Late Acute Rejection After Liver Transplantation: The Western Canada Experience Alnoor Rdmji, * Eric M. Yosbidu,* Vincent G. Buin,' Normun M. Knetemun," Cburles H. Scudumore, Mung M. MU,' Urs P. Steinbrecber, * Kluus S. Gu@eund,l Siefiied R. Erb, * Nilufdr Purtovi,' Stephen 'W: Cbung,fJdmes Sbupiro," und Winnie KS. Won?
'
Acute rejection usually occurs within 3 months posttransimmunosuppressants,such as tacrolimusand mycoplantation. Most centers reduce immunosuppression over phenolate mofetil, have reported lower incidence, 6 to 12months to minimize opportunistic infection, milder severity, and less steroid-resistant acute rejecmalignancy, and drugtoxicity. Pretransplant disease and tion.6-8 Accordingly, most centers now wean patients low immunosuppression have been reported in associafrom immunosuppression in the first year posttranstion with late acute rejection(LAR). The objective ofthis study was to determine the incidence, predictive factors, plantation and attempt to discontinue steroids in the and outcomes of LAR via retrospective review of adult first 6 months.9 In most cases, a significant degree of liver transplant recipients in Western Canada from1989 graft immunotolerance occurs,possibly throughthe to 2000. LAR was defined as biopsy-proven acute rejecmechanism of microchimerism,l 0 and maintenance tion occurring more than 180 days posttransplantation. immunosuppression can be successfully tapered to minPatient characteristics,immunosuppression, and outcome were determined. Both a univariate and multiple imal levels. logistic regression analysis were performed. LAR occurred Acute rejection occurring after the immediate and in 97(23%) of415 patients morethan 180days posttransearly posttransplantation period is termed late acute plantation. Median follow-up was 402 days (range, 180 to rejection (LAR); however, there is no uniform defini3137days); 79% of LAR episodes were graded mild. At the tion. Despite the fact that there are reports of patients A total of 73% time of LAR, 33% were on a steroid taper. of LAR episodes were treated with pulse intravenous ste- who are able to completely withdraw from immunoroids, and 5% were steroid-resistant. In the univariate suppression withoutadverse effects,11,12there is a conanalysis, patients undergoing transplantation for viral etitinued risk ofrejection in patients who have had tapered LAR. ologies and older agewereassociatedwithless Immunosuppression was significant in a multiple logistic from immunosuppression. Importantly, LAR canbe associated with arisk of graft lossand morbidity.l 3 > I 4In regression model, but not with a proportional hazards model. On multivariate analysis, only patients undergoprevious investigations of LAR, multiple factors have ing transplantationfor viral etiologies remained resistant been assessed, searching for possible associations. to LAR (hazard ratio, 0.52; range, 0.34 to 0.93, P = .02). Underlying liver disease and cyclosporine levels have There was a trend toward increased chronic rejection in been reportedly associated with LAR2,5,l5;however, patients who developed LAR (P= .04). LAR is common published studies have failed to consistently show an and occurs after more than 1 year posttransplantation. Patients undergoing transplantation for viral etiologies association between rejection and HLA compatibility, seem to havealowerriskof There maybe an increased risk of chronic rejection in those developing (Liver Trunspl2002;8:945-951.) From the *DepartmentsofMedicine and fSurgey,the University of
LAR.
LAR.
