Risk Factor For Chronic Rejection Research Articles

Incidence and risk factors for chronic rejection in pediatric liver transplantation.

Chronic rejection (CR) is a progressive immunological injury that frequently leads to long-term liver allograft dysfunction and loss. Although CR remains an important indication for retransplantation, as transplant immunosuppression has evolved, its prevalence in adults undergoing liver transplantation (LT) has declined. However, the incidence and factors that lead to CR in pediatric LT are poorly defined. Therefore, we sought to systematically measure CR's incidence and assess both the risk factors for developing CR and outcomes in a large cohort of pediatric recipients of LT. In this single-center study, we retrospectively analyzed and compared relevant recipient characteristics, surgical details, immunosuppression, graft, and patient survival in the CR and control groups over a 17-year period. After a median time of 1.9 years after LT, 19/356 recipients of LT (5.3%) developed CR in our cohort. Posttransplant lymphoproliferative disorder ( p = 0.01), infections ( p = 0.02), autoimmune liver diseases (HR = 7.3, p = <0.01), Black race (HR = 11.5, p = 0.01), and 2 or more episodes of T cell mediated rejection (HR = 5.1, p = <0.01) were associated with CR development. The retransplantation rate among CR cases was 15.8% at a median follow-up time of 4.1 years. Overall, patient survival was lower in the CR group (78.9%) versus controls (91.1%). While CR incidence in our pediatric cohort was lower than previously reported rates of >12%, the CR group had a higher graft failure rate that required retransplantation and lower overall patient survival. Thus, identifying risk factors may warrant specialized immunosuppression protocols and closer posttransplantation monitoring to reduce the risk of morbidity and mortality from CR.

Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection.

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.

Factors Associated with Chronic Rejection in Liver Transplant Recipients: A Retrospective Cohort Study From Shiraz Organ Transplant Center.

Identification of chronic rejection risk factors in liver transplant recipients is critical for early detection and prevention of further graft loss. We investigated characteristics of liver transplant recipients who had experienced chronic rejection and the associated risk factors versus patients without chronic rejection. Data from 3022 adult liver transplant recipients between 2011 and 2018 were analyzed; of these, 80 patients had experienced chronic rejection. The control group included 98 randomly selected liver transplant recipients who did not have chronic rejection. The age of the recipients and the donors was significantly lower in the group with chronic rejection versus the group without chronic rejection.The results indicated that chronic rejection was significantly associated with the sex of the recipients (hazard ratio 3.2, 95% CI 1.77-6.08; P < .001) and with the sex concordance between the recipients and donors (hazard ratio 2.93, 95% CI 1.67-5.13; P < .001, respectively). Also, in the group without chronic rejection, there were no male donors; however, the group with chronic rejection had mostly male donors (P <.001). Cold ischemia time was longer in patients with chronic rejection versus that shown in the control group (P = .031), and there was a significant difference between the 2 groups in acute rejection frequency (P < .001). Recipient sex and sex concordance were independent risk factors for chronic rejection. Most transplantrecipients with chronic rejection responded to medicaltreatment, and the rate of graftloss was low among our recipients.

The incidence and risk factors of chronic rejection in acutely rejected pediatric liver transplantation

Background. Chronic graft rejection (CR) represents an increasing concern in pediatric liver transplantation (LT). Risk factors of CR in this population are uncertain. In present study, we aimed to ascertain if clinical parameters could predict the occurrence of CR in LT children.Methods. We retrospectively analyzed the results from 47 children who had experienced acute hepatic rejection in Namazee hospital, Shiraz, Iran during 2007–2017.Results. Out of 47 children, 22 (46.8%) and 25 (53.2%) were boys and girls respectively. Ascites, gastrointestinal bleeding, and spontaneous bacterial peritonitis were observed in 20 (44.4%), 14 (31.1%), and 4 (9.1%) respectively. Posttransplant vascular and biliary complications were observed in 3 (7%) and 4 (9.3%) cases respectively. The mean time from LT to normalization of liver enzymes was 14.2 ± 7.5 days. The mean of acute rejection episodes was 1.4 ± 0.6 (median = 1 (22, 46.8%), range of 1–3). Six (12.7%) patients experienced CR. The mean time from LT to CR was 75 ± 28.4 days. A significant association was found between CR and patients’ condition (being inpatient or outpatient) before surgery (P = 0.03). No significant relationship was found between CR and post-transplant parameters except for biliary complications (P = 0.01). Both biliary complication (RR = 33.7, 95% CI: 2.2–511, P = 0.01) and inpatient status (RR = 10.9, 95% CI: 1.1–102.5, P = 0.03) significantly increased the risk of CR.Conclusion. Being hospitalized at the time of LT, and development of biliary complications might predict risk factors for development of CR in LT children.

