The clinical course of the 16 patients with PSC recurrence after the first liver transplantation is shown in Figure 2. After PSC recurrence, graft failure occurred within a median of 33 months (range, 9-131 months) in 15 of the 16 patients, case 16 being the exception. Among patients who experienced graft failure, 10 (no. 1-10) underwent retransplantation using a graft from a blood-related living-donor (n = 7), unrelated living-donor (n = 1) or deceased-donor (n = 2). Among these 10 cases, 6 patients developed re-recurrence of PSC at a median of 10 months (range, 7-16 months) after retransplantation, with 1 patient passing away 2 months after the retransplantation (no. 10). Liver failure developed in 3 (no. 1-3) of the 6 patients with PSC rerecurrence. Among these 3 patients, 1 (no. 1) underwent a third transplantation using a deceased-donor graft, but experienced a third recurrence of PSC at 53 months after the third transplantation. The other 2 patients were on a waiting list for DDLT at the end-point of analysis for our study. Therefore, 6 of the 7 patients (no. 1-7) who underwent retransplantation for PSC developed a PSC rerecurrence over the 2-year follow-up. Among the 6 patients (no. 11-16) who did not undergo retransplantation, 5 patients died, 12 to 106 months after PSC recurrence.
Risk Factors for PSC Recurrence
Factors that could predict PSC recurrence were analyzed by comparing patients with (n = 16) and without (n = 24) PSC recurrence, after excluding the 5 patients who had ABO-incompatible LDLTs (n = 4) or hepatic artery thrombosis (n = 1). The results of all factors analyzed are summarized in Table S1, SDC (http://links.lww.com/TXD/A56) with representative results presented in Table 2. Recipient and donor HLA-DR15 status was analyzed in detail, as HLA-DR 15 is more frequently reported in recipients (18/39; 46%) than the incidence of HLA-DR 15 (14.8%) in Japan. On univariate log-rank analysis, the following factors were significantly associated with PSC recurrence: younger than 30 years at the time of PSC diagnosis (P = 0.031), positive donor HLA-DR15 status (P = 0.014), positive donor and recipient HLA-DR15 status (P = 0.028), active IBD after liver transplantation (P = 0.006), and positive CMV antigenemia within 3 months after liver transplantation (P = 0.019). No other significant associations were identified, including donor-recipient blood-relationship; HLA-A-, -B-, and -DR-matched number; and IBD before liver transplantation. On multivariate analysis, active IBD after liver transplantation was retained as a significant predictor of PSC recurrence (HR, 4.86; 95% CI, 1.61-14.7; P = 0.005).
Risk Factors for Graft Failure
The same variables were analyzed to identify predictive factors of graft failure, comparing the group of patients with (n = 30) and without (n = 15) graft failure (Table 2 and Table S1, SDC, http://links.lww.com/TXD/A56). The following predictive factors of graft failure were identified on univariate log-rank analysis: younger than 30 years at the time of PSC diagnosis (P = 0.005), female donor (P = 0.029), HLA-DR15 positive donor and recipient status (P = 0.032), and bacteremia within 1 year after liver transplantation (P = 0.014). On multivariate analysis, younger than 30 years at the time of PSC diagnosis (HR, 3.77; 95% CI, 1.28-11.1; P = 0.016) and bacteremia within 1 year after liver transplantation (HR, 2.38; 95% CI, 1.07-5.30; P = 0.034) were retained as independent predictors.
To evaluate the possible association between specific bacteria in blood and graft failure, a detailed analysis of blood culture to graft failure was performed, including the data from 42 patients for whom blood culture data were available (Table 3). The presence of Enterococcus sp (P = 0.014) and coagulase-negative Staphylococcus (P = 0.023) in blood culture was significantly associated with graft failure, with a tendency for graft failure for most other bacteria as well.