P
osttransplant survivalhas continuedtoimprove such that both patients and clinicians can anticipate a l-year survival of 85% and 3-year survival of 78Yo.l With improvedpatientand graft survival, increasingattention is being focused on long-term maintenance immunosuppression with a view to minimizing the adverse effects of immunosuppressive drugs. Although acute rejection continues to be a frequent posttransplantation most acute rejection occurs in the first 3 months posttransplantation3 and more patients die of infection thanrejection, suggesting a possible historic trend toward overimmunosuppression.5 In the past decade, studies of the newer
British Columbia, Vancouver, BC; the #Department of Pharmacy, the Vancouver GeneralHospital and the British Columbia Transplant Socieg, Vancouver, BC; and the Departments of §Medicine and JJSurgey, the University ofAlberta, Edmonton, AB, Canada. Results of this study werepresented in posterform at the 50th Annual Meeting of the American Association for the Study of Liver Disease, October 2000, D a l h , X . Supported in partby an unrestricted researchgrant fiom FujisawaCanada, Inc. Address reprint requests to Eric M . Yoshida,MD, FRCPC, Division of Gastroenterology,Vancouver GeneralHospital, 100-2647 Willow St, Vancouver, BC, V52 3P1, Canada. Telephone: 604-875-5371; FAX: 604-875-5447; E-mail: eyoshida@interchange. ubc.ca Copyright 0 2002 by the American Association for the Study of Liver Diseases 1527-6465/02/0810-0014$35.00/0 doi:l 0.1053/jlts.2002.34969
Liver Transplantation, Vol8, N o l0 (October), 2002:pp 945-951
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Ramji et a1
cytomegalovirus (CMV) mismatch,gender, and preservation injury.I6-l9 Overall, there havebeenrelatively few studies of LAR after liver transplantation. Immunosuppression, in particular, has not been well studied in this context. The schedule oflong-term immunosuppressive maintenance therapy remains largely empiric, and center-specific. Moreover, withinmost centers, patients are treated with the same immunosuppression schedules andthe underlying assumption is that all grafts have similar risks ofrejection. The last study of LAR was performed at oneof our two centers in 1993,12 and LAR continues to occur despite the greater varietyof available immunosuppressive agents since that time. We decided to review LAR in Western Canada to determine its incidence, predictive factors, and outcome. In particular, we were interested in the immunosuppression regimen.
Patients and Methods A retrospective chart review was performed on all liver transplant recipients from the two transplant centers in Western Canada,EdmontonandVancouver,between1989and March 2000. The study period incorporated the conversion from gelatin capsule cyclosporine (Sandimmune; NomartisQC) microemulsion to cyclosporine Canada, Domal, (Neoral; Nomartis-Canada) in 1993 and the introduction of tacrolimus (Prograf; Fujisawa-Canada, Markham, ON), mycophenolatemofetil(Cellcept;Roche-Canada,Mississauga, O N ) in 1996, and sirolimus (Rapamune; Wyeth-AyerstCanada,Toronto,ON)in1999.Muromonab-CD3 (Othoclone OKT3; Janssen-Ortho, Toronto, ON) was used forinitialpostoperativeinductionimmunosuppressionin Vancouver from 1989 and discontinued inearly 1996. Similarly, Minnesota ALG as an initial induction agent was discontinued in Edmonton in 1993. LAR was defined as clinically suspected (on the basis of elevated liver enzymes) and biopsy-proven acute rejection, occurring at or more than 180 days after transplantation. Exclusion criteria wereage less than 18 years, and a follow-up period of less than 6 months. Incases in which a patient had more than one LAR, only the first biopsy-proven rejection was counted as an event. Demographic characteristics collected included recipient age, gender, underlying liver disease at transplantation,C M V status, and induction and maintenance immunosuppression. Underlying liver disease was categorized into autoimmune, viral, alcoholic, or primary nonviral hepatoma. Transplantation for toxin-induced metabolic diseases, fulminant hepatitis, and cryptogenic states were combined. The autoimmune (PBC), primary category included primary biliary cirrhosis sclerosingcholangitis(PSC),andautoimmunehepatitis. Viral etiology included hepatitis B, hepatitis C, concurrent alcoholic liver disease with hepatitisB or C, and hepatocellu-
lar carcinoma secondary to hepatitis B or C. Donor characteristics of age, gender, and C M V status were also collected. Severity of LAR was categorized as histologically mild, moderate, or severe acute rejectionz0; biochemical measures were included. Immunosuppression and steroid taper, including drug dosages and drug serum levels atrejection,and changes within the prior 8 weeks were noted. Patients were followed up for response to rescue therapy. Early acute rejection(EAR) was defined as histologicallyconfirmedacute rejection occurring less than 180 days posttransplantation. Chronic rejection(CR) was diagnosed by standard histologic criteria.21 Patients were followed up through the last visit or communicationwiththetransplantationclinics.Immunosuppression regimen and serum levels within 2 months of final follow-up were considered. Further duration of steroid discontinuation or last steroid dose was recorded. Patients were followed up for progression to chronic rejection, recurrent or de novo liver disease, malignancy, graft failure with retransplantation, and death. Univariate and multivariate analysis were conducted for predictive factors and outcome measuresLAR. of Categorical complications of LAR (chronic rejection, recurrent disease, malignancy,retransplantation,anddeath) were compared between patients with and without LAR by Chi-squared or Fisher’s exact test. Student’s t-test or Wilcoxon rank sum test was used to analyze continuous variables. Because of thevariation in follow-up duration of the cohort, predictive (categorical variables) factors are determined by examining LAR-free survival usingunivariateandmultivariateCox regression. Multivariate analysis was also performed using multiple logistic regression, both forward and backward stepwise. T h e level of significance for a two-tailed test was set at .05 (P< .OS). Analyses were performed using the computer statistical software package SAS, version 8.0 (SAS Inc, Cary, NC).