A novel mechanism for immune regulation after human lung transplantation

ObjectiveLung transplantation is therapeutic for end-stage lung disease, but survival is limited due to bronchiolitis obliterans syndrome and restrictive chronic lung allograft dysfunction. We sought a common denominator in lung transplant recipients, analyzing risk factors that trigger immune responses that lead to bronchiolitis obliterans syndrome. MethodsWe collected blood from patients who underwent lung transplant at our institution. Exosomes were isolated from the sera of recipients with risk factors for chronic rejection and from stable recipients. Exosomes were analyzed with western blot, using antibodies to lung self-antigens K alpha 1 tubulin and collagen-V, costimulatory molecules (costimulatory molecule 80, costimulatory molecule 86), transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells, hypoxia-inducible factor 1α, Class II Major Histocompatibility Complex Transactivator), and 20S proteasome. ResultsOf the 90 patients included, we identified 5 with grade 3 primary graft dysfunction, 5 without, 15 with respiratory viral infection, 10 with acute rejection, 10 with donor-specific antibodies (DSA), 5 without DSA, and 10 who were stable for exosome isolation. Recipients with grade 3 primary graft dysfunction, respiratory viral infection, acute rejection, and DSA had exosomes containing self-antigens; exosomes from stable recipients did not. Exosomes from recipients with grade 3 primary graft dysfunction, acute rejection, and DSA also demonstrated costimulatory molecule 80, costimulatory molecule 86, major histocompatibility complex class II, transcription factor, and 20S proteasome. ConclusionsTransplanted lungs with grade 3 primary graft dysfunction, symptomatic respiratory viral infection, acute rejection, and immune responses induce exosomes that contain self-antigens, costimulatory molecules, major histocompatibility complex class II, transcription factors, and 20S proteasome. Release of circulating exosomes post-transplant from the aforementioned stress-inducing insults augment immunity and may play an important role in the pathogenesis of bronchiolitis obliterans syndrome.

Effect of recipient gender and donor-specific antibodies on antibody-mediated rejection after heart transplantation.

Gender-difference regarding antibody-mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor-specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single-institution 6-year cohort (2010-2015), time to AMR was assessed, comparing men with women by survival analysis with a 1-year death-censored follow-up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA-, size- and sex-mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard-ratio [adj. HR]=1.78 [1.06-2.99]), P=.03) and the presence of pfDSA (adj. HR=3.20 [1.80-5.70], P<.001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR=2.2 (P=.026) and MFI of pfDSA (per 1 MFI-increase) adj. HR=1.0002 (P<.0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender-related difference in the severity of pfDSA.

Viral Respiratory Tract Infection During the First Postoperative Year Is a Risk Factor for Chronic Rejection After Lung Transplantation.

Chronic lung allograft dysfunction (CLAD) is the major limiting factor for long-term survival in lung transplant recipients. Viral respiratory tract infection (VRTI) has been previously associated with CLAD development. The main purpose of this study was to evaluate the long-term effects of VRTI during the first year after lung transplantation in relation to CLAD development. Ninety-eight patients undergoing lung transplantation were prospectively enrolled between 2009 and 2012. They were monitored for infections with predefined intervals and on extra visits during the first year, the total follow-up period ranged between 5 and 8 years. Nasopharyngeal swab and bronchoalveolar lavage samples were analyzed using a multiplex polymerase chain reaction panel for respiratory pathogens. Data regarding clinical characteristics and infectious events were recorded. Viral respiratory tract infection during the first year was identified as a risk factor for long-term CLAD development (P = 0.041, hazard ratio 1.94 [1.03-3.66]) in a time-dependent multivariate Cox regression analysis. We also found that coronavirus in particular was associated with increased risk for CLAD development. Other identified risk factors were acute rejection and cyclosporine treatment. This study suggests that VRTI during the first year after lung transplantation is associated with long-term CLAD development and that coronavirus infections in particular might be a risk factor.

MiR-199b-5p Regulates Immune-Mediated Allograft Rejection after Lung Transplantation Through the GSK3β and NF-κB Pathways.