Association of Bacteria in Bile Culture With PSC Recurrence and Graft Failure
We next analyzed the association between bacteria in bile culture to PSC recurrence (Table 4). Among our patients who underwent liver transplantation for PSC, a bile culture was not obtained within 1-year posttransplantation in 4 patients, and the results for 3 other patients were not available. Therefore, these 7 patients were excluded from this analysis. Three (18%) of 17 patients in whom more than 2 bacterial strains were detected in bile culture within 1 year after liver transplantation had PSC recurrence, whereas 8 (50%) of 16 patients with 0 to 2 bacterial strains detected in bile culture experienced PSC recurrence after liver transplantation, suggesting that the number of bacterial strains in bile culture tended to be inversely correlated to PSC recurrence (P = 0.068). The detailed analysis of bacterial strains in bile culture revealed the following inverse association between the presence of bacteria/fungi in bile culture and PSC recurrence (Table 4): gram-negative rods (P = 0.041), Enterobacteriaceae (P = 0.023), and Candida sp (P = 0.048).
With regard to the association of bacterial strains in bile culture with graft failure (Table 4), the presence of Klebsiella sp in bile culture was significantly associated with graft failure (P = 0.010).
Based on the 20-year experience with LDLTs in our center, we report a high rate of PSC recurrence after liver transplantation and high graft mortality after PSC recurrence. The rate of graft failure at 10 years after liver transplantation, estimated by Kaplan-Meier analysis, was 67.2%. The cumulative incidence rate of PSC recurrence at 10 years after liver transplantation, analyzed by a competing risk method in our cohort, was 45.8%. Sixteen (40%) of 40 patients experienced a recurrence of PSC at a median of 30 months after liver transplantation, with 15 (94%) of these patients progressing to graft failure, even in cases of retransplantation.
A systematic review on PSC recurrence after liver transplantation reported a recurrence rate of PSC of 17% (161 of 949 patients) after liver transplantation for PSC, with a weighted recurrence rate based on the 14 studies included in the analysis of 11%.7 Moreover, 3 recent large multicenter studies in the United Kingdom, Germany, and the United States,8,9,11 which included long-term clinical course outcomes after liver transplantation, reported rates of PSC recurrence and graft failures which were lower than those in our current study. Using the same methods to calculate recurrence and survival rates as in our study, Gordon et al8 and Hildebrand et al11 reported rates 22.4% and 36.0% for PSC recurrence, and 10.5% and 37.6% for graft failure at 10 years after liver transplantation, respectively. Ravikumar et al9 reported that 81 (14.3%) of 679 patients who underwent a first liver transplantation for PSC developed a recurrence of PSC over a median follow-up of 9 years, with progression to graft failure identified in 37 (48.7%) patients. A Canadian single center experience by Moncrief et al12 showed that 15 of 59 patients (25%) who underwent liver transplantation for PSC developed PSC recurrence in a median follow-up of 68 months, with a rate of graft failure at 10 years after liver transplantation of 32.4%. Compared with these studies, our results clearly demonstrated a higher rate of PSC recurrence and higher rate of graft failure.
The specific reasons for the higher rate of PSC recurrence in our institute are unknown. The clinical characteristics of our study participants and our study design, including follow-up periods, protocol of immunosuppression, procedure for liver transplantation, and diagnostic criteria for PSC recurrence, are not different from those of previous reports.4-9 Our accuracy in diagnosis for PSC recurrence is also unquestionable, with all patients with PSC recurrence experiencing a rapid progression in disease status after diagnosis, these clinical findings providing evidence of PSC recurrence. Moreover, the diagnosis was confirmed by histopathological examination of the extracted liver graft at the time of retransplantation. The fact that PSC rerecurrence after retransplantation occurred in most of recipients is indicative of the likelihood of an important contribution of recipient-specific factors to recurrence of PSC. It is possible that ethnicity will be an important contributing factor to consider, with all of our patients being Japanese. Characteristics of PSC in Japan were revealed by a recent nationwide survey, identifying a second peak of PSC in the sixth decade of life and a low prevalence of IBD (37%).13 These results suggest differences in Japanese patients with PSC from those in the United States and in European countries. Race-specific differences might, therefore, explain the higher recurrence rate of PSC in our study group than in other previously reported studies. A report from another Japanese institute confirms this possibility, with PSC recurrence identified in 4 of 9 patients after liver transplantation.14
HLA typing is one of the factors that varies among races. We confirmed the importance of donor HLA-DR15 for PSC recurrence in our current study, which was in agreement with our findings in a previous study.5 This result suggests that HLA, or other genes located around HLA, in the liver (or bile duct) plays an important role in the pathogenesis of PSC. Since the donor HLA-DR15 contained both HLA-DR1501 and HLA-DR1502, as analyzed in our previous report,5 the association between liver HLA and PSC recurrence would not be caused by HLA-DR15 itself, but by the other genes associated with HLA-DR15.