Results During the study period, 524 transplantationswere performed in 506 recipients. One hundred nine transplantations were excluded because aoffollow-up ofless than 6 monthsfromtransplantationor because the recipient was not anadult (age at transplantless than 18 years). Four hundred fifteen transplantations in 397 recipients werereviewed for episodesof LAR, with median follow-up of 1180 days (range, 18 1 to 3756 days). The study population consisted of 234 (56%) male and 181 (44%) female patients. The most commonindications for transplantation wereend-stage liver disease secondaryto chronicviral hepatitis (33%). Hepatitis C accounted for 105 (25.5%)transplantations, hepatitis B for 27 (6.5%), and hepatitis B and C coinfection for 2(0.5%). One hundred twenty-two (29.5%) patients underwent transplantation for autoimmune diseases, with the majority (16. l YO)being for
Acute Late
TaMo l. Reasons for Liver T
Etiology of
Disease Liver
Viral 18 Chronic HBV carcinoma HBV + hepatocellular (0.5) HBV + HCV (0.2) 1 + alcohol HBV HBV + HDV (0.2) HCV HCV + alcohol carcinoma (1.5) 6 HCV + hepatocellular HAV Acute Immune-mediated Autoimmune hepatitis cirrhosis biliary Primary Primary sclerosing cholangitis diseaseliver Alcoholic Alcohol (1 Alcohol + hepatocellular carcinoma (0.5) 2 Others Retransplantation Cryptogenic (1.7) Fulminant 7 failureliver Miscellaneous
r
Rejection in Western Canada
~
~
No. of Patients (%) (N = 415) 136 (32.8) (4.4) 8 (1.9) 2 1 81 (19.5) 18 (4.3)
122 (29.4) 23 (5.5) 67 (16.1) 32 (7.7) 46 (11.1) 44 0.6) 111 (26.7) 26 (6.3) 29 (7.0) 49 (11.8)
p
947
remained LAR-free during the study period (Table 2). ~ ~of liver ~ disease ~ at transplantationwas a signifEtiology icant factor. Those patients undergoing transplantation with a pretransplantdiagnosis of viral liver disease were less likely to develop LAR (hazard ratio, 0.55; range, 0.33 to 0.91). The age of a patientwas also a predictive factor for LAR. The patients who developed LAR were younger, with mean a age of45.7 years, compared with 49. l years in those who did not develop LAR (P= .O 1). Patients undergoing transplantation at one of the tenters (Alberta) wereless likelyto develop LAR compared with thoseat the other center (hazard ratio, 0.66; range, 0.44 to 0.98). Recipient gender and CMV status and EARS were not predictiveof the developmentof LAR. In those who had an episode of EAR (n = 203), treatmentwithintravenous steroids was associated with lower risk of LAR (hazard ratio, 0.41; range, 0.23 to 0.71). In theanalysis of maintenance immunosuppression, cyclosporine was compared with tacrolimus. Immunosuppression either at the time of transplantation or at the timeof LAR (or at follow-up for those who did not develop LAR) were predictive of LAR only if LAR was categorized as a binary variable (i.e., present or absent) and analyzedbylogisticregression. In this analysis,
PBC. Alcoholic liver disease accounted for 46 (1 1.1Yo) transplantations (Table 1). Table 2. Demographic Characterkics md Predictive In this group of 4 15 transplantations, there were 97 Factors €or LAR:Univariatt:Analysis, LAR-Free Sunrival episodes of LAR (23%). LAR occurred at a median (Cox Regression) posttransplantation time of 402 days (range, 180 to 3 137 days). The posttransplantation period between 6 Hazard Ratio P months and1 year accounted for 43% of LAR episodes. Characteristics Patient (95% CI) Value At LAR, 32 (33%)of patients had undergone asteroid disease liver Viral 0.55 (0.33-0.91) .02 taper within the prior 8 weeks, 15 (16%) were not on Transplantation (0.44-0.98) 0.66site .04 any steroids, and 48 (50%) had a steroid dose of predMale donor 1.04 (0.62-1.72) .89 Male 0.80 (0.54-1.19) .27 nisone 5 mg or less daily. In those whodeveloped LAR, recipient 5 45 y) 1.18 (0.79-1.76) .41 Young recipient (age 17 (l8%) hadhadsubtherapeutic cyclosporine or Recipient CMV positivity 0.92 (0.60-1.40) .69 tacrolimus levels at least once during the preceding 8 Use of intravenous steroids in weeks, 4 in the tacrolimus group (level 5 5 ng/mL) and FAR 0.41 (0.23-0.71) .002 13 in the cyclosporine group (level 5 