6 months in combined heart-kidney recipients may be due to early development of partial graft tolerance. Similar results been reported in combined pancreas-kidney transplants for type I diabetes mellitus
, which compared 14 combined transplants to eight pancreas after-kidney transplantations. The 1-year patient and graft survival rates of 100% and 88% in the combined pancreas-kidney group were superior to the 96% and 62% observed in the pancreas after-kidney group. Of 15 acute pancreatic allograft rejection episodes, only four occurred in the combined kidney-pancreas group and the remaining 11 occurred in the pancreas-after kidney group. Although substantially lower survival has been reported for the combined heart-lung transplantation, the incidence of histological and treated episodes of cardiac allograft rejection have been reported to be substantially lower in such patients, when compared with the isolated heart transplant recipient (6) . In a 6-year Stanford heart-lung transplantation experience, only one episode of cardiac rejection was observed (7) . Further evidence for a beneficial effect on allograft tolerance of simultaneous multiorgan transplant has recently been observed in studies of heart-kidney transplantation in MHC class-I disparate miniature swine (8) . Allograft survival was substantially longer in animals that received dual-organ transplants compared with those that underwent isolated heart transplantation, and tolerance to the cardiac allograft occurred early after transplantation. (9)
Early cardiac allograft tolerance in multiorgan recipients. For induction of graft tolerance in clinical practice, several approaches have been used. These strategies either render the allograft less immunogenic by minimizing alloantigeneic differences between donor and recipient, or suppress the recipient's immune system with pharmacologic agents . Previous studies have also examined the role of administration of high doses of antigens or repeated administration of lower doses of alloantigens in the induction of graft tolerance. The incidence of graft tolerance, particularly in patients who had incidentally received multiple allogeneic blood transfusions before renal transplantation or those who were intentionally transfused repeatedly, is increased. Administration of high doses of peptides derived from polymorphic regions of donor MHC molecules or with soluble donor MHC molecules has been reported to induce specific T-cell tolerance (10) . An explanation for the lower rate of rejection observed in this study might be an analogous process that occurs when the heart is transplanted along with another organ that has a higher MHC-related antigenic load, such as a kidney. The quantitative presence of MHC class II and I antigens in the kidneys is 18-fold and 14-fold higher than that of the heart, respectively (10) . It is plausible that coexistence of an organ with quantitatively higher, but qualitatively similar, antigenic determinants may help induce partial tolerance to the organ of lower antigenic expression. The lower reported incidence of cardiac rejection in both heart-lung and heart-kidney recipients support this hypothesis. Although partial tolerance may play a role in the lower rate of rejection observed in present study, it is also possible that double organ transplants received a greater cumulative amount of immunosuppressive agents. The high incidence of renal dysfunction and malignancies observed in our group of patients suggests that a greater intensity of immunosuppression was used. (11)
The hypothesis that the heart, in the presence of another extra-thoracic organ, can develop partial tolerance early after cardiac allograft transplantation may be explained by a recently proposed immunologic paradigm in which transplantation is seen as a bidirectional and mutually canceling immune reaction between the host and the graft itself
. Hematopoietic stem cells from the allograft quickly develop proliferative cellular oases to coexist with recipient precursor stem cells, particularly in the recipient's bone marrow and other lymphoid organs (12) . These niduses constitute a growth factor-rich microenvironment perpetuated by a coexisting chimeric community of donor and host leukocytes. HLA class I molecules seem to be essential for the engraftment of donor hematopoietic stem cells (13) . Dendritic cells, the most prominent donor leukocytes in organ transplant recipients, may lack costimulatory molecules, such as B7, and may, therefore, become potentially tolerogenic (14) . A potent donor “veto” cell population has been demonstrated in the blood of tolerant human kidney recipients as an additional product of the mutual cell engagement (15) . The most important determinant of the establishment of spontaneous chimerism is the quantitative profile of leukocytes in the transplanted organs (16) . Although the liver is the most favorable organ, such events do occur in heart transplantation, but on a significantly smaller scale. Thus, the presence of an additional organ may facilitate partial tolerance to the heart as well (17) . (13, 17)