As mentioned above, the nationwide survey of Japanese patients with PSC identified 2 age peaks for PSC occurrence, one at 35 to 40 years of age and the other at 65 to 70 years of age.13 In our current study, the median age of the study population at the time of diagnosis of PSC was 23 years (range, 1-60 years). Therefore, the majority of patients who underwent liver transplantation for PSC were in the younger age peak. In fact, we identified age <30 years at the time of PSC diagnosis as a risk factor of PSC recurrence and graft failure after liver transplantation. Therefore, Japanese patients with PSC can be divided into several subpopulations, with young PSC patients being susceptible to PSC recurrence after transplantation and likely to form a typical PSC subpopulation.
Active IBD after liver transplantation was identified as a factor for PSC recurrence on multivariate analysis. Because the presence and activity of IBD before transplantation is not associated with PSC recurrence after transplantation, the development of IBD activity after liver transplantation may have a causative relationship to PSC recurrence. Interestingly, Hildebrand et al11 reported results compatible to ours, demonstrating that patients with IBD, ulcerative colitis, and, in particular, those with an active colitis after liver transplantation were at a significantly higher risk for PSC recurrence. Furthermore, Alabraba et al4 reported that patients who underwent colectomy, before or during liver transplantation, were significantly less likely to develop PSC recurrence than patients who did not undergo colectomy at the time of transplantation or underwent colectomy postliver transplantation. From these results, we can consider that maintaining a remission state of IBD after liver transplantation may be a key protective factor against PSC recurrence after liver transplantation.
In our current study, we extensively analyzed the association between bacteria in bile and blood cultures with PSC recurrence and graft failure after liver transplantation. Surprisingly, positive findings of some bacteria/fungi in bile culture were negatively associated with PSC recurrence, indicating that these bacteria in bile after liver transplantation may exert a protective role against PSC recurrence. We suspect that stenosis of the biliary anastomosis would lower the bacteria in bile culture and could be involved in the pathogenesis of PSC recurrence. However, we did not identify a significant relationship between biliary anastomotic complication and the number of bacteria in bile culture. There might be a mechanism by which an early immune response to bacteria in bile duct would increase tolerance to an autoimmune reaction later. Overall, however, bacteremia within 1 year of liver transplantation was a significant risk factor for graft failure. Because most bacteria species in blood cultures were associated with an increased risk of graft failure, bacteremia itself, and not specific bacteria, would be a cause high mortality.
Initially, we expected that immunosuppressants used after liver transplantation might have been effective in offering protection from PSC recurrence, as well as in suppressing the progression of PSC after recurrence. Therefore, we analyzed the relationship between immunosuppressant therapy and PSC recurrence and graft failure in detail. However, we did not identify any effect of immunosuppressants on the rate of PSC recurrence or graft failure. It is possible that a more intensive immunosuppression therapy will be effective in preventing PSC recurrence and/or its progression. However, high dose of immunosuppressants would increase the risk of infection, with bacteremia itself being a risk factor for graft failure after liver transplantation, as we report in our study.
Limitations of this study were the retrospective study design and small sample size. Because the medical record did not include the detailed clinical information, such as the frequency of defecation and the erythrocyte sedimentation rate, the severity of IBD could not be analyzed. We have previously reported our 10-year experience with liver transplantation among 30 patients with PSC in 2009, and this report is an extension of the previous analysis.
In conclusion, PSC frequently recurred and progressed to graft failure after liver transplantation for PSC. Both genetic factors, including liver HLA type, and environmental factors, including IBD, CMV, and bacteria in bile duct, would contribute to the recurrence of PSC as well as to its progression. Maintaining an inactive status of IBD might offer protection against PSC recurrence. Further studies with a larger number of patients are required to clarify the risk factors for PSC recurrence in Japan and other Asian countries.
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