100ng/mL). Immunosuppression: Cyclosporine regimen at When evaluated by biopsy, 79% of LAR episodes were time transplantation* of 1.30 (0.57-2.97) .54 graded as mild, 18% as moderate, and 3% as severe Cyclosporine regimen at rejection. The majority of LAR episodes (70%) were of time LAR* 0.36 (0.19-0.69) .002 treated with intravenous steroids (i.e.,pulse methylCyclosporine maintenance regimen last atFollow-up* 1.60 (0.87-2.94) .l3 prednisolone), and the rest of the rejection episodes were treated with an increase in oral prednisone or a Abbreviations: LAR, late acute rejection;CMV, cytomegalovirus; EAR, early acute rejection. change in calcineurin inhibitor agent(i.e., cyclosporine *Risk of LAR with cyclosporine versus tacrolimus regimens at to tacrolimus). Six percent of LAR episodes were stethree observation points: initial timeof transplantation time roid-resistant and required OKT3. of LAR, and time of last follow-up (i.e., long-term maintenance regimen). Univariate analysis ofpatient characteristics ofthose who developed LAR were compared with those who
948
Ramji et al
LAR was more likely to develop in patients who were
1.oo treated with maintenancecyclosporine compared with 0.95 tacrolimus, 28% versus 14% respectively (P= .006). When the data set was analyzed with a Cox propor0.90 tional hazards model, in which the likelihood ofLAR0.85 free survival overtime was examined, immunosuppres0.80 sion was not predictive of LAR (hazard ratio, 1.6; range, 0.87 to 2.94). In the study cohort, we note thatpatients 0.75 treated with tacrolimus had a shorter median follow-up 0.70 when compared with patients treated with cyclospor0.65 ine, 844 days versus 1429 days (P<.OOl). In the subgroup of patients who developed LAR, the LAR-free 0.60 survival was longer in those whowere on cyclosporine at the time of LAR (hazard ratio, 0.36; range, 0.19 to 0 1000 2000 3000 0.69). Kaplan-Meier plots of LAR-free survivalaccordDays Post Transplant ing to various predictive factors are shown in Figure 1 . The independence of predictivefactors was analyzed using multivariateanalysis: etiology at transplantation, 0.95 age, gender, presence of prior EAR, and maintenance immunosuppression. O n multivariate analysis, only patients undergoing transplantation with a pretransplantation diagnosis of viral liver disease(hazard ratio, 0.80 0.52; range, 0.34 to 0.93, P = .O2) were found to be less 0.75 likely to develop an episodeof LAR. 0.70 Patients were followed up for CR, recurrent liver cyclosporine 0.65 disease, biliary complications, graft loss, and death. In patients with anLAR episode, CR developed in 9 (9%), I v whereas CR developed in only 12 (4%) patients who -~~ts n did not have an LAR episode. Overall the number of 0 1000 2000 3000 casesof CR that developed is low. There was no Days Post Transplant increased risk ofrecurrent liver disease, biliary complications, graft loss, or death in patients who had experiFigure 1. Kaplan-Meier plots of LAR-free survival based enced an LAR episode (Table3). on univariate precictors.(A) Etiologyof liver disease(hazard ratio,0.55; 0.33-0.91; P = .02). (B) Immunosuppression (at time of LAR for those with LAR and at last fol-
‘m ’,
I
Discussion
The majority of acute rejection (40% to 60%) occurs in the first few months after liver transplantation,3,6J and most centers aim to taper off steroids in the first 6 monthsposttransplantationandminimizemaintenance immunosuppression within the first year. Although this reductionintheimmunosuppression regimen is driven by the need to reduce the risks of immunosuppression,includingopportunistic infection, malignancy, and drugtoxicity, it is also clear that LAR canoccur. In ourstudy, we found a 23% incidence of LAR,with more than half of these episodesoccurring morethan 1 year posttransplantation. Other studies have reported lower rates of LAR (7% to 10%).2,22~3 Our finding of a higher rate of LAR may be related to the longer median follow-up time in our study,because more than 50% of LAR cases occurred after the first
I
I
low-up evaluation for thosewith no LAR) (hazard ratio, 1.60; 0.87-2.04; P = .14).
