Renal dysfunction is common among patients undergoing orthotopic liver transplantation (OLT) (
). Renal function is unlikely to improve after OLT, unless it is the result of hepatorenal syndrome ( 1 ). As a result, combined liver-kidney transplantation (LKT) has been performed in patients with liver failure and irreversible renal insufficiency ( 2 ). Controversy exists as to whether simultaneous LKT with organs from the same donor confers an immunologic- and allograft-enhancing effect on the kidney allograft ( 2–4 ). Earlier reports suggest that the hepatic allograft protected the kidney from hyperacute rejection even in patients with preformed lymphocytotoxic antibodies ( 5,6 ). Others showed that the incidence of acute cellular rejection was lower, and that the rate of renal allograft survival was superior in patients undergoing combined LKT compared with patients undergoing kidney alone transplantation (KAT) ( 7–9 ). These reports, however, involved small numbers of patients from single centers ( 5 ). Theories for the immuno-protection conferred by the liver include hepatic elimination of preformed lymphocytotoxic antibodies ( 5–13 ), neutralization of antibodies by release of soluble class I antigen ( 14 ), and development of hematopoietic chimerism ( 15,16 ). However, a previous analysis of the United Network for Organ Sharing (UNOS) database between 1987 and 1995 did not demonstrate a difference in rejection rate or kidney graft survival after LKT ( 17 ). The outcome of LKT is especially germane because the current allocation system for liver transplant recipients in the United States favors patients with renal failure. 18
These conflicting findings led us to undertake a more extensive analysis using the UNOS Scientific Renal Transplant Registry Database from October 1987 to September 2001, which now has more than three times the number of patients and a considerably longer follow-up since the previous study was published. This study compares the clinical outcomes of simultaneous combined LKT with the contra-lateral kidneys used for KAT or combined pancreas-kidney transplantation (PKT) and evaluates the factors that may account for the differences in survival.
PATIENTS AND METHODS
From October 1987 to October 2001, combined LKTs with organs from 899 cadaver donors were reported to the UNOS. Among these 899 cadaver donors, 800 contralateral kidneys from the same donors were used in 628 patients undergoing KAT and 172 patients undergoing simultaneous PKT. Data on the remaining 99 contralateral kidneys were missing. These 800 paired control patients were the basis of this analysis, which included follow-up information reported to UNOS through October 2001.
Graft, patient, and rejection-free survival rates were estimated with the use of the product-limit method. For graft survival, the death of a recipient was treated as a graft failure regardless of graft function status at the time of patient death. For functional graft survival, all patient deaths except deaths with a functioning graft were treated as failure. For rejection-free graft survival, the end point for all patients was based on the first rejection episode after transplantation. Graft loss resulting from acute or chronic rejection was considered as rejection in rejection-free graft survival. Graft loss resulting from nonimmunologic causes and patient death were censored in rejection-free graft survival. A multivariate Cox regression analysis was performed to determine the risk factors for graft rejection among patients who survived at least 3 months beyond transplantation. The following potential risk factors were studied in this rejection-free multivariate analysis: age, percent peak panel reactive antibody (PRA), duration of dialysis, race, cold ischemia time, human leukocyte antigen (HLA) matching, and types of transplant (LKT, KAT, or PKT).
The Wilcoxon rank-sum test was used to compare continuous variables, the chi-square test was used to compare categoric variables, and the log-rank test was used to evaluate differences in the survival curves for the three groups of recipients. Whenever the results of HLA-A, B, or DR antigen typing for donor or recipient were not available, the cases were treated as HLA-mismatched transplants. All statistical tests were two-tailed.
The demographic and clinical characteristics of the three groups (LKT, KAT, PKT) are shown in
Table 1. There were no significant differences among the groups with respect to the recipient height or sex, or to the donor weight, sex, or race. There were younger recipients, higher PRA, longer duration of dialysis, more African American recipients, longer cold ischemia time, and more zero HLA-A, B, and DR antigen-mismatched transplants in the KAT group compared with the LKT group. In the PKT group, there were significantly younger and less-sensitized recipients, shorter duration of dialysis, fewer retransplants, and fewer grafts from younger donors and trauma donors than in the LKT group. At the time of transplantation, approximately half of the LKT patients were hospitalized (50% were in the intensive care unit or on life support). In contrast, only 3% of KAT and 1% of PKT patients were hospitalized at the time of transplant ( P <0.0001). Table 1:
Table 1. Characteristics of Recipients, Donors, and Transplants
Graft and patient survival rates were significantly lower among LKT patients compared with KAT (
P <0.001) and PKT patients ( P <0.001) ( Fig. 1). The decreased graft and patient survival rates among LKT patients were caused by the higher patient mortality rate, particularly during the first 3 months posttransplant. Indeed, after excluding patients who died during the first 3 months, graft survival was comparable among the three groups. Functional graft survival was also comparable ( Fig. 2). Among the patients who died during the first 12 months, infection as the major cause of death occurred more often among LKT patients (8%) compared with KAT (2%) ( P <0.001) and PKT patients (2%) ( P <0.01). Figure 1:
Comparison of graft and patient survival rates of patients undergoing liver-kidney transplantation (LKT), pancreas-kidney transplantation (PKT), and kidney alone transplantation (KAT).