Emerging evidence indicates that acute rejection mainly associated with the inflammatory response is an independent risk factor for chronic rejection after lung transplantation. Monocytes are the main pro-inflammatory leukocytes infiltrating around the lesions and play vital roles in triggering the acute rejection. In the rat lung transplantation model, lipopolysaccharide (LPS)-induced severe acute rejection was strongly associated with advanced chronic rejection. The exact regulatory mechanism of pro-inflammation in monocytes is not yet clear. In this study, we identified a novel anti-inflammatory effect of miR-199b-5p (miR-199b) through the GSK3β and NF-κB pathways. THP-1 monocytes treated with LPS showed a significant decrease in miR-199b that is inversely correlated to GSK3β expression and NF-κB activation. Furthermore, the NF-κB-associated inflammatory response was reduced due to the overexpression of miR-199b targeting GSK3β, which was rescued by the inhibition of miR-199b. These results indicated that miR-199b attenuated the inflammatory response at least partly through the GSK3β/NF-κB signaling pathways in monocytes. Our data point toward a potentially important role for miR-199b in the inhibition of rejection after lung transplantation.

English

Kidney transplantation to treat end-stage renal disease has evolved rapidly from the first successful transplantations to the current widespread use of grafts from both cadaveric and living donors. But acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate possible mechanisms, we describe a comparison between different proteins expression profile of acute rejection and the controls. Through two-dimensional difference gel electrophoresis, mass spectral techniques microarray analysis and quantitative real-time RT-PCR confirmation, marked change in expression level of 37 protein spots was observed in allograft rejection group. Among them, expression levels of 24 protein spots were up-regulated, while expression levels of 13 protein spots were down-regulated. Among 37 protein spots, 29 obtained satisfactory peptide mass fingerprinting. We identified 6 proteins in acute rejection after renal transplantation. Then, we investigated PDIA3 levels in serum and transplanted kidney, PDIA3 mRNA and protein expression level. Our data thus indicate that PDIA3 might be potentially involved into the occurrence and development of acute rejection response in renal transplantation. Key words: PDIA3, mass spectrum, acute rejection, renal transplantation.

Low Serum Testosterone as a New Risk Factor for Chronic Rejection in Heart Transplanted Men

Among the various complications of heart transplantation (HTx), the vasculopathy of the allograft (CAV), a phenomenon of chronic rejection, is still a serious problem. Recently, the literature has shown that low testosterone levels in men are associated with cardiovascular disease. In this study, we evaluated the influence of testosterone plasma levels on CAV development. We studied, with a prospective observational study, all consecutive male HTx patients evaluated from May 2010 to June 2011 at our center. All subjects underwent accurate medical history collection, physical examination, biochemical blood tests, hormone levels, transthoracic Doppler echocardiography, coronary flow velocity reserve assessment, and coronary angiogram. HTx subjects with CAV had significant lower total testosterone plasma levels (12.9±3.9 vs. 15.8±5.8 nmol/L), free testosterone (0.26±0.07 vs. 0.31±0.08 nmol/L), and coronary flow velocity reserve (2.35±0.60 vs. 2.81±0.78 s) with respect to No-CAV patients. Considering the patients as a whole group, a significant negative relation was found between free and total testosterone plasma levels and some cardiovascular risk factors (cholesterol and fasting blood glucose). A significant linear inverse relation was found between total and free testosterone plasma levels and CAV grading. Only free testosterone plasma levels were independent predictors for CAV. We showed for the first time the influence of testosterone plasma levels on CAV development: indirectly increasing traditional risk factors and directly with a probable influence on alloimmune response.

Acute Cellular and Antibody-Mediated Allograft Rejection

Survival post-lung transplantation remains limited to ∼ 50% at 5 years, far below survival after other solid organ transplants. Allograft rejection is a major cause of this limited survival. At least a third of lung transplant recipients experience acute rejection within 1 year posttransplantation. Acute rejection, though rarely a direct cause of death, represents the principal risk factor for chronic rejection, which is the greatest obstacle to long-term post-lung transplant survival. This article reviews in detail the two major subtypes of acute rejection: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). ACR is diagnosed primarily by bronchoscopic transbronchial biopsies and is defined as perivascular or peribronchiolar lymphocytic infiltrates in the absence of infection. AMR remains poorly defined but is thought to involve anti-donor antibodies, allograft dysfunction, and pathological evidence of lung tissue injury or deposition of complement. Pathophysiological mechanisms, clinical presentation, clinical significance, known risk factors, and treatment strategies are discussed. Additionally, the limitations of current diagnostic modalities for both ACR and AMR are explained. Emerging data on the importance of donor-specific and non-donor-specific anti-human leukocyte antigen (anti-HLA) antibodies as well as non-HLA antibodies are presented. Larger cohorts have improved statistical analyses in recent years, leading to a clearer understanding of important topics related to ACR and AMR. Further collaborative studies and multicenter trials will be key in further advancing lung transplantation knowledge and improving outcomes in years to come.