year posttransplantation and the mean follow-up time was longer in those cases in which LAR developed, compared withthose in which it did not. Thediffering incidences may also be reflectivedifferent of definitions ofwhat constitutes LAR (i.e., more than6 v 12 months posttransplantation)or greatercenter-specific histologic surveillance of thesepatients. In our study we found that the etiologyofliver disease at the time of transplantation was predictive of LAR. Patients undergoing transplantationfor viral liver disease had fewer LAR episodes as determined by multivariateanalysis(hazard ratio, 0.52). Previous studies5,l5 have alsodescribed lower rates of acute rejection in those undergoing transplantation for viral liver dis-
949
Late Acute Rejection in Western Canada
Complication
LAR (%) (n = 97)
NOLAR (Yo) (n = 318)
Chronic rejection Recurrent disease Malignancy Retransplantation Death
ease. The mechanism by which patients with primary viral disease seem to be less likely to develop LARis unclear. Some have suggesteda persistent defect in cellmediated immunity.5,*5,23 It is alsoaccepted that patients undergoingtransplantation for hepatitis C who are treated for rejection have a higherrate of disease r e c ~ r r e n c e In .~~ patients with hepatitis C and elevated liver biochemistry, sometimes onlyclearly moderate to severe episodes ofacute rejection are treated and histologically mild episodes on a background of graft hepatitis may be managedexpectantly.Furthermore,the biochemical and histologic findings in recurrent hepatitis C and mild rejection can be similar, thereby creating an element of uncertainty in the actual diagnosis. Theoretically, possible episodes of rejection may becategorized as grafi hepatitis, especially if they do notlead to treatment with increased immunosuppression, thereby creating aclassification bias. In our cohort, we think thatthis is unlikely because diseaserecurrence was similar in patients with and without LAR. LAR episodes in our patients also resolved with therapy, which would be atypical for viral grafi hepatitis. Autoimmune liver diseases have previously beenreported to be a risk factor for increased acute rejection, particularly in the first 6 months po~ttransplantation.59~5 It has been suggested that this is secondary to a hyperactive immune system. In our study, we could not detect astatistically significant increasedriskof LAR in this group of patients. Whenourcohort was categorized into immune versus nonimmune etiology, there was a trend toward increased LAR in theautoimmunegroup, but this did not reach significance (hazard ratio, 1.5; P = 3). In our cohort, patients with EAR did not have an increased risk of LAR. This finding is consistent with findings that have been reported previously.2 Interestingly, we found that patients treated with intravenous steroids for EAR had a lower risk of LAR. This may suggest that in somepatients who do notdevelop EAR, either immunologicanergymay not be completely
Odds Ratio CI)(95% 2.58 (1.05-6.33) 4.13 (0.52-33.0) 0.93 (0.30-2.91) 1.68 (0.61-4.61) 0.95 (0.48-1.90)
P Value .04 .l8 .9 1 .3 1 .89
achieved with standard maintenance immunosuppression despite normalliver biochemistry, and thegraft is at risk of immunologic rejection when immunosuppressive medications are tapered, or anepisode of EAR somehow increases the likelihoodof later immunologic tolerance. LAR as a reflection of incomplete immunologic anergy/toleranceis supported by reports that LAR has been associatedwith subtherapeuticlevels of cyclosporineinup to 50% of patients withInour patients, we found that at the time of LAR, 33% of patients had undergone a recent prednisonetaper, and 18% had had subtherapeuticlevels ofimmunosuppression during the prior 8 weeks. We were not, however, able to show that the overall maintenance steroid dose was different in patients developing LAR. In terms of steroid-resistant rejection, our cohort showed a relatively low rate,with only6% requiring OKT3. There is little published information onsteroid-resistant LAR In the three large clinical tacrolimus versus cyclosporine studies,GJ,25a lower riskof EAR was reported in thetacrolimusarm. When we looked attacrolimus versus cyclosporine use as a variable for increased risk of LAR, we found tacrolimus was less likely to be associated with LAR on logistic regression analysis, but this same finding was not present when the datawere analyzedusing a Cox proportional