Comparison of functional graft survival rates of patients undergoing LKT, PKT, and LKT.
There was a significantly higher rate of dialysis required during the first week among the KAT recipients (27%) compared with the LKT (18%) (
P <0.001) and PKT recipients (8%) ( P <.001). However, the incidence of rejection requiring treatment during the initial hospital stay was similar among the three groups. The mean serum creatinine levels at discharge were significantly lower among the LKT (1.7±1.3 mg/dL, P <0.001) and PKT recipients (1.8±1.4 mg/dL) compared with the KAT recipients (3.0±2.6 mg/dL, P <.001). The mean length of hospital stay was the longest among the LKT recipients (32.6±2.0 days) compared with the KAT (13.0±1.0 days, P <0.001) and KPT recipients (20.9±19.4 days, P <0.001).
When zero HLA-A, B, and DR antigen-mismatched transplants were excluded, the overall rejection-free survival rate of the LKT patients was significantly higher than those of the KAT and PKT patients. The 1-, 3- and 5-year survival rates were 71%, 64%, and 57% among the LKT patients compared with 62%, 55%, and 44% among the KAT patients and 57%, 48%, and 47% among the PKT patients (
P <0.001 vs. KAT, P =0.001 vs. PKT), respectively. These differences were more apparent among HLA-mismatched and sensitized patients (PRA>10%) ( Fig. 3). The results of multivariate Cox regression analysis are shown in Table 2. The risk of allograft rejection was significantly higher among the KAT and PKT recipients compared with the LKT recipients after adjusting for other factors. Other significant risk factors of graft rejection among recipients who survived more than 3 months were age less than 50 years, PRA less than 10%, African American race, and HLA-mismatched grafts. Figure 3:
Comparison of rejection-free graft survival of sensitized and human leukocyte antigen (HLA)-mismatched patients undergoing LKT, PKT, and KAT who survived longer than 3 months after transplantation.
Table 2. Results of multivariate Cox regression analysis for rejection-free survival
The incidence of acute rejection requiring treatment during the initial hospital stay was comparable among the three groups: LKT recipients (13.9%) versus KAT recipients (15.8%) versus KPT recipients (17.4%) (
P =not significant). However, the 6-month cumulative acute rejection rate was significantly lower among LKT recipients (21.5%) versus KAT recipients (30.1%, P <.001) versus KPT recipients (33.1%, P <.001).There was a significantly lower incidence of graft loss resulting from chronic rejection among LKT patients compared with the other two groups (LKT group 2% vs. KAT group 8%, P <0.001; LKT group 2% vs. PKT group 6%, P <0.001) ( Table 3). Table 3:
Table 3. Primary causes of graft loss
Approximately 20% of patients undergoing OLT demonstrate renal insufficiency (
), and approximately 2% of patients undergoing OLT require combined LKT ( 1 ). Despite earlier reports suggesting improved kidney graft survival in LKT recipients, this benefit was not supported by an analysis of the Kidney Transplant Registry database comparing the outcomes of kidneys used in combined LKT with contralateral kidneys that were used in KAT ( 19 ). Our analysis is of a similar design but with three times as many patients, an additional 5 years of follow-up, and inclusion of contralateral kidneys used in PKT. Nevertheless, we confirmed the previous findings of Katznelson and Cecka ( 18 ) that graft and patient survival rates were significantly lower in the LKT group compared with the KPT and KAT groups. We showed that the decreased overall survival rate resulted from the high posttransplant mortality rate occurring during the first 12 months, particularly during the first 3 months, which was related to the severity of these patients’ pretransplant medical conditions as evidenced by the proportion of patients hospitalized in intensive care units at the time of transplantation. Hospitalization in the intensive care unit at the time of transplant and renal failure have been independently associated with decreased 6-month survival among patients undergoing OLT ( 18 ). As demonstrated in this study, sepsis was the most common cause of death among patients who died during the first year after OLT ( 1,3,20–22 ). If patients who died during the first 3 months were censored, long-term graft and patient survival rates in the three groups were similar. 21