Pre-Transplant Antibodies to Kα1Tubulin and Collagen V in Lung Transplantation: Correlation with Disease, Primary Graft Dysfunction, Donor Specific HLA Antibodies, and Chronic Rejection

Purpose Immune responses to lung self-antigens (SAgs), Kα1Tubulin (Kα1T) and Collagen V (ColV), have been implicated as risk factors for chronic rejection following lung transplantation (LTx). The goal is to determine the prevalence of pre-existing antibodies (Abs) to these SAgs in diseases leading to organ failure and investigate their role in primary graft dysfunction (PGD) and chronic rejection. Methods and Materials Pre- and post-Tx sera from 317 LTx patients for diagnoses (COPD: 161, IPF: 50, CF: 55 and Other: 51) between 2000 and 2011 at Washington University (n: 296) and Cleveland Clinic (n: 21) were analyzed for donor specific Abs (DSA) by Flow PRA, Abs to ColV and Kα1T by ELISA and cytokine levels by LUMINEX assay. Subsequent diagnoses of PGD and bronchiolitis obliterans syndrome (BOS) were made in accordance with ISHLT guidelines. Results Pre-Tx, 18% with COPD, 44% with IPF (P 0.7) had Abs to Sags. The incidence of PGD was higher in patients with pre-Tx Abs to these Sags compared to those without (80-88% to 42-54%, p Conclusions Patients with CF and IPF demonstrated a significantly increased incidence of Abs to lung Sags, Kα1T and ColV. Patients with pre-Tx Abs to Sags were at increased risk for developing PGD, DSA and BOS, therefore strategies to deplete pre-existing Abs to Sags should be considered in order to improve outcomes after LTx.

Transcription factor activity profile of acute rejection after kidney transplantation

Transcription factors (TFs) play a central role in regulating gene expression and in providing an interconnecting regulatory between related pathway elements. Currently, the wide-spread use of kidney transplantation to treat end-stage renal disease has evolved rapidly since the initial successful transplantations from both cadaveric and living donors. However, acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate the possible mechanisms, we describe a comparison between TF' activity profile of acute rejection and controls. Through TF assay analysis and electrophoretic mobility shaft assay confirmation, we identified the activities of TFs in acute rejection after kidney transplantation. From a total of 345 screened TFs, 99 activity-differential TFs were found, of which 95 showed increased activity and four showed decreased activity. Our data indicate that TFs may be potentially involved in the pathogenesis of acute rejection, and can help to prevent, diagnose and treat acute rejection after kidney transplantation. The TF array methods could simplify the assay of multiple TFs and may facilitate high-throughout profiling of large numbers of TFs.

Assessment of different biomarkers provides valuable diagnostic standards in the evaluation of the risk of acute rejection

Acute rejection (AR) is a strong risk factor for chronic rejection in renal transplant recipients. Accurate and timely diagnosis of AR episodes is very important for disease control and prognosis. Therefore, objectively evaluated the immune status of patients is essential in the field of post-transplantation treatment. This longitudinal study investigated the usefulness of five biomarkers, human leukocyte antigen (HLA)-G5 and sCD30 level in sera, intracellular adenosine triphosphate (iATP) release level of CD4(+) T cells, and granzyme B/perforin expression in peripheral blood mononuclear cells (PBMCs) and biopsies, to detect AR and the resolution of biomarkers in a total of 84 cases of renal transplantation. The data demonstrated that recipients with clinical or biopsy proven rejection significantly increased iATP release level of CD4(+) T cells, and elevated sCD30 but lowered HLA-G5 level in sera compared with individuals with stable graft function. Expression levels of granzyme B and perforin were also elevated in PBMCs and graft biopsies of AR patients. Taken together, we identified that upregulation of sCD30, iATP, granzyme B, perforin, and downregulation of HLA-G5 could provide valuable diagnostic standards to identify those recipients in the risk of AR. And iATP may be a better biomarker than others for predicting the graft rejection episode.