Lack of concurrence of rejection episodes in the transplanted organs. We had initially hypothesized that if the heart were relatively “protected” from rejection when transplanted in association with another organ of higher MHC-related antigenic load, the frequency of surveillance endomyocardial biopsies in such patients might be reduced, in favor of biochemical surveillance of the renal allograft. This hypothesis was based on subprimate, primate, and initial clinical studies demonstrating synchronous cellular rejection of the two organs in early studies of heart-lung transplantation . Subsequent studies in heart-lung recipients have confirmed a lower frequency and less severe episodes of rejection in cardiac allografts, and suggest a limited role of endomyocardial biopsy when transbronchial biopsies are performed (18, 19) . However, the occurrence of graft rejection in the heart-kidney transplants was found to be temporally independent in the two organs. The incidence of treated rejection was slightly higher in cardiac than in the renal allografts, despite the greater MHC-related antigen load of the renal allografts. This observation may partly be due to repetitive acquisition of histological specimens for identification of rejection in the cardiac allografts and the tendency of clinicians to treat episodes of mild cardiac rejection (International Society of Heart and Lung Transplantation grade ≤2) based upon a change in the clinical status of the patients (8, 20, 21) . Conversely, renal rejection almost always was suspected solely upon biochemical parameters, and an unknown number of less severe episodes of renal rejection may have been missed, due to the lack of frequent histopathologic surveillance of renal allografts. The temporal discordance of rejection in the two organs underscores the necessity of ongoing organ-specific surveillance. (22)
Limitations of the study and conclusions. By the nature of its voluntary, retrospective, and observational design, the study suffers from possible selection bias owing to incomplete retrieval of data. Although survival data were available on the entire cohort of 82 patients, data on cardiac and renal allograft rejection were not submitted in 26 patients. It is possible that the rejection frequency or treatment in this group may have differed from the study population and their lack of inclusion may have skewed incidence of rejection in a more favorable manner. In addition, although comparisons of the study population were made to published data for isolated heart transplants performed in the same era, posttransplant management, particularly the type and intensity of immunosuppression, may have varied at institutions that were not involved in multiorgan transplantation. Furthermore, detection of renal allograft rejection based on a substantial decline in renal function, rather than on histological criteria, may have failed to detect subclinical episodes of renal allograft rejection; the conclusion that rejection episodes do not occur concurrently in the heart and kidney may not be valid. The finding of discordance between cardiac and renal allograft rejection could have been further exaggerated by the lower threshold of the clinicians for treating suspected cardiac rejection.
Despite these limitations, this is the first study to examine clinical outcomes in combined heart-kidney transplantation. These findings suggest that such multiorgan transplantation can be performed in carefully selected patients with acceptable 6- to 24- month survival rates. Further, the frequency of cardiac allograft rejection may be somewhat lower in these patients than in recipients of isolated heart transplants. Finally, because the episodes of cardiac and renal allograft rejection seldom occur concurrently, organ-specific rejection surveillance, particularly serial endomyocardial biopsies, remains necessary.
Worsening renal function in most patients with advanced heart failure awaiting transplantation usually indicates severe end-organ compromise and often precludes transplantation. The findings of this study suggest that combined heart-kidney transplant may be an acceptable option in a small subset of potential heart transplant recipients. The lower 2-year survival rate for the combined procedure, although statistically not significant, suggests that long-term outcome data are urgently needed before a final decision can be made as to whether this approach represents a rational/optimal utilization of scarce donor resources.
Actuarial survival in combined heart-kidney and isolated heart allograft recipients. The data for 82 patients undergoing combined transplantation were compared with 14,340 patients registered with UNOS database. There was no significant difference in the intermediate-term survival between the two groups (
P=0.20). -, Combined heart-kidney transplant; -----, isolated heart transplant. Figure 2:
Representative sections of biopsies obtained simultaneously from cardiac (A) and renal (B) allografts in a combined heart-kidney transplant recipient. (A) Endomyocardium reveals markedly widened interstitial spaces and interstitial hemorrhage. There are scattered macrophages, T cells, and eosinophils. These findings were consistent with humoral rejection. (B) The renal biopsy demonstrated tubulitis (arrowheads), in addition to patchy inflammatory infiltrate composed of mononuclear cells, eosinophils, and polymorphonuclear cells.
Cardiac allograft rejection-free survival in combined heart-kidney and isolated heart allograft recipients. The data collected for 59 patients undergoing combined transplantation from 29 centers were compared to published data on 911 isolated heart recipients in the TCRD-database
. The statistical comparison between the two groups was not possible due to lack of confidence intervals in the published data. -, Combined heart-kidney transplant; -----, isolated heart transplant.
Abbreviations: CI, confidence interval; TCRD, Transplant Cardiologists' Research database; UNOS, United Network for Organ Sharing; UNOS-SR, United Network for Organ Sharing Scientific Registry.
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