A potentially inherent flaw in any overall comparison between KAT and simultaneous LKT or KPT is the inability to control for the differences in baseline characteristics among the three groups. Cold ischemia time will invariably be longer in KAT because of the less urgent nature of KAT compared with LKT and PKT. Indeed, in this study, the preoperative parameters of the LKT and KPT groups were well matched, especially with respect to cold ischemia time, which had a significant bearing on the early renal allograft function during the initial hospitalization. Graft function was superior for LKT and PKT patients when compared with KAT patients, and this was apparently because of the significantly shorter cold ischemia time of allografts for LKT and PKT patients. However, with respect to early acute rejection rates, the three groups were similar during the early perioperative period. Despite the comparable cold ischemia time of the LKT and PKT groups, the cumulative rate of acute cellular rejection of the PKT group at 6 months was similar to the KAT group and significantly higher than the LKT group. This indicates a possible immunologic advantage with LKT that is not seen with PKT and KAT.
The potential allograft-enhancing effect of the liver allograft on other organs from the same donor is controversial. Animal studies involving pig and rat models have shown that liver allografts confer a state of immune tolerance that extends to grafts of other organs, including kidney, heart, and skin transplants (
). Several immunologic mechanisms for this phenomenon have been proposed. The development of anti-idiotypic antibodies to major histocompatibility complex (MHC) class I and II antibodies immediately after OLT inhibits activity against mismatched donor HLA antigen, and the failure of this to occur results in early graft loss, indicating an important role of anti-idiotypic antibodies to anti-MHC antibodies in the tolerance of allografts ( 15,23 ). In addition, absorption of lymphocytotoxic antibodies onto reticuloendothelial cells of the liver allograft may also explain the resistance of the liver to antibody-mediated rejection ( 24,25 ). Soluble MHC class 1 molecule, which is principally made in the liver ( 14 ), may inhibit cytotoxic T-lymphocyte activity. Another important mechanism is the development of hematopoietic chimerism occurring after liver transplantation. If maintained, this would inhibit cell- and antibody-mediated injury to kidney allografts ( 25 ). Knoop, Pratt, and Hutchison also proposed the important role of T-suppressor cells in promoting tolerance after OLT ( 17 ). 26
In contrast with renal transplantation, histocompatibility testing, and T- and B-cell crossmatches are not heavily weighted before OLT or LKT from the same donor, despite a few studies showing a deleterious effect of a positive crossmatch on liver allograft survival and rejection (
). Earlier reports showed that combined LKT from the same donor conferred an allograft-enhancing effect on the renal allograft even in patients with strong crossmatches and HLA-incompatible transplants ( 27–29 ). In their series of 12 patients, Fung et al. showed that all four patients with a positive crossmatch converted to a negative crossmatch along with a decrease in PRA after LKT ( 8,11 ). Most of the case series from single centers have reported a lower incidence of acute and chronic rejection of the renal allograft in LKT compared with KAT. However, a later study from the same institution reported decreased patient and graft survival among those with a positive crossmatch and high levels of PRA with 50% of graft loss in patients as the result of cellular rejection ( 7 ). 30
Katznelson and Cecka demonstrated identical functional renal graft survival in patients with more than two HLA mismatches or high pretransplant levels of PRA (PRA >50%) in the KAT and LKT groups (
). In contrast, our analysis supports the belief that the liver is enhancing to the renal allograft. Among HLA-mismatched and sensitized patients, rejection-free survival was highest among the LKT patients. Graft loss secondary to chronic rejection was also significantly lower among the LKT patients. The reasons for these divergent findings compared with the findings of Katznelson and Cecka are not apparent except that our study had substantially more patients and a longer follow-up. 18 CONCLUSION
The medical condition of patients undergoing combined LKT is more serious compared with patients undergoing KAT and KPT, which accounts for the high rate of peri-transplant mortality in LKT patients. Our data provide further clinical evidence that the liver allograft may confer an allograft-enhancing effect in the kidney. The full utility of LKT may be reached when peri-transplant intensive care management for liver failure has matured.
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