PDIA3 mRNA expression and IL-2, IL-4, IL-6, and CRP levels of acute kidney allograft rejection in rat

Kidney transplantation to treat end-stage renal disease has evolved rapidly from the first successful transplantations to the current widespread use of grafts from both cadaveric and living donors. But acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate possible mechanisms, we describe a comparison between differentially proteins expression and immune markers profile (IL-2, IL-4, IL-6, and CRP) of acute rejection and the controls. Through quantitative real-time RT-PCR confirmation, PDIA3 mRNA and protein expression levels in serum and transplanted kidney in experiment group was significantly (P<0.05) higher than that in control group. Immunity analysis showed that plasma IL-2, IL-4, IL-6, and CRP levels were higher in experimental rats than those in control rats. Our data thus indicate that PDIA3 might be potentially involve into the occurence and development of acute rejection response in renal transplantation and increased plasma IL-2, IL-4, IL-6, and CRP levels play an important role to prevent acute kidney allograft rejection in rats.

236 Latent Infection with P. aeruginosa Prevents the Maintenance of Lung Allograft Acceptance in a MyD88 Dependent Manner

Pseudomonas aeruginosa (PA) infection following lung transplantation in cystic fibrosis patients is a reported independent risk factor for chronic rejection. However, the mechanisms that link PA infection to lung allograft rejection remain unclear. We asked if latent PA infection prevents lung allograft acceptance in mice.

Immunological Challenges of Cardiac Transplantation: The need for Better Animal Models to Answer Current Clinical Questions

In the last decade, two advances have shifted attention from cellular rejection to antibody-mediated rejection (AMR) of cardiac transplants. First, more sensitive diagnostic tests for detection of AMR have been developed. Second, improvements in immunosuppression have made severe acute cellular rejection uncommon, but have had less effect on AMR. Antibodies can contribute to graft rejection by activation of complement, by activation of vascular endothelial and smooth muscle cells, and by activation of neutrophils, macrophages or natural killer cells. Because acute rejection is a risk factor for chronic rejection in all types of organ transplants, it is has been proposed that AMR can cause chronic rejection. Small animal models need to be developed to gain further insights into AMR and the role of antibodies in chronic graft arteriopathy. This article reviews the current clinical data and existing mouse models for AMR.

Lung allograft rejection: diagnosis and management

Rejection remains a common complication after lung transplantation and has adversely affected long-term outcomes. This manuscript reviews the various manifestations of rejection after lung transplantation and provides an update of recent developments. The grading scheme for lymphocytic bronchiolitis was updated in 2007, and recent studies demonstrate that this disease is an important and independent risk factor for chronic rejection. Furthermore, a role for humoral immunity has become more apparent in recent years, although this role remains enigmatic in lung transplantation. Finally, a new subtype of bronchiolitis obliterans syndrome, termed neutrophilic reversible allograft dysfunction, has been proposed based on the response to treatment with azithromycin. Acute rejection and lymphocytic bronchiolitis are major risk factors for chronic rejection, which remains the primary obstacle to better outcomes after lung transplantation.

Combined Cytomegalovirus Prophylaxis in Lung Transplantation: Effects on Acute Rejection, Lymphocytic Bronchitis/Bronchiolitis, and Herpesvirus Infections

Lung transplantation recipients are at high risk for herpesvirus infections. We evaluated the effect of combined cytomegalovirus (CMV) prophylaxis on CMV pneumonia, acute rejection episodes (ARE), lymphocytic bronchitis/bronchiolitis (LB), and obliterans bronchiolitis (OB) diagnosed in 180 transbronchial biopsies (TBB) of lung transplant recipients. At our center, 25 patients (control group; 1999–2002) received acyclovir for 12 months and 21 recipients (study group; 2003–2007) received combined CMV prophylaxis consisting of CMV-IG (Cytotect Biotest) for 12 months and ganciclovir or valganciclovir from postoperative day 21 for 3 weeks. Among the study group (since 2005), CMV shell vial viral culture and Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and HHV-7 DNA were determined on BAL specimens. In the study group, the number of LB was significantly lower than in the control group (2% vs 11%; P = .04). Similar results were obtained for ARE (6% vs 17%; P = .04). No difference was observed in OB (5% vs 5%; P = .53, NS). A reduction trend was found in CMV pneumonia (2% vs 7%; P = .23, NS). Logistic regression analysis showed a relationship between prophylaxis and a reduced prevalence of ARE (odds ratio [OR] 3.25, confidence interval [CI] 1.12–9.40; P = .03). Finally, in the study group, BAL EBV-DNA positivity and EBV-CMV coinfections were low (6% and 0%, respectively) compared with other herpesviruses and with the literature. Our data suggested the efficacy of combined CMV prophylaxis to prevent ARE and LB, 2 risk factors for chronic rejection, and a possible role to reduce the trend toward CMV pneumonia and EBV infections.

Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.