hazards model. An important difference between these two statistical models is the temporal factor. A multiple logistic regression model does not take time into account assumes and that all events occur at a similar time point. The proportional hazards model assesses the riskof the events occurring over time. It could be argued that because tacrolimus is a slightlynewer immunosuppression agent than cyclosporine, these patients would have .a shorter follow-up period. Patients who were on tacrolimus therapy could therefore favorably be biasedtoward an apparentlower risk ofrejection. Because the median time to LAR in ourstudy was 400 days and the median time of follow-upfor the tacrolimus group was 844.days (1429 days for the cyclosporine group), this seems less
Ramji et al
likely. Because the proportional hazards model assessed a relativelysmall number of events over a longperiod of time, itis also possiblethat afailure to find asignificant difference reflected a type I1 error. Another aspect of our study was that the time period included a period when Canadian centers where changing the cyclosporineformulationfromthe gelatin capsule(Sandimmune)tothe microemulsion preparation(Neoral). These two differing formulations of cyclosporine were grouped together in our analysis, but it is possible that because there are pharmacokinetic differences between theproducts, our analysismayhave had somebias againstcyclosporine. With regard to the two other newer immunosuppressive agents, mycophenolate mofetil and sirolimus, there were not enough patients to allow any meaningful analysis. Another interesting aspect of this study was that on univariate analysis, thetransplantcenter seemed to affect the risk of LAR, with one center experiencing more LARS than the other. We note that there was no difference in the type of immunosuppression, primary indication for transplantation, or length of follow-up between the two transplant centers. There may be several reasons for this apparent difference in specific-specific risk of LAR. Half of the patients at one of the centers (Alberta) were followed up by a regional clinic in anothercity where liver biopsy was less readily available. This introduces thepossibility of surveillance bias in which alower risk of LAR may be a result of underdiagnosis when the definition of rejection is made on histologic grounds. Another possibility is that the specific center thatexperienced a greater likelihood of LAR may have been more willing to biopsy patients on the basis of abnormalliver biochemistry, thereby increasing the chances of a positive diagnosis. Because the overall outcome between the two centers in terms of patient and graft survival is similar, this may suggest that very mild cases of LAR,which are more likely to be missed if patients/physicians wish to avoid liverbiopsies, may not be a significant prognosticator of poor long-term outcomes. We note that in theearly 1990s, Dousset et a126 reportedthatsome casesofbiopsy-confirmed mild acute rejection may resolvespontaneously without any change in immunosuppressive therapy. Undoubtedly, some cases of biopsy-unconfirmed acute rejection may behave similarly. Lastly,we foundthat LAR was associated with increased chronic rejection (odds ratio, 2.58; P = .04), although the sample size wassmall, which may explain why wecould not show anincrease in recurrentdisease, retransplantation, or death in LAR patients. Backman et a127have shown that the most common causes of late
graft loss(more than 1 year posttransplantation) are chronic rejection and recurrent hepatitis; therefore, an association between LAR and CR could be a concern, making predictive factors for significant LAR important to assess. In summary, LAR is common and occurs beyond 1 year posttransplantation. Patientsundergoing transplantation for viral hepatitis seem to have a lesser riskof LAR, although the reasons for this are not clear. There may be an increased risk of chronic rejection in some patients in whomLAR develops; therefore, continuous monitoring of immunosuppression andliver biochemistry appears to be a perpetual necessity.
Acknowledgments The authors gratefully thank the nursing staff of the liver transplant clinics of the Vancouver General Hospital (University of British Columbia), the University of Alberta, and the Universityof Calgary for their dedicated support of these